A Study Evaluating The Safety, Tolerability, Pharmacokinetics, And Efficacy Of Venetoclax In Combination With Atezolizumab, Carboplatin, And Etoposide In Participants With Untreated Extensive-Stage Small Cell Lung Cancer (ES-SCLC).
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| ClinicalTrials.gov Identifier: NCT04422210 |
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Recruitment Status :
Active, not recruiting
First Posted : June 9, 2020
Last Update Posted : January 26, 2021
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Sponsor:
Hoffmann-La Roche
Information provided by (Responsible Party):
Hoffmann-La Roche
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Brief Summary:
A study consisting of a dose-escalation phase and a dose-expansion phase to evaluate the safety, tolerability, pharmacokinetics, and efficacy of venetoclax in combination with atezolizumab, carboplatin, and etoposide.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Small Cell Lung Cancer | Drug: Venetoclax Drug: Atezolizumab Drug: Carboplatin Drug: Etoposide | Phase 1 |
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 62 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Sequential Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | A Phase Ib Dose-Escalation and Dose-Expansion Study Evaluating The Safety, Tolerability, Pharmacokinetics, And Efficacy Of Venetoclax In Combination With Atezolizumab, Carboplatin, And Etoposide In Patients With Untreated Extensive-Stage Small Cell Lung Cancer. |
| Actual Study Start Date : | September 22, 2020 |
| Estimated Primary Completion Date : | July 6, 2024 |
| Estimated Study Completion Date : | December 21, 2024 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Lung cancer
| Arm | Intervention/treatment |
|---|---|
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Experimental: Dose Escalation (Arm A1) (Maintenance only)
Cohort A1: Participants with ES-SCLC who have completed 4-6 cycles of carboplatin and etoposide first-line induction chemotherapy, with or without atezolizumab, will be administered continuous maintenance therapy with Venetoclax (400mg) once daily (QD) from Day 1 to 21 and Atezolizumab (1200mg) every 3 weeks (Q3W) on Day 1.
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Drug: Venetoclax
Venetoclax will be administered orally at escalating doses from 200mg to 800mg as 100mg tablets as per the dosing schedules described above. Drug: Atezolizumab Atezolizumab will be administered via intravenous (IV) infusion at a fixed dose of 1200mg as per the dosing schedules described above. |
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Experimental: Dose Escalation (Arm A2) (Maintenance only)
Cohort A2: Participants with ES-SCLC who have completed 4-6 cycles of carboplatin and etoposide first-line induction chemotherapy, with or without atezolizumab, will be administered continuous maintenance therapy with Venetoclax (800mg) once daily (QD) from Day 1 to 21 and Atezolizumab (1200mg) every 3 weeks (Q3W) on Day 1.
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Drug: Venetoclax
Venetoclax will be administered orally at escalating doses from 200mg to 800mg as 100mg tablets as per the dosing schedules described above. Drug: Atezolizumab Atezolizumab will be administered via intravenous (IV) infusion at a fixed dose of 1200mg as per the dosing schedules described above. |
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Experimental: Dose Escalation (Arm A3) (Maintenance only)
Cohort A3: Participants with ES-SCLC who have completed 4-6 cycles of carboplatin and etoposide first-line induction chemotherapy, with or without atezolizumab, will be administered continuous maintenance therapy with Venetoclax (200mg) once daily (QD) from Day 1 to 21 and Atezolizumab (1200mg) every 3 weeks (Q3W) on Day 1. This cohort maybe explored if Dose-Limiting Toxicities (DLTs) are experienced and adverse events are thought to be potentially mitigated with a lower dose of venetoclax.
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Drug: Venetoclax
Venetoclax will be administered orally at escalating doses from 200mg to 800mg as 100mg tablets as per the dosing schedules described above. Drug: Atezolizumab Atezolizumab will be administered via intravenous (IV) infusion at a fixed dose of 1200mg as per the dosing schedules described above. |
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Experimental: Dose Escalation (Arm B1) (Induction + Maintenance)
Cohort B1: Participants with ES-SCLC will be administered non-continuous induction therapy with Venetoclax (200mg) once daily (QD) from Day 1 to 7, Atezolizumab (1200mg) every 3 weeks (Q3W) on Day 1, Carboplatin (5mg/mL/min) on Day 1 and Etoposide (100mg/m^2) on Days 1-3. Participants who tolerate study treatment without excessive toxicity, and have not undergone disease progression will then proceed to maintenance treatment with venetoclax plus atezolizumab. The venetoclax dose for the maintenance setting in Arm B will be the dose that has been cleared in the maintenance only arm (Arm A) of the study (maintenance RP2D, RP2D-M).
