Venetoclax and Irinotecan in Relapsed/Refractory SCLC

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).

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.

Eligibility 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