A Phase 1 Study of the PARP Inhibitor ABT-888 in Combination with Temozolomide in Acute Leukemias.
1.1.1. To define the maximum tolerated dose (MTD) and Recommended Phase II Dose (RP2D) of ABT-888 administered in combination with temozolomide in patients with acute leukemias. 1.1.2. To evaluate the feasibility, safety, and toxicity of administering ABT-888 in combination with temozolomide in patients with acute leukemias. 1.2. Secondary Objectives 1.2.1. To document responses in acute leukemias. 1.2.2. To observe the pharmacokinetics of both ABT-888 and temozolomide when administered alone and in combination. 1.2.3. To study the pharmacodynamics: a) to determine the levels of poly(ADP-ribose)(PAR) before and after administration of ABT-888 and temozolomide in patient leukemia blasts; b) to analyze methyl-guanine methyl-transferase (MGMT) protein levels in primary leukemia blasts; c) to quantify the induction of Î³-H2AX and RAD51 foci in patient leukemia blasts after treatment.
Tumor Types: Adults 18 years and older with relapsed or refractory acute myelogenous leukemia (AML); relapsed or refractory pre-B- or T-cell acute lymphoblastic leukemia (ALL); Ph+ ALL [t(9;22)] if failed intolerance/resistance) at least 2 different tyrosine kinase inhibitors (TKIs) or have a mutation associated with resistance to TKIs (T315I); chronic myelogenous leukemia (CML) in accelerated or blastic phase if failed (intolerance/resistance) at least 2 different TKIs or have a mutation associated with resistance to TKIs (T315I); AML arising in the setting of antecedent myelodysplasia (MDS) or myeloproliferative disorder (MPD); therapyrelated AML; ï¿½de novoï¿½ AML or pre-B- or T-cell ALL in adults 60 years and older who are not candidates for induction chemotherapy due to poor-risk features including adverse cytogenetics or are unwilling to receive intensive induction chemotherapy. Performance Status: ECOG 0-2 Abnormal Organ Function Permitted: ï¿½ Multilineage Bone Marrow failure ï¿½ Total or direct bilirubin less than 2mg/dl ï¿½ AST(SGOT)/ALT(SGPT) less than 5 X institutional upper limit of normal ï¿½ Serum creatinine ï¿½ 2mg/dl Prior Therapy: ï¿½ ï¿½ 3 weeks off cytotoxic chemotherapy (6 weeks for BCNU or mitomycin) and ï¿½ 2 weeks off radiotherapy ï¿½ all biologic agents including hematopoietic growth factors, imatinib or similar TKIs, should be stopped at least 1 week prior to treatment on the study. If using hydroxyurea, corticosteroids, or leukopheresis for blast count control, patients must be off ï¿½ 24 hrs before starting treatment on the study. ï¿½ ï¿½ 4 weeks from autologous hematopoietic stem cell transplantation (ASCT) ï¿½ ï¿½ 60 days post-allogeneic SCT (alloSCT), no evidence of graft vs. host disease, and ï¿½ 2 weeks off all immunosuppressive therapy.
Treatment Plan: A single-dose of ABT-888 will be given once on day 1 of cycle 1 to examine the pharmacokinetics of ABT-888 given alone. This single dose will be half of the subsequent total daily dose. No ABT-888 will be given on day 2 or 3. Subsequent doses of ABT-888 in cycle 1 will be administered orally twice daily on days 4 through 12. Temozolomide will be administered orally once a day on days 3 through 9 in cycle 1. Each treatment cycle will last 28 days, however, since temozolomide starts on day 3 in cycle 1, cycle 2 will be initiated no earlier than day 30 of cycle 1 (day 28 from the start of temozolomide). In cycle 2 and subsequent cycles the ABT-888 will be administered on days 1 through 8 at the dose level administered in cycle 1. Temozolomide will be administered on days 1 through 5 at the dose level administered in cycle 1. If treatment results in prolonged myelosuppression ( greater than 4 weeks delay in subsequent cycle administration) then the administration of both temozolomide and ABT-888 will be shortened by 1 day. Two dose de-escalations will be allowed from cycle 2 onward (first de-escalation: ABT-888 days 1-7 + temozolomide days 1-4; second de-escalation ABT-888 days 1-6 + temozolomide days 1-3).
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