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.

Veliparib in combination with whole brain radiation therapy in patients with brain metastases: results of a phase 1 study.

Veliparib, a potent, oral PARP inhibitor, potentiates the antitumor activity of radiation therapy and crosses the blood-brain barrier. This was a phase 1 dose-escalation study evaluating the safety, and secondarily the antitumor activity of veliparib in combination with whole brain radiation therapy (WBRT) in patients with brain metastases, in order to power future trials. Patients with brain metastases from primary solid tumors were treated with WBRT (30.0 or 37.5 Gy in 10 or 15 fractions) and veliparib (escalating doses of 10-300 mg, orally BID). Safety and tumor response were assessed. Observed survival was compared to predicted survival based on a published nomogram. Eighty-one patients (median age 58 years) were treated. The most common primary tumor types were non-small cell lung (NSCLC; n = 34) and breast cancer (n = 25). The most common AEs deemed possibly related to veliparib (AEs, ≥15 %) were fatigue (30 %), nausea (22 %), and decreased appetite (15 %). Fatigue (5 %), hypokalemia and hyponatremia (3 % each) were the only Grade 3/4 AEs deemed possibly related to veliparib observed in ≥2 patients. Although this was an uncontrolled study, preliminary efficacy results were better than predicted: the median survival time (MST, 95 % CI) for the NSCLC subgroup was 10.0 mo (3.9-13.5) and for the breast cancer subgroup was 7.7 mo (2.8-15.0) compared to a nomogram-model-predicted MST of 3.5 mo (3.3-3.8) and 4.9 mo (4.2-5.5). The addition of veliparib to WBRT did not identify new toxicities when compared to WBRT alone. Based on encouraging safety and preliminary efficacy results, a randomized, controlled phase 2b study is ongoing.

A phase 1 study evaluating the pharmacokinetics and preliminary efficacy of veliparib (ABT-888) in combination with carboplatin/paclitaxel in Japanese subjects with non-small cell lung cancer (NSCLC).

INTRODUCTION: Veliparib is a potent, orally bioavailable PARP inhibitor that enhances efficacy of DNA-damaging chemotherapeutic agents. The study objectives were to determine the recommended phase 2 dose (RPTD) of veliparib plus carboplatin and paclitaxel, and assess pharmacokinetics (PK), tolerability, and preliminary efficacy in Japanese patients with solid tumors. METHODS: Carboplatin (AUC 6 mg/mL min) and paclitaxel (200 mg/m(2)) were administered on day 3 of a 21-day cycle. Oral veliparib (40, 80, or 120 mg BID) was administered on days 1-7. Patients received ≤6 cycles. Adverse events (AEs) were reported using NCI-CTCAE version 4.03, PK parameters were analyzed using noncompartmental methods, and responses were measured by RECIST version 1.1. RESULTS: Twelve patients with non-small cell lung cancer (NSCLC) were treated. Common treatment-emergent AEs, consistent with toxicities associated with carboplatin and paclitaxel, included leukopenia (100 %), neutropenia (100 %), anemia (83 %), thrombocytopenia (75 %), increased alanine aminotransferase (67 %), and increased aspartate aminotransferase (67 %). Grade 3/4 AEs (in ≥2 patients) included neutropenia (100 %), leukopenia (33 %), anemia (25 %), and hyponatremia (17 %). No AEs led to veliparib, carboplatin, or paclitaxel interruption; no DLTs were observed. The RPTD was determined to be 120 mg BID. Veliparib C max and AUC were approximately dose proportional. Six partial responses were observed. CONCLUSIONS: Veliparib PK was not impacted by carboplatin and paclitaxel. The safety profile was manageable. The 120 mg BID RPTD confirmed in Japanese patients is the dose being evaluated in global studies of veliparib. Preliminary efficacy suggests veliparib may enhance carboplatin and paclitaxel activity, providing benefit to patients with NSCLC.

Phase I/II study of pemetrexed with or without ABT-751 in advanced or metastatic non-small-cell lung cancer.

PURPOSE: ABT-751 is an antimitotic and vascular disrupting agent with potent preclinical anticancer activity. We conducted a phase I and randomized double-blind phase II study of pemetrexed with ABT-751 or placebo in patients with recurrent advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS: One hundred seventy-one patients received intravenous pemetrexed 500 mg/m(2) day 1 and oral ABT-751 or placebo days 1 to 14 of 21-day cycles. The primary end point was progression-free survival (PFS). Secondary end point included overall survival (OS); pharmacokinetic and pharmacodynamic parameters were also analyzed. RESULTS: The recommended phase II dose of ABT-751 with pemetrexed is 200 mg. Fatigue, constipation, anemia, nausea, and diarrhea were the most common toxicities in both study arms. No pharmacokinetic interactions were observed. Median PFS in the ABT-751 arm was 2.3 months versus 1.9 for placebo (P = .819, log-rank) for the intention-to-treat population. However, differences in PFS (P = .112, log-rank) and OS (P = .034, log-rank; median 3.3 v 8.1 months) favoring ABT-751 were seen in the squamous NSCLC subgroup. Baseline circulating tumor cell concentrations were predictive of improved OS (P = .013). Changes from baseline of greater than 20% in plasma levels of placenta growth factor (P = .056), squamous cell carcinoma antigen (P = .03), and cytokeratin 19 fragment antigen 21-1 (P = .01) were markers best associated with improved OS. CONCLUSION: Addition of ABT-751 to pemetrexed is well-tolerated, but does not improve outcome in unselected patients with recurrent NSCLC. ABT-751 may have therapeutic potential in squamous NSCLC. Exploratory cellular and molecular analyses in this study identified biomarkers that may correlate with survival.