Carboplatin, Etoposide, and Atezolizumab With or Without Trilaciclib (G1T28), a CDK4/6 Inhibitor, in Extensive-Stage SCLC

• Sponsor: G1 Therapeutics, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03041311
• Collaborator: Roche-Genentech (Industry)
• Enrollment: 107
• Locations: 45
• Arms: 2
• Actual Duration (Months): 40
• Patients Per Site: 2.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This was a study to investigate the potential clinical benefit of trilaciclib (G1T28) in preserving the bone marrow and the immune system, and enhancing antitumor efficacy when administered with carboplatin, etoposide, and atezolizumab (E/P/A) therapy in first line treatment for patients with newly diagnosed extensive-stage SCLC.

The study was a randomized, double-blinded, placebo-controlled design. Approximately, 100 patients were randomized to trilaciclib + E/P/A or placebo + E/P/A in the study.

Condition or Disease	Intervention/Treatment	Phase
Small Cell Lung Cancer	Drug: Trilaciclib; Drug: Placebo; Drug: Carboplatin; Drug: Etoposide; Drug: Atezolizumab	Phase 2

Detailed Description

The posted results represent the final results from Study G1T28-05, a Phase 2 study of carboplatin, etoposide, and atezolizumab with or without trilaciclib (G1T28) in patients with untreated extensive-stage small cell lung cancer (SCLC).

The final myelopreservation efficacy results are from database lock 1 (data cut-off [DCO] 17 Aug 2018). The final anti-tumor efficacy data (BOR, DOR, PFS) are from a second database lock 2 (DCO 28 June 2019) that occurred to support the trilaciclib New Drug Application (NDA). Final overall survival and safety data are reported from the final study database lock (DCO 11 Dec 2020, last patient last visit date of 29 October 2020).

Please note the last patient last visit date description above which is recorded as the study completion date. Following the last patient last visit, the final database lock occurred a few weeks later which accounts for the discrepancy between the study completion date and the reported assessment time frames.

Study Design

• Study Type: Interventional
• Actual Enrollment: 107 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Phase 2 Study of Carboplatin, Etoposide, and Atezolizumab With or Without Trilaciclib in Patients With Untreated Extensive-Stage Small Cell Lung Cancer (SCLC)
• Actual Study Start Date: Jun 29, 2017
• Actual Primary Completion Date: Aug 17, 2018
• Actual Study Completion Date: Oct 29, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: trilaciclib+etoposide/carboplatin/atezolizumab Induction: Patients received trilaciclib 240 mg/m² administered intravenously (IV) once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target area under the concentration-time curve (AUC) = 5 milligrams per milliliter per minute (mg/mL/min) to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity or discontinuation by the patient or investigator.	Drug: Trilaciclib; Trilaciclib IV; Other Names: G1T28 ; Drug: Carboplatin; Carboplatin IV; Other Names: Paraplatin ; Drug: Etoposide; Etoposide IV; Other Names: VP-16 ; Drug: Atezolizumab; Atezolizumab IV; Other Names: Tecentriq
Experimental: placebo+etoposide/carboplatin/atezolizumab Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was be administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity or discontinuation by the patient or investigator.	Drug: Placebo; Placebo IV; Drug: Carboplatin; Carboplatin IV; Other Names: Paraplatin ; Drug: Etoposide; Etoposide IV; Other Names: VP-16 ; Drug: Atezolizumab; Atezolizumab IV; Other Names: Tecentriq

Outcome Measures

Primary Outcome Measures

1. Duration of Severe (Grade 4) Neutropenia in Cycle 1 [Evaluated for Cycle 1 of the Induction Period (i.e., from randomization to the end of Cycle 1, each cycle = 21 days).]

   Duration of severe neutropenia (DSN; days) was defined as the number of days from the date of the first absolute neutrophil count (ANC) value of <0.5 × 10⁹/L observed between start of cycle and end of cycle to the date of the first ANC value ≥0.5 × 10⁹/L that met the following criteria: (1) occurred after the ANC value of <0.5 × 10⁹/L and (2) no other ANC values <0.5 × 10⁹/L occurred between this day and end of cycle. DSN was set to 0 for patients who did not experience severe neutropenia in a cycle, including those that were randomized and not treated. Data from unscheduled visits and the actual assessment date (rather than visit date) were included in the derivation.

2. Number of Participants With at Least 1 Occurrence of Severe (Grade 4) Neutropenia [Induction Period. From date of randomization, 21 day treatment cycles up to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.]

   The occurrence of severe (Grade 4) neutropenia (SN) was a binary variable. If a patient had at least 1 absolute neutrophil count value <0.5 × 10^9/L during the Induction Period, the patient was assigned as Yes to the occurrence of SN; otherwise, it was No.

Secondary Outcome Measures

1. All-Cause Dose Reductions [Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.]

   Dose reductions are not permitted for trilaciclib or atezolizumab. Dose reductions for E/P are derived from changes in the protocol-specified dose on the dosing page and correspond to the reductions for toxicity specified in the protocol. No more than 2 dose reductions of E/P in total were allowed for any patient. Simultaneous reduction in the doses of etoposide and carboplatin were counted as 1 dose reduction.

2. Number of Participants With at Least 1 Occurrence of RBC Transfusion on/After Week 5 (Proportion of Patients) [Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 374 days.]

   For this endpoint, the occurrence during the Induction Period was defined as a binary variable (Yes or No); Yes, if total number of events ≥1 was observed, No for other scenarios. If a patient did not have an event, a value of 0 was assigned to that patient. Each red blood cell transfusion with a unique start date on/after Week 5 on study during the Induction was defined as a separate event.

3. Occurrence of Granulocyte Colony-Stimulating Factor (G-CSF) Administration (Proportion of Patients) [Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.]

   For this endpoint, the occurrence during the Induction Period was defined as a binary variable (Yes or No); Yes, if total number of events ≥1 was observed, No for other scenarios. If a patient did not have an event, a value of 0 was assigned to that patient. Any G-CSF administration in a cycle during the Induction Period was defined as a separate event. A patient with at least 1 cycle with G-CSF administration during an induction cycle or the Induction Period was considered to have occurrence of G-CSF administration.

4. Overall Survival (OS) [From date of randomization to date of death due to any cause, assessed up to a maximum of 38.1 months.]

   Overall survival was calculated as the time (months) from date of randomization to the date of death due to any cause. Patients who did not die during the study were censored at the date last known to be alive. Patients lacking data beyond the date of randomization had their survival time censored at date of randomization. Overall survival was not censored if a patient received other anti-tumor treatments after the study drugs. Overall survival was calculated using the Kaplan-Meier method.

5. Major Adverse Hematologic Events (MAHE) (Composite Endpoint) [Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.]

   The composite endpoint "major adverse hematologic events" (MAHE) included the following aspects of myelosuppression: All-cause hospitalizations - Each recorded preferred term (PT) with a unique start date was counted as an event. All-cause dose reductions - Dose reductions were permitted for E/P but not for trilaciclib or atezolizumab. No more than 2 dose reductions were allowed. Each dose reduction was counted as a separate event. Febrile neutropenia-Each febrile neutropenia event with a unique start date during the Induction Period was defined as a separate event. Prolonged severe neutropenia (SN)-Each cycle with a severe neutropenia duration greater than 5 days was counted as an event, with the date of the first Grade 4 laboratory value defined as the start date for the time-to-first event analysis. Red blood cell (RBC) transfusion on/after Week 5-Each RBC transfusion with a unique start date on/after Week 5 on study during the Induction Period was defined as a separate event.

6. Best Overall Response [From date of randomization, up to four 21-day cycles of Induction therapy, followed by 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 724 days.]

   For all patients, the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) tumor response data were used to determine each patient's visit response (TPR = time point response). Per RECIST v1.1 for target lesions and assessed by CT/MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameters of target lesions; Progressive Disease (PD), >=20% increase in the sum of the longest diameter of target lesions, Stable Disease, neither sufficient shrinkage or increase to quality for PR or PD. Objective Response Rate (ORR) = CR + PR. The TPR at each visit was determined in 2 ways: (1) derived programmatically at the time of analysis using the information from target lesions, non-target lesions, and new lesions based on data collected through eCRF; and (2) judged by the investigator as collected in the eCRF. Results shown here are from the programmatically derived assessments.

7. Duration of Objective Response (Complete Response or Partial Response) [From date of randomization, up to four 21-day cycles of Induction therapy, followed by 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 724 days.]

   Duration of Response (DOR) is the time between first response by RECIST Version 1.1 of CR or PR and the first date that progressive disease is documented by RECIST Version 1.1, or death. Patients who do not experience PD or death will be censored at the last tumor assessment date. Only those patients with confirmed responses will be included in this analysis.

8. Progression-Free Survival [From date of randomization, up to four 21-day cycles of Induction therapy, followed by 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 724 days.]

   Progression-free survival (PFS) was defined as the time (number of months) from date of randomization until date of documented radiologic disease progression per RECIST v1.1 or death due to any cause, whichever came first.

9. Number of Participants With at Least 1 Occurrence of Febrile Neutropenia [Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.]

   The criterion for identifying febrile neutropenia was if the preferred term for an adverse event was "FEBRILE NEUTROPENIA." Any occurrence of a febrile neutropenia event during the induction treatment period is defined as a binary variable (Yes or No); Yes if total number of febrile neutropenia events ≥ 1 is observed, No for other scenarios. Each febrile neutropenia event with a unique start date during the induction treatment period was defined as a separate event.

10. Number of Participants With at Least 1 Occurrence of Grade 3 or 4 Hematologic Laboratory Abnormalities [Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.]

    The occurrence of Grade 3 and 4 hematologic toxicities was a binary endpoint. If a patient had at least 1 cycle with at least 1 Grade 3 or 4 hematologic toxicities during the Induction Period, the patient was assigned as "Yes" to the occurrence of Grade 3 and 4 hematologic toxicities; otherwise, it was "No". If a patient did not have an event, the value of 0 was assigned to that patient.

11. Number of Participants With at Least 1 Occurrence of Erythropoiesis Stimulating Agent (ESA) Administration [Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.]

    Any ESA administration in a cycle during the Induction Period was defined as a separate event. A patient with at least 1 cycle with ESA administration during an induction cycle or the Induction Period was considered to have occurrence of ESA administration. The criterion to select proper records was as follows: If the chemical subgroup from WHO-DD Version September 2017 (ie TEXT4 for CODE4) takes the value "OTHER ANTIANEMIC PREPARATIONS," the medication was classified as ESAs.

12. Number of Participants With at Least 1 Occurrence of Platelet Transfusion [Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.]

    Any occurrence of a platelet transfusion during the induction treatment period was defined as a binary variable (Yes or No); Yes if total number of febrile neutropenia events ≥ 1 is observed, No for other scenarios. If the patient did not have an event, the value of 0 was assigned to that patient. Each platelet transfusion event with a unique start date during the induction treatment period was defined as a separate event.

13. Number of Participants With at Least 1 Occurrence of Infection Serious Adverse Events (SAEs) [Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.]

    Any occurrence of an infection SAE during the induction treatment period was defined as a binary variable (Yes or No); Yes if total number of febrile neutropenia events ≥ 1 is observed, No for other scenarios. If the patient did not have an event, the value of 0 was assigned to that patient. The criterion for identifying the proper infection SAE records was as follows: if the system organ class (SOC) from Medical Dictionary for Regulatory Activities (MedDRA) Version 20.1 takes value "INFECTIONS AND INFESTATIONS," and the AE was a serious event.

14. Number of Participants With at Least 1 Occurrence of Pulmonary Infection Serious Adverse Events (SAEs) [Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.]

    Any occurrence of a pulmonary SAE during the induction treatment period was defined as a binary variable (Yes or No); Yes if total number of febrile neutropenia events ≥ 1 is observed, No for other scenarios. If the patient did not have an event, the value of 0 was assigned to that patient. Each pulmonary infection SAE with a unique start date during the induction treatment period was defined as separate event. The criterion for identifying the proper pulmonary infection SAE records was as follows: The SOC from MedDRA Version 20.1 took the value "INFECTIONS AND INFESTATIONS," the adverse event was a serious event, and the PT took values from the following list of PTs under the category of pulmonary infection adverse events: bronchiolitis, bronchitis, infectious pleural effusion, influenza, pneumonia, pneumonia bacterial, respiratory tract infection, upper respiratory tract infection, and viral upper respiratory tract infection.

15. Number of Participants With at Least 1 Occurrence of IV Antibiotic Uses [Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.]

    Occurrence of an IV antibiotics administration during the induction treatment period is defined as a binary variable (Yes or No); Yes if total number of IV antibiotics administration ≥ 1 is observed, No for other scenarios. Each IV antibiotic with a unique start date during the induction treatment period will be defined as a separate event. The criteria for identifying an IV antibiotic administration event was (1) if the therapeutic subgroup from WHO-DD Version September 2017 (ie, TEXT2 for CODE2) takes the value "ANTIBACTERIALS FOR SYSTEMIC USE," and (2) the route of medication was "intravenous" or the route was "other" with the detailed specification as "IVPB."

16. Duration of Study Drug Exposure (Induction Period and Maintenance Period) [From date of first dose, up to four 21-day cycles of Induction therapy, followed by 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 1162 days.]

    Induction period duration of exposure (days) = Day 1 of last induction cycle - Cycle 1 Day 1 of induction phase + 21. Maintenance period duration of exposure (days) = Day 1 of the last maintenance cycle -Cycle 1 Day 1 of maintenance phase + 21.

17. Number of Cycles Completed (Induction Period and Maintenance Period) [From date of first dose, up to four 21-day cycles of Induction therapy, followed by 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 49 cycles.]

    Patients were considered to have started a cycle if they have received at least one dose of any study drug (carboplatin, etoposide, atezolizumab or trilaciclib).

18. Relative Dose Intensity of Trilaciclib/Placebo, Carboplatin, Etoposide, Atezolizumab (Induction Period) and Atezolizumab (Maintenance Period) [From date of first dose, up to four 21-day cycles of Induction therapy, followed by 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 724 days.]

    Relative dose intensity is defined as 100% times the actual dose intensity divided by the planned dose intensity. The planned dose intensity is defined as the cumulative planned dose through the study divided by (number of cycles * 3 weeks)

19. Number of Participants With Any Cycle Delays and the Number of Cycles Delayed (Induction Period) [Induction Period. From date of first dose, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.]

    After Cycle 1, patients need to meet pre-specified laboratory parameter criteria before initiating Cycle 2 and each subsequent cycle of chemotherapy. A "Cycle Day Status" page asks if the cycle was delayed. If the start of the current cycle was delayed (the site answers "Yes"), this will be counted as a delay. Cycle delays could occur for management of toxicity (hematologic or non-hematologic) or for administrative/logistic reasons. The reason for each cycle delay was captured in the eCRF if it was related to AEs. Reasons other than AEs were not captured.

20. Number of Participants With Any Cycle Delays and the Number of Cycles Delayed (Maintenance Period) [Maintenance Period. From date of first maintenance dose, 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 1160 days.]

    After Cycle 1, patients need to meet pre-specified laboratory parameter criteria before initiating Cycle 2 and each subsequent cycle of chemotherapy. A "Cycle Day Status" page asks if the cycle was delayed. If the start of the current cycle was delayed (the site answers "Yes"), this will be counted as a delay. Cycle delays could occur for management of toxicity (hematologic or non-hematologic) or for administrative/logistic reasons. The reason for each cycle delay was captured in the eCRF if it was related to AEs. Reasons other than AEs were not captured.

21. Number of Participants With Any Missed Doses [for Each Study Drug: Trilaciclib/Placebo, Carboplatin and Etoposide] (Induction Period) [Induction Period. From date of first dose, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.]

    Missed doses are identified on the dosing page of each study drug based on the question "Was the dose given?". The missed dose information will be obtained for each study drug. For a study drug, if the last record of response to question "Was the dose given?" is No, it will not be considered as a missed dose but instead considered to be end of treatment if both criteria below are met: (1) No other study drugs are given on the same day, and (2) No study drugs are given subsequently.

22. Number of Participants With Any Missed Doses of Atezolizumab (Overall Treatment Period) [From date of first dose, up to four 21-day cycles of Induction therapy, followed by 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 1162 days.]

    Missed doses are identified on the dosing page of each study drug based on the question "Was the dose given?". The missed dose information will be obtained for each study drug. For a study drug, if the last record of response to question "Was the dose given?" is No, it will not be considered as a missed dose but instead considered to be end of treatment if both criteria below are met: (1) No other study drugs are given on the same day, and (2) No study drugs are given subsequently.

23. Number of Participants With Any Dose Interruptions [for Each Study Drug: Trilaciclib/Placebo, Carboplatin and Etoposide] (Induction Period) [Induction Period. From date of first dose, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.]

    Dose interruptions were defined as interruption of infusion, regardless of whether the study drug was continued after the interruption.

24. Number of Participants With Any Interrupted Doses of Atezolizumab (Overall Treatment Period) [From date of first dose, up to four 21-day cycles of Induction therapy, followed by 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 1162 days.]

    Dose interruptions were defined as interruption of infusion, regardless of whether the study drug was continued after the interruption.

25. Number of Participants With Any Dose Reductions of Carboplatin and Etoposide (Induction Period) [Induction Period. From date of first dose, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.]

    No dose reductions were allowed for trilaciclib or atezolizumab during the study.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Male or female subjects aged ≥18 years

• Unequivocally confirmed diagnosis of SCLC by histology or cytology, preferably including the presence of neuroendocrine features by immunohistochemistry

• Extensive-stage SCLC

• At least 1 target lesion that is measurable by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

• Adequate organ function

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2

• Predicted life expectancy of ≥3 months

• Able to understand and sign an informed consent

Exclusion Criteria:

• Limited-stage SCLC

• Prior chemotherapy for limited or extensive-stage SCLC

• Prior treatment with immunotherapies including but not limited to cluster of differentiation 137 agonists or immune checkpoint blockade therapies (such as anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1(PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) therapeutic antibodies).

• Presence of symptomatic brain metastases requiring immediate treatment with radiation therapy or steroids.

• Malignancies other than SCLC within 3 years prior to randomization, with the exception of those with negligible risk of metastasis or death treated with expected curative outcome

• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan

• Active, known, suspected autoimmune disease requiring systemic treatment in the past 2 years

• Uncontrolled ischemic heart disease or uncontrolled symptomatic congestive heart failure

• Known history of stroke or cerebrovascular accident within 6 months prior to enrollment

• Serious active infection at the time of enrollment

• Psychiatric illness/social situations that would limit study compliance

• Other uncontrolled serious chronic disease or conditions that in the investigator's opinion could affect compliance or follow-up in the protocol

• Known human immunodeficiency virus, known active hepatitis B, or hepatitis C

• Radiotherapy to any site or radiotherapy within 2 weeks prior to enrollment

• Receipt of any investigational medication within 4 weeks prior to enrollment

• Administration of attenuated vaccine within 4 weeks before enrollment or anticipation that such a live attenuated vaccine will be required during the study

• Influenza vaccination should be given during influenza season only (approx. Oct to March). Patients must not receive live, attenuated influenza vaccine (eg, FluMist) within 4 weeks prior to enrollment at any time during the study, and at least 5 months after the last dose of atezolizumab.

• Patients with a condition requiring systemic treatment with either corticosteroids ( > 10 mg daily prednisone equivalents) or other immunosuppressive medications (including but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 14 days of study drug administration. Inhaled or topical steroids ad adrenal replacement dosed > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.

• Hypersensitivity to any of the components of the formulation of etoposide or etoposide phosphate

• Hypersensitivity to carboplatin or other platinum-containing compounds or to mannitol

• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

• Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies

• Legal incapacity or limited legal capacity

• Pregnant or lactating women

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beverly Hills Cancer Center	Beverly Hills	California	United States	90211
2	St. Jude Heritage Healthcare	Fullerton	California	United States	92835
3	Loma Linda University	Loma Linda	California	United States	92350
4	UCLA Medical Center - Santa Monica Hematology And Oncology	Santa Monica	California	United States	90404
5	Redwood Regional Medical Group (RRMG) - Fountain Grove	Santa Rosa	California	United States	95403
6	Singing River Health System	Whittier	California	United States	90603
7	Piedmont Cancer Institute	Atlanta	Georgia	United States	30318
8	Northside Hospital - Georgia Cancer Specialists	Atlanta	Georgia	United States	30341
9	Joliet Oncology-Hematology Associates	Joliet	Illinois	United States	60435
10	Horizon Oncology Center	Lafayette	Indiana	United States	47905
11	Ochsner Clinic Foundation	New Orleans	Louisiana	United States	70121
12	St. Louis Cancer Care, LLP, North County	Bridgeton	Missouri	United States	63044
13	The Alvin J. Siteman Cancer Center - Center for Advanced Med	Saint Louis	Missouri	United States	63110-1094
14	Summit Medical Group, P.A.	Morristown	New Jersey	United States	07962
15	Northern Westchester Hospital	Mount Kisco	New York	United States	10549
16	Trinity Health - Trinity CancerCare Center	Minot	North Dakota	United States	58701
17	Oklahoma University - Peggy and Charles Stephenson Cancer Center	Oklahoma City	Oklahoma	United States	73117
18	Gibbs Cancer Center	Spartanburg	South Carolina	United States	29303
19	Valley Cancer Associates	Harlingen	Texas	United States	78550
20	Millennium Oncology	Houston	Texas	United States	77090
21	Virginia Cancer Specialists	Arlington	Virginia	United States	22031
22	Blue Ridge Cancer Care	Blacksburg	Virginia	United States	24060
23	Fort Belvoir Community Hospital	Fort Belvoir	Virginia	United States	22060
24	Complex Oncology Center - Burgas	Burgas		Bulgaria	8000
25	Multiprofile Hospital for Active Treatment "Serdika", Sofia	Sofia		Bulgaria	1303
26	Multiprofile Hospital for Active Treatment "Serdika"	Sofia		Bulgaria	1303
27	East Tallinn Central Hospital Ltd., Clinic of Internal Medicine, Center for Oncology	Tallinn		Estonia	11312
28	CHU Caen De La Côte De Nacre	Caen		France	14033
29	Centre Oscar Lambret	Lille		France	59020
30	Daugavpils Regional Hospital, Department of Oncology	Daugavpils		Latvia	LV-5417
31	Pauls Stradiņš Clinical University Hospital, Oncology Clinic	Riga		Latvia	LV-1002
32	Hospital Universitario Son Espases	Palma	Islas Baleares	Spain	07120
33	Hospital Teresa Herrera	A Coruña	La Coruña	Spain	15006
34	Hospital Universitario Puerta de Hierro Majadahonda	Majadahonda	Madrid	Spain	28222
35	Hospital Clínico	San Carlos	Madrid	Spain	28040
36	H.U. Quirón Dexeus, Hospital Universitario	Barcelona		Spain	08028
37	Hospital Clinic de Barcelona- Servicio de Oncología Médica	Barcelona		Spain	08036
38	Hospital Universitario Ramón y Cajal	Madrid		Spain	28034
39	Hospital 12 de Octubre	Madrid		Spain	28041
40	H. Donostia, Hospital Donostia- Servicio de Oncología	San Sebastián		Spain	20014
41	Hospital Universitario Ntra. Sra. de Valme	Sevilla		Spain	41014
42	Hospital Arnau de Vilanova	Valencia		Spain	46015
43	Chernivtsi Regional Clinical Oncology Center	Chernivtsi		Ukraine	58013
44	Dnipropetrovsk City Multispecialty Clinical Hospital #4	Dnipro		Ukraine	49102
45	Lviv State Regional Treatment and Diagnostics Oncology Center	Lviv		Ukraine	79031

Sponsors and Collaborators

• G1 Therapeutics, Inc.
• Roche-Genentech

Investigators

• Study Director: Clinical Contact, G1 Therapeutics, Inc.

