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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).

NCT04422210

Description:

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.

Related Conditions:
  • Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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).
  • 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.

Clinical Trial IDs

  • ORG STUDY ID: GO41864
  • SECONDARY ID: 2019-004487-22
  • NCT ID: NCT04422210

Conditions

  • Small Cell Lung Cancer

Interventions

DrugSynonymsArms
VenetoclaxDose Escalation (Arm A1) (Maintenance only)
AtezolizumabDose Escalation (Arm A1) (Maintenance only)
CarboplatinDose Escalation (Arm B1) (Induction + Maintenance)
EtoposideDose Escalation (Arm B1) (Induction + Maintenance)

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Dose Escalation (Arm A1) (Maintenance only)ExperimentalCohort 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.
  • Venetoclax
  • Atezolizumab
Dose Escalation (Arm A2) (Maintenance only)ExperimentalCohort 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.
  • Venetoclax
  • Atezolizumab
Dose Escalation (Arm A3) (Maintenance only)ExperimentalCohort 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.
  • Venetoclax
  • Atezolizumab
Dose Escalation (Arm B1) (Induction + Maintenance)ExperimentalCohort 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).
  • Venetoclax
  • Atezolizumab
  • Carboplatin
  • Etoposide
Dose Escalation (Arm B2) (Induction + Maintenance)ExperimentalCohort 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).
  • Venetoclax
  • Atezolizumab
  • Carboplatin
  • Etoposide
Dose Escalation (Arm B3) (Induction + Maintenance)ExperimentalCohort 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).
  • Venetoclax
  • Atezolizumab
  • Carboplatin
  • Etoposide
Dose Escalation (Arm B4) (Induction + Maintenance)ExperimentalCohort 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).
  • Venetoclax
  • Atezolizumab
  • Carboplatin
  • Etoposide
Dose ExpansionExperimentalIf 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.
  • Venetoclax
  • Atezolizumab
  • Carboplatin
  • Etoposide

Eligibility 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).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of Participants with Adverse Events (AEs)
Time Frame:Up to 49 months
Safety Issue:
Description:Determined according to the National Cancer Institute Common Technology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0)

Secondary Outcome Measures

Measure:Duration of Response (DOR)
Time Frame:Up to 24 months
Safety Issue:
Description: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.
Measure:Progression Free Survival (PFS)
Time Frame:Up to 24 months
Safety Issue:
Description: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.
Measure:Overall Survival (OS) after Enrolment
Time Frame:Up to 49 months
Safety Issue:
Description:Defined as the time from enrolment to death from any cause.
Measure:Progression Free Survival (PFS) rate at 6 months
Time Frame:Up to 18 months
Safety Issue:
Description: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.
Measure:Overall Survival (OS) Rate at 1 year
Time Frame:Up to 18 months
Safety Issue:
Description:Defined as the percentage of participants who have not experienced death from any cause at 1 year.
Measure:Plasma Concentrations (ng/mL) of Venetoclax at specified timepoints
Time Frame:Up to 24 months
Safety Issue:
Description:
Measure:Serum Concentrations (ng/mL) of Atezolizumab at specified timepoints
Time Frame:Up to 24 months
Safety Issue:
Description:
Measure:Plasma Concentrations (ng/mL) of Carboplatin at specified timepoints
Time Frame:Up to 24 months
Safety Issue:
Description:
Measure:Plasma Concentrations (ng/mL) of Etoposide at specified timepoints
Time Frame:Up to 24 months
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Hoffmann-La Roche

Last Updated

June 5, 2020