Abstract
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 level . | Veliparib Oral Daily Days 1–8 . | Topotecan Continuous IV Days 3–7 . | Carboplatin Continuous IV Days 3–7 . | Clinical 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 level . | Veliparib Oral Daily Days 1–8 . | Topotecan Continuous IV Days 3–7 . | Carboplatin Continuous IV Days 3–7 . | Clinical 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) |
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.
No relevant conflicts of interest to declare.
Author notes
Asterisk with author names denotes non-ASH members.
