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 .

Multicenter phase II efficacy trial of toremifene in tamoxifen-refractory patients with advanced breast cancer.

1993 ◽  
Vol 11 (2) ◽  
pp. 345-350 ◽  
Author(s):  
C L Vogel ◽  
I Shemano ◽  
J Schoenfelder ◽  
R A Gams ◽  
M R Green
Keyword(s):  
Breast Cancer ◽  
Treatment Failure ◽  
Advanced Breast Cancer ◽  
Phase Ii ◽  
Stable Disease ◽  
Objective Response ◽  
Metastatic Breast ◽  
Advanced Breast ◽  
Cross Resistance ◽  
High Dose

PURPOSE To explore further the efficacy of high-dose toremifene in patients with advanced breast cancer who had failed to respond to tamoxifen or whose disease had progressed on tamoxifen. PATIENTS AND METHODS One hundred two perimenopausal or postmenopausal women with metastatic breast cancer refractory to tamoxifen were entered onto a phase II clinical trial of toremifene at a dose of 200 mg/d. The study patients consisted of 28 primarily refractory patients; 43 patients who had relapsed after a prior tamoxifen response; and 31 patients who had relapsed while receiving adjuvant tamoxifen. This was a heavily pretreated group of patients, with 65% having failed chemotherapeutic attempts and 72% having failed two or more hormonal therapies. Forty-nine percent of patients had visceral dominant disease. RESULTS The objective response rate was 5% (95% confidence interval [CI], 3% to 7%). The median time to treatment failure (TTF) was 10.9 months for the five responders. An additional 23% of patients had stable disease for a median TTF of 7.8 months, whereas the patients who experienced treatment failure had a median TTF of 2.1 months. Whether those patients with stable disease derived clinical benefit or simply had slow progression in an intrinsically indolent disease presentation is uncertain. Common toxicities were generally mild and similar to those encountered with tamoxifen. CONCLUSION We conclude that there is major cross-resistance between tamoxifen and toremifene and that only occasional tamoxifen-refractory patients will have objective responses to toremifene.

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 .

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 .

scholarly journals Implementation and Feasibility of Electronic Patient-Reported Outcome (ePRO) Data Entry in the PRAEGNANT Real-Time Advanced and Metastatic Breast Cancer Registry

2017 ◽  
Vol 77 (08) ◽  
pp. 870-878 ◽  
Author(s):  
Markus Wallwiener ◽  
Felix Heindl ◽  
Sara Brucker ◽  
Florin-Andrei Taran ◽  
Andreas Hartkopf ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Advanced Breast Cancer ◽  
Cancer Registry ◽  
Data Entry ◽  
Metastatic Breast ◽  
Advanced Breast ◽  
Patient Reported ◽  
Trial Staff ◽  
Breast Cancer Registry

Abstract Purpose Patient-reported outcomes (PROs) have been incorporated into clinical trials for many symptoms and medical conditions. A transition from paper-based capture of PROs to electronic PROs (ePROs) has recently started. This study reports on the feasibility of ePRO assessment in a prospective registry including molecular data for patients with advanced breast cancer. Methods As part of the PRAEGNANT network, patients were invited by clinical trial staff, physicians, and nurses to complete three standardized Internet-based questionnaires (EQ 5D 5 L, CES-D and IPAQ). Feasibility was assessed by the staff members who assigned the user accounts by the patients. The completeness of the questionnaires was also assessed. Results Fifteen of 17 patients who were asked agreed to participate to complete the PRO questionnaires (EQ-5D-5L and CES-D). However, the IPAQ (physical activity) questionnaire was only validly completed by 9 patients. Feasibility was ranked better by the physicians and dedicated clinical trial staff than by the nursing staff. Conclusions Incorporating ePRO questionnaires into an advanced breast cancer registry is feasible, and no major hurdles were reported. Involving stakeholders from the start, the application is tailored to the capacities and abilities of both patients and clinical staff. The patientsʼ compliance was better with some questionnaires, but others may present difficulties.

Cisplatin and VP16 in Metastatic Breast Carcinoma as a Third-Line Chemotherapy: A Randomized Study Comparing Low versus High Doses of Cisplatin

1995 ◽  
Vol 81 (4) ◽  
pp. 241-244 ◽  
Author(s):  
Guido Ceci ◽  
Giancarlo Bisagni ◽  
Giorgio Cocconi ◽  
Carmelina Rodinò ◽  
Virginio Belsanti ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Low Dose ◽  
Objective Response ◽  
Metastatic Breast ◽  
Advanced Breast ◽  
High Dose ◽  
Severe Toxicity ◽  
Third Line ◽  
Line Chemotherapy

Aims and background The study was designed to define the activity of the combination of cisplatin and etoposide as third-line chemotherapy for advanced breast cancer and to investigate the role of the dosage of cisplatin on the effectiveness of the combination. Methods Ninety-five eligible patients with advanced breast cancer who had failed or relapsed on two previous lines of chemotherapy were randomized to receive cisplatin at a high dose (100 mg/m2 i.v. day 1, arm A) or a low dose (60 mg/m2 day 1, arm B), combined with etoposide (100 mg/m2 i.v. days 4, 6 and 8). Cycles were repeated every 3 weeks. Results Of the 78 patients evaluable for response (39 in arm A and 39 in arm B), 9 (12%) showed complete or partial response, 5 (13%) in the high-dose arm and 4 (10%) in the low-dose arm. One complete response was seen in the high-dose arm and none in the low-dose arm. The only 2 patients with brain involvement showed an objective response (one CR in arm A and one PR in arm B). Median time to progression was 14 weeks in arm A and 10 weeks in arm B, median duration of remission 28 and 34 weeks, and survival 36 and 35 weeks, respectively. The differences were not significant. As expected, the patients in the high-dose arm experienced more severe toxicity. One toxic death was observed in each arm due to sepsis in agranulocytosis. The difference was statistically significant regarding nausea and vomiting. Neurotoxicity and ototoxicity were not relevant problems in this patient setting. Conclusions Considering the very poor prognostic factors presented by these patients, the combination showed a certain activity, and further evaluation in earlier stages of disease is warranted. A particular responsiveness on brain metastases is suggested. The dose of cisplatin was not proven to be of significant importance.

A Phase II Clinical Trial of Flutamide in the Treatment of Advanced Breast Cancer

1988 ◽  
Vol 74 (1) ◽  
pp. 53-56 ◽  
Author(s):  
Tiping Zhao ◽  
Guifen He
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Advanced Breast Cancer ◽  
Cancer Patients ◽  
Phase Ii ◽  
Transient Response ◽  
Postmenopausal Breast Cancer ◽  
Phase Ii Clinical Trial ◽  
Advanced Breast ◽  
Breast Cancer Patients

An antiandrogenic agent flutamide was used in the treatment of one male and 14 female postmenopausal breast cancer patients. Only a mild and transient response was seen in 2 female patients. Therefore, flutamide cannot be used solely in the treatment of female postmenopausal breast cancer.

Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. CRA501-CRA501 ◽  
Author(s):  
A. Tutt ◽  
M. Robson ◽  
J. E. Garber ◽  
S. Domchek ◽  
M. W. Audeh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Annual Meeting ◽  
Clinical Oncology ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Parp Inhibitor ◽  
Advanced Breast ◽  
Final Text

CRA501 The full, final text of this abstract will be available in Part II of the 2009 ASCO Annual Meeting Proceedings, distributed onsite at the Meeting on May 30, 2009, and as a supplement to the June 20, 2009, issue of the Journal of Clinical Oncology. [Table: see text]

