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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).

Mizugaki H, Yamamoto N, Nokihara H, Fujiwara Y, Horinouchi H, Kanda S, Kitazono S, Yagishita S, Xiong H, Qian J, Hashiba H, Shepherd SP, Giranda V, Tamura T - Cancer Chemother. Pharmacol. (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Partial response to veliparib 40 mg BID and carboplatin and paclitaxel. CT images at baseline (a, c) and following treatment (15 weeks; b, d) in an approximately 70-year-old male with advanced NSCLC
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Fig2: Partial response to veliparib 40 mg BID and carboplatin and paclitaxel. CT images at baseline (a, c) and following treatment (15 weeks; b, d) in an approximately 70-year-old male with advanced NSCLC

Mentions: Eleven patients had at least one measurable lesion at baseline and comprised the efficacy analysis population. The overall response rate was 55 % (6/11 patients, 95 % CI 23.4–83.3 %). Six patients achieved a PR (n = 2, 40 mg BID and n = 4, 120 mg BID); of these, 3 achieved PR at the first CT scan. Four patients achieved stable disease (SD) (n = 2, 80 mg BID and n = 2, 120 mg BID). One (80 mg BID) developed progressive disease (PD). The median PFS was 92 days (range 21–143). The best percent change from baseline in the sum of target lesions is presented in Fig. 1. The greatest percent decrease from baseline in the sum of target lesions occurred in cycle 4 for 1 patient (40 mg BID) and in cycle 2 for 1 patient (120 mg BID). For all other patients, the greatest percent decrease from baseline in the sum of target lesions occurred following completion of the combination regimen. Figure 2 shows a CT image at baseline and following treatment in a patient with advanced NSCLC who achieved a PR following treatment (40 mg BID).Fig. 1


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).

Mizugaki H, Yamamoto N, Nokihara H, Fujiwara Y, Horinouchi H, Kanda S, Kitazono S, Yagishita S, Xiong H, Qian J, Hashiba H, Shepherd SP, Giranda V, Tamura T - Cancer Chemother. Pharmacol. (2015)

Partial response to veliparib 40 mg BID and carboplatin and paclitaxel. CT images at baseline (a, c) and following treatment (15 weeks; b, d) in an approximately 70-year-old male with advanced NSCLC
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4612330&req=5

Fig2: Partial response to veliparib 40 mg BID and carboplatin and paclitaxel. CT images at baseline (a, c) and following treatment (15 weeks; b, d) in an approximately 70-year-old male with advanced NSCLC
Mentions: Eleven patients had at least one measurable lesion at baseline and comprised the efficacy analysis population. The overall response rate was 55 % (6/11 patients, 95 % CI 23.4–83.3 %). Six patients achieved a PR (n = 2, 40 mg BID and n = 4, 120 mg BID); of these, 3 achieved PR at the first CT scan. Four patients achieved stable disease (SD) (n = 2, 80 mg BID and n = 2, 120 mg BID). One (80 mg BID) developed progressive disease (PD). The median PFS was 92 days (range 21–143). The best percent change from baseline in the sum of target lesions is presented in Fig. 1. The greatest percent decrease from baseline in the sum of target lesions occurred in cycle 4 for 1 patient (40 mg BID) and in cycle 2 for 1 patient (120 mg BID). For all other patients, the greatest percent decrease from baseline in the sum of target lesions occurred following completion of the combination regimen. Figure 2 shows a CT image at baseline and following treatment in a patient with advanced NSCLC who achieved a PR following treatment (40 mg BID).Fig. 1

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus