Venetoclax and Irinotecan in Relapsed/Refractory SCLC

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