Trilaciclib, a CDK4/6 Inhibitor, in Patients With Early-Stage Triple Negative Breast Cancer

Sponsor

G1 Therapeutics, Inc. (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT05112536

Collaborator

(none)

Enrollment

Locations

Arm

15.2

Anticipated Duration (Months)

2.4

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the mechanism of action, as well as the safety and efficacy of trilaciclib in combination with standard of care treatment in the neoadjuvant setting of early-stage triple negative breast cancer (TNBC).

This study will have four phases: 1) Screening Phase, 2) Trilaciclib Lead-In Phase, 3) Treatment Phase, and 4) Surgery and Follow-Up Phase. After a screening phase of up to 21 day, each participant will receive trilaciclib single-dose monotherapy during the lead-in phase, followed by a tumor biopsy. During the treatment phase, each participant will receive trilaciclib with standard of care chemotherapy. Immunotherapy may be included during the treatment phase, per standard of care. 3-5 weeks following conclusion of the treatment phase, each participant will undergo definitive surgery. A 30-day Safety Follow-up Visit will occur 30 days after the last dose of trilaciclib and an End of Study Visit will occur within 14 days after definitive surgery.

Condition or Disease	Intervention/Treatment	Phase
Triple Negative Breast Cancer Breast Cancer	Drug: Trilaciclib Drug: Cylophosphamide Drug: Doxorubicin Drug: Paclitaxel Drug: Carboplatin (Investigator discretion) Biological: Pembrolizumab (Investigator discretion)	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

24 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 2, Open-Label, Single-Arm Study of Single-Dose Lead-In and Neoadjuvant Trilaciclib and Chemotherapy in Patients With Early-Stage Triple Negative Breast Cancer (TNBC)

Actual Study Start Date :

Nov 19, 2021

Anticipated Primary Completion Date :

Aug 8, 2022

Anticipated Study Completion Date :

Feb 24, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Trilaciclib plus chemotherapy Trilaciclib lead-in, followed by trilaciclib plus anthracycline/cyclophosphamide, then trilaciclib plus taxane chemotherapy: Lead-in trilaciclib (240mg/m2) single dose monotherapy Trilaciclib (240mg/m2) + doxorubicin (60 mg/m2) + cyclophosphamide (600 mg/m2) + pembrolizumab (per Investigator discretion; 400mg) Trilaciclib (240mg/m2) + paclitaxel (80 mg/m2) + carboplatin (per Investigator discretion; AUC 1.5)	Drug: Trilaciclib Trilaciclib is administered IV as monotherapy during the lead-in phase and administered prior to chemotherapy on each day chemotherapy is administered during the treatment phase. Other Names: COSELA® G1T28 Drug: Cylophosphamide Cyclophosphamide administered IV every 2 weeks for the first 4 cycles (1-4), each cycle 2 weeks in length. Other Names: CYTOXAN® Drug: Doxorubicin Doxorubicin administered as an IV bolus every 2 weeks for the first 4 cycles (1-4), each cycle 2 weeks in length. Other Names: ADRIAMYCIN® Drug: Paclitaxel Paclitaxel administered weekly for the last 12 cycles (cycles 5-16), each cycle 1 week in length. Other Names: TAXOL® Drug: Carboplatin (Investigator discretion) Carboplatin, if given, is administered IV weekly at the start of paclitaxel administration, for the last 12 cycles (cycles 5-16). Other Names: PARAPLATIN® Biological: Pembrolizumab (Investigator discretion) Pembrolizumab, if given, is administered IV every 6 weeks throughout the treatment phase (cycles 1, 4, 9, 15). Other Names: KEYTRUDA®

Arm

Intervention/Treatment

Experimental: Trilaciclib plus chemotherapy

Trilaciclib lead-in, followed by trilaciclib plus anthracycline/cyclophosphamide, then trilaciclib plus taxane chemotherapy: Lead-in trilaciclib (240mg/m2) single dose monotherapy Trilaciclib (240mg/m2) + doxorubicin (60 mg/m2) + cyclophosphamide (600 mg/m2) + pembrolizumab (per Investigator discretion; 400mg) Trilaciclib (240mg/m2) + paclitaxel (80 mg/m2) + carboplatin (per Investigator discretion; AUC 1.5)

Drug: Trilaciclib

Trilaciclib is administered IV as monotherapy during the lead-in phase and administered prior to chemotherapy on each day chemotherapy is administered during the treatment phase.

Other Names:

COSELA®

G1T28

Drug: Cylophosphamide

Cyclophosphamide administered IV every 2 weeks for the first 4 cycles (1-4), each cycle 2 weeks in length.

Other Names:

CYTOXAN®

Drug: Doxorubicin

Doxorubicin administered as an IV bolus every 2 weeks for the first 4 cycles (1-4), each cycle 2 weeks in length.

Other Names:

ADRIAMYCIN®

Drug: Paclitaxel

Paclitaxel administered weekly for the last 12 cycles (cycles 5-16), each cycle 1 week in length.

