Datasets:

pdf2dataset

/

448e9ae5045d4508a1da19913c4b6f92

like 0

n engl j med 364;3 nejm. org january 20, 2011 205The new england journal of medicine established in 1812 january 20, 2011 vol. 364 no. 3 Iniparib plus Chemotherapy in Metastatic Triple-Negative Breast Cancer Joyce O'Shaughnessy, M. D., Cynthia Osborne, M. D., John E. Pippen, M. D., Mark Yoffe, M. D., Debra Patt, M. D., Christine Rocha, M. Sc., Ingrid Chou Koo, Ph. D., Barry M. Sherman, M. D., and Charles Bradley, Ph. D. * Abstract From Baylor Charles A. Sammons Cancer Center (J. O., C. O., J. E. P. ), US Oncology (J. O., C. O., J. E. P., M. Y., D. P. ), and Texas Oncology, Dallas (J. O., C. O., J. E. P. ) — all in Dallas; Cancer Centers of North Caro-lina, Raleigh (M. Y. ); Texas Oncology Can-cer Center, Austin (D. P. ); and Bi Par Sci-ences, South San Francisco, CA (C. R., I. C. K., B. M. S., C. B. ). Address reprint re-quests to Dr. O'Shaughnessy at Baylor Charles A. Sammons Cancer Center, 3535 Worth St., Collins Building, Dallas, TX 75246, or at joyce. oshaughnessy@ usoncology. com. *Additional study investigators are listed in the Supplementary Appendix, avail-able at NEJM. org. This article (10. 1056/NEJMoa1011418) was published on January 5, 2011, at NEJM. org. N Engl J Med 2011;364:205-14. Copyright © 2011 Massachusetts Medical Society. Background Triple-negative breast cancers have inherent defects in DNA repair, making this can-cer a rational target for therapy based on poly(adenosine diphosphate-ribose) poly-merase (PARP) inhibition. Methods We conducted an open-label, phase 2 study to compare the efficacy and safety of gemcitabine and carboplatin with or without iniparib, a small molecule with PARP-inhibitory activity, in patients with metastatic triple-negative breast cancer. A total of 123 patients were randomly assigned to receive gemcitabine (1000 mg per square meter of body-surface area) and carboplatin (at a dose equivalent to an area under the concentration-time curve of 2) on days 1 and 8 — with or without iniparib (at a dose of 5. 6 mg per kilogram of body weight) on days 1, 4, 8, and 11 — every 21 days. Primary end points were the rate of clinical benefit (i. e., the rate of objective response [complete or partial response] plus the rate of stable disease for ≥6 months) and safety. Additional end points included the rate of objective response, progression-free survival, and overall survival. Results The addition of iniparib to gemcitabine and carboplatin improved the rate of clini-cal benefit from 34% to 56% (P = 0. 01) and the rate of overall response from 32% to 52% (P = 0. 02). The addition of iniparib also prolonged the median progression-free survival from 3. 6 months to 5. 9 months (hazard ratio for progression, 0. 59; P = 0. 01) and the median overall survival from 7. 7 months to 12. 3 months (hazard ratio for death, 0. 57; P = 0. 01). The most frequent grade 3 or 4 adverse events in either treat-ment group included neutropenia, thrombocytopenia, anemia, fatigue or asthenia, leukopenia, and increased alanine aminotransferase level. No significant difference was seen between the two groups in the rate of adverse events. Conclusions The addition of iniparib to chemotherapy improved the clinical benefit and survival of patients with metastatic triple-negative breast cancer without significantly in-creased toxic effects. On the basis of these results, a phase 3 trial adequately powered to evaluate overall survival and progression-free survival is being conducted. (Fund-ed by Bi Par Sciences [now owned by Sanofi-Aventis]; Clinical Trials. gov number, NCT00540358. ) The New England Journal of Medicine Downloaded from nejm. org on September 10, 2016. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved.

