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Phase I/Ib study of olaparib and carboplatin in women with triple negative breast cancer.

ABSTRACT: To investigate the safety, activity, and potential biomarkers of response to olaparib and carboplatin combination in sporadic triple negative breast cancer (TNBC). EXPERIMENTAL DESIGN: Metastatic or recurrent TNBC patients with no germline BRCA mutation or with BRCAPro scores <10% and a negative family history were eligible. A 3+3 dose escalation tested olaparib capsules (400mg bid, days1-7) with carboplatin AUC3-5 on day1 or 2 every 21 days, ? 8 cycles, with olaparib 400mg bid maintenance. Peripheral blood mononuclear cells were collected for polymorphisms and PAR levels, and paired tumor biopsies (pre-/post-cycle 1) for proteomics and apoptosis endpoints.28 women were treated (median 5 prior regimens [0-12]). Dose-limiting toxicity was thrombocytopenia, and symptomatic hyponatremia with carboplatin AUC5. The maximum tolerated dose was olaparib 400mg bid+carboplatin AUC4. Grade 3 and 4 adverse events included neutropenia (36%), thrombocytopenia (11%), and anemia (11%). Responses included 1 complete response (CR; 69+months) and 5/27 partial responses (19%; median 4months [4-7]), for a response rate of 22%. Biomarker findings did not correlate with response. The long-term CR patient with prior negative BRCA testing was found to have deletion of BRCA1 exons1-2.The olaparib/carboplatin combination is tolerable and has modest activity in sporadic TNBC patients. Further evaluation of predictive biomarkers to identify those with BRCA wild type who had response is warranted.

SUBMITTER: Lee JM

PROVIDER: S-EPMC5668030 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Phase I/Ib study of olaparib and carboplatin in women with triple negative breast cancer.

Lee Jung-Min JM Hays John L JL Chiou Victoria L VL Annunziata Christina M CM Swisher Elizabeth M EM Harrell Maria I MI Yu Minshu M Gordon Nicolas N Sissung Tristan M TM Ji Jiuping J Figg William D WD Minasian Lori L Lipkowitz Stanley S Wood Bradford J BJ Doroshow James J Kohn Elise C EC

Oncotarget 20170325 45

<h4>Purpose</h4>To investigate the safety, activity, and potential biomarkers of response to olaparib and carboplatin combination in sporadic triple negative breast cancer (TNBC). EXPERIMENTAL DESIGN: Metastatic or recurrent TNBC patients with no germline <i>BRCA</i> mutation or with BRCAPro scores <10% and a negative family history were eligible. A 3+3 dose escalation tested olaparib capsules (400mg bid, days1-7) with carboplatin AUC3-5 on day1 or 2 every 21 days, ≤ 8 cycles, with olaparib 400m ...[more]

PMID: 29108297

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Project description:BackgroundOlaparib has single-agent activity against breast/ovarian cancer (BrCa/OvCa) in germline BRCA1 or BRCA2 mutation carriers (gBRCAm). We hypothesized addition of olaparib to carboplatin can be administered safely and yield preliminary clinical activity.MethodsEligible patients had measurable or evaluable disease, gBRCAm, and good end-organ function. A 3 + 3 dose escalation tested daily oral capsule olaparib (100 or 200mg every 12 hours; dose level1 or 2) with carboplatin area under the curve (AUC) on day 8 (AUC3 day 8), then every 21 days. For dose levels 3 to 6, patients were given olaparib days 1 to 7 at 200 and 400 mg every 12 hours, with carboplatin AUC3 to 5 on day 1 or 2 every 21 days; a maximum of eight combination cycles were permitted, after which daily maintenance of olaparib 400mg every12 hours continued until progression. Dose-limiting toxicity was defined in the first two cycles. Peripheral blood mononuclear cells were collected for polymorphism analysis and polyADP-ribose incorporation. Paired tumor biopsies (before/after cycle 1) were obtained for biomarker proteomics and apoptosis endpoints.ResultsForty-five women (37 OvCa/8 BrCa) were treated. Dose-limiting toxicity was not reached on the intermittent schedule. Expansion proceeded with olaparib 400mg every 12 hours on days 1 to 7/carboplatin AUC5. Grade 3/4 adverse events included neutropenia (42.2%), thrombocytopenia (20.0%), and anemia (15.6%). Responses included 1 complete response (1 BrCa; 23 months) and 21 partial responses (50.0%; 15 OvCa; 6 BrCa; median = 16 [4 to >45] in OvCa and 10 [6 to >40] months in BrCa). Proteomic analysis suggests high pretreatment pS209-eIF4E and FOXO3a correlated with duration of response (two-sided P < .001; Pearson's R (2) = 0.94).ConclusionsOlaparib capsules 400mg every 12 hours on days 1 to 7/carboplatin AUC5 is safe and has activity in gBRCAm BrCa/OvCa patients. Exploratory translational studies indicate pretreatment tissue FOXO3a expression may be predictive for response to therapy, requiring prospective validation.

Project description:Importance:The value of platinum-based adjuvant chemotherapy in patients with triple-negative breast cancer (TNBC) remains controversial, as does whether BRCA1 and BRCA2 (BRCA1/2) germline variants are associated with platinum treatment sensitivity. Objective:To compare 6 cycles of paclitaxel plus carboplatin (PCb) with a standard-dose regimen of 3 cycles of cyclophosphamide, epirubicin, and fluorouracil followed by 3 cycles of docetaxel (CEF-T). Design, Setting, and Participants:This phase 3 randomized clinical trial was conducted at 9 cancer centers and hospitals in China. Between July 1, 2011, and April 30, 2016, women aged 18 to 70 years with operable TNBC after definitive surgery (having pathologically confirmed regional node-positive disease or node-negative disease with tumor diameter >10 mm) were screened and enrolled. Exclusion criteria included having metastatic or locally advanced disease, having non-TNBC, or receiving preoperative anticancer therapy. Data were analyzed from December 1, 2019, to January 31, 2020, from the intent-to-treat population as prespecified in the protocol. Interventions:Participants were randomized to receive PCb (paclitaxel 80 mg/m2 and carboplatin [area under the curve?=?2] on days 1, 8, and 15 every 28 days for 6 cycles) or CEF-T (cyclophosphamide 500 mg/m2, epirubicin 100 mg/m2, and fluorouracil 500 mg/m2 every 3 weeks for 3 cycles followed by docetaxel 100 mg/m2 every 3 weeks for 3 cycles). Main Outcomes and Measures:The primary end point was disease-free survival (DFS). Secondary end points included overall survival, distant DFS, relapse-free survival, DFS in patients with germline variants in BRCA1/2 or homologous recombination repair (HRR)-related genes, and toxicity. Results:A total of 647 patients (mean [SD] age, 51 [44-57] years) with operable TNBC were randomized to receive CEF-T (n?=?322) or PCb (n?=?325). At a median follow-up of 62 months, DFS time was longer in those assigned to PCb compared with CEF-T (5-year DFS, 86.5% vs 80.3%, hazard ratio [HR]?=?0.65; 95% CI, 0.44-0.96; P?=?.03). Similar outcomes were observed for distant DFS and relapse-free survival. There was no statistically significant difference in overall survival between the groups (HR?=?0.71; 95% CI, 0.42-1.22, P?=?.22). In the exploratory and hypothesis-generating subgroup analyses of PCb vs CEF-T, the HR for DFS was 0.44 (95% CI, 0.15-1.31; P?=?.14) in patients with the BRCA1/2 variant and 0.39 (95% CI, 0.15-0.99; P?=?.04) in those with the HRR variant. Safety data were consistent with the known safety profiles of relevant drugs. Conclusions and Relevance:These findings suggest that a paclitaxel-plus-carboplatin regimen is an effective alternative adjuvant chemotherapy choice for patients with operable TNBC. In the era of molecular classification, subsets of TNBC sensitive to PCb should be further investigated. Trial Registration:ClinicalTrials.gov Identifier: NCT01216111.

Project description:Abstract Background. Epidermal growth factor receptor (EGFR) is a targetable molecule in basal-like breast cancer, which comprises most “triple negative” breast cancer (TNBC), the only breast cancer subtype without established targeted therapy. Methods. In this randomized phase II trial, metastatic TNBC patients received the anti-EGFR antibody cetuximab (250mg/kg/week iv) with carboplatin (AUC2/wk iv) added on progression, or concomitant cetuximab + carboplatin. Molecular subtyping was done on archival specimens and those with accessible tumors provided fresh tissue, before and after 7-14 days of therapy, for microarray analyses to explore EGFR pathway inhibition. Results. Of 102 TNBC patients 74% were of the basal-like molecular subtype. Response rate to cetuximab was 6% (2/31), and was 16% (4/25) to cetuximab + carboplatin after progression. Upfront cetuximab + carboplatin produced responses in 17% (12/71); 31% responded or had prolonged disease stabilization. Time to progression was 2.1 months (95% CI 1.8-5.5) and overall survival 10.4 months (95% CI 7.7-13.1) for those treated with the combination regimen. Among 16 patients with evaluable serial biopsies, genomic patterns of the EGFR pathway showed activated status in 13 and inhibition by therapy in 5. Conclusions. While most TNBC were basal-like, a significant proportion were different subtypes. The aggressive nature of metastatic TNBC leads to limited survival. Despite a promising preclinical rationale and evidence of EGFR pathway activation in most, targeted treatment with cetuximab as a single agent had marginal activity and cetuximab added to carboplatin demonstrated modest activity. Serial biopsies as part of metastatic breast cancer studies are feasible, and this study confirmed that the EGFR pathway was inhibited by therapy in only a minority suggesting ligand-independent activation in most tumors. Tissue acquisition and drug selection based upon individualized pathway activation status should be an important part of future studies of TNBC. This series contains 36 microarrays that are from 18 patients with fresh frozen tissue available from the metastatic site. Pretreatment samples (Bx0) are available for two patients. Pretreatment and post single agent treatment (7-14 days after start of treatment with cetuximab; BxSingle) are available for three patients. Pretreatment and post combination treatment (7-14 days after start of treatment with cetuximab plus carboplatin; BxCombo) are available for eight patients. Two patients have a pretreatment sample, a sample after 7-14 days of treatment with single agent cetuximab, and a third sample 7-14 days on cetuximab plus carboplatin after switching to the combination arm upon progression on the single agent arm. Samples were hybridized with Stratagene common reference spiked with RNA from two breast cancer cell lines (ME16C and MCF-7) on Custom 1x44K Agilent microarrays. Arrays were scanned on an Axon 4000B scanner and analyzed with GenePix Pro software.

Dataset Information

Phase I/Ib study of olaparib and carboplatin in women with triple negative breast cancer.

Publications

Phase I/Ib study of olaparib and carboplatin in women with triple negative breast cancer.

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