Study Documents (Full-Text)

• Study Protocol - Sep 14, 2018
• Statistical Analysis Plan: Region 2 - Nov 1, 2018

More Information

Publications

• Daniel D, Kuchava V, Bondarenko I, Ivashchuk O, Reddy S, Jaal J, Kudaba I, Hart L, Matitashvili A, Pritchett Y, Morris SR, Sorrentino JA, Antal JM, Goldschmidt J. Trilaciclib prior to chemotherapy and atezolizumab in patients with newly diagnosed extensive-stage small cell lung cancer: A multicentre, randomised, double-blind, placebo-controlled Phase II trial. Int J Cancer. 2020 Dec 21. doi: 10.1002/ijc.33453. [Epub ahead of print]
• Weiss J, Goldschmidt J, Andric Z, Dragnev KH, Gwaltney C, Skaltsa K, Pritchett Y, Antal JM, Morris SR, Daniel D. Effects of Trilaciclib on Chemotherapy-Induced Myelosuppression and Patient-Reported Outcomes in Patients with Extensive-Stage Small Cell Lung Cancer: Pooled Results from Three Phase II Randomized, Double-Blind, Placebo-Controlled Studies. Clin Lung Cancer. 2021 Sep;22(5):449-460. doi: 10.1016/j.cllc.2021.03.010. Epub 2021 Mar 26.

• Responsible Party: G1 Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT03041311
• Other Study ID Numbers: G1T28-05; 2017-000358-20
• First Posted: Feb 2, 2017
• Last Update Posted: May 6, 2022
• Last Verified: Apr 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by G1 Therapeutics, Inc.: Small Cell Lung Cancer; CDK4/6 Inhibitor; Immune Checkpoint Inhibitor
• Additional relevant MeSH terms: Lung Neoplasms; Small Cell Lung Carcinoma; Carboplatin; Etoposide; Atezolizumab

Study Results

Participant Flow

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.
Period Title: Overall Study
STARTED	54	53
COMPLETED	0	0
NOT COMPLETED	54	53

Baseline Characteristics

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab	Total
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily on Days prior to E/P/A 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity or discontinuation by the patient or investigator.	Total of all reporting groups
Overall Participants	54	53	107
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	27 50%	27 50.9%	54 50.5%
>=65 years	27 50%	26 49.1%	53 49.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63 (8.4)	64 (8.3)	64 (8.3)
Sex: Female, Male (Count of Participants)
Female	13 24.1%	19 35.8%	32 29.9%
Male	41 75.9%	34 64.2%	75 70.1%
Race/Ethnicity, Customized (Count of Participants)
White	53 98.1%	51 96.2%	104 97.2%
Black or African American	0 0%	1 1.9%	1 0.9%
Native Hawaiian or Pacific Islander	1 1.9%	0 0%	1 0.9%
Other	0 0%	1 1.9%	1 0.9%
Region of Enrollment (participants) [Number]
Latvia	3 5.6%	3 5.7%	6 5.6%
United States	20 37%	22 41.5%	42 39.3%
Ukraine	11 20.4%	8 15.1%	19 17.8%
Bulgaria	6 11.1%	7 13.2%	13 12.1%
France	0 0%	2 3.8%	2 1.9%
Estonia	2 3.7%	3 5.7%	5 4.7%
Spain	1 1.9%	3 5.7%	4 3.7%
Georgia	11 20.4%	5 9.4%	16 15%
Body Weight at Screening (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	79.2 (17.32)	72.4 (14.42)	75.8 (16.25)
Height at Screening (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	171.1 (7.62)	168.6 (10.21)	169.9 (9.04)
BMI at Screening (kg/m²) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m²]	27.10 (5.907)	25.45 (4.618)	26.28 (5.347)
Body Surface Area (m²) at Screening (m²) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [m²]	1.91 (0.198)	1.82 (0.205)	1.86 (0.205)
ECOG Performance Status (Count of Participants)
0-1	46 85.2%	46 86.8%	92 86%
2	8 14.8%	7 13.2%	15 14%

Outcome Measures

1. Primary Outcome

Title	Duration of Severe (Grade 4) Neutropenia in Cycle 1
Description	Duration of severe neutropenia (DSN; days) was defined as the number of days from the date of the first absolute neutrophil count (ANC) value of <0.5 × 10⁹/L observed between start of cycle and end of cycle to the date of the first ANC value ≥0.5 × 10⁹/L that met the following criteria: (1) occurred after the ANC value of <0.5 × 10⁹/L and (2) no other ANC values <0.5 × 10⁹/L occurred between this day and end of cycle. DSN was set to 0 for patients who did not experience severe neutropenia in a cycle, including those that were randomized and not treated. Data from unscheduled visits and the actual assessment date (rather than visit date) were included in the derivation.
Time Frame	Evaluated for Cycle 1 of the Induction Period (i.e., from randomization to the end of Cycle 1, each cycle = 21 days).

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) analysis set included all randomized patients. Analysis using the ITT analysis set were conducted on the basis of the randomly assigned treatment.

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.
Measure Participants	54	53
Mean (Standard Deviation) [days]	0 (1.0)	4 (4.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trilaciclib+Etoposide/Carboplatin/Atezolizumab, Placebo+Etoposide/Carboplatin/Atezolizumab
	Comments	Treatment difference was evaluated using a nonparametric analysis of covariance (ANCOVA). The nonparametric ANCOVA included study baseline ANC value as covariate, stratification factors of ECOG performance status (0 to 1 versus 2) and brain metastases (Yes versus No), and treatment as a fixed effect.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	A Hochberg-based gatekeeping procedure was used to control the global familywise error rate across the multiple null hypotheses (for 2 primary and 3 key secondary endpoints) in a strong sense at a 1-sided 0.025 level.
	Method	non-parametric ANCOVA
	Comments	Hochberg-based gatekeeping procedure

2. Primary Outcome

Title	Number of Participants With at Least 1 Occurrence of Severe (Grade 4) Neutropenia
Description	The occurrence of severe (Grade 4) neutropenia (SN) was a binary variable. If a patient had at least 1 absolute neutrophil count value <0.5 × 10^9/L during the Induction Period, the patient was assigned as Yes to the occurrence of SN; otherwise, it was No.
Time Frame	Induction Period. From date of randomization, 21 day treatment cycles up to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) analysis set included all randomized patients. Analysis using the ITT analysis set were conducted on the basis of the randomly assigned treatment.

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was be administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.
Measure Participants	54	53
Count of Participants [Participants]	1 1.9%	26 49.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trilaciclib+Etoposide/Carboplatin/Atezolizumab, Placebo+Etoposide/Carboplatin/Atezolizumab
	Comments	The occurrence of SN was a binary variable. Treatment group difference was analyzed using a modified Poisson regression model to account for the variable duration of the Induction Period for each patient. The model included baseline ANC count as a covariate, the stratification factors of ECOG performance status (0 to1 vs. 2) and brain metastases (Yes vs. No), and treatment as a fixed effect. The logarithm transformation of # of Induction cycles was included as an offset variable in the modeling.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	A Hochberg-based gatekeeping procedure was used to control the global familywise error rate across the multiple null hypotheses (for 2 primary and 3 key secondary endpoints) in a strong sense at a 1-sided 0.025 level.
	Method	Modified Poisson
	Comments	Hochberg-based gatekeeping procedure

3. Secondary Outcome

Title	All-Cause Dose Reductions
Description	Dose reductions are not permitted for trilaciclib or atezolizumab. Dose reductions for E/P are derived from changes in the protocol-specified dose on the dosing page and correspond to the reductions for toxicity specified in the protocol. No more than 2 dose reductions of E/P in total were allowed for any patient. Simultaneous reduction in the doses of etoposide and carboplatin were counted as 1 dose reduction.
Time Frame	Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) analysis set included all randomized patients. Analysis using the ITT analysis set were conducted on the basis of the randomly assigned treatment.

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was be administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.
Measure Participants	54	53
Number [Events/Cycle]	0.021	0.085

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trilaciclib+Etoposide/Carboplatin/Atezolizumab, Placebo+Etoposide/Carboplatin/Atezolizumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0195
	Comments	A Hochberg-based gatekeeping procedure was used to control the global familywise error rate across the multiple null hypotheses (for 2 primary and 3 key secondary endpoints) in a strong sense at a 1-sided 0.025 level.
	Method	negative binomial regression
	Comments	Hochberg-based gatekeeping procedure

4. Secondary Outcome

Title	Number of Participants With at Least 1 Occurrence of RBC Transfusion on/After Week 5 (Proportion of Patients)
Description	For this endpoint, the occurrence during the Induction Period was defined as a binary variable (Yes or No); Yes, if total number of events ≥1 was observed, No for other scenarios. If a patient did not have an event, a value of 0 was assigned to that patient. Each red blood cell transfusion with a unique start date on/after Week 5 on study during the Induction was defined as a separate event.
Time Frame	Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 374 days.

