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. We now report results from a phase I clinical trial (NCT01495351) combining bortezomib with Veliparib in relapsed / refractory MM.
The primary objectives of this study were to evaluate the safety, tolerability and MTD of Veliparib in combination with bortezomib; secondary objectives included pharmacodynamic and pharmacogenomic studies for an in vivo assessment of Veliparib effect on PARP activity in PBMCs and sorted bone marrow plasma cells and to determine DDR genes expression levels and genomic aberrations in MM cells. Adults with an ECOG 0 to 2, and adequate organ function were eligible. Patients previously refractory to bortezomib were allowed. Patients received oral Veliparib on days 1 to 14, bortezomib (1.3 mg/m2) and dex (20 mg) on days 1, 4, 8 and 11 for up to eight 21-day cycles followed by 6 maintenance cycles where bortezomib was 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 DLTs in cycle 1. AEs were evaluated according to NCI-CTCAE v4.0. Response was assessed according to IMWG criteria.
At data cut-off (July 2013), 19 were enrolled and 18 completed a least 1 cycle and are evaluable for response assessment. The median age is 61 (47-80), median time from diagnosis 5.1 years (1.1- 10.0), median creatinine: 73 umol/l (56-145), albumin 35 g/l (25-42), b2: 2.7 mg/l (1.6-12.8), ISS stage II or IIII in 68.7%. Median number of prior therapy: 3 (1-9) with 89.5% exposed to lenalidomide (84.2% refractory), 78.9% exposed to bortezomib (47.3% refractory) and 21% refractory to pomalidomide; del17p was detected in 60%, t(4;14) and t(14;16) present in 1 patient each. One DLT was encountered at the 100 mg level however the MTD is not yet reached. Grade 3-4 AEs include thrombocytopenia 37.5%; anemia in 12.5%, diarrhea in 12.5%; sensory neuropathy grade 1 in 37.5%. Response to therapy include CR in 4/18, VGPR+PR in 3/18, MR+SD in 9/18, PD in 2/18, for an overall response rate ≥ PR in 38.9% and ≥ SD in 81.2%. In bortezomib non-refractory patients 54.5% achieved a ≥ PR. The median PFS is 4.92 months (2-14.2) with 70.8% alive at 18 months (median OS not reached). The median DOR is 12 months (7.27-16.7). 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. Significant (68 to 96%) reduction of PARP activity (poly-ADP-ribose levels) was achieved in vivo in PBMCs and BM sorted CD138+ cells between pre-treatment day 1 and post-treatment day 11 samples. Other biological studies, included analysis of RNA sequenome in CD138 cells pre- (day 1) and post-treatment (day 11). Cuffdiff analysis identified genes and splice variants differentially modulated by the study treatments. SNVs calling did identify mutations in genes involved in homologous recombination (HR) including RAD51, RNF8, RNF168 and ATM (n=1 each). Patients harbouring these mutations achieved at least a PR with the exception of one patient with coexisting TP53BP1 mutation within its tudor domain. Such mutation is recognized to rescue HR-deficient cells from the effect of PARP inhibitors.
Veliparib in combination with bortezomib and dexamethasone appears to be well tolerated with evidence of significant anti-tumor activity in this heavily pre-treated population. Further dose escalation of Veliparib continues to determine the MTD of this combination.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.