Table 1.

Key clinical trials of PARP inhibitors in combination with various chemotherapeutic agents and related hematologic toxicities

CombinationTumor typeResponseHematologic toxicityTrial design
Phase I:Advanced solid tumors and lymphomasCR: none reportedDLT: neutropenia, thrombocytopenia; 3 of 6 pts enrolled on DL1 experienced DLTsStarting dose of:
ABT-888 (veliparib) + topotecanKummar et al. (2011)PR: none reported SD: 4/24Gr 3/4: neutropenia 20.8%Veliparib 10 mg PO BID D1–7+Topotecan 1.2 mg/m2/day D1-5
febrile neutropenia 8.3%
thrombocytopenia 12.5%
Phase I:Advanced solid tumorsCR: none reportedDLT: febrile neutropenia, leucopenia, neutropeniaEscalating doses of Veliparib PO BID D1–14 + irinotecan 100 mg/m2 D1,8
ABT-888 (veliparib) + irinotecanMR: 2/28 PR: 5/28 SD: 10/28
LoRusso et al. (2011)
Phase I:Breast cancer and advanced solid tumorsCR: none reportedDLT: febrile neutropeniaEscalating doses of veliparib 50–150 mg PO BID D1-4 + doxorubicin 60 mg/m2 D3 + cyclophosphamide 600 mg/m2 D3
ABT-888 (veliparib) + doxorubicin + cyclophosphamidePR: 3/18 (TNBC; BRCA mutation) SD: 8/18 (breast cancer)
Tan et al. (2011)
Phase I:Advanced solid tumors and lymphomasCR: none reportedGr 2–4 lymphopenia 34.3%Escalating doses of veliparib 20–80 mg PO daily for 7,14,or 21 days + escalating doses of cyclophosphamide 50–100 mg for 21 days
ABT-888 (veliparib) + oral cyclophosphamidePR: 7/35 (6 BRCA mutation) SD: 6/35 (3 BRCA mutation)
Kummar et al. (2012)
Phase II:Metastatic breast cancer(unconfirmed)Gr 3/4: neutropenia 11.4%Veliparib 40 mg PO BID D1–7
ABT-888 (veliparib) + temozolomide (TMZ)CR: 1/24 PR: 2/24 SD: 7/24thrombocytopenia 20%TMZ 150 mg/m2 PO daily D1–5
Isakoff et al. (2010)
Randomized, double-blind, placebo-controlled trial ABT-888 (veliparib) + TMZ vs. TMZ aloneMetastatic melanomaNo statistically significant improvement in PFS or OSGr 3/4 hematologic toxicities: TMZ alone 38% Veliparib 20 mg + TMZ 54% Veliparib 40 mg + TMZ 57%1:1:1 randomization to: Placebo BID + TMZ, veliparib 20 mg BID + TMZ, or veliparib 40 mg BID + TMZ
Middleton et al. (2011)
Phase I:Stage I: advanced solid tumorsCR: 1/32No DLTsStage I: TMZ 100 mg/m2/day + escalating doses rucaparib to PARP inhibitory dose (PID)
AG-014699/PF-01367338 (rucaparib) + TMZ Plummer et al. (2008)Stage II: chemo-naïve metastatic melanomaPR: 2/32 SD: 7/32Myelosuppresion seen in 13% pts with rucaparib 18 mg/m2/day + TMZ 200 mg/m2/dayStage II: Rucaparib fixed at PID + TMZ escalating doses up to 200 mg/m2/day
Phase I:AZD-2281 (olaparib) + gemcitabine + cisplatinGiaccone et al. (2010)Advanced solid tumorsCR: 0/21PR: 2/21 (1 BRCA mutation) SD: none reportedDLT: febrile neutropenia, thrombocytopenia;Starting dose of:
2 of first 3 pts enrolled on DL1 experienced DLTs Gr 3/4: neutropenia 61% lymphopenia 61% thrombocytopenia 57%Olaparib 100 mg PO BID D1–4 Gemcitabine 500 mg/m2 D3–10
Cisplatin 60 mg/m2 D3
Phase I:BRCA-1/2 mutation carriers breast and ovarian cancerCR: none reportedDLT: thrombocytopenia and delayed neutropenic recoveryEscalating doses of olaparib continuously or D1–7 + escalating doses of carboplatin (AUC 3–5) on D2 or D8
AZD-2281 (olaparib) + carboplatinPR: 8/23 (ovarian cancer)Gr 3/4: anemia 10%
Lee et al. (2011)3/4 (breast cancer) SD: 11/23 (ovarian cancer)1/1 (breast cancer)Thrombocytopenia 20%
Neutropenia 17%
Phase I:Advanced solid tumors; Expansion phase in chemo-naïve stage III/IV melanomaCR: 0/40 PR: 2/40 SD: 8/40DLT: neutropenia, thrombocytopeniaEscalating doses of olaparib 10–100 mg PO BID D1–7 + dacarbazine 600–800 mg/m2 D1
AZD-2281 (olaparib) + dacarbazineGr 3/4: anemia 5%
Khan et al. (2011)Neutropenia 22.5%
Thrombocytopenia 7.5%
Phase I/II:Triple-negative breast cancerCR: none reported PR: 7/19 SD: none reportedDLT: neutropenia requiring dose delay and GCSF prophylaxisOlaparib 200 mg PO BID + paclitaxel 90 mg/m2 IV weekly for 3 of 4 weeks
AZD-2281 (olaparib) + paclitaxel
Dent et al. (2010)

CR, complete response; MR, moderate response; PR, partial response; SD, stable disease.