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) analysis set included all randomized patients. Analysis using the ITT analysis set were conducted on the basis of the randomly assigned treatment.

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.
Measure Participants	54	53
Count of Participants [Participants]	7 13%	11 20.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trilaciclib+Etoposide/Carboplatin/Atezolizumab, Placebo+Etoposide/Carboplatin/Atezolizumab
	Comments	Treatment group difference was analyzed using a modified Poisson regression model. The model included baseline hemoglobin as a covariate, the stratification factors of ECOG performance status (0 to 1 versus 2) and brain metastases (Yes versus No) and treatment as a fixed effect. The logarithm transformation of the number of weeks on treatment was included as an offset variable in the model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1335
	Comments	A Hochberg-based gatekeeping procedure was used to control the global familywise error rate across the multiple null hypotheses (for 2 primary and 3 key secondary endpoints) in a strong sense at a 1-sided 0.025 level.
	Method	Modified Poisson
	Comments	Hochberg-based gatekeeping procedure

5. Secondary Outcome

Title	Occurrence of Granulocyte Colony-Stimulating Factor (G-CSF) Administration (Proportion of Patients)
Description	For this endpoint, the occurrence during the Induction Period was defined as a binary variable (Yes or No); Yes, if total number of events ≥1 was observed, No for other scenarios. If a patient did not have an event, a value of 0 was assigned to that patient. Any G-CSF administration in a cycle during the Induction Period was defined as a separate event. A patient with at least 1 cycle with G-CSF administration during an induction cycle or the Induction Period was considered to have occurrence of G-CSF administration.
Time Frame	Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) analysis set included all randomized patients. Analysis using the ITT analysis set were conducted on the basis of the randomly assigned treatment.

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.
Measure Participants	54	53
Count of Participants [Participants]	16 29.6%	25 47.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trilaciclib+Etoposide/Carboplatin/Atezolizumab, Placebo+Etoposide/Carboplatin/Atezolizumab
	Comments	Treatment group difference was analyzed using a modified Poisson regression model to account for the variable duration of the Induction Period for each patient. The model included baseline absolute neutrophil count as a covariate, the stratification factors of ECOG performance status (0 to 1 versus 2) and brain metastases (Yes versus No), and treatment as a fixed effect. The logarithm transformation of number of Induction cycles was included as an offset variable in the modeling.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0686
	Comments	A Hochberg-based gatekeeping procedure was used to control the global familywise error rate across the multiple null hypotheses (for 2 primary and 3 key secondary endpoints) in a strong sense at a 1-sided 0.025 level.
	Method	Modified Poisson
	Comments	Hochberg-based gatekeeping procedure

6. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival was calculated as the time (months) from date of randomization to the date of death due to any cause. Patients who did not die during the study were censored at the date last known to be alive. Patients lacking data beyond the date of randomization had their survival time censored at date of randomization. Overall survival was not censored if a patient received other anti-tumor treatments after the study drugs. Overall survival was calculated using the Kaplan-Meier method.
Time Frame	From date of randomization to date of death due to any cause, assessed up to a maximum of 38.1 months.

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT Analysis Set)

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity or discontinuation by the patient or investigator.	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity or discontinuation by the patient or investigator.
Measure Participants	54	53
25%	7.2	6.7
Median	12.0	12.8
75%	20.6	22.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trilaciclib+Etoposide/Carboplatin/Atezolizumab, Placebo+Etoposide/Carboplatin/Atezolizumab
	Comments
	Type of Statistical Test	Superiority
	Comments	For time-to-event variable, the Kaplan-Meier method was used to estimate its within group median value, 25% and 75% percentile values.
Statistical Test of Hypothesis	p-Value	0.9942
	Comments	The 2-sided p-value was obtained from the stratified log-rank test to account for the stratification factors.
	Method	Log Rank
	Comments	stratified log-rank test
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.64 to 1.52
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.218
	Estimation Comments	The HR and its 95% CI were calculated using the Cox proportional hazard regression model with treatment and stratification factors of ECOG performance status (0 to 1 versus 2) and presence of brain metastases (Yes versus No).

7. Secondary Outcome

Title	Major Adverse Hematologic Events (MAHE) (Composite Endpoint)
Description	The composite endpoint "major adverse hematologic events" (MAHE) included the following aspects of myelosuppression: All-cause hospitalizations - Each recorded preferred term (PT) with a unique start date was counted as an event. All-cause dose reductions - Dose reductions were permitted for E/P but not for trilaciclib or atezolizumab. No more than 2 dose reductions were allowed. Each dose reduction was counted as a separate event. Febrile neutropenia-Each febrile neutropenia event with a unique start date during the Induction Period was defined as a separate event. Prolonged severe neutropenia (SN)-Each cycle with a severe neutropenia duration greater than 5 days was counted as an event, with the date of the first Grade 4 laboratory value defined as the start date for the time-to-first event analysis. Red blood cell (RBC) transfusion on/after Week 5-Each RBC transfusion with a unique start date on/after Week 5 on study during the Induction Period was defined as a separate event.
Time Frame	Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) analysis set included all randomized patients. Analysis using the ITT analysis set were conducted on the basis of the randomly assigned treatment.

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.
Measure Participants	54	53
Major adverse hematologic events (MAHE)	0.132	0.058
All-cause hospitalizations	0.032	0.030
All-cause dose reductions	0.021	0.085
Febrile neutropenia TEAEs	0.002	0.004
RBC transfusions on/after Week 5	0.017	0.026
Prolonged SN (>5 days)	0.005	0.170

8. Secondary Outcome

Title	Best Overall Response
Description	For all patients, the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) tumor response data were used to determine each patient's visit response (TPR = time point response). Per RECIST v1.1 for target lesions and assessed by CT/MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameters of target lesions; Progressive Disease (PD), >=20% increase in the sum of the longest diameter of target lesions, Stable Disease, neither sufficient shrinkage or increase to quality for PR or PD. Objective Response Rate (ORR) = CR + PR. The TPR at each visit was determined in 2 ways: (1) derived programmatically at the time of analysis using the information from target lesions, non-target lesions, and new lesions based on data collected through eCRF; and (2) judged by the investigator as collected in the eCRF. Results shown here are from the programmatically derived assessments.
Time Frame	From date of randomization, up to four 21-day cycles of Induction therapy, followed by 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 724 days.

Outcome Measure Data

Analysis Population Description

Response Evaluable Analysis Set

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily on Days prior to E/P/A 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity or discontinuation by the patient or investigator.
Measure Participants	50	52
Complete Response (CR)	0 0%	1 1.9%
Partial Response (PR)	28 51.9%	32 60.4%
Stable Disease (SD)	20 37%	14 26.4%
Progressive Disease (PD)	2 3.7%	2 3.8%
Not Evaluable (NE)	0 0%	2 3.8%
Missing	0 0%	1 1.9%
Objective response rate (CR+PR)	28 51.9%	33 62.3%

9. Secondary Outcome

Title	Duration of Objective Response (Complete Response or Partial Response)
Description	Duration of Response (DOR) is the time between first response by RECIST Version 1.1 of CR or PR and the first date that progressive disease is documented by RECIST Version 1.1, or death. Patients who do not experience PD or death will be censored at the last tumor assessment date. Only those patients with confirmed responses will be included in this analysis.
Time Frame	From date of randomization, up to four 21-day cycles of Induction therapy, followed by 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 724 days.

Outcome Measure Data

Analysis Population Description

Response Evaluable Analysis Set

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.
Measure Participants	28	33
25%	4.4	3.0
Median	5.6	4.3
75%	8.3	5.0

10. Secondary Outcome

Title	Progression-Free Survival
Description	Progression-free survival (PFS) was defined as the time (number of months) from date of randomization until date of documented radiologic disease progression per RECIST v1.1 or death due to any cause, whichever came first.
Time Frame	From date of randomization, up to four 21-day cycles of Induction therapy, followed by 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 724 days.

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.
Measure Participants	54	53
25%	3.7	4.0
Median	5.9	5.4
75%	8.5	6.4

11. Secondary Outcome

Title	Number of Participants With at Least 1 Occurrence of Febrile Neutropenia
Description	The criterion for identifying febrile neutropenia was if the preferred term for an adverse event was "FEBRILE NEUTROPENIA." Any occurrence of a febrile neutropenia event during the induction treatment period is defined as a binary variable (Yes or No); Yes if total number of febrile neutropenia events ≥ 1 is observed, No for other scenarios. Each febrile neutropenia event with a unique start date during the induction treatment period was defined as a separate event.
Time Frame	Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT Analysis Set)

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity or discontinuation by the patient or investigator.	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity or discontinuation by the patient or investigator.
Measure Participants	54	53
Count of Participants [Participants]	1 1.9%	3 5.7%

12. Secondary Outcome

Title	Number of Participants With at Least 1 Occurrence of Grade 3 or 4 Hematologic Laboratory Abnormalities
Description	The occurrence of Grade 3 and 4 hematologic toxicities was a binary endpoint. If a patient had at least 1 cycle with at least 1 Grade 3 or 4 hematologic toxicities during the Induction Period, the patient was assigned as "Yes" to the occurrence of Grade 3 and 4 hematologic toxicities; otherwise, it was "No". If a patient did not have an event, the value of 0 was assigned to that patient.
Time Frame	Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.
Measure Participants	54	53
Count of Participants [Participants]	23 42.6%	43 81.1%

13. Secondary Outcome

Title	Number of Participants With at Least 1 Occurrence of Erythropoiesis Stimulating Agent (ESA) Administration
Description	Any ESA administration in a cycle during the Induction Period was defined as a separate event. A patient with at least 1 cycle with ESA administration during an induction cycle or the Induction Period was considered to have occurrence of ESA administration. The criterion to select proper records was as follows: If the chemical subgroup from WHO-DD Version September 2017 (ie TEXT4 for CODE4) takes the value "OTHER ANTIANEMIC PREPARATIONS," the medication was classified as ESAs.
Time Frame	Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.
Measure Participants	54	53
Count of Participants [Participants]	3 5.6%	6 11.3%

14. Secondary Outcome

Title	Number of Participants With at Least 1 Occurrence of Platelet Transfusion
Description	Any occurrence of a platelet transfusion during the induction treatment period was defined as a binary variable (Yes or No); Yes if total number of febrile neutropenia events ≥ 1 is observed, No for other scenarios. If the patient did not have an event, the value of 0 was assigned to that patient. Each platelet transfusion event with a unique start date during the induction treatment period was defined as a separate event.
Time Frame	Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.
Measure Participants	54	53
Count of Participants [Participants]	1 1.9%	2 3.8%

15. Secondary Outcome

Title	Number of Participants With at Least 1 Occurrence of Infection Serious Adverse Events (SAEs)
Description	Any occurrence of an infection SAE during the induction treatment period was defined as a binary variable (Yes or No); Yes if total number of febrile neutropenia events ≥ 1 is observed, No for other scenarios. If the patient did not have an event, the value of 0 was assigned to that patient. The criterion for identifying the proper infection SAE records was as follows: if the system organ class (SOC) from Medical Dictionary for Regulatory Activities (MedDRA) Version 20.1 takes value "INFECTIONS AND INFESTATIONS," and the AE was a serious event.
Time Frame	Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.
Measure Participants	54	53
Count of Participants [Participants]	3 5.6%	7 13.2%

16. Secondary Outcome

Title	Number of Participants With at Least 1 Occurrence of Pulmonary Infection Serious Adverse Events (SAEs)
Description	Any occurrence of a pulmonary SAE during the induction treatment period was defined as a binary variable (Yes or No); Yes if total number of febrile neutropenia events ≥ 1 is observed, No for other scenarios. If the patient did not have an event, the value of 0 was assigned to that patient. Each pulmonary infection SAE with a unique start date during the induction treatment period was defined as separate event. The criterion for identifying the proper pulmonary infection SAE records was as follows: The SOC from MedDRA Version 20.1 took the value "INFECTIONS AND INFESTATIONS," the adverse event was a serious event, and the PT took values from the following list of PTs under the category of pulmonary infection adverse events: bronchiolitis, bronchitis, infectious pleural effusion, influenza, pneumonia, pneumonia bacterial, respiratory tract infection, upper respiratory tract infection, and viral upper respiratory tract infection.
Time Frame	Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.	Induction: Patients will receive placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² will be administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin will be administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg will be administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients will receive maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.
Measure Participants	54	53
Count of Participants [Participants]	2 3.7%	5 9.4%

17. Secondary Outcome

Title	Number of Participants With at Least 1 Occurrence of IV Antibiotic Uses
Description	Occurrence of an IV antibiotics administration during the induction treatment period is defined as a binary variable (Yes or No); Yes if total number of IV antibiotics administration ≥ 1 is observed, No for other scenarios. Each IV antibiotic with a unique start date during the induction treatment period will be defined as a separate event. The criteria for identifying an IV antibiotic administration event was (1) if the therapeutic subgroup from WHO-DD Version September 2017 (ie, TEXT2 for CODE2) takes the value "ANTIBACTERIALS FOR SYSTEMIC USE," and (2) the route of medication was "intravenous" or the route was "other" with the detailed specification as "IVPB."
Time Frame	Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m2 was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.
Measure Participants	54	53
Count of Participants [Participants]	10 18.5%	12 22.6%

18. Secondary Outcome

Title	Duration of Study Drug Exposure (Induction Period and Maintenance Period)
Description	Induction period duration of exposure (days) = Day 1 of last induction cycle - Cycle 1 Day 1 of induction phase + 21. Maintenance period duration of exposure (days) = Day 1 of the last maintenance cycle -Cycle 1 Day 1 of maintenance phase + 21.
Time Frame	From date of first dose, up to four 21-day cycles of Induction therapy, followed by 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 1162 days.

Outcome Measure Data

Analysis Population Description

Safety analysis

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.
Measure Participants	52	53
Induction Period	83 (15.6)	88 (20.5)
Maintenance Period	223 (253.3)	232 (271.0)

19. Secondary Outcome

Title	Number of Cycles Completed (Induction Period and Maintenance Period)
Description	Patients were considered to have started a cycle if they have received at least one dose of any study drug (carboplatin, etoposide, atezolizumab or trilaciclib).
Time Frame	From date of first dose, up to four 21-day cycles of Induction therapy, followed by 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 49 cycles.

Outcome Measure Data

Analysis Population Description

Safety analysis

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.
Measure Participants	52	53
Induction Period	4 (0.6)	4 (0.8)
Maintenance Period	10 (11.9)	10 (11.3)

20. Secondary Outcome

Title	Relative Dose Intensity of Trilaciclib/Placebo, Carboplatin, Etoposide, Atezolizumab (Induction Period) and Atezolizumab (Maintenance Period)
Description	Relative dose intensity is defined as 100% times the actual dose intensity divided by the planned dose intensity. The planned dose intensity is defined as the cumulative planned dose through the study divided by (number of cycles * 3 weeks)
Time Frame	From date of first dose, up to four 21-day cycles of Induction therapy, followed by 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 724 days.

Outcome Measure Data

Analysis Population Description

Safety Analysis

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.
Measure Participants	52	53
Trilaciclib/Placebo	94.6 (7.65)	91.1 (10.68)
Carboplatin	95.3 (7.65)	89.1 (12.25)
Etoposide	93.4 (9.59)	87.7 (13.92)
Atezolizumab (Induction)	94.1 (9.54)	91.0 (11.26)
Atezolizumab (Maintenance)	93.5 (11.45)	94.2 (10.19)

21. Secondary Outcome

Title	Number of Participants With Any Cycle Delays and the Number of Cycles Delayed (Induction Period)
Description	After Cycle 1, patients need to meet pre-specified laboratory parameter criteria before initiating Cycle 2 and each subsequent cycle of chemotherapy. A "Cycle Day Status" page asks if the cycle was delayed. If the start of the current cycle was delayed (the site answers "Yes"), this will be counted as a delay. Cycle delays could occur for management of toxicity (hematologic or non-hematologic) or for administrative/logistic reasons. The reason for each cycle delay was captured in the eCRF if it was related to AEs. Reasons other than AEs were not captured.
Time Frame	Induction Period. From date of first dose, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.

