Venetoclax and Irinotecan in Relapsed/Refractory SCLC

Study Overview
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Brief Summary
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This study is a single-arm, open-label, multicenter phase 1/2 trial designed to establish the recommended phase 2 dose (RP2D) of daily oral venetoclax when given in combination with irinotecan in patients with relapsed or refractory small cell lung cancer (SCLC).

Detailed Description
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Irinotecan will be given at 60 mg/m2 on days 1, 8, and 15 of each 28-day cycle. A 3+3 dose escalation design will be followed until the maximum tolerated dose (MTD) of venetoclax has been determined. Once the MTD is established, a RP2D that is the same as or less than the MTD will be determined. If no RP2D can be determined, the study will close to accrual. The RP2D will be used in an expansion cohort based on a Simon's two-stage minimax design to evaluate efficacy.

Official Title
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A Phase 1/2 Study of Venetoclax and Irinotecan in Relapsed/Refractory Small Cell Lung Cancer

Conditions
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Relapsed Small Cell Lung Cancer, Refractory Small Cell Lung Carcinoma

Intervention / Treatment
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* Drug: Venetoclax 50 MG
* Drug: Venetoclax 100 MG
* Drug: Venetoclax 200 MG
* Drug: Venetoclax 400
* Drug: Venetoclax 600
* Drug: Irinotecan 60 mg/m2
* Drug: Venetoclax (RP2D)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological diagnosis of SCLC Disease progression or recurrence during or after platinum-based therapy, unless platinum-based therapy was contraindicated Phase 1: Measurable or evaluable disease according to RECIST v1.1 Phase 2: Measurable disease according to RECIST v1.1 Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Age ≥ 18 years Adequate bone marrow function as defined below: Absolute neutrophil count (ANC) ≥ 1,500/mm3 Platelet count ≥ 100,000/mm3 Hemoglobin ≥ 8.0 g/dL Adequate renal function as defined below: Serum creatinine ≤ upper limit of normal (ULN) for the lab or a calculated creatinine clearance ≥ 40 mL/min Adequate hepatic function as defined below: Total bilirubin ≤ 1.5 x ULN for the laboratory Aspartate aminotransferase (AST) ≤ 2.5 x ULN for the laboratory Alanine aminotransferase (ALT) ≤ 2.5 x ULN for the laboratory Persons with known HIV seropositivity are eligible if they meet the following criteria: CD4 count ≥ 200/mm3 Undetectable HIV viral load on standard PCR-based test On a stable regimen of highly active anti-retroviral therapy (HAART) that does not include protocol contraindicated agents No ongoing requirement for concurrent antibiotics or antifungal agents for the prevention of HIV-associated opportunistic infections Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Ongoing requirement for any non-study anticancer therapy Ongoing or planned treatment with any of the following: Greater than 10 mg prednisone daily or equivalent Immunosuppressive agents Strong or moderate CYP3A inhibitor or inducer, or a narrow-therapeutic sensitive substrate P-gp inhibitor or narrow-therapeutic sensitive P-gp substrate If any of these agents have been used, patients must be off them for ≥ 1 week before initiation of study treatment. Any investigational agent within 21 days prior to the first dose of the investigational drugs Has consumed grapefruit, grapefruit products, Seville oranges, or starfruit within 3 days before initiation of study treatment. Phase 2 portion only: Previous systemic anticancer therapy other than platinum-based therapy Known leptomeningeal metastases Known untreated brain metastases Hypersensitivity to irinotecan, venetoclax, or their excipients Diarrhea ≥ grade 1 Ongoing need for antidiarrheal agents Active uncontrolled infection, ongoing or within 2 weeks before initiating treatment Known homozygosity for the UGT1A1*28 allele Note: Study-specific UGT1A1 testing is not required Inability to swallow oral medications and/or malabsorption Pregnancy or breastfeeding Medical, psychological, or social condition that, in the opinion of the investigator, may increase the patient's risk or limit the patient's adherence with study requirements

