CeLEBrATE: Efficacy and Safety Study of a New Therapeutic Strategy in the Treatment of Extended-Disease Small-Cell Lung Cancer

Sponsor

Gruppo Oncologico Italiano di Ricerca Clinica (Other)

Overall Status

Recruiting

CT.gov ID

NCT04730999

Collaborator

Roche Pharma, Italy (Other), YGHEA, CRO Division of Ecol Studio spa (Other), Dr. Luca Boni U.O. Epidemiologia Clinica, IRCCS Ospedale Policlinico San Martino - IST NORD CBA (Other)

Enrollment

Locations

Arm

51.5

Anticipated Duration (Months)

3.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Small cell lung cancer (SCLC) is an aggressive type of neuroendocrine tumor with the majority of patients (about 60-70%) being diagnosed with metastatic disease and with a median survival ranging from 7 to 12 months. Combination chemotherapy (CT), namely a platinum and etoposide-based regimen, represents the cornerstone of treatment for extended disease (ED) SCLC. Despite this the duration of response is short and nearly all patients develop disease relapse or progression. The recent approval of atezolizumab in combination with carboplatin and etoposide as first line in patients with ED SCLC is surely a step forward in the understanding the molecular landscape and treatment of this complex tumor, but new therapeutic approaches need to be explored.

This trial aims to assess the efficacy in terms of 1 year survival a new therapeutic strategy that combines to the standard CT (carboplatin and etoposide), two drugs indicated in the tratment of several types of tumors: bevacizumab and atezolizomab.

The treatment will start with an induction phase during which eligible patients will receive, by intravenous way, a combination of the above mentioned drugs according to a specific administration regimen. This phase will last about 18 weeks. Therafter the treatment will proceed with a maintenence phase lasting for a maximum of 54 weeks during which the patients will receive only atezolizumab and bevacizumab, by intravenous way, according to a specific administration regimen. Treatment will be discontnued in case of disease progression, unacceptable toxicity, patient refusal or loss of clinical benefit (for atezolizumab). During the study period the patients will undergo to periodic visits and laboratory, radiologic assessments to monitor the efficacy and the safety of the ongoing treatment.

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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

52 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase II, Single Arm Study of CarbopLatin Plus Etoposide With Bevacizumab and Atezolizumab in Patients With exTEnded-disease Small-cell Lung Cancer (SCLC)

Actual Study Start Date :

Jul 1, 2020

Anticipated Primary Completion Date :

Jun 1, 2023

Anticipated Study Completion Date :

Oct 17, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Single Arm Induction phase (6 cycles, 21 days duration): carboplatin, etoposide, bevacizumab and atezolizumab. Maintenance phase (12 cycles, 21 days duration): bevacizumab and atezolizumab	Drug: Etoposide Induction phase: 100 mg/sqm on days 1-3, for a maximum of 6 cycles (each one of 21 days duration). Intravenous administration. Treatment will continue until progression of disease, unacceptable toxicity, patient refusal. Drug: Carboplatin Induction phase: AUC 5 on day 1 for a maximum of 6 cycles (each one of 21 days duration). Intravenous administration. Treatment will continue until progression of disease, unacceptable toxicity, patient refusal. Drug: Bevacizumab Induction phase: 7.5 mg/kg on day 1, for a maximum of 6 cycles (each one of 21 days duration). Intravenous administration. Maintenance phase: 7.5 mg/kg on day 1, for a maximum of 12 cycles (each one of 21 days duration). Intravenous administration. In both phases, the treatment will continue until progression of disease, unacceptable toxicity, patient refusal. Drug: Atezolizumab Induction phase: flat dosing of 1200 mg on day 1, for a maximum of 6 cycles ( each one of 21 days duration). Intravenous administration. Maintenance phase: flat dosing of 1200 mg on day 1, for a maximum of 12 cycles (each one of 21 days duration). Intravenous administration. In both phases, the treatment will continue until progression of disease, unacceptable toxicity, patient refusal, loss of clinical benefit.

Arm

Intervention/Treatment

Experimental: Single Arm

Induction phase (6 cycles, 21 days duration): carboplatin, etoposide, bevacizumab and atezolizumab. Maintenance phase (12 cycles, 21 days duration): bevacizumab and atezolizumab

Drug: Etoposide

Induction phase: 100 mg/sqm on days 1-3, for a maximum of 6 cycles (each one of 21 days duration). Intravenous administration. Treatment will continue until progression of disease, unacceptable toxicity, patient refusal.

Drug: Carboplatin

Induction phase: AUC 5 on day 1 for a maximum of 6 cycles (each one of 21 days duration). Intravenous administration. Treatment will continue until progression of disease, unacceptable toxicity, patient refusal.

Drug: Bevacizumab

Induction phase: 7.5 mg/kg on day 1, for a maximum of 6 cycles (each one of 21 days duration). Intravenous administration. Maintenance phase: 7.5 mg/kg on day 1, for a maximum of 12 cycles (each one of 21 days duration). Intravenous administration. In both phases, the treatment will continue until progression of disease, unacceptable toxicity, patient refusal.

Drug: Atezolizumab

Induction phase: flat dosing of 1200 mg on day 1, for a maximum of 6 cycles ( each one of 21 days duration). Intravenous administration. Maintenance phase: flat dosing of 1200 mg on day 1, for a maximum of 12 cycles (each one of 21 days duration). Intravenous administration. In both phases, the treatment will continue until progression of disease, unacceptable toxicity, patient refusal, loss of clinical benefit.

Outcome Measures

Primary Outcome Measures

Overall Survival [Interval between the date of enrolment and the date of death from any cause, up to a maximum of 25 months.]
Percentage of patients surviving 1 year after study treatment end

Secondary Outcome Measures

Incidence and severity of Treatment-Emergent Adverse Events [Safety and Tolerability] [Interval between the date of enrolment and the date of death from any cause, up to a maximum of 15 months]
Frequency of adverse events. Severity of adverse events measured according to NCI Common Toxicity Criteria Adverse Event (CTCAE), version 5.0.
Overall Response Rate (ORR) [Interval between the date of enrolment and the date of death from any cause, up to a maximum of 13 months.]
The sum of complete response (CR) + partial response (PR). Tumor responses will be evaluated according to standard RECIST 1.1 criteria. Patients with no tumor assessment after baseline will be classified as non-responders.
Progression-Free Survival (PFS) [Interval between the date of enrolment and the date of progressive disease, or death, up to a maximum of 13 months.]
The time of survival without progression of disease confirmed according to to standard RECIST 1.1 criteria.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically or cytological documented small cell lung cancer (SCLC) or poorly differentiated (G3) neuroendocrine carcinoma of the lung
Extensive stage disease (disease which cannot be encompassed in a single radiation portal including pleural dissemination and supraclavicular node metastasis)
No prior chemotherapy or treatment with another systemic anti-cancer agent (Note: Patients who have received prior chemoradiotherapy for limited-stage SCLC must have been treated with curative intent and experienced a treatment-free interval of at least 6 months since last chemotherapy, radiotherapy or chemoradiotherapy cycle from diagnosis of extended-disease SCLC)
No need for concomitant chest irradiation
Males or females, age ≥18 years
ECOG performance status 0-1
Life expectancy > 12 weeks
Adequate hepatic and renal functions [i.e. total bilirubin < 1.5 times the ULN; - AST and ALT < 3.0 times the ULN (AST and ALT < 5.0 x ULN is acceptable if the liver has tumor involvement); Albumin≥ 25 g/L (2.5 g/dL); serum creatinine ≤1.5 times the ULN or creatinine clearance, calculated according to the formula of Cockcroft and Gault > 60 ml/min; urine dipstick for proteinuria <2+. If urine dipstick is >2+, 24-hour urine must demonstrate ≤ 1 g of protein in 24 hours]
Adequate hematologic function, as evidenced by an absolute neutrophil count (ANC) ≥1500/µL, hemoglobin ≥9 g/dL (5.58 mmol/L), and platelets ≥100,000/µL.
Adequate coagulation function as defined by International Normalized Ratio (INR) ≤1.5 and a partial thromboplastin time (PTT) (PTT/aPTT) ≤ 1.5 x upper limits of normal [ULN]. Patients on full-dose anticoagulation must be on a stable dose (minimum duration 14 days) of oral anticoagulant or low molecular weight heparin (LMWH). If receiving warfarin, the patient must have an INR ≤3.0. For heparin and LMWH there should be no active bleeding (that is, no bleeding within 14 days prior to first dose of protocol therapy) or pathological condition present that carries a high risk of bleeding (for example, tumor involving major vessels or known varices).
Negative HIV test at screening with respect of any applicable law and the indication of Atezolizumab use.
Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening. Please note: The HBV DNA test will be performed only for patients who have a positive total HBcAb test
Negative hepatitis C virus (HCV) antibody test at screening.
Female patients of childbearing potential must have a negative serum pregnancy test within 72 hours prior to first dose of protocol therapy.
Male patients who are sexually active must use effective contraception during treatment with chemotherapy and for at least 6 months after the final dose of chemotherapy to avoid exposing the embryo. Men must refrain from donating sperm during this same period.
For female patients of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception that results in a low failure rate (< 1% per year) when used consistently and correctly, and to continue its use for 6 months after the last dose of atezolizumab or bevacizumab. Such methods include: combined (estrogen and progestogen containing) hormonal contraception, progestogen-only hormonal contraception associated with inhibition of ovulation together with another additional barrier method always containing a spermicide, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner (on the understanding that this is the only one partner during the whole study duration), and sexual abstinence.
Ability to comply with the study protocol, in the investigator's judgment
Written informed consent