Other Names:

TAXOL®

Drug: Carboplatin (Investigator discretion)

Carboplatin, if given, is administered IV weekly at the start of paclitaxel administration, for the last 12 cycles (cycles 5-16).

Other Names:

PARAPLATIN®

Biological: Pembrolizumab (Investigator discretion)

Pembrolizumab, if given, is administered IV every 6 weeks throughout the treatment phase (cycles 1, 4, 9, 15).

Other Names:

KEYTRUDA®

Outcome Measures

Primary Outcome Measures

Immune-based mechanism of action [Up to 8 days]
Evaluated 7 days after a single-dose of trilaciclib, measured by the change in CD8 T cells/regulatory T cells (Treg) ratio in tumor tissue.

Secondary Outcome Measures

Pathologic Complete Response (pCR) rate [Up to 26 weeks]
Rate of pCR using the definition of ypT0/Tis ypN0 (i.e., no invasive residual tumor in breast or nodes; noninvasive breast residuals allowed) as assessed by the local pathologist.
Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) [Up to 28 weeks]
Safety/tolerability as per CTCAE version 5.0

Other Outcome Measures

Intratumoral immune profile characterization following trilaciclib [Up to 26 weeks]
Characterization of molecular and immune changes based on CD8+ T cell and Treg infiltration, quantified by RNA profiling of tumor tissue before study treatment, during study treatment, and at definitive surgery.
Kinetics of the immune response in peripheral blood [Up to 26 weeks]
Longitudinal immune changes in peripheral blood, measured by frequency of immune subsets and profiling of activation, maturation, and exhaustion status.
Kinetics of T cell function and polyfunctionality [Up to 26 weeks]
Ex-vivo measurement of cytokine production to determine T cell function and polyfunctionality.
Molecular biomarkers for clinical responsiveness [Up to 26 weeks]
pCR in patients by gene signatures determined in the tumor at baseline.
CDK4/6 dependence for clinical responsiveness [Up to 26 weeks]
pCR in patients by subgroups according to CDK4/6 dependence signatures.
PD-L1 status and clinical responsiveness [Up to 26 weeks]
pCR in patients by subgroups according to PD-L1 status, as measured by IHC.
Immune response and clinical responsiveness [Up to 26 weeks]
pCR in patients by frequency of immune subsets, immunological markers, and cytokines.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Suitability of therapy and patient intends to undergo curative surgery
Documented diagnosis of estrogen receptor (ER)-negative and progesterone receptor (PR)-negative tumor
Primary tumor ≥ 2 cm with any nodal status
Provide archival tissue for the baseline tissue sample
ECOG performance status of 0 or 1
Demonstrates adequate organ function
Research tumor biopsies including at least one on-treatment biopsy (and additional biopsy at baseline, if required)
Participants of child bearing potential must be willing to use 2 forms of contraception during the study and for 6 months following study treatment

Exclusion Criteria:

Prior systemic therapies or radiation for current breast cancer
History of invasive malignancy ≤3 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer
History of breast cancer including ipsilateral ductal carcinoma in situ (DCIS) treated with radiotherapy at any time
Previous exposure to doxorubicin of more than 200 mg/m2 (as lifetime exposure to doxorubicin is not to exceed 450 mg/m2)
For patients who will receive pembrolizumab:
History of active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy is not considered a form of systemic treatment
Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drugs
History of (non-infectious) pneumonitis that required steroids or current pneumonitis
Known history of active tuberculosis (Bacillus Tuberculosis)
History of severe hepatic impairment
Uncontrolled ischemic heart disease or uncontrolled symptomatic congestive heart failure (Class II-IV as defined by the New York Heart Association [NYHA] functional classification system)
Known history of stroke, cerebrovascular accident, severe/unstable angina, myocardial infarction, or coronary angioplasty/stenting/bypass grafting within 6 months prior to enrollment
Known serious active infection (e.g., human immunodeficiency virus [HIV], hepatitis B or C, tuberculosis).
Women who are pregnant or breastfeeding
Participation in other studies involving active treatment with investigational drug(s)
Prior hematopoietic stem cell or bone marrow transplantation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Providence Medical Foundation	Fullerton	California	United States	92835
2	Cancer and Blood Specialty Clinic	Los Alamitos	California	United States	90720
3	UCLA Department of Medicine - Hematology/Oncology	Santa Monica	California	United States	90404
4	PIH Health	Whittier	California	United States	90602
5	Orlando Health Cancer Institute	Orlando	Florida	United States	32806
6	Nebraska Hematology-Oncology, P.C.	Lincoln	Nebraska	United States	68506
7	Duke University Medical Center	Durham	North Carolina	United States	27710
8	Texas Oncology - Austin Central	Austin	Texas	United States	78731
9	Texas Oncology - Baylor Charles A. Sammons Cancer Center	Dallas	Texas	United States	75246
10	Virginia Oncology Associates	Norfolk	Virginia	United States	23502