Abstract

Abstract 3276

PARP is activated in response to DNA single strand (SS) breaks and is pivotal to the base excisional repair pathway for chemotherapy-damaged DNA. The orally bioavailable PARP inhibitor V delays DNA repair and potentiates the cytotoxicity of multiple classes of chemotherapy drugs including topoisomerase I inhibitors and platinating agents in leukemia cell lines. A previous clinical trial of T+C yielded promising results in adults with refractory acute leukemia at the maximum tolerated dose (MTD) of T 1.6 mg/m2/d + C 150 mg/m2/d by intravenous continuous infusion (IVCI) × 120 hrs. We are conducting a Phase I dose-escalation trial of V given orally twice daily Days 1–8 with T+C given by 120 hr IVCI Days 3–7.

 Acute Myelogenous Leukemia (AML, 33 patients) Acute Lymphoblastic Leukemia (ALL, 4 patients) 
Median Age (range) 570 (40-75) 55 (42-62) 
Relapsed  
No. Prior CRs 2 (1-3)  
Prior Stem Cell Transplant 
Refractory 25 
No. Primary Refractory 10 
No. Prior Regimens 3 (1-4) 3 (1-4) 
Prior Stem Cell Tranpslant 
Secondary AML 12  
Anecedent Hematologic Dx  
Treatment-Related  
Cytogenetics   
Intermediate 10 
Adverse: Single/Complex 7/16 2 Ph+ (1 with complex) 
BRCA-1/BRCA-2 1 (mutation)/ 1 (13q14 deletion) 
 Acute Myelogenous Leukemia (AML, 33 patients) Acute Lymphoblastic Leukemia (ALL, 4 patients) 
Median Age (range) 570 (40-75) 55 (42-62) 
Relapsed  
No. Prior CRs 2 (1-3)  
Prior Stem Cell Transplant 
Refractory 25 
No. Primary Refractory 10 
No. Prior Regimens 3 (1-4) 3 (1-4) 
Prior Stem Cell Tranpslant 
Secondary AML 12  
Anecedent Hematologic Dx  
Treatment-Related  
Cytogenetics   
Intermediate 10 
Adverse: Single/Complex 7/16 2 Ph+ (1 with complex) 
BRCA-1/BRCA-2 1 (mutation)/ 1 (13q14 deletion) 

Deaths due to myocardial infarct and splenic infarcts with ascites occurred in one pt each when C 150 mg/m2 was added to V 10 mg BID and T 1.3 mg/m2, resulting in adjustment of the dose escalation schema for C and T. Of 27 pts treated at doses of V 10–20 mg orally BID Days1-8 and T 1.0–1.2 mg/m2/d + C 120–150 mg/m2/d for 120 hrs IVCI Days 3–7, 8 (30%) have experienced > grade 3 non-hematologic toxicity, 4 (15%) have had grade 4 toxicity and 1 (4%) died from sepsis with multi-organ failure. Overall response rate is 22% (2 CR, 1 CRi, 3 PR), with 4 in relapsed AML, 1 each in refractory AML and refractory ALL. Pharmacokinetic (PK) studies in pt plasma, marrow supernatant, and marrow blasts demonstrated that V does not accumulate with multiple dose administrations in plasma but does in marrow, is not altered by T or C administration, and is detectable in marrow supernatant and cells. Nuclear staining for phosphorylated histone H2AX (γH2AX) demonstrated that V 10 mg BID increased DNA damage by > 2-fold in 11/22 (50%) on Day 1 and 13/18 (72 %) on Day 4 after 24 hrs of T+C. A PAR ELISA demonstrated that V suppresses PAR levels to <50% of pretreatment values in 21/29 (72%) blood and 9/13 (69%) marrow samples. The MTD has not been reached and dose escalation is ongoing.

Disclosures:

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.