Phase II trial of a PARP inhibitor in somatic BRCA mutant metastatic breast cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS1113-TPS1113
Author(s):  
Neelima Vidula ◽  
Nora K. Horick ◽  
Erica Blouch ◽  
Amalia Rivera ◽  
Erin Basile ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Massachusetts General Hospital ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Metastatic Breast ◽  
Parp Inhibition ◽  
The Impact

TPS1113 Background: Poly(ADP-ribose) polymerase (PARP) inhibitors are now approved for patients with germline BRCA1/2 mutated HER2 negative metastatic breast cancer (MBC). However, germline BRCA1/2 mutations only account for 5-10% of breast cancer. We previously demonstrated that a subset of MBC may harbor somatic BRCA1/2 mutations detectable by cell-free DNA (cfDNA) (Vidula, SABCS, 2017). We hypothesize that somatic BRCA1/2 mutant MBC may also respond to PARP inhibition, similar to ovarian cancer, where PARP inhibition is efficacious in both somatic and germline tumors (Oza, 2017). Methods: This single arm, open label, phase II clinical trial is evaluating the efficacy of talazoparib, a PARP inhibitor, in 30 patients with somatic pathogenic BRCA1/2 mutant MBC identified by cfDNA. Patients may have triple-negative disease with receipt of at least 1 prior chemotherapy regimen, or hormone receptor positive, HER2 negative disease with at least 1 prior hormone therapy for MBC. Patients may have received a prior platinum, in the absence of progression on platinum chemotherapy. Patients must not have a known germline BRCA1/2 mutation. Patients will be treated with talazoparib 1 mg daily until progression, unacceptable toxicity, or withdrawal of consent, with clinical exams monthly, scans (CT chest, abdomen, and pelvis, and bone scan as appropriate) every 3 months, and serial cfDNA collected monthly. The primary endpoint is progression-free survival, as defined by RECIST 1.1. Subjects are enrolled in a 2-stage design, which provides 80% power to demonstrate that treatment is associated with “success” (PFS > 12 weeks) in ³ 53% patients (4% alpha). Additional endpoints include objective response rate and toxicity (per NCI CTCAE version 5.0). Correlative endpoints include determining changes in BRCA1/2 mutant allele fraction, genomic evolution including emergence of BRCA reversion mutations, and the impact of biomarker changes on outcomes. This trial is currently enrolling patients at the Massachusetts General Hospital. Successful completion of this study may help expand the patient population that is able to benefit from PARP inhibition. Clinical trial information: NCT03990896 .

Phase II multicenter study of talazoparib for somatic BRCA1/2 mutant metastatic breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS1110-TPS1110
Author(s):  
Neelima Vidula ◽  
Erica Blouch ◽  
Nora K. Horick ◽  
Erin Basile ◽  
Senthil Damodaran ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Metastatic Breast ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Patient Reported

TPS1110 Background: PARP inhibitors are approved for the treatment of HER2 negative metastatic breast cancer (MBC) with germline BRCA1/2 mutations, based on phase III studies demonstrating an improvement in progression-free survival (PFS) compared to chemotherapy in this population and better patient reported outcomes (Robson, NEJM, 2017; Litton, NEJM, 2018). However, germline BRCA1/2 mutations account for only 5-10% of breast cancer, limiting the current clinical applicability of PARP inhibitors. Somatic BRCA1/2 mutations are detectable in circulating cell-free DNA (cfDNA) in ̃13.5% of patients with MBC; in pre-clinical models, pathogenic somatic BRCA1/2 mutations have been shown to respond to PARP inhibition (Vidula, CCR, 2020). The purpose of this study is to evaluate the efficacy of talazoparib, a PARP inhibitor, in patients with MBC who have somatic BRCA1/2 mutations detectable in cfDNA, in the absence of a germline BRCA1/2 mutation, which we hypothesize will be effective in this setting. This study may help expand the population of patients with MBC who benefit from PARP inhibitors. Methods: This is an investigator initiated multicenter, single arm, phase II clinical trial studying the efficacy of talazoparib in 30 patients with MBC who have pathogenic somatic BRCA1/2 mutations detected in cfDNA. Patients with MBC who are found to have pathogenic somatic BRCA1/2 mutations detected in cfDNA in the absence of a germline BRCA1/2 mutation are eligible. Patients may have triple negative (with ≥ 1 prior chemotherapy), or hormone receptor positive/HER2 negative breast cancer (with ≥ 1 prior hormone therapy). Patients may have received any number of prior lines of chemotherapy, including a prior platinum (in the absence of progression). They must have adequate organ function and ECOG performance status ≤2, and should not have previously received a PARP inhibitor. Patients are treated with talazoparib 1 mg daily until disease progression or intolerability, with serial imaging using CT chest/abdomen/pelvis and bone scan performed at baseline and every 12 weeks, and cfDNA collection every 4 weeks. Primary endpoint is PFS by RECIST 1.1. Patients are being enrolled in a two-stage design with 80% power to demonstrate that the treatment is associated with “success” (PFS > 12 weeks) in ≥53% patients (4% alpha). Secondary endpoints include objective response rate and safety (NCI CTCAE v 5.0). Exploratory analyses include studying serial changes in cfDNA BRCA1/2 mutant allelic frequency and comparing pre-and post-treatment cfDNA for the emergence of BRCA1/2 reversion and resistance mutations. This study is activated and open at Massachusetts General Hospital, where 2 patients are completing screening. It is also opening soon at 6 other academic centers (NCT03990896). Grant support includes a Pfizer ASPIRE award and 2020 Conquer Cancer Foundation of ASCO – Breast Cancer Research Foundation – Career Development Award. Clinical trial information: NCT03990896 .

A phase II clinical trial of talazoparib monotherapy for PALB2 mutation-associated advanced breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS1109-TPS1109
Author(s):  
Joshua James Gruber ◽  
Wyatt Gross ◽  
Alex McMillan ◽  
James M. Ford ◽  
Melinda L. Telli
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Advanced Breast Cancer ◽  
Phase Ii ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Metastatic Breast ◽  
Advanced Breast ◽  
Recist 1.1 ◽  
Palb2 Mutation

TPS1109 Background: PALB2 (Partner and Localizer of BRCA2) plays a critical role in the maintenance of genomic integrity through its role in the Fanconi anemia and homologous recombination DNA repair pathways. Our recently reported phase II clinical trial (Gruber, et al. JCO 2019) showed that talazoparib monotherapy was associated with single agent activity in germline PALB2 (gPALB2) mutation-associated advanced breast cancers. Of 5 patients with a germline PALB2 mutation, all 5 had reduction in target lesions > 20% with 3 of 5 achieving a RECIST 1.1 response. All patients had visceral metastases and were heavily pretreated; one response occurred in a patient with 8 prior lines of therapy for metastatic breast cancer. Clinical activity of the PARP inhibitor olaparib was also demonstrated in breast cancer patients with gPALB2 mutations in the Olaparib Expanded trial (TBCRC 048). Thus, we believe there is significant value in generating additional PARP inhibitor monotherapy data in subjects with advanced PALB2 mutation-associated breast cancer. We propose this phase II trial to better estimate the rate of RECIST 1.1 objective response in this patient population. Methods: This is a single-arm, two-stage, non-randomized study to assess the objective response rate (ORR) of talazoparib monotherapy in patients with PALB2 mutation-associated advanced breast cancer. Eligible subjects will be adults with inoperable locally advanced or metastatic breast cancer with a germline or somatic PALB2 mutation with 0-3 prior therapies for advanced disease. Eligible patients must have a deleterious or suspected deleterious mutation in PALB2 on a CLIA approved commercial germline or next generation sequencing tumor assay. Study treatment is talazoparib 1 mg PO daily. In stage 1, ORR will be assessed after 15 patients; if at least 2 responses are observed then an additional 15 patients will be enrolled; if less than 2 responses are observed the study will be terminated. The primary objective is to evaluate whether talazoparib monotherapy can induce a 30% ORR in subjects with advanced breast cancer associated with a PALB2 mutation. Response will be assessed by RECIST 1.1. Secondary objectives include safety, PFS, clinical benefit rate, and patient-reported quality-of-life. Exploratory endpoints will assess for the presence of PALB2 loss-of-heterozygosity, biallelic mutations, correlation of ctDNA profile with treatment response and the correlation of germline versus somatic mutations with response rate. This trial is currently activated and enrolling at Stanford Cancer Center and it is expected that 4 additional sites will be added. Conclusion: This trial will evaluate gPALB2 as a biomarker for PARP inhibitor monotherapy in advanced or metastatic HER2- breast cancer. Clinical trial information: pending .