Outcome Measure Data

Analysis Population Description

Safety analysis

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.
Measure Participants	52	53
Number of patients with any cycle delays	18 33.3%	31 58.5%
0 cycles	34 63%	22 41.5%
1 cycle	14 25.9%	18 34%
2 cycles	2 3.7%	10 18.9%
3 or more cycles	2 3.7%	3 5.7%

22. Secondary Outcome

Title	Number of Participants With Any Cycle Delays and the Number of Cycles Delayed (Maintenance Period)
Description	After Cycle 1, patients need to meet pre-specified laboratory parameter criteria before initiating Cycle 2 and each subsequent cycle of chemotherapy. A "Cycle Day Status" page asks if the cycle was delayed. If the start of the current cycle was delayed (the site answers "Yes"), this will be counted as a delay. Cycle delays could occur for management of toxicity (hematologic or non-hematologic) or for administrative/logistic reasons. The reason for each cycle delay was captured in the eCRF if it was related to AEs. Reasons other than AEs were not captured.
Time Frame	Maintenance Period. From date of first maintenance dose, 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 1160 days.

Outcome Measure Data

Analysis Population Description

Safety analysis

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was be administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.
Measure Participants	52	53
Number of patients with any cycle delays	21 38.9%	26 49.1%
0 cycles	20 37%	21 39.6%
1 cycle	10 18.5%	12 22.6%
2 cycles	6 11.1%	6 11.3%
3 or more cycles	5 9.3%	8 15.1%

23. Secondary Outcome

Title	Number of Participants With Any Missed Doses [for Each Study Drug: Trilaciclib/Placebo, Carboplatin and Etoposide] (Induction Period)
Description	Missed doses are identified on the dosing page of each study drug based on the question "Was the dose given?". The missed dose information will be obtained for each study drug. For a study drug, if the last record of response to question "Was the dose given?" is No, it will not be considered as a missed dose but instead considered to be end of treatment if both criteria below are met: (1) No other study drugs are given on the same day, and (2) No study drugs are given subsequently.
Time Frame	Induction Period. From date of first dose, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.

Outcome Measure Data

Analysis Population Description

Safety analysis

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients receives maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.
Measure Participants	52	53
Trilaciclib/Placebo	3 5.6%	0 0%
Carboplatin	1 1.9%	0 0%
Etoposide	3 5.6%	0 0%

24. Secondary Outcome

Title	Number of Participants With Any Missed Doses of Atezolizumab (Overall Treatment Period)
Description	Missed doses are identified on the dosing page of each study drug based on the question "Was the dose given?". The missed dose information will be obtained for each study drug. For a study drug, if the last record of response to question "Was the dose given?" is No, it will not be considered as a missed dose but instead considered to be end of treatment if both criteria below are met: (1) No other study drugs are given on the same day, and (2) No study drugs are given subsequently.
Time Frame	From date of first dose, up to four 21-day cycles of Induction therapy, followed by 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 1162 days.

Outcome Measure Data

Analysis Population Description

Safety analysis

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.
Measure Participants	52	53
Count of Participants [Participants]	3 5.6%	3 5.7%

25. Secondary Outcome

Title	Number of Participants With Any Dose Interruptions [for Each Study Drug: Trilaciclib/Placebo, Carboplatin and Etoposide] (Induction Period)
Description	Dose interruptions were defined as interruption of infusion, regardless of whether the study drug was continued after the interruption.
Time Frame	Induction Period. From date of first dose, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.

Outcome Measure Data

Analysis Population Description

Safety analysis

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.
Measure Participants	52	53
Trilaciclib/placebo	3 5.6%	0 0%
Carboplatin	0 0%	1 1.9%
Etoposide	2 3.7%	3 5.7%

26. Secondary Outcome

Title	Number of Participants With Any Interrupted Doses of Atezolizumab (Overall Treatment Period)
Description	Dose interruptions were defined as interruption of infusion, regardless of whether the study drug was continued after the interruption.
Time Frame	From date of first dose, up to four 21-day cycles of Induction therapy, followed by 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 1162 days.

Outcome Measure Data

Analysis Population Description

Safety analysis

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.
Measure Participants	52	53
Count of Participants [Participants]	1 1.9%	0 0%

27. Secondary Outcome

Title	Number of Participants With Any Dose Reductions of Carboplatin and Etoposide (Induction Period)
Description	No dose reductions were allowed for trilaciclib or atezolizumab during the study.
Time Frame	Induction Period. From date of first dose, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.

Outcome Measure Data

Analysis Population Description

Safety analysis

Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab	Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.	Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.
Measure Participants	52	53
Etoposide	3 5.6%	14 26.4%
Carboplatin	1 1.9%	13 24.5%