ID_1_Phase II_ OShaughnessy 2011.pdf

The new england journal of medicine n engl j med 364;3 nejm. org january 20, 2011 206Metastatic triple-negative brea st cancer — which is estrogen-receptor (ER)-negative and progesterone-recep-tor (PR)-negative and has no overexpression of human epidermal growth factor receptor type 2 (HER2) — is an aggressive subtype of breast can-cer marked by higher rates of visceral and central nervous system metastases and poorer disease-specific survival than hormone receptor-positive subtypes. 1-4 Patients with triple-negative breast cancer treated with preoperative chemotherapy have higher rates of pathological complete re-sponse than patients with hormone receptor-positive breast cancer. 5,6 However, patients in whom metastatic disease develops have a very poor prognosis, with a median survival of ap-proximately 1 year. 7 No standard-of-care therapy exists for patients with metastatic triple-negative breast cancer, and therefore they have an un-met need. Accounting for 15 to 20% of all cases of breast cancer,1,8,9 triple-negative breast cancer shares clinical and pathological features with hereditary BRCA1-related breast cancers. In sporadic triple-negative breast cancer, dysregulation of BRCA1, a protein with critical roles in the homologous-recombination-dependent DNA-repair pathway, has been attributed to a number of mechanisms, including BRCA1-promoter methylation and over-expression of the negative regulators ID4 and HMG. 10-13 Other defects in homologous-recom-bination pathways have also been implicated in the tumorigenesis of triple-negative breast cancer (including aberrations in MRE11-RAD50-NBS1, ATM, p53, and PALB2),14-17 providing a strong rationale for developing new agents that exploit DNA-repair defects in these cancers. Poly(adenosine diphosphate-ribose) polymer-ase 1 (PARP1), an important regulator of the DNA base-excision-repair pathway, has emerged as a therapeutic target for triple-negative breast cancer. Preclinical studies have shown that com-bining PARP1 inhibitors with platinum che-motherapy agents, which induce DNA damage through adducts and cross-linking, potentiates chemotherapeutic cytotoxicity. 18,19 Iniparib (also known as BSI-201) is an anticancer agent with PARP inhibitory activity in preclinical models. Although the full mechanism of its antitumor activity is still under investigation, iniparib en-hances the anti pro liferative and cytotoxic effects of carboplatin and gemcitabine in in vitro mod-els of triple-negative breast cancer. 19,20 In clini-cal studies, the combination of gemcitabine and carboplatin chemotherapy has demonstrated ac-tivity in patients with metastatic breast cancer, with rates of response ranging from 26 to 34%. 21-23 This phase 2 study was designed to evaluate whether iniparib could potentiate the antitumor effects of gem cita bine and carboplat-in with acceptable toxicity levels. Phase 1-1b studies of iniparib alone and ini-parib in combination with chemotherapy in pa-tients with advanced solid tumors have shown iniparib to have mild toxicity, with no maximal dose reached in terms of side effects. 24,25 In the present study, we investigated the efficacy and safety of iniparib in combination with gemcita-bine and carboplatin chemotherapy in patients with metastatic triple-negative breast cancer. Methods Patients Inclusion criteria for the study were female sex, an age of 18 years or older, and a diagnosis of metastatic breast cancer with measurable disease that was histologically documented as ER-nega-tive, PR-negative, and not having overexpression of HER2. Other inclusion criteria were Eastern Cooperative Oncology Group performance status score (which ranges from 0 to 5) of 0 or 1, with 0 representing a patient who is fully active and able to carry out predisease performance without restrictions, and 1 representing a patient who is restricted with respect to physically strenuous activity but is ambulatory and able to carry out work of a light or sedentary nature, (e. g., light housework or office work)26; and adequate bone marrow, hepatic, and renal function. Central nervous system metastases were permitted if the patient did not require glucocorticoids or brain radiotherapy and if brain metastases were clini-cally stable. Up to two prior chemotherapy regi-mens for metastatic disease were permitted, as was prior adjuvant or neoadjuvant chemo therapy, with the exception of treatment with gemcita-bine, carboplatin, cisplatin, or a PARP inhibitor. All patients provided written informed con-sent before enrollment. All tests (immunohisto-chemistry for ER, PR, and HER2 and fluores-cence in situ hybridization for HER2) were done according to each institution's standards and were performed with the use of archived-tissue specimens, the majority of which were derived from primary breast cancers. The New England Journal of Medicine Downloaded from nejm. org on September 10, 2016. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved.

ID_1_Phase II_ OShaughnessy 2011.pdf

Iniparib plus Chemotherapy in Triple-Negative Breast Cancer n engl j med 364;3 nejm. org january 20, 2011 207Study Design The study was approved by the central institution-al review board of US Oncology (www. usoncology . com) and complied with the provisions of the Good Clinical Practice guidelines. The study was sponsored by Bi Par Sciences (now a wholly owned subsidiary of Sanofi-Aventis). The study was de-signed by the principal academic investigator and lead academic author in collaboration with other academic authors and authors from Bi Par Sciences. Data collection and analysis were performed by ICON Clinical Research in collaboration with the sponsor. The academic authors vouch for the com-pleteness and accuracy of the data, the data analy-ses, and the fidelity of this report to the study protocol (available with the full text of this arti-cle at NEJM. org). The article was written by one academic and one industry author, with editorial assistance provided by the sponsor, and was re-viewed by all coauthors and the sponsor. This multicenter, open-label, randomized, phase 2 study was conducted at 20 centers within the US Oncology network. Patients were recruited from September 2007 through March 2009. All eligible patients were randomly assigned, in a 1:1 ratio, to receive gemcitabine plus carboplatin, ei-ther alone (the chemotherapy-alone group) or in combination with iniparib (the iniparib group). Assignment to treatment groups was conducted by means of an integrated web randomization system. Randomization was not stratified accord-ing to study center. Primary end points were the rate of clinical benefit (defined as the percentage of patients who had a complete response, a partial response, or stable disease for at least 6 months), as well as safety and tolerability of iniparib. Secondary end points were the overall rate of response and pro-gression-free survival, defined as the time from randomization to confirmation of disease pro-gression or death. Overall survival (defined as the time from randomization until the date of death) was not prespecified as an end point but was analyzed to explore the potential effect of inipa-rib on survival. Treatment Patients received chemotherapy as follows: during each 21-day period, on days 1 and 8, intravenous gemcitabine (1000 mg per square meter of body-surface area) over a 30-minute period and carbo-platin (at a dose equivalent to an area under the concentration-time curve of 2) over a 60-minute period. This regimen was administered either alone or together with intravenous iniparib (4. 0 mg per kilogram) over a 60-minute period, on days 1, 4, 8, and 11. The protocol was amended in January 2008 to increase the iniparib dose to 5. 6 mg per kilogram on the basis of emerging phase 1 safety data. Twenty patients received the lower iniparib dose before the amendment and thereafter had the dose increased to 5. 6 mg per kilogram. Patients randomly assigned to the chemotherapy-alone group were allowed to cross over to receive inipa-rib plus gemcitabine and carboplatin if disease progression occurred. Assessment Tumor response was based on investigator assess-ment of target and nontarget lesions and was as-sessed by means of computed tomography or mag-netic resonance imaging at baseline and every 6 weeks thereafter, in the absence of clinically evident disease progression. Tumor measurements according to the modified Response Evaluation Criteria in Solid Tumors, version 1. 0, were used to evaluate tumor response and to establish dis-ease progression (for details, see the Supplemen-tary Appendix, available at NEJM. org). 27 Safety was assessed with the use of standard clinical and laboratory tests (hematologic tests, blood chemical tests, and urinalysis) throughout the study period until 30 days after the last dose of a study drug was administered. Adverse event grades were defined on the basis of the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. 0 (http://ctep. cancer . gov/protocol Development/electronic_applications/ docs/ctcaev3. pdf). Serious adverse events were monitored and reported to Med Watch and the ICON safety group by the primary investigator at each site. Statistical Analysis The primary objective of the trial was to estimate the rate of clinical benefit in the iniparib group. We calculated that with a sample size of 60 pa-tients per group, assuming that the observed rate of clinical benefit in the iniparib group was ap-proximately 0. 60 (or 60%), the half-width of the exact 90% binomial confidence interval would be approximately equal to 0. 11. In particular, for an observed rate of clinical benefit of 0. 60, the exact 90% binomial confidence interval was 0. 49 to 0. 71. In contrast, the anticipated rate of clinical The New England Journal of Medicine Downloaded from nejm. org on September 10, 2016. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved.

ID_1_Phase II_ OShaughnessy 2011.pdf

The new england journal of medicine n engl j med 364;3 nejm. org january 20, 2011 208benefit in the chemotherapy-alone group was as-sumed to be approximately 0. 45. If the rate of clinical benefit in the iniparib group was 0. 674 or greater, then — on the basis of a one-sided test of equality of proportions at the 5% level of sig-nificance — the trial would have a power of at least 80% to detect an increase from the rate of clinical benefit of 0. 45 in the chemotherapy-alone group. In each of the two groups, the primary effi-cacy end point (i. e., the rate of clinical benefit) and the overall rate of response were estimated, and the exact two-sided 95% confidence interval was calculated. The rates of clinical benefit and the overall rates of response in the two groups were compared with the use of the Pearson chi-square test. Efficacy end points of progression-free and overall survival were estimated, and 95% confidence intervals were calculated by means of the Kaplan-Meier method. The