Venetoclax and Irinotecan in Relapsed/Refractory SCLC

Sponsor

Virginia Commonwealth University (Other)

Overall Status

Withdrawn

CT.gov ID

NCT04543916

Collaborator

AbbVie (Industry)

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Relapsed Small Cell Lung Cancer Refractory Small Cell Lung Carcinoma	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)	Phase 1/Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

Dose escalation will proceed within each cohort. Phase II is the expansion cohort at the recommended phase 2 dose found in phase 1Dose 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)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Jun 30, 2021

Anticipated Primary Completion Date :

May 30, 2028

Anticipated Study Completion Date :

Jun 30, 2028

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Phase 1: Determine the recommended phase 2 dose (RP2D) of venetoclax with irinotecan in patients with relapsed or refractory SCLC [90 Days]
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
Phase 2: Evaluate the efficacy of venetoclax with irinotecan in patients with relapsed or refractory SCLC [180 Days]
The RP2D will be used in an expansion cohort based on a Simon's two-stage minimax design to evaluate efficacy.

Secondary Outcome Measures

Assess the frequency of adverse events (AEs) [120 Days]
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.
Evaluate the antitumor effects of venetoclax and irinotecan in combination. [180 Days]
Evaluate the anti tumor effects of tumor response based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1).
Observe survival in relapsed or refractory SCLC patients receiving venetoclax in combination with irinotecan [180 Days]
Progression-free survival and overall survival of patients with relapsed or refractory SCLC receiving venetoclax in combination with irinotecan

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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