Adverse Events

Time Frame	Treatment-emergent adverse events collected beginning with informed consent through 30 days after last dose of study drug. Treatment emergent serious adverse events collected through 90 days after last dose of study drug, assessed up to a maximum of 1192 days (maximum duration of exposure plus 30 days).
Adverse Event Reporting Description	Adverse events were assessed using the safety analysis set, which included all randomized patients who received at least 1 dose of any study drug (etoposide, carboplatin, atezolizumab, or trilaciclib). Analyses using the safety analysis set were conducted based on the actual treatment received.
Arm/Group Title	Trilaciclib+Etoposide/Carboplatin/Atezolizumab		Placebo+Etoposide/Carboplatin/Atezolizumab
Arm/Group Description	Induction: Patients received trilaciclib 240 mg/m² administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.		Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle. Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.
All Cause Mortality
	Trilaciclib+Etoposide/Carboplatin/Atezolizumab		Placebo+Etoposide/Carboplatin/Atezolizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	42/54 (77.8%)		44/53 (83%)
Serious Adverse Events
	Trilaciclib+Etoposide/Carboplatin/Atezolizumab		Placebo+Etoposide/Carboplatin/Atezolizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/52 (32.7%)		25/53 (47.2%)
Blood and lymphatic system disorders
Neutropenia	0/52 (0%)	0	4/53 (7.5%)	4
Thrombocytopenia	0/52 (0%)	0	3/53 (5.7%)	3
Anaemia	1/52 (1.9%)	2	1/53 (1.9%)	1
Febrile neutropenia	1/52 (1.9%)	1	1/53 (1.9%)	1
Cardiac disorders
Acute coronary syndrome	1/52 (1.9%)	1	0/53 (0%)	0
Atrial fibrillation	1/52 (1.9%)	1	0/53 (0%)	0
Endocrine disorders
Inappropriate antidiuretic hormone secretion	1/52 (1.9%)	1	0/53 (0%)	0
Gastrointestinal disorders
Retroperitoneal haemorrhage	1/52 (1.9%)	1	0/53 (0%)	0
General disorders
Non-cardiac chest pain	1/52 (1.9%)	1	1/53 (1.9%)	1
Asthenia	0/52 (0%)	0	1/53 (1.9%)	2
Oedema peripheral	0/52 (0%)	0	1/53 (1.9%)	1
Pyrexia	0/52 (0%)	0	1/53 (1.9%)	1
Infections and infestations
Pneumonia	3/52 (5.8%)	5	8/53 (15.1%)	8
Sepsis	0/52 (0%)	0	2/53 (3.8%)	2
Urinary Tract Infection	1/52 (1.9%)	1	1/53 (1.9%)	1
Bronchiolitis	0/52 (0%)	0	1/53 (1.9%)	1
Bronchitis	0/52 (0%)	0	1/53 (1.9%)	1
Cellulitis	0/52 (0%)	0	1/53 (1.9%)	1
Empyema	0/52 (0%)	0	1/53 (1.9%)	2
Meningoencephalitis herpetic	0/52 (0%)	0	1/53 (1.9%)	2
Injury, poisoning and procedural complications
Fall	0/52 (0%)	0	1/53 (1.9%)	1
Hip fracture	1/52 (1.9%)	1	0/53 (0%)	0
Investigations
Platelet count decreased	0/52 (0%)	0	1/53 (1.9%)	1
Metabolism and nutrition disorders
Dehydration	0/52 (0%)	0	2/53 (3.8%)	2
Failure to thrive	0/52 (0%)	0	1/53 (1.9%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/52 (1.9%)	5	2/53 (3.8%)	2
Nervous system disorders
Cerebrovascular accident	1/52 (1.9%)	1	1/53 (1.9%)	1
Balance disorder	0/52 (0%)	0	1/53 (1.9%)	1
Cognitive disorder	0/52 (0%)	0	1/53 (1.9%)	1
Generalised tonic-clonic seizure	0/52 (0%)	0	1/53 (1.9%)	1
Ischaemic stroke	1/52 (1.9%)	1	0/53 (0%)	0
Paraneoplastic neurological syndrome	0/52 (0%)	0	1/53 (1.9%)	1
Psychiatric disorders
Confusional state	0/52 (0%)	0	1/53 (1.9%)	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	2/52 (3.8%)	2	2/53 (3.8%)	2
Dyspnoea	1/52 (1.9%)	1	2/53 (3.8%)	2
Pneumonitis	1/52 (1.9%)	1	1/53 (1.9%)	1
Haemoptysis	1/52 (1.9%)	1	0/53 (0%)	0
Hypoxia	0/52 (0%)	0	1/53 (1.9%)	1
Pulmonary embolism	0/52 (0%)	0	1/53 (1.9%)	1
Respiratory distress	1/52 (1.9%)	1	0/53 (0%)	0
Skin and subcutaneous tissue disorders
Angioedema	1/52 (1.9%)	1	0/53 (0%)	0
Vascular disorders
Deep vein thrombosis	1/52 (1.9%)	1	0/53 (0%)	0
Thrombosis	1/52 (1.9%)	1	0/53 (0%)	0
Other (Not Including Serious) Adverse Events
	Trilaciclib+Etoposide/Carboplatin/Atezolizumab		Placebo+Etoposide/Carboplatin/Atezolizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	49/52 (94.2%)		52/53 (98.1%)
Blood and lymphatic system disorders
Anaemia	19/52 (36.5%)	60	32/53 (60.4%)	122
Neutropenia	19/52 (36.5%)	35	28/53 (52.8%)	85
Thrombocytopenia	7/52 (13.5%)	14	21/53 (39.6%)	44
Leukopenia	4/52 (7.7%)	5	14/53 (26.4%)	38
Endocrine disorders
Hypothyroidism	3/52 (5.8%)	3	7/53 (13.2%)	7
Hyperthyroidism	2/52 (3.8%)	3	6/53 (11.3%)	6
Gastrointestinal disorders
Nausea	20/52 (38.5%)	36	18/53 (34%)	30
Constipation	5/52 (9.6%)	6	12/53 (22.6%)	15
Diarrhoea	9/52 (17.3%)	13	6/53 (11.3%)	10
Vomiting	6/52 (11.5%)	10	5/53 (9.4%)	6
Stomatitis	3/52 (5.8%)	3	3/53 (5.7%)	5
Abdominal pain	1/52 (1.9%)	1	4/53 (7.5%)	5
Dyspepsia	4/52 (7.7%)	4	0/53 (0%)	0
General disorders
Fatigue	16/52 (30.8%)	24	20/53 (37.7%)	32
Asthenia	8/52 (15.4%)	17	9/53 (17%)	21
Non-cardiac chest pain	5/52 (9.6%)	5	7/53 (13.2%)	7
Pyrexia	8/52 (15.4%)	8	4/53 (7.5%)	5
Oedema peripheral	4/52 (7.7%)	4	4/53 (7.5%)	4
Chills	2/52 (3.8%)	2	4/53 (7.5%)	5
Gait disturbance	1/52 (1.9%)	1	3/53 (5.7%)	3
Infections and infestations
Urinary tract infection	5/52 (9.6%)	7	3/53 (5.7%)	4
Pneumonia	4/52 (7.7%)	4	3/53 (5.7%)	4
Upper respiratory tract infection	3/52 (5.8%)	4	3/53 (5.7%)	5
Bronchitis	3/52 (5.8%)	4	2/53 (3.8%)	2
Injury, poisoning and procedural complications
Infusion related reaction	5/52 (9.6%)	11	2/53 (3.8%)	2
Fall	2/52 (3.8%)	3	4/53 (7.5%)	6
Investigations
Platelet count decreased	5/52 (9.6%)	10	13/53 (24.5%)	63
Neutrophil count decreased	3/52 (5.8%)	11	11/53 (20.8%)	50
White blood cell count decreased	7/52 (13.5%)	20	6/53 (11.3%)	25
Aspartate aminotransferase increased	6/52 (11.5%)	11	2/53 (3.8%)	4
Alanine aminotransferase increased	5/52 (9.6%)	10	2/53 (3.8%)	4
Blood alkaline phosphatase increased	4/52 (7.7%)	5	3/53 (5.7%)	6
Blood creatinine increased	3/52 (5.8%)	4	4/53 (7.5%)	5
Blood lactate dehydrogenase increased	3/52 (5.8%)	5	4/53 (7.5%)	8
Weight decreased	4/52 (7.7%)	5	3/53 (5.7%)	3
Lipase increased	1/52 (1.9%)	2	5/53 (9.4%)	10
Weight increased	3/52 (5.8%)	3	0/53 (0%)	0
Metabolism and nutrition disorders
Dehydration	5/52 (9.6%)	6	9/53 (17%)	11
Decreased appetite	4/52 (7.7%)	5	9/53 (17%)	10
Hyperglycaemia	5/52 (9.6%)	11	3/53 (5.7%)	3
Hyponatraemia	4/52 (7.7%)	13	4/53 (7.5%)	4
Hypokalaemia	4/52 (7.7%)	6	2/53 (3.8%)	2
Hyperkalaemia	3/52 (5.8%)	7	1/53 (1.9%)	1
Musculoskeletal and connective tissue disorders
Back pain	5/52 (9.6%)	10	3/53 (5.7%)	3
Arthralgia	5/52 (9.6%)	5	2/53 (3.8%)	2
Muscular weakness	3/52 (5.8%)	3	3/53 (5.7%)	3
Muscle spasms	2/52 (3.8%)	2	3/53 (5.7%)	4
Pain in extremity	2/52 (3.8%)	2	3/53 (5.7%)	3
Nervous system disorders
Dizziness	9/52 (17.3%)	11	9/53 (17%)	13
Headache	9/52 (17.3%)	13	6/53 (11.3%)	9
Tremor	1/52 (1.9%)	1	3/53 (5.7%)	3
Dysgeusia	0/52 (0%)	0	3/53 (5.7%)	3
Psychiatric disorders
Anxiety	3/52 (5.8%)	8	5/53 (9.4%)	5
Confusional state	2/52 (3.8%)	2	4/53 (7.5%)	5
Insomnia	0/52 (0%)	0	4/53 (7.5%)	4
Renal and urinary disorders
Urinary incontinence	1/52 (1.9%)	4	3/53 (5.7%)	5
Respiratory, thoracic and mediastinal disorders
Dyspnoea	8/52 (15.4%)	13	13/53 (24.5%)	20
Cough	8/52 (15.4%)	8	8/53 (15.1%)	12
Haemoptysis	3/52 (5.8%)	3	5/53 (9.4%)	7
Oropharyngeal pain	2/52 (3.8%)	2	3/53 (5.7%)	4
Productive cough	1/52 (1.9%)	1	4/53 (7.5%)	4
Wheezing	3/52 (5.8%)	3	2/53 (3.8%)	2
Dysphonia	1/52 (1.9%)	1	3/53 (5.7%)	3
Epistaxis	0/52 (0%)	0	3/53 (5.7%)	3
Skin and subcutaneous tissue disorders
Alopecia	7/52 (13.5%)	8	18/53 (34%)	21
Pruritus	8/52 (15.4%)	9	3/53 (5.7%)	3
Rash	5/52 (9.6%)	10	4/53 (7.5%)	5
Rash maculo-papular	0/52 (0%)	0	3/53 (5.7%)	11
Vascular disorders
Hypertension	3/52 (5.8%)	6	3/53 (5.7%)	4
Flushing	3/52 (5.8%)	4	2/53 (3.8%)	2
Hypotension	1/52 (1.9%)	1	3/53 (5.7%)	4
Phlebitis	3/52 (5.8%)	4	0/53 (0%)	0

Limitations/Caveats

Limitation of the trial is small numbers of subjects, since it is a Phase 2 clinical trial. Small sample size may have reduced the ability to observe statistically significant treatment effects on secondary myelopreservation measures (i.e. occurrence of FN AEs, infections and antibiotics usage).

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.