Exclusion Criteria:

The patient has experienced any Grade 3-4 gastrointestinal bleeding within 3 months prior to first dose of protocol therapy.
The patient has a history of deep vein thrombosis (DVT), pulmonary embolism (PE), or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered "significant") during the 3 months prior to first dose of protocol therapy.
Symptomatic brain metastases or spinal cord compression (CT or MRI of the head is required within 4 weeks prior to registration) requiring immediate radiotherapy for palliation. Asymptomatic patients with treated or untreated CNS lesions are eligible, provided that all of the following criteria are met:

Presence outside the CNS of measurable disease per RECIST v1.1 B. No history of intracranial hemorrhage, spinal cord hemorrhage or heorrhagic intracranial lesions C. No stereotactic radiotherapy or whole brain radiotherapy within 14 days prior to initiation of study treatment or neurosurgical resection within 28 days prior to initiation of study treatment D. Concurrent therapy of corticosteroids ≤ 10 mg of oral prednisone or equivalent and/or anticonvulsant therapy at a stable dose E. Metastases are limited to the cerebellum or the supratentorial region (i.e., no metastases to the midbrain, pons, medulla or spinal cord) F. No evidence of interim progression between completion of CNS directed therapy (if administered) and initiation of study treatment

History of leptomeningeal disease
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently) Patients with indwelling catheters (e.g., Pleurocath) are allowed.
Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected calcium > ULN)
Active tubercolosis
Significant traumatic injury or radiotherapy involving an extensive field within the last 4 weeks prior to first dose of study treatment or anticipation of the need for major surgery during study treatment. Palliative radiotherapy to a limited field is allowed if concluded at least 2 weeks prior enrolment.
The patient experienced hemoptysis (defined ≥ one-half teaspoon of bright red blood per episode) within 2 months prior to first dose of protocol therapy or with radiographic evidence of intratumor cavitation.
Other malignancies (previous or current), except for adequately treated in situ carcinoma of the uterine cervix, basal or squamous cell carcinoma of the skin, localized prostate cancer surgically treated with curative intent or ductal carcinoma in situ treated surgically treated with curative intent or if previous malignancy was more than 5 years prior and there are no signs or symptoms of recurrence
The patient has experienced any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to first dose of protocol therapy.
The patient has uncontrolled or poorly-controlled hypertension (>150 mmHg systolic or

100 mmHg diastolic for >4 weeks) despite standard medical management. Anti-hypertensive therapy to achieve these parameters is allowable.

Prior history of hypertensive crisis or hypertensive encephalopathy
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to registration
The patient has a prior history of gastrointestinal or non-gastrointestinal fistula as well as gastrointestinal perforation (within 6 months of first dose of protocol therapy) or risk factors for perforation.
The patient has a serious or non-healing wound, ulcer, or bone fracture within 28 days prior to first dose of protocol therapy.
Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation)
Major surgery (including open biopsy) within 28 days prior to first dose of protocol therapy, or minor surgery/subcutaneous venous access device placement within 7 days prior to the first dose of protocol therapy. The patient has elective or planned major surgery to be performed during the course of the clinical trial.
Prior allogeneic stem cell or solid organ transplantation
Patients with any underlying medical condition that might be aggravated by treatment or which cannot be controlled i.e. patients with active serious infection, diabetes mellitus, pericardial effusion.
Concomitant treatment with any other anti-cancer drug
Treatment with any other investigational agent, or participation in another clinical trial within 30 days prior to starting study treatment
Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contra-indicates the use of an investigational drug or puts the patient at high risk for treatment-related complications
Active, known or suspected autoimmune disease. Subjects with hypothyroidism only requiring hormone replacement, type I diabetes or autoimmune skin disorders not requiring systemic treatments are permitted to enroll.
Patient has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted.
Active infection requiring therapy.
Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), Hepatitis B (HBV) or Hepatitis C (HCV)
History of idiopathic pulmonary fibrosis, including pneumonitis, drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, CD137 agonists.
Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 drug elimination half-lives (whichever is longer) prior to initiation of study treatment.
Any condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of registration. Steroid doses of ≤ 10 mg daily prednisone equivalent are permitted.
History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
History of allergies or hypersensitivity to any study drugs or study drug components.
The patient is pregnant or breast-feeding

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	UOC di Oncologia Medica - AOU Policlinico S. Orsola Malpighi	Bologna	Italy	40138
2	UOC Oncologia Medica - PO A.Perino - ASL di Brindisi	Brindisi	Italy	72100
3	UOC Medicina Oncologica - Ospedale di Carpi - Azienda USL di Modena	Carpi	Italy	41012
4	UO di Oncologia - Istituti Ospitalieri di Cremona - ASST Di Cremona	Cremona	Italy	26100
5	UOC Oncologia Medica - AO S. Croce e Carle di Cuneo	Cuneo	Italy	12100
6	UOC di Oncologia Ematologia - AOU di Ferrara	Ferrara	Italy	44124
7	UOC Oncologia Medica 1 - AOU Careggi	Firenze	Italy	50134
8	Oncologia medica - Policlinico San Martino	Genova	Italy	16132
9	UOC Oncologia Medica - Ospedale San Salvatore	L'Aquila	Italy	67100
10	UOC Oncologia Medica - Azienda ULSS9 Veneto	Legnago	Italy	37045
11	Dip. Oncologia-Ematologia - UO Oncologia - AOU Policlinico di Modena	Modena	Italy	41124
12	UOC Oncologia Medica - AORN "A. Cardarelli"	Napoli	Italy	80131
13	Istituto Oncologico Veneto IRCCS	Padova	Italy	35128
14	UOC di Oncologia Medica - AOU di Parma	Parma	Italy	43126
15	Dipartimento di Oncologia ASUIUD	Udine	Italy	33100

Sponsors and Collaborators

Gruppo Oncologico Italiano di Ricerca Clinica
Roche Pharma, Italy
YGHEA, CRO Division of Ecol Studio spa
Dr. Luca Boni U.O. Epidemiologia Clinica, IRCCS Ospedale Policlinico San Martino - IST NORD CBA

Investigators

Principal Investigator: Andrea Ardizzoni, Dr, S. Orsola-Malpighi University Hospital - Dept. Oncology-Haematology
Study Chair: Karim Rihawi, Dr, S. Orsola-Malpighi University Hospital - Dept. Oncology-Haematology