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Drug: Venetoclax
Venetoclax will be administered orally at escalating doses from 200mg to 800mg as 100mg tablets as per the dosing schedules described above. Drug: Atezolizumab Atezolizumab will be administered via intravenous (IV) infusion at a fixed dose of 1200mg as per the dosing schedules described above. Drug: Carboplatin Carboplatin will be administered via IV infusion at a dose of 5mg/mL/min as per the dosing schedules described above. Drug: Etoposide Etoposide will be administered via IV infusion at a dose of 100mg/m^2 as per the dosing schedules described above. |
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Experimental: Dose Escalation (Arm B2) (Induction + Maintenance)
Cohort B2: Participants with ES-SCLC will be administered non-continuous induction therapy with Venetoclax (400mg) once daily (QD) from Day 1 to 7, Atezolizumab (1200mg) every 3 weeks (Q3W) on Day 1, Carboplatin (5mg/mL/min) on Day 1 and Etoposide (100mg/m^2) on Days 1-3. Participants who tolerate study treatment without excessive toxicity, and have not undergone disease progression will then proceed to maintenance treatment with venetoclax plus atezolizumab. The venetoclax dose for the maintenance setting in Arm B will be the dose that has been cleared in the maintenance only arm (Arm A) of the study (maintenance RP2D, RP2D-M).
|
Drug: Venetoclax
Venetoclax will be administered orally at escalating doses from 200mg to 800mg as 100mg tablets as per the dosing schedules described above. Drug: Atezolizumab Atezolizumab will be administered via intravenous (IV) infusion at a fixed dose of 1200mg as per the dosing schedules described above. Drug: Carboplatin Carboplatin will be administered via IV infusion at a dose of 5mg/mL/min as per the dosing schedules described above. Drug: Etoposide Etoposide will be administered via IV infusion at a dose of 100mg/m^2 as per the dosing schedules described above. |
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Experimental: Dose Escalation (Arm B3) (Induction + Maintenance)
Cohort B3: Participants with ES-SCLC will be administered non-continuous induction therapy with Venetoclax (800mg) once daily (QD) from Day 1 to 7, Atezolizumab (1200mg) every 3 weeks (Q3W) on Day 1, Carboplatin (5mg/mL/min) on Day 1 and Etoposide (100mg/m^2) on Days 1-3. Participants who tolerate study treatment without excessive toxicity, and have not undergone disease progression will then proceed to maintenance treatment with venetoclax plus atezolizumab. The venetoclax dose for the maintenance setting in Arm B will be the dose that has been cleared in the maintenance only arm (Arm A) of the study (maintenance RP2D, RP2D-M).
|
Drug: Venetoclax
Venetoclax will be administered orally at escalating doses from 200mg to 800mg as 100mg tablets as per the dosing schedules described above. Drug: Atezolizumab Atezolizumab will be administered via intravenous (IV) infusion at a fixed dose of 1200mg as per the dosing schedules described above. Drug: Carboplatin Carboplatin will be administered via IV infusion at a dose of 5mg/mL/min as per the dosing schedules described above. Drug: Etoposide Etoposide will be administered via IV infusion at a dose of 100mg/m^2 as per the dosing schedules described above. |
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Experimental: Dose Escalation (Arm B4) (Induction + Maintenance)
Cohort B4: Participants with ES-SCLC will be administered non-continuous induction therapy with Venetoclax (800mg) once daily (QD) from Day 1 to 14, Atezolizumab (1200mg) every 3 weeks (Q3W) on Day 1, Carboplatin (5mg/mL/min) on Day 1 and Etoposide (100mg/m^2) on Days 1-3. Participants who tolerate study treatment without excessive toxicity, and have not undergone disease progression will then proceed to maintenance treatment with venetoclax plus atezolizumab. The venetoclax dose for the maintenance setting in Arm B will be the dose that has been cleared in the maintenance only arm (Arm A) of the study (maintenance RP2D, RP2D-M).
|
Drug: Venetoclax
Venetoclax will be administered orally at escalating doses from 200mg to 800mg as 100mg tablets as per the dosing schedules described above. Drug: Atezolizumab Atezolizumab will be administered via intravenous (IV) infusion at a fixed dose of 1200mg as per the dosing schedules described above. Drug: Carboplatin Carboplatin will be administered via IV infusion at a dose of 5mg/mL/min as per the dosing schedules described above. Drug: Etoposide Etoposide will be administered via IV infusion at a dose of 100mg/m^2 as per the dosing schedules described above. |
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Experimental: Dose Expansion
If the Recommended Phase II Dose (RP2D) for Venetoclax during induction is established, then the dose-expansion cohort will continue to test venetoclax in both induction and maintenance. Participants will be administered non-continuous induction therapy with Venetoclax (RP2D-I/induction RP2D), Atezolizumab (1200mg) every 3 weeks (Q3W) on Day 1, Carboplatin (5mg/mL/min) on Day 1 and Etoposide (100mg/m^2) on Days 1-3 followed by continuous maintenance therapy with Venetoclax (RP2D-M) and Atezolizumab (1200mg) every 3 weeks (Q3W) on Day 1. If significant toxicity and DLTs in induction preclude identification of an RP2D for venetoclax in induction treatment, then the safety and efficacy of venetoclax will only be investigated in dose-expansion in the maintenance setting. Participants will be administered continuous maintenance therapy with Venetoclax (RP2D-M) and Atezolizumab (1200mg) every 3 weeks (Q3W) on Day 1.
|
Drug: Venetoclax
Venetoclax will be administered orally at escalating doses from 200mg to 800mg as 100mg tablets as per the dosing schedules described above. Drug: Atezolizumab Atezolizumab will be administered via intravenous (IV) infusion at a fixed dose of 1200mg as per the dosing schedules described above. Drug: Carboplatin Carboplatin will be administered via IV infusion at a dose of 5mg/mL/min as per the dosing schedules described above. Drug: Etoposide Etoposide will be administered via IV infusion at a dose of 100mg/m^2 as per the dosing schedules described above. |
Primary Outcome Measures :
- Percentage of Participants with Adverse Events (AEs) [ Time Frame: Up to 49 months ]Determined according to the National Cancer Institute Common Technology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0)
- Overall Response Rate (ORR) [ Time Frame: Up to 24 months ]Defined as the percentage of participants with a Complete Response (CR) or Partial Response (PR) on two consecutive occasions >= 28 days apart, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1).
Secondary Outcome Measures :
- Duration of Response (DOR) [ Time Frame: Up to 24 months ]Defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first, as determined by the investigator according to RECIST v1.1.
- Progression Free Survival (PFS) [ Time Frame: Up to 24 months ]Defined as the time from enrolment to the first occurrence of disease progression or relapse or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1.
- Overall Survival (OS) after Enrolment [ Time Frame: Up to 49 months ]Defined as the time from enrolment to death from any cause.
- Progression Free Survival (PFS) rate at 6 months [ Time Frame: Up to 18 months ]Defined as the percentage of participants who have not experienced disease progression, relapse, or death from any cause at 6 months, as determined by the investigator according to RECIST v1.1.
- Overall Survival (OS) Rate at 1 year [ Time Frame: Up to 18 months ]Defined as the percentage of participants who have not experienced death from any cause at 1 year.
- Plasma Concentrations (ng/mL) of Venetoclax at specified timepoints [ Time Frame: Up to 24 months ]
- Serum Concentrations (ng/mL) of Atezolizumab at specified timepoints [ Time Frame: Up to 24 months ]
- Plasma Concentrations (ng/mL) of Carboplatin at specified timepoints [ Time Frame: Up to 24 months ]
- Plasma Concentrations (ng/mL) of Etoposide at specified timepoints [ Time Frame: Up to 24 months ]
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
Dose Escalation, Maintenance Arm A:
- Participants with ES-SCLC who have completed 4-6 cycles of carboplatin and etoposide induction chemotherapy, with or without atezolizumab, as their first-line therapy for extensive-stage disease and have responded (CR or PR) or have Stable Disease (SD) are eligible for the maintenance arm of the study.
- All side effects attributed to prior anti-cancer therapy must have resolved to Grade 1 or baseline.
- A maximum of 8 weeks (56 days) is allowed between last chemotherapy dose (Cycle 4, Day 3) given in induction and the start of maintenance therapy.
Dose Escalation, Induction Arm B:
- Participants with no prior systemic treatment for ES-SCLC are eligible for this study.
- ANC >= 1,500 cells/µL without granulocyte colony-stimulating factor support.
Dose Expansion, Maintenance-Only:
- Participants with ES-SCLC who have completed 4 cycles of carboplatin and etoposide induction chemotherapy and at least 3 cycles of atezolizumab as their first-line therapy for extensive-stage disease and have responded (CR or PR) or have SD are eligible for the maintenance arm of the study.
Dose Escalation (Arms A and B) and Dose Expansion:
- Ability to comply with the study protocol, in the investigator's judgement.
- ECOG performance status of 0 or 1.
- Participants must be able to swallow pills.
- Histologically or cytologically confirmed diagnosis of ES-SCLC per the Veterans Administration Lung Study Group (VALG) staging system.
- Participants who 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 prior to diagnosis of ES-SCLC.
- Participants with a history of treated CNS metastases that are currently asymptomatic.
- Measurable disease, as defined by RECIST v1.1. Baseline measurements and evaluation of all sites of disease must be obtained =<4 weeks prior to enrollment.
- Eligible to receive a carboplatin-based chemotherapy regimen.
- Adequate hematologic and end-organ function.
- Participants must submit a pre-treatment tumor tissue sample.
- Participants must submit a blood sample for exploratory biomarker research before treatment, on-study, and following progression of disease.
- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse), use non-hormonal contraceptive methods and refrain from donating eggs.
- Women who are not postmenopausal (>=12 months of non-therapy-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result within 14 days prior to initiation of study drug.
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom and agreement to refrain from donating sperm.
Exclusion Criteria:
- Use of non-protocol-specified anti-cancer therapies or other combination partners with carboplatin/etoposide during induction.
- Symptomatic or actively progressing CNS metastases.
- Pregnant or breastfeeding, or intending to become pregnant during the study.
- Spinal cord compression not definitively treated with surgery and/or radiation or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for >= 1 week prior to enrollment.
- Leptomeningeal disease.
- Uncontrolled pleural effusion, pericardial effusion or ascites requiring recurrent drainage procedures (once a month or more frequently).
- Uncontrolled or symptomatic hypercalcemia.
- History of malignancy other than SCLC within 5 years prior to enrollment.
- History of autoimmune disease.
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
- Positive HIV infection.
- Active Hepatitis B and C infection (HBV/HCV).
- Active Tuberculosis infection.
- Known infection with human T-cell leukemia virus 1.
- Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization.
- Significant cardiovascular disease.
- Major surgical procedure within 28 days prior to enrollment or anticipation of need for major surgical procedure during the course of the study.
- Prior allogenic bone marrow transplantation or solid organ transplant.
- Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the participant at high risk for treatment complications.
- Illnesses or conditions that interfere with their capacity to understand, follow, and/or comply with study procedures.
- Treatment with investigational therapy with therapeutic intent within 28 days prior to enrollment.
- Administration of a live, attenuated vaccine within 4 weeks before enrollment or anticipation that such a live attenuated vaccine will be required during the study.
- Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti-PD-1, and anti-PD-L1 therapeutic antibodies.
- Treatment with systemic immunosuppressive medications within 1 week prior to enrollment.
- History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
- Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation.
- History of allergic reactions to carboplatin or etoposide or to any of its excipients (etoposide).
- Known hypersensitivity to venetoclax or to any of its excipients.
- Administration of Steroid therapy for anti-neoplastic intent, strong or moderate CYP3A inhibitors or strong or moderate CYP3A inducers within 7 days prior to the first dose of study drug.
- Consumption of grapefruit, grapefruit products, Seville oranges (including marmalade-containing Seville oranges), or starfruit (carambola) within 3 days prior to the first dose of study drug.
- Malabsorption syndrome or other condition that would interfere with enteral absorption.
- Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator's judgement.
- Inability or unwillingness to swallow a large number of tablets.
- History of inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis) or active bowel inflammation (e.g., diverticulitis).
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04422210
Locations
Show 18 study locations
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
| Study Director: | Clinical Trials | Hoffmann-La Roche |
| Responsible Party: | Hoffmann-La Roche |
| ClinicalTrials.gov Identifier: | NCT04422210 |
| Other Study ID Numbers: |
GO41864 2019-004487-22 ( EudraCT Number ) |
| First Posted: | June 9, 2020 Key Record Dates |
| Last Update Posted: | January 26, 2021 |
| Last Verified: | January 2021 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm). |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Additional relevant MeSH terms:
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Lung Neoplasms Small Cell Lung Carcinoma Respiratory Tract Neoplasms Thoracic Neoplasms Neoplasms by Site Neoplasms Lung Diseases Respiratory Tract Diseases Carcinoma, Bronchogenic Bronchial Neoplasms |
Carboplatin Etoposide Atezolizumab Venetoclax Antineoplastic Agents Antineoplastic Agents, Phytogenic Topoisomerase II Inhibitors Topoisomerase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |