Safety Of Veliparib Research Articles

MO18-5 Efficacy and safety of veliparib with first-line chemotherapy as combination therapy in OC: a systematic review

MO18-5 Efficacy and safety of veliparib with first-line chemotherapy as combination therapy in OC: a systematic review

Efficacy and safety of veliparib plus chemotherapy for the treatment of lung cancer: A systematic review of clinical trials.

As a poly-ADP ribose polymerase (PARP) inhibitor, veliparib has been identified as a potential therapeutic agent for lung cancer. The present study aimed to conduct a systematic review of clinical trials investigating the efficacy and safety of veliparib for treating lung cancer. PubMed, Scopus, the Web of Science, and Google Scholar were systematically searched up to October 30, 2022. Only randomized controlled trials (RCTs) evaluating the efficacy or safety of veliparib in the treatment of lung cancer patients were included. Studies were excluded if they were not RCTs, enrolled healthy participants or patients with conditions other than lung cancer, or investigated therapeutic approaches other than veliparib. The Cochrane risk-of-bias tool was used for quality assessment. The seven RCTs (n = 2188) showed that patients treated with a combination of veliparib and chemotherapy had a significantly higher risk of adverse events, when compared to the control arm. There was no statistically significant difference in overall survival (OS) between those treated with veliparib plus chemotherapy and those receiving the standard therapies. Only two trials demonstrated an improvement in progression-free survival (PFS), and only one study found an increase in objective response rate (ORR). Furthermore, adding veliparib to standard chemotherapy showed no benefit in extending the duration of response (DoR) in any of the studies. Only a small number of studies have found veliparib to be effective, in terms of improved OS, PFS, and ORR, while the majority of studies found no benefit for veliparib over standard treatment.

Safety of veliparib in combination with chemotherapy and as maintenance in front-line ovarian cancer: Results in BRCAm, hrd, and whole populations from the velia trial

Objective: The phase 3 VELIA trial demonstrated that veliparib dosed concurrently with carboplatin/paclitaxel and continued as maintenance monotherapy resulted in a statistically significant improvement in progression-free survival compared to carboplatin/paclitaxe alone in patients with newly diagnosed stage III–IV high-grade serous ovarian, fallopian tube, and peritoneal cancer. It has been hypothesized that while DNA repair deficiencies may improve response to PARP inhibition, they may also render patients with BRCA mutations (BRCAm) or homologous recombination-deficient (HRD) tumors more sensitive to treatment-related toxicities.

Abstract PD4-01: First-line veliparib plus carboplatin/paclitaxel in patients with HER2-negative advanced/metastatic gBRCA-associated breast cancer: Planned subgroup analysis from the phase 3 BROCADE3 trial

Abstract Background: BROCADE3 (NCT02163694) evaluated the PARP inhibitor veliparib in combination with carboplatin/paclitaxel (C/P) vs placebo + C/P in patients with HER2-negative locally advanced/metastatic breast cancer and a germline BRCA1/2 mutation. In the intent-to-treat (ITT) population, investigator-assessed median progression-free survival (PFS) was 14.5 months for veliparib vs 12.6 months for placebo (hazard ratio=0.71 [95% CI 0.57-0.88], p=0.002); 75th percentile PFS was 39.9 months for veliparib vs 20.7 months for placebo. In this preplanned analysis, we evaluated efficacy and safety of veliparib plus C/P in patients with no previous cytotoxic chemotherapy for metastatic disease. Methods: Patients with ≤2 prior lines of cytotoxic chemotherapy for metastatic breast cancer were randomized 2:1 to C/P with veliparib or C/P with placebo. Veliparib (120 mg p.o. BID) or placebo was given on Days −2 to 5, C (AUC 6 mg/mL/min IV) on Day 1, and P (80 mg/m2 IV) on Days 1, 8, and 15 (21-day cycles). Patients who discontinued both C and P for toxicity or reasons other than disease progression could continue veliparib/placebo monotherapy until progression. Monotherapy dose was 300 mg BID, increasing to 400 mg BID if tolerated. Although randomization was not stratified by lines of prior cytotoxic chemotherapy, the treatment arms were well-balanced with respect to this baseline characteristic. The primary endpoint was PFS as assessed by investigator. Secondary endpoints included overall survival (OS), clinical benefit rate (CBR), and objective response rate (ORR). Adverse events were monitored throughout the study. Analysis of PFS in patients with no prior cytotoxic therapy for metastatic disease was pre-planned. Results: In the ITT population, 337 patients (81% of the entire cohort) received treatment as first line and were randomized to veliparib plus C/P and 172 patients to placebo plus C/P. Most patients received prior cytotoxic chemotherapy in the neo-adjuvant/adjuvant setting (66%, placebo plus C/P; 70%, veliparib plus C/P). Among the 81% of patients in each arm who had no prior cytotoxic chemotherapy in the metastatic setting, median PFS was longer in patients receiving veliparib plus C/P compared to placebo plus C/P (16.6 mo vs 13.1 mo), and median PFS for both arms was over 1 year (Table). Proportion of patients with a serious AE was 30.9% for placebo plus C/P and 33.1% for veliparib plus C/P; proportion with an AE leading to study drug discontinuation was 10.8% for placebo plus C/P and 15.6% for veliparib plus C/P. Additional safety data will be presented. Conclusions: In patients with HER2-negative advanced/metastatic breast cancer and a germline BRCA1/2 mutation who had no prior cytotoxic chemotherapy for metastatic disease, veliparib with C/P demonstrated an improvement in median PFS over C/P alone. This benefit was durable with 25% of patients alive and progression free at nearly 4 years. Table. Efficacy in patients with no prior cytotoxic chemotherapy for metastatic disease.Veliparib + C/P, n=274Placebo + C/P, n=139mPFS per INV (mo, 95% CI)16.6 (13.4, 18.7)13.1 (11.4, 14.5)PFS HR (95% CI)0.69 (0.54, 0.88)PFS 75th percentile (mo, 95% CI)46.3 (29.3, NR)22.6 (16.5, 27.2)mPFS per ICR (mo, 95% CI)21.5 (18.7, 29.2)14.0 (12.5, 16.5)PFS HR (95% CI)0.63 (0.47, 0.84)PFS 75th percentile (mo, 95% CI)NR33.3 (19.7, NR)mOS (mo, 95% CI) [interim]36.0 (32.0, 43.1)29.9 (26.0, 39.3)OS HR (95% CI)0.92 (0.68, 1.2)CBR at 24 weeks (% [95% CI])92.8 (90.0, 94.9)93.4 (89.1, 96.0)ORR (% [95% CI])79.7 (74.0, 84.7)76.3 (67.4, 83.8) C/P, carboplatin and paclitaxel; CBR, clinical benefit rate; HR, hazard ratio; m, median; mo, months; NR, not reached; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; INV, investigator; ICR, independent central review. Citation Format: Banu K. Arun, Hyo S. Han, Bella Kaufman, Hans Wildiers, Michael Friedlander, Jean-Pierre Ayoub, Shannon L. Puhalla, Bruce A. Bach, Matthew Dudley, Christine K. Ratajczak, David Maag, Véronique Diéras. First-line veliparib plus carboplatin/paclitaxel in patients with HER2-negative advanced/metastatic gBRCA-associated breast cancer: Planned subgroup analysis from the phase 3 BROCADE3 trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD4-01.

Phase 3 study evaluating efficacy and safety of veliparib (V) plus carboplatin (Cb) or Cb in combination with standard neoadjuvant chemotherapy (NAC) in patients (pts) with early stage triple-negative breast cancer (TNBC).

