Targeting deregulated DNA damage repair (DDR) pathways has lead to the discovery of novel therapeutics that result in contextual synthetic lethality such as poly-ADP-ribose polymerase 1 (PARP1) inhibition in tumors with homozygous loss of BRCA1/2 genes. We have recently shown that inhibition of the 26S proteasome induces a “BRCAness” state in myeloma (MM) cells and sensitizes them to the PARP inhibitor Veliparib by blocking homology-mediated repair of DNA breaks (Neri P, Blood 2011). The results of these studies are the subject of this phase I clinical trial combining bortezomib with Veliparib in relapsed and/or refractory MM (ClinicalTrials.gov: NCT01495351).
The primary objectives of this study were to evaluate the safety, tolerability and MTD of Veliparib in combination with bortezomib and dexamethasone; secondary objectives included pharmacodynamic and pharmacogenomic studies for an in vivo assessment of Veliparib effect on PARP activity in peripheral blood mononuclear cells (PBMCs) and sorted CD138 bone marrow plasma cells and to determine expression levels and genomic aberrations of DDR genes in MM cells. Adults with an ECOG 0 to 2, and adequate renal, hepatic, and hematologic function were eligible. Patients previously refractory to bortezomib were allowed on trial as long as they didn't progress on bortezomib in their last line of therapy. Patients received oral Veliparib on days 1 to 14, bortezomib (1.3 mg/m2) and dexamethasone (20 mg) on days 1, 4, 8 and 11 for up to eight 21-day cycles followed by 6 maintenance cycles where bortezomib and dexamethasone are given weekly. Veliparib dose escalation, from a starting dose of 20 mg PO bid, followed a modified Fibonacci dose escalation scheme based on the occurrence of dose-limiting toxicities (DLTs) in cycle 1. Adverse events (AEs) were evaluated according to NCI-CTCAE v4.0. Response was assessed according to IMWG criteria.
At data cut-off (August 2012), MM patients were enrolled and treated at the 20, 40 and 60 mg PO bid of Veliparib. The median age is 61 (47–78), median time from diagnosis 6 years (1.4- 7.4), median creatinine: 69 umol/l (56–110), albumin 37 g/l (32–42), β2: 3 mg/l (1.64–6.11), ISS stage II or IIII in 50%. Median number of prior therapy: 3 (1–9) with prior ASCT in 87.5%, prior thalidomide in 25%, prior lenalidomide 75%, prior pomalidomide 12.5% and prior bortezomib 62.5% (refractory 37.5%, relapsed 25%). FISH studies revealed del 17p in 37.5% and one with t(14,16). Patients completed a median of 5 cycles (range 1–9) with treatment ongoing in six patients. No DLT was encountered and the MTD has not yet been reached with the current cohort receiving 60 mg PO bid of Veliparib. Grade 3–4 AEs in all cycles included transient thrombocytopenia grade 3 in 37.5%; grade 3 anemia in 12.5%. Other grade 3 non-hematological toxicities included diarrhea in 12.5%; sensory neuropathy grade 1 in 37.5% with only one patient developing grade 2 neuropathy. Median time to response was 15 days (range 13–36), response to therapy included sCR + CR + nCR in 37.5%, VGPR+PR in 12.5%, MR in 37.5%, for an overall response rate ≥PR in 50% and ≥MR in 87.5%. With a median follow-up of 4 months (range 1.7–6.7), Kaplan-Meyer estimates for PFS and OS at 8 months were 70% and 80% respectively. In order to determine the biologically optimal dose (BOD) of Veliparib in vivo correlative studies included the measurements of PARP activity (poly-ADP-ribose or PAR levels) in PBMCs and sorted CD138+ cells. The median PAR levels in PBMCs for patients treated with 20 mg Veliparib on pre-treatment day 1, post-treatment day 4 and day 11 were 3413, 951.3 and 1111.6 pg/107 cells respectively (reduction of 67.4 %). At the 40 mg level, PBMCs PAR levels on days 1, 4 and 11 were 1268.25, 251 and 111.3 pg/107 cells (91.2% reduction). In sorted CD138+ cells, at the 40 mg dose level, the median PAR levels were 2771.3 (day1 pre-treatment), 249.6 and 360 (days 4 and 11 post-treatment) pg/107cells with an 87% reduction. Other biological studies, including analysis of RNA sequenome in CD138 cells pre- and post-treatment are undergoing.
Veliparib administered orally in combination with bortezomib and dexamethasone appears to be well tolerated with evidence of significant anti-tumor activity in relapsed or refractory MM patients. PARP1-2 inhibition is confirmed in MM cells in vivo and further dose escalation of Veliparib continues to determine the MTD of this combination.
Neri:Johnson ans Johnson: Research Funding. Keats:Tgen: Employment. Bahlis:Johnson and Johnson: Honoraria, Research Funding; Celgene: Honoraria.
Asterisk with author names denotes non-ASH members.