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dose escalation will proceed within each cohort. Phase II is the expansion cohort at the recommended phase 2 dose found in phase 1
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level 1<br>Venetoclax 50mg by mouth once daily and Irinotecan 60 mg/m2 intravenously (IV) on days 1, 8, and 15 | Drug: Venetoclax 50 MG<br>* Escalating doses to determine recommended phase 2 dose (RP2D)<br>Drug: Irinotecan 60 mg/m2<br>* Intravenously (IV), days 1, 8, and 15<br>|
| Experimental: Dose Level 2<br>Venetoclax 100mg by mouth once daily and Irinotecan 60 mg/m2 intravenously (IV) on days 1, 8, and 15 | Drug: Venetoclax 100 MG<br>* Escalating doses to determine recommended phase 2 dose (RP2D)<br>Drug: Irinotecan 60 mg/m2<br>* Intravenously (IV), days 1, 8, and 15<br>|
| Experimental: Dose Level 3<br>Venetoclax 200mg by mouth once daily and Irinotecan 60 mg/m2 intravenously (IV) on days 1, 8, and 15 | Drug: Venetoclax 200 MG<br>* Escalating doses to determine recommended phase 2 dose (RP2D)<br>Drug: Irinotecan 60 mg/m2<br>* Intravenously (IV), days 1, 8, and 15<br>|
| Experimental: Dose Level 4<br>Venetoclax 400mg by mouth once daily and Irinotecan 60 mg/m2 intravenously (IV) on days 1, 8, and 15 | Drug: Venetoclax 400<br>* Escalating doses to determine recommended phase 2 dose (RP2D)<br>Drug: Irinotecan 60 mg/m2<br>* Intravenously (IV), days 1, 8, and 15<br>|
| Experimental: Dose Level 5<br>Venetoclax 600mg by mouth once daily and Irinotecan 60 mg/m2 intravenously (IV) on days 1, 8, and 15 | Drug: Venetoclax 600<br>* Escalating doses to determine recommended phase 2 dose (RP2D)<br>Drug: Irinotecan 60 mg/m2<br>* Intravenously (IV), days 1, 8, and 15<br>|
| Experimental: Phase 2 Expansion Cohort<br>Venetoclax recommended phase 2 dose (RP2D) by mouth once daily and Irinotecan 60 mg/m2 intravenously (IV) on days 1, 8, and 15 | Drug: Irinotecan 60 mg/m2<br>* Intravenously (IV), days 1, 8, and 15<br>Drug: Venetoclax (RP2D)<br>* orally, once per day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Determine the recommended phase 2 dose (RP2D) of venetoclax with irinotecan in patients with relapsed or refractory SCLC | Recommended phase 2 dose (RP2D) of venetoclax in combination with irinotecan that is less than or equal to the maximum tolerated dose (MTD). A 3+3 dose escalation design will be followed until the maximum tolerated dose (MTD) of venetoclax has been determined. Patients assigned to a dose level of venetoclax greater than 50 mg will undergo a ramp-up phase during the first week of irinotecan | 90 Days | 
| Phase 2: Evaluate the efficacy of venetoclax with irinotecan in patients with relapsed or refractory SCLC | The RP2D will be used in an expansion cohort based on a Simon's two-stage minimax design to evaluate efficacy. | 180 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the frequency of adverse events (AEs) | Assess adverse events (AEs) characterized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE V 5.0) to determine safety and toxicity of the combination of venetoclax and irinotecan. | 120 Days | 
| Evaluate the antitumor effects of venetoclax and irinotecan in combination. | Evaluate the anti tumor effects of tumor response based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). | 180 Days | 
| Observe survival in relapsed or refractory SCLC patients receiving venetoclax in combination with irinotecan | Progression-free survival and overall survival of patients with relapsed or refractory SCLC receiving venetoclax in combination with irinotecan | 180 Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed SCLC, Refractory SCLC