520 Background: Clinical studies suggest that TNBC is sensitive to DNA-damaging agents, including Cb. V is a potent PARP inhibitor that may enhance the antitumor activity of such agents. We present primary response data from a phase 3 randomized, placebo-controlled study (NCT02032277) evaluating the addition of V + Cb or Cb to neoadjuvant paclitaxel (P) followed by doxorubicin + cyclophosphamide (AC). Methods: Pts with histologically confirmed, invasive TNBC (T2–T4 N0–2 or T1 N1–2) amenable to surgical resection were randomized 2:1:1 to (Arm A) P 80 mg/m2 weekly + Cb AUC 6 mg/mL/min q3 weeks + V 50 mg PO BID; (Arm B) P + Cb + PO placebo; or (Arm C) P + IV placebo + PO placebo, for 12 weeks followed by AC (60 mg/m2 or 600 mg/m2 q2 or 3 weeks) × 4. Primary endpoint was pathologic complete response (pCR) in breast and nodes with > 80% power at 2-sided α of 0.05 using pair-wise comparisons for A vs B and A vs C to detect significant treatment effects using Χ2 test; secondary endpoint was rate of conversion to eligibility for breast conservation surgery (BCS). Adverse events (AEs) were assessed with NCI CTCAE V4.0. Results: Six hundred thirty-four pts (median age 50 years; range 22–79) were randomized to Arms A (n = 316), B (n = 160), or C (n = 158). Baseline characteristics were well balanced. No pCR difference was observed between Arms A and B (53.2% vs 57.5% p = 0.36), but pCR in Arm A was higher than Arm C (53.2% vs 31.0% p < 0.001). In non-prespecified analysis, pCR in Arm B was also higher than Arm C (57.5% vs 31.0% p < 0.001). Among pts ineligible for BCS at screening (n = 141), 62% were eligible after NAC in Arm A vs 44% each in Arms B (p = 0.13) and C (p = 0.14). Grade 3–4 AEs (Arms A/B/C, 86%/85%/45%) and serious AEs (30%/27%/14%) neutropenia, thrombocytopenia, anemia, nausea, and vomiting were increased with the addition of Cb; V did not impact toxicity. Median cycles of NAC were not reduced with V + Cb + P or Cb + P vs P. Conclusions: Addition of V to neoadjuvant Cb + P followed by AC did not increase pCR rate in breast and nodes in stage II–III TNBC, while addition of V + Cb or Cb alone to P followed by AC did. Cb (+/– V) increased toxicity but did not impact delivery of NAC. Clinical trial information: NCT02032277.

Veliparib in combination with whole-brain radiation therapy for patients with brain metastases from non-small cell lung cancer: results of a randomized, global, placebo-controlled study

Veliparib is a potent, orally bioavailable, poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor that crosses the blood–brain barrier and has been shown to potentiate the effects of radiation in preclinical and early clinical studies. This phase 2, randomized, global study evaluated the efficacy and safety of veliparib in combination with whole-brain radiation therapy (WBRT) in patients with brain metastases from non-small cell lung cancer (NSCLC). Three-hundred and seven patients with brain metastases from NSCLC were randomized 1:1:1 to WBRT (30 Gy in 10 fractions) plus 50 mg veliparib twice daily (BID; n = 103), 200 mg veliparib BID (n = 102), or placebo BID (n = 102). Treatment began within 28 days of diagnosis. Tumor response and safety were assessed; the primary endpoint was overall survival (OS). Patients who received ≥1 dose of treatment were included in the safety analysis. All randomized patients were included in the efficacy endpoint analyses. Patient characteristics were well balanced between treatment arms. Median OS was 185 days for patients treated with WBRT plus placebo and 209 days for WBRT plus veliparib (50 or 200 mg). No statistically significant differences in OS, intracranial response rate, and time to clinical or radiographic progression between any of the treatment arms were noted. No differences were observed in adverse events (all grades) across treatment arms; nausea, fatigue, alopecia, and headache were the most commonly reported. No new safety signals were identified for veliparib. A significant unmet need for therapies that improve the outcomes of patients with brain metastases from NSCLC remains.

Abstract CT149: Assessment of the cardiac safety of veliparib in a thorough QT/QTc study at therapeutic doses in patients with relapsed/refractory solid tumors: a randomized, placebo-controlled crossover study

Abstract Veliparib is a potent oral poly(ADP-ribose) polymerase inhibitor that impairs DNA damage repair and shows single-agent activity in tumors with homologous recombination repair defects as well as in combination with DNA-damaging chemotherapies. Nonclinical studies suggested a potential risk of QT prolongation at the peak plasma concentration (Cmax) achieved at the maximum tolerated dose for veliparib monotherapy (400 mg twice daily). This phase 1, single-dose, double-blind, placebo (PBO)-controlled, randomized crossover study (NCT02009631) evaluated the effect of veliparib on corrected QT (QTc) interval in patients (pts) with relapsed/refractory solid tumors. Methods: Eligible pts (?18 years) with metastatic or unresectable solid tumors and ECOG PS ?1 received single-dose oral veliparib (200 mg [V200], 400 mg [V400]) or PBO in a 6-sequence, 3-period crossover design, with ?3-day interperiod washout time. The primary objective was to assess the effect of veliparib on QT interval with Fridericia's correction (QTcF). Lack of clinically relevant effect on QTc interval was shown if the 95% upper confidence bound (UCB) for the maximum baseline-adjusted QTcF difference between veliparib and PBO (??QTcF) for the 400 mg dosing was <10 msec (ICH E14 guidelines). Pharmacokinetics and safety were also evaluated. Results: Forty-seven pts (85% female; median age 58 years) were enrolled and analyzed. After single-dose administration, maximum ??QTcF of V400 compared to PBO was 6.4 msec with a 95% UCB of 8.9 msec; for V200 the maximum ??QTcF was 3.6 msec, with a 95% UCB of 6.1 msec. Mean time to maximum plasma concentration (Tmax) was similar for V200 (2.4 ± 0.7 h) and V400 (2.5 ± 0.6 h). Mean Cmax was 1.32 ± 0.38 μg/mL and 2.61 ± 0.85 μg/mL, and total exposure (AUC?) was 12.0 ± 3.98 μg•h/mL and 25.5 ± 8.37 μg•h/mL, for V200 and V400, respectively. Treatment-emergent adverse events (TEAEs) were experienced by 36.2%, 48.9%, and 47.8% of pts while receiving V200, V400, and placebo, respectively. Most common TEAEs were nausea (12.8%) and myalgia (8.5%) while receiving V200; nausea (8.5%) and vomiting (8.5%) while receiving V400; and nausea (6.5%) while receiving PBO. TEAEs were mainly grade 1/2, with grade 3 vomiting and depression experienced by 1 pt each. The most common TEAE possibly related to study drug was nausea (19.1%), reported in 8.5%, 6.4%, and 4.3% of pts while receiving V200, V400, and PBO, respectively. One pt discontinued treatment after the V200-V400 sequence due to study drug-unrelated AEs. There were no deaths or serious AEs. Conclusions: Single-dose veliparib (200 or 400 mg) did not exhibit clinically relevant QT prolongation greater than the 10 msec threshold per ICH E14 guideline. Citation Format: Wijith Munasinghe, Anthony Tolcher, Emiliano Calvo, Michael Gordon, Mathilde Jalving, Judith de Vos-Geelen, Diane M. Medina, Dennis M. Bergau, Silpa Nuthalapati, David M. Hoffman, Stacie L. Shepherd, Hao Xiong. Assessment of the cardiac safety of veliparib in a thorough QT/QTc study at therapeutic doses in patients with relapsed/refractory solid tumors: a randomized, placebo-controlled crossover study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT149.

Pilot study of veliparib (ABT-888) with temozolomide (TMZ) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

224 Background: Castration-resistant PC tumors exhibit increased PARP activity (critical enzymes for DNA damage repair). Veliparib is a novel, oral, potent inhibitor of PARP-1 and PARP-2. Preclinically, resistance to oral TMZ treatment in the PC3-Luc prostate cancer mouse model was reversed when mice were treated with veliparib. Based on the synergistic interaction, we evaluated the efficacy and safety of veliparib + TMZ in mCRPC pts. Methods: Eligible pts had mCRPC, PSA>2 ng/mL, progressed on at least one docetaxel based therapy and adequate organ function. Pts received veliparib 40 mg BID Days (D) 1-7 and TMZ D1-5 in 28D cycle (C) until disease progression (PD) or unacceptable toxicities. Tumor response was assessed every 8 weeks. Primary objective: Efficacy based on rate of PSA decline of 30% or greater. Secondary objectives: safety, RECIST objective response rate, progression-free survival (PFS), overall survival (OS) and biomarker analyses. A sample size of 25 pts provided 76% power to differentiate between PSA response rates of 5 and 20% at 1-sided type I error rate of 0.1. Results: 26 pts were enrolled; median age 67 years [55, 81]; median baseline PSA 107 ng/ml (6.9, 4584.4); 7/26 (27%) had 2 prior therapies. Median Cs of veliparib + TMZ received were 2 (range 1–9). Most frequent treatment related adverse events (AE) were fatigue (50%), nausea (38%) and constipation (23%). Grade 3/4 AEs in >10% of pts was thrombocytopenia (15%). All pts are off therapy. 25 pts were PSA response evaluable; 2 pts had a confirmed PSA response; 1 pt had a 37% decrease in PSA while the other pt had a 96% decrease in PSA and a 40% reduction in tumor size. 4/25 pts had stable disease for a minimum of 4 months (m). Median PFS was 2.1 m [95% CI: 1.8, 3.9]; 11/26 pts have died with median OS of 9.1 m [95% CI: 5.5, 11.7]. There was a negative correlation between change from baseline in circulating tumor cells and PFS. Conclusions: Veliparib + TMZ were well tolerated with evidence of some activity. Due to lack of activity of TMZ in CRPC,veliparib-induced potentiation of TMZ may not be clinically significant. Other combinations will be explored with higher doses of veliparib. Biomarker data will be presented.