Abstract 3634

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.

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.

Dose levelVeliparib Oral Daily Days 1–8Topotecan Continuous IV Days 3–7Carboplatin Continuous IV Days 3–7Clinical Responses/#Pts
1A 10 mg p.o. BID 1.0 mg/m2/day — 1/3(CRi) 
1B 10 mg p.o. BID 1.3 mg/m2/day — 1/3(CR) 
2A 10 mg p.o. BID 1.3 mg/m2/day 150 mg/m2 IV 0/4 
2C 10 mg p.o. BID 1.0 mg/m2 IV 120 mg/m2 IV 2/6(CRi, PR) 
2D 10 mg p.o BID 1.2 mg/m2 IV 120 mg/m2 IV 1/6(PR) 
2E 10 mg p.o. BID 1.2 mg/m2 IV 150 mg/m2 IV 2/6(CR, CRi) 
3C 20 mg p.o. BID 1.0 mg/m2 IV 120 mg/m2 IV 0/6 
3D 20 mg p.o BID 1.2 mg/m2 IV 120 mg/m2 IV 2/6(CR, PR) 
3E 20 mg p.o. BID 1.2 mg/m2 IV 150 mg/m2 IV 2/6(CR, CR) 
4 40 mg p.o. BID 1.2 mg/m2 IV 150 mg/m2 IV 2/6(CR, CR) 
5§ 80 mg p.o. BID 1.2 mg/m2 IV 150 mg/m2 IV 2/4(CR, CRi) 
Dose levelVeliparib Oral Daily Days 1–8Topotecan Continuous IV Days 3–7Carboplatin Continuous IV Days 3–7Clinical Responses/#Pts
1A 10 mg p.o. BID 1.0 mg/m2/day — 1/3(CRi) 
1B 10 mg p.o. BID 1.3 mg/m2/day — 1/3(CR) 
2A 10 mg p.o. BID 1.3 mg/m2/day 150 mg/m2 IV 0/4 
2C 10 mg p.o. BID 1.0 mg/m2 IV 120 mg/m2 IV 2/6(CRi, PR) 
2D 10 mg p.o BID 1.2 mg/m2 IV 120 mg/m2 IV 1/6(PR) 
2E 10 mg p.o. BID 1.2 mg/m2 IV 150 mg/m2 IV 2/6(CR, CRi) 
3C 20 mg p.o. BID 1.0 mg/m2 IV 120 mg/m2 IV 0/6 
3D 20 mg p.o BID 1.2 mg/m2 IV 120 mg/m2 IV 2/6(CR, PR) 
3E 20 mg p.o. BID 1.2 mg/m2 IV 150 mg/m2 IV 2/6(CR, CR) 
4 40 mg p.o. BID 1.2 mg/m2 IV 150 mg/m2 IV 2/6(CR, CR) 
5§ 80 mg p.o. BID 1.2 mg/m2 IV 150 mg/m2 IV 2/4(CR, CRi) 
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Of 56 pts treated at doses of V 10–80 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, 25 (45%) have experienced > grade 3 non-hematologic toxicity, 6(11%) have had grade 4 toxicity and 1 (4%) died from sepsis with multi-organ failure. Overall response rate is 27% (8CR, 4 CRi, 3 PR), with 7 in relapsed AML, 7 in refractory AML and 1 refractory ALL. Pharmacokinetic (PK) studies in pt plasma, marrow supernatant, and marrow blasts demonstrated that V is detectable in marrow supernatant and cells, does not accumulate with multiple dose administrations in plasma but does in marrow, and is not altered by T or C administration. 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 30/41 (73%) blood and 3/4 patients at V 40mg per day dose level had greater than 80% suppression of PAR. The MTD has not been reached and dose escalation is ongoing.

Disclosures:

No relevant conflicts of interest to declare.

Topics:
adenosine diphosphate ribose, carboplatin, leukemia, acute, poly(adp-ribose) polymerases, veliparib, chemotherapy regimen, toxic effect, ascites, brachial plexus neuritis, cytotoxicity

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2011 by The American Society of Hematology
2011
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