PIKHER2: A phase Ib/II study evaluating safety and efficacy of oral BKM120 in combination with lapatinib in HER2-positive, PI3K-activated, trastuzumab-resistant advanced breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS663-TPS663 ◽  
Author(s):  
Anthony Goncalves ◽  
Nicolas Isambert ◽  
Mario Campone ◽  
Veronique Dieras ◽  
Jean Marie Boher ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Phase Ii ◽  
Dose Escalation ◽  
Objective Response ◽  
Mtor Pathway ◽  
Advanced Breast ◽  
Her2 Positive ◽  
Safety And Efficacy ◽  
Phase Ib

TPS663 Background: Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)-pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. BKM120 is an oral pan-class I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110α. PIKHER2 study will evaluate safety and efficacy of oral, daily lapatinib-BKM120 combination in HER2-positive, trastuzumab-resistant advanced breast cancer (ABC) with activated PI3K/AKT/mTOR pathway. Methods: This open label, single arm, multi-center study includes a phase Ib dose-escalation part and a phase II expansion part at the recommended dose (RP2D). Primary objectives include determination of the maximum-tolerated dose (MTD) of BKM120 in combination with lapatinib in trastumuzab-resistant HER2-positive ABC (phase Ib part) and evaluation of the activity of BKM120-lapatinib combination at RP2D as measured by objective response rate (ORR) in patients with activated PI3K/AKT/mTOR pathway, as defined by PTEN-negative by IHC and/or somatic mutations (exons 9 and 20) of PIK3CA and/or overexpression of phospho-AKT by IHC (phase II part). Secondary objectives include safety and tolerability of the combination, clinical benefit and progression-free survival, pharmacokinetic profiles, biological and pharmacodynamic correlates. Main eligibility criteria are PS ≤ 1, HER2-positive ABC resistant to trastuzumab, documented activated PI3K/AKT/mTOR pathway (phase II part only). A modified CRM using an adaptive Bayesian model guides the dose escalation of both agents with a maximum of 24 patients planned to be enrolled in phase Ib part. Efficacy will be tested according to a standard 2-stage Simon design under the following unacceptable and desirable hypotheses: H0, ORR <= 10% (unacceptable rate) vs. H1, ORR >=30% (desirable rate). A maximum of 35 patients with activated PI3K/AKT/mTOR pathway is planned to be enrolled in phase II part with an interim look after 18 evaluable patients will have been recruited. Clinical trial information: NCT01589861.

A phase II clinical trial to analyze olaparib response in patients with BRCA1 and/or BRCA2 promoter methylation with advanced breast cancer (GEICAM/2015-06 COMETA-Breast study).

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. TPS1114-TPS1114
Author(s):  
Juan De La Haba ◽  
Angel Guerrero-Zotano ◽  
Jose Alejandro Perez-Fidalgo ◽  
Santiago Gonzalez Santiago ◽  
Montserrat Muñoz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Advanced Breast Cancer ◽  
Phase Ii ◽  
Promoter Methylation ◽  
Phase Ii Clinical Trial ◽  
Advanced Breast

scholarly journals PARP inhibitor treatment of advanced breast cancer beyond the BRCA-mutated type: a meta-analysis

2021 ◽  
Author(s):  
Feifei Yan ◽  
Qi Jiang ◽  
Mengye He ◽  
Peng Shen
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Sequential Analysis ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Parp Inhibitors ◽  
Advanced Breast ◽  
Trial Sequential Analysis

Background: We conducted this meta-analysis to compare the efficacy and safety of PARP inhibitors with or without chemotherapy versus chemotherapy alone for advanced breast cancer. Methods: A meta-analysis and trial sequential analysis were performed using RevMan 5.2 analysis software. Results: Six eligible randomized clinical trials involving 2080 patients were included. Regimens containing PARP inhibitors were significantly associated with higher objective response rate, longer progression-free survival and overall survival. The PARP inhibitor regimen group had a significantly higher rate of grade ≥3 thrombocytopenia than the chemotherapy-only group. Conclusion: Regimens containing PARP inhibitors are effective and safe for BRCA-mutated advanced breast cancer patients. The efficacy appears to be only marginal in patients with BRCA status unselected.

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