scholarly journals TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes

2020 ◽  
Vol 38 (36) ◽  
pp. 4274-4282 ◽  
Author(s):  
Nadine M. Tung ◽  
Mark E. Robson ◽  
Steffen Ventz ◽  
Cesar A. Santa-Maria ◽  
Rita Nanda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Homologous Recombination ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Objective Response ◽  
Metastatic Breast ◽  
Parp Inhibition ◽  
Mutation Carriers ◽  
Metastatic Setting

PURPOSE Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved for the treatment of human epidermal growth factor receptor 2 (HER2)–negative metastatic breast cancer (MBC) in germline (g) BRCA1/ 2 mutation carriers. Olaparib Expanded, an investigator-initiated, phase II study, assessed olaparib response in patients with MBC with somatic (s) BRCA1/ 2 mutations or g/s mutations in homologous recombination (HR)–related genes other than BRCA1/2. METHODS Eligible patients had MBC with measurable disease and germline mutations in non- BRCA1/ 2 HR-related genes (cohort 1) or somatic mutations in these genes or BRCA1/ 2 (cohort 2). Prior PARPi, platinum-refractory disease, or progression on more than two chemotherapy regimens (metastatic setting) was not allowed. Patients received olaparib 300 mg orally twice a day until progression. A single-arm, two-stage design was used. The primary endpoint was objective response rate (ORR); the null hypothesis (≤ 5% ORR) would be rejected within each cohort if there were four or more responses in 27 patients. Secondary endpoints included clinical benefit rate and progression-free survival (PFS). RESULTS Fifty-four patients enrolled. Seventy-six percent had estrogen receptor–positive HER2-negative disease. Eighty-seven percent had mutations in PALB2, s BRCA1/ 2, ATM, or CHEK2. In cohort 1, ORR was 33% (90% CI, 19% to 51%) and in cohort 2, 31% (90% CI, 15% to 49%). Confirmed responses were seen only with g PALB2 (ORR, 82%) and s BRCA1/ 2 (ORR, 50%) mutations. Median PFS was 13.3 months (90% CI, 12 months to not available/computable [NA]) for g PALB2 and 6.3 months (90% CI, 4.4 months to NA) for s BRCA1/ 2 mutation carriers. No responses were observed with ATM or CHEK2 mutations alone. CONCLUSION PARP inhibition is an effective treatment for patients with MBC and g PALB2 or s BRCA1/ 2 mutations, significantly expanding the population of patients with breast cancer likely to benefit from PARPi beyond g BRCA1/ 2 mutation carriers. These results emphasize the value of molecular characterization for treatment decisions in MBC.

Randomized, Placebo-Controlled, Double-Blind, Phase II Study of Axitinib Plus Docetaxel Versus Docetaxel Plus Placebo in Patients With Metastatic Breast Cancer

2011 ◽  
Vol 29 (18) ◽  
pp. 2459-2465 ◽  
Author(s):  
Hope S. Rugo ◽  
Alison T. Stopeck ◽  
Anil A. Joy ◽  
Stephen Chan ◽  
Shailendra Verma ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Adjuvant Chemotherapy ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Objective Response ◽  
Metastatic Breast ◽  
Double Blind ◽  
The Difference ◽  
To Receive

Purpose This multicenter, randomized, double-blind, phase II study assessed safety and efficacy of axitinib plus docetaxel in metastatic breast cancer (MBC). Patients and Methods Women with MBC were randomly assigned 2:1 to receive docetaxel 80 mg/m2 once every 3 weeks plus axitinib 5 mg twice per day (combination arm) or placebo (placebo arm), following a lead-in phase I trial. The primary end point was time to progression (TTP). Results In all, 168 patients were enrolled; 112 were randomly assigned to axitinib and 56 to placebo. Median TTP was numerically longer in the combination arm than in the placebo arm (8.1 v 7.1 months), but this difference was not statistically significant (hazard ratio, 1.24; 95% CI, 0.82 to 1.87; one-sided P = .156). The difference in median TTP was greatest among patients who had received prior adjuvant chemotherapy (9.2 v 7.0 months; P = .043, prespecified subgroup analysis). Objective response rate was higher in the combination arm (41.1% v 23.6%; P = .011). The most common grades 3 to 4 treatment-related adverse events (combination/placebo) included diarrhea (10.8%/0%), fatigue (10.8%/5.4%), stomatitis (12.6%/1.8%), mucositis (9.0%/0%), asthenia (7.2%/0%), and hypertension (4.5%/0%). Three patients in the combination arm experienced serious thromboembolic events (one death). Febrile neutropenia was more frequent in the combination arm (15.3% v 7.1%); rates of other hematologic toxicities were comparable. Increased toxicity with axitinib was generally managed by dose reduction and/or growth factor support. Conclusion The addition of axitinib to docetaxel did not improve TTP in first-line MBC treatment. Combination therapy may be more effective in patients previously exposed to adjuvant chemotherapy.

A phase II trial of the PARP inhibitor veliparib (ABT888) and temozolomide for metastatic breast cancer.

2010 ◽  
Vol 28 (15_suppl) ◽  
pp. 1019-1019 ◽  
Author(s):  
S. J. Isakoff ◽  
B. Overmoyer ◽  
N. M. Tung ◽  
R. S. Gelman ◽  
V. L. Giranda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Parp Inhibitor ◽  
Metastatic Breast

MERiDiAN: A phase III, randomized, double-blind study of the efficacy, safety, and associated biomarkers of bevacizumab plus paclitaxel compared with paclitaxel plus placebo, as first-line treatment of patients with HER2-negative metastatic breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS1142-TPS1142 ◽  
Author(s):  
David Miles ◽  
Leonardo Faoro ◽  
Yan V. Wang ◽  
Joyce O'Shaughnessy
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Metastatic Breast Cancer ◽  
Objective Response ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Double Blind Study ◽  
Clinical Trial Registry ◽  
Double Blind ◽  
Treatment Benefit

TPS1142^ Background: Bevacizumab (BV), a humanized monoclonal antibody targeting the angiogenic VEGF, has demonstrated activity in patients with metastatic breast cancer (MBC). Plasma VEGF-A levels ([VEGF-A]p) appear to positively correlate with the effect of BV on progression-free survival (PFS) in MBC, metastatic pancreatic, and advanced gastric cancers. The MERiDiAN study will prospectively investigate (1) whether baseline [VEGF-A]ppredict treatment benefit with BV, (2) efficacy of BV with weekly paclitaxel (P), based on previously observed differences in the magnitude of benefit compared with BV + non-P chemotherapies. Methods: MERiDiAN is a global, randomized, double-blind, phase III study enrolling patients with HER2-negative MBC (first patient was enrolled in August 2012). The co-primary endpoints are PFS by investigator assessment in the intent-to-treat (ITT) population, and PFS in the subgroup with high baseline [VEGF-A]p. Secondary endpoints are overall survival (OS), 1-year survival, objective response rate and duration, and safety. Exploratory objectives include assessing the predictive or prognostic potential of blood, DNA and tumor tissue markers, and genetic variants involved in angiogenesis and tumorigenesis, with regard to BV efficacy and safety.Patients will be randomized 1:1 to either P 90 mg/m2 IV weekly (qw) for 3 weeks followed by a 1-week rest and BV 10 mg/kg every 2 weeks (q2w) until disease progression (PD); or P 90 mg/m2IV qw for 3 weeks followed by a 1-week rest and placebo 10 mg/kg q2w until PD. An interim analysis of OS will be performed at the time of the primary PFS analysis. Clinical Trial Registry Number NCT01663727. Clinical trial information: NCT01663727.

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