Phase 1/1b Trial of Talazoparib and Gemtuzumab Ozogamicin in Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia

Background: Poly (ADP-ribose) polymerase (PARP) enzymes are involved in repair of single-strand DNA breaks through base excision repair pathways. Inhibitors of PARP are approved for the treatment of BRCA1/2-mutant malignancies where they result in compromise of dual DNA damage repair pathways, leading to induction of double-strand DNA breaks during replication and ultimately cell death. We have previously demonstrated (Portwood et al, ASH 2019 abstract) that PARP inhibitors can reduce in vitro acute myeloid leukemia (AML) growth and can synergistically enhance the anti-leukemic activity of antibody-drug conjugates containing DNA-damaging cytotoxic agents in preclinical human AML models. Talazoparib (Tala) is a novel selective PARP inhibitor which has been shown to exert more potent growth inhibitory effects across a panel of human AML cell lines than four other PARP inhibitors (veliparib, olaparib, rucaparib, niraparib). Gemtuzumab ozogamicin (GO) is an approved drug consisting of an antibody against human CD33 (gemtuzumab) linked to a cytotoxic component (calicheamicin).

Hypothesis: We hypothesize that the combination of Tala + GO will be well tolerated and will result in improved clinical efficacy as compared with historical outcomes of GO monotherapy in patients with relapsed or refractory (R/R) AML.

Objectives: The primary objectives of this study are (a) to determine the safety and tolerability of Tala + GO therapy in R/R AML; (b) to determine the overall response rate (ORR = complete remission (CR) + complete remission with incomplete hematologic recovery (CRi)) of combination therapy in patients with R/R AML. Additional anti-leukemic effects will be reported including complete remission rate, best response rate, duration of remission, leukemia-free survival, transfusion independence, and overall survival. Exploratory aims include measurable residual disease, evidence of PARP inhibition and DNA damage, feasibility of subsequent allogeneic stem cell transplant, and quality of life.

Study Design: This open-label multi-center, Phase 1/1b trial is designed to determine whether the combination of Tala and GO represents a safe and effective approach for R/R AML. Eligible patients are adults aged ≥18 years with CD33-positive AML whose disease has failed to respond to and/or has recurred following at least one prior line of chemotherapy. There are two parts of the study: dose escalation and dose expansion. The dose escalation portion will establish the recommended Phase 2 dose (RP2D) of Tala in combination with GO. Cohorts of 3 subjects will be treated at one of three dose levels of Tala (0.5 mg, 0.75 mg, and 1 mg orally daily) in combination with fixed doses of GO (3 mg/m²/day on days 1,4, and 7, capped to one 4.5 mg vial) using a standard 3+3 subject cohort dose evaluation. Treatment will be given in 28-day cycles. The dose limiting toxicity (DLT) window will be Cycle 1 Day 1 to 28. Therapy may be given in the outpatient setting. Following determination of the RP2D, an expansion cohort of patients will be treated with the combination of Tala + GO for preliminary assessment of toxicities and anti-leukemic efficacy. Bone marrow assessment will be performed on Day 28 of Cycles 1 and 2. Safety and activity will be assessed using descriptive statistical analysis. If a patient achieves CR/CRi after cycles 1-2, the GO dose will be reduced to a maintenance dose of 2 mg/m² on day 1 only of every subsequent cycle until disease progression or for a maximum of 6 total cycles of therapy. Patients not achieving a clinical response after 2 cycles will stop treatment. Treatment duration will be up to six months. This trial was activated in July 2020 and is registered at ClinicalTrials.gov (NCT04207190). Accrual is ongoing.