Phase I/II study of AT-101 in combination with topotecan in patients with relapsed or refractory small cell lung cancer after prior platinum containing first line chemotherapy

Abstract

19004 Background: Antiapoptotic members of the Bcl-2 protein family are expressed in the tumor tissue of the majority of patients (pts) with small cell lung cancer (SCLC) and are associated with chemo-resistance. AT-101, an oral, pan Bcl-2 family protein inhibitor has demonstrated activity in SCLC models, including those that express Mcl-1 and are resistant to other Bcl-2 inhibitors. Methods: Pts ≥18 years of age, PS 0–1, with sensitive and resistant relapsed SCLC after first line chemotherapy were eligible. Two serial cohorts of pts were treated with topotecan 1.25 mg/m2 daily and AT-101 daily at doses of 30–40 mg on days 1–5, q21 days. Adverse Events (AEs) were graded by the NCI CTCAE v. 3.0. Efficacy assessments were performed q6-wks. Results: Eleven pts (5 female/6 male; ages 42–76) were treated in phase I; 5 pts received 40 mg of AT-101 and 6 pts 30 mg. AE data was available in 10/11 pts. The Dose Limiting Toxicity (DLT) in the 40 mg cohort was Grade (G) 4 ANC lasting > 7 days in 2 pts. There were no DLTs in the 30 mg cohort; however, G4 neutropenia and thrombocytopenia occurred (lasting < 7 days) in 2 pts and 1 pt, respectively. Most common (>20%) AEs (all grades): anemia, neutropenia (90%); fatigue (80%); thrombocytopenia (70%); constipation, nausea (60%); hyperglycemia, vomiting (40%) and dyspnea, hyponatremia and leukopenia (30%). Grade 3/4 related events included: neutropenia (70%); thrombocytopenia (40%); anemia (20%) and hyponatremia, hypophosphatemia, leukopenia, lymphopenia, constipation, dizziness and nausea (10%). There were two deaths due to disease progression (PD). Nine pts had stable disease; 1 pt a partial response, and 1 pt PD as their best response. Conclusions: AT-101 has a manageable safety profile at the doses studied. The DLTs and other cytopenias observed were consistent with the known rates of G4 cytopenias of topotecan alone. Despite the occurrence of protocol defined DLTs, there appears to be little difference in the rate of G4 cytopenias in the doses tested. Therefore, the Phase 2 dose of AT-101 with topotecan is 40 mg along with recommended use of myeloid growth factors. The Phase 2 portion of this study is currently enrolling pts. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Ascenta Therapeutics, Inc. Ascenta Therapeutics, Inc.