Venetoclax and Irinotecan in Relapsed/Refractory SCLC

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

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).

Study Overview

• Status: Withdrawn
• Conditions: Relapsed Small Cell Lung Cancer; Refractory Small Cell Lung Carcinoma
• Intervention / Treatment: Drug: Venetoclax 50 MG; Drug: Irinotecan 60 mg/m2; Drug: Venetoclax 100 MG; Drug: Venetoclax 200 MG; Drug: Venetoclax 400; Drug: Venetoclax 600; Drug: Venetoclax (RP2D)

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 Type: Interventional
• Phase: Phase 2; Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / 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: Irinotecan 60 mg/m2; Intravenously (IV), days 1, 8, and 15; Drug: Venetoclax 100 MG; Escalating doses to determine recommended phase 2 dose (RP2D)
Experimental: Dose Level 3; Venetoclax 200mg 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 200 MG; Escalating doses to determine recommended phase 2 dose (RP2D)
Experimental: Dose Level 4; Venetoclax 400mg 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 400; Escalating doses to determine recommended phase 2 dose (RP2D)
Experimental: Dose Level 5; Venetoclax 600mg 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 600; Escalating doses to determine recommended phase 2 dose (RP2D)
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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Virginia Commonwealth University
• Collaborators: AbbVie
• Investigators: Principal Investigator: Sosipatros Boikos, MD, Massey Cancer Center

Study record dates

Study Major Dates

• Study Start (Anticipated): June 30, 2021
• Primary Completion (Anticipated): May 30, 2028
• Study Completion (Anticipated): June 30, 2028

Study Registration Dates

• First Submitted: September 2, 2020
• First Submitted That Met QC Criteria: September 2, 2020
• First Posted (Actual): September 10, 2020

Study Record Updates

• Last Update Posted (Actual): March 3, 2021
• Last Update Submitted That Met QC Criteria: March 1, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Relapsed SCLC; Refractory SCLC
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Small Cell Lung Carcinoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Venetoclax; Irinotecan
• Other Study ID Numbers: MCC-17-13842; HM20019851 (Other Identifier: Virginia Commonwealth University Massey Cancer Center)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No