Venetoclax and Irinotecan in Relapsed/Refractory SCLC

• ClinicalTrials.gov Identifier: NCT04543916
• Recruitment Status: Withdrawn
• First Posted: September 10, 2020
• Last Update Posted: March 3, 2021
• Sponsor: Virginia Commonwealth University
• Collaborator: AbbVie
• Information provided by (Responsible Party): Virginia Commonwealth University

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 (Clinical Trial)
• 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 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
• Estimated Study Start Date: June 30, 2021
• Estimated Primary Completion Date: May 30, 2028
• Estimated Study Completion Date: June 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 :

1. Phase 1: Determine the recommended phase 2 dose (RP2D) of venetoclax with irinotecan in patients with relapsed or refractory SCLC [ Time Frame: 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
2. Phase 2: Evaluate the efficacy of venetoclax with irinotecan in patients with relapsed or refractory SCLC [ Time Frame: 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 :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Sponsors and Collaborators

Virginia Commonwealth University

AbbVie

Investigators

• Principal Investigator: Sosipatros Boikos, MD; Massey Cancer Center

More Information

• Responsible Party: Virginia Commonwealth University
• ClinicalTrials.gov Identifier: NCT04543916
• Other Study ID Numbers: MCC-17-13842; HM20019851 ( Other Identifier: Virginia Commonwealth University Massey Cancer Center )
• First Posted: September 10, 2020
• Last Update Posted: March 3, 2021
• Last Verified: March 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Virginia Commonwealth University:

Relapsed SCLC; Refractory SCLC

Additional relevant MeSH terms:

Lung Neoplasms; Small Cell Lung Carcinoma; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Irinotecan; Venetoclax; Topoisomerase I Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents