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Clinical Trial
. 2023 Apr;198(3):487-498.
doi: 10.1007/s10549-023-06889-0. Epub 2023 Feb 28.

A phase 1 study of veliparib (ABT-888) plus weekly carboplatin and paclitaxel in advanced solid malignancies, with an expansion cohort in triple negative breast cancer (TNBC) (ETCTN 8620)

Monica K Malhotra  1 , Shalu Pahuja #  1 , Brian F Kiesel  2   3 , Leonard J Appleman  1   2 , Fei Ding  4 , Yan Lin  5   6 , Hussein A Tawbi  1   2 , Ronald G Stoller  1   2 , James J Lee  1   2 , Chandra P Belani  7 , Alice P Chen  8   9 , Vincent L Giranda  10 , Stacie Peacock Shepherd  10 , Leisha A Emens  1   11 , S Percy Ivy  12 , Edward Chu  1   2   13 , Jan H Beumer  14   15   16   17 , Shannon Puhalla  18   19   20
Affiliations
Clinical Trial

A phase 1 study of veliparib (ABT-888) plus weekly carboplatin and paclitaxel in advanced solid malignancies, with an expansion cohort in triple negative breast cancer (TNBC) (ETCTN 8620)

Monica K Malhotra et al. Breast Cancer Res Treat. 2023 Apr.

Abstract

Background: Veliparib is a poly-ADP-ribose polymerase (PARP) inhibitor, and it has clinical activity with every 3 weeks carboplatin and paclitaxel. In breast cancer, weekly paclitaxel is associated with improved overall survival. We aimed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib with weekly carboplatin and paclitaxel as well as safety, pharmacokinetics, and preliminary clinical activity in triple negative breast cancer (TNBC).

Methods: Patients with locally advanced/metastatic solid tumors and adequate organ function were eligible. A standard 3 + 3 dose-escalation design was followed by a TNBC expansion cohort. Veliparib doses ranging from 50 to 200 mg orally bid were tested with carboplatin (AUC 2) and paclitaxel (80 mg/m2) given weekly in a 21-day cycle. Adverse events (AE) were evaluated by CTCAE v4.0, and objective response rate (ORR) was determined by RECIST 1.1.

Results: Thirty patients were enrolled, of whom 22 had TNBC. Two dose-limiting toxicities were observed. The RP2D was determined to be 150 mg PO bid veliparib with weekly carboplatin and paclitaxel 2 weeks on, 1 week off, based on hematologic toxicity requiring dose reduction in the first 5 cycles of treatment. The most common grade 3/4 AEs included neutropenia, anemia, and thrombocytopenia. PK parameters of veliparib were comparable to single-agent veliparib. In 23 patients with evaluable disease, the ORR was 65%. In 19 patients with TNBC with evaluable disease, the ORR was 63%.

Conclusion: Veliparib can be safely combined with weekly paclitaxel and carboplatin, and this triplet combination has promising clinical activity.

Keywords: DNA damage; PARP; Pharmacokinetics; Phase 1 study; Solid tumors; Triple negative breast cancer; Veliparib.

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Conflict of interest statement

Jan Beumer’s institute received research support from AbbVie. Leisha Emens has received research support from Aduro Biotech, AstraZeneca, Breast Cancer Research Foundation, Corvus, Department of Defense, EMD Serono, Genentech, HeritX, Inc., Maxcyte, Merck, National Cancer Institute, NSABP Foundation, Roche, Translational Breast Cancer Research Consortium, and has served as a consultant for AbbVie, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Genentech, Gritstone, Lilly, Macrogenics, Medimmune, Molecuvax, Novartis, Peregrine, Replimune, Roche, Syndax, and Vaccinex. She has also received royalties from Aduro Biotech. Shannon Puhalla has received research support from AbbVie, Pfizer, Lilly, Novartis, Incyte, Covance-Bayer, AstraZeneca, Genentech, Medivation and has been a consultant for AbbVie, MedImmune, Celldex, Puma, Pfizer, AstraZeneca, Esai, and Nanostring. Stacie Shepherd is a former employee of Abbott, AbbVie, and Corcept and holds Abbott, AbbVie, and Corcept stocks.

Figures

Figure 1.
Figure 1.
Administration schedule of veliparib (V), carboplatin (C) and paclitaxel (T) in the dose-escalation and dose-expansion phase. D=day. The blue arrow in the center represents the protocol amendment. Doses of veliparib, carboplatin, and paclitaxel at each dose level (DL) in the dose-escalation and in the dose- expansion phase. AUC=area under the curve; DL=dose level; BID=twice daily.
Figure 2.
Figure 2.
Pattern of dose modification of veliparib, carboplatin, and paclitaxel over time. Dose changes in veliparib, carboplatin, and paclitaxel across each dose level in dose escalation phase and in the dose expansion phase with the cycle numbers on the X axis and number of patients on the Y axis.
Figure 3.
Figure 3.
Swimmers plot representing the time on treatment and the response status. Duration of treatment and response in patients treated with veliparib combined with paclitaxel and carboplatin. Time on treatment is plotted for patients with RECIST and responses. One patient transitioned to single-agent veliparib via expanded access after cycle 38. Two patients were not evaluable (NA) for response. Symbols indicate the initiation of clinical benefit/response as indicated in the figure key. Progressive disease (PD) is indicated by an “X”, while an off-study event unrelated to PD is indicated by an open box.
Figure 4.
Figure 4.
Pharmacokinetics. (A) Veliparib Cmax across investigated dose levels (p-value from ANOVA testing of dose-normalized Cmax = 0.055). (B) Veliparib AUC0-12 across investigated dose levels SD (p-value from ANOVA testing of dose-normalized AUC0-12= 0.284). (C) Carboplatin Cmax across investigated veliparib dose levels (p-value=0.670). (D) Carboplatin AUC0-∞ across investigated veliparib dose levels (p-value=0.757). (E) Paclitaxel Cmax across investigated veliparib dose levels (p-value 0.431). (F) Paclitaxel AUC0-∞ across investigated veliparib dose levels (p-value 0.554). All points represent mean PK parameter and error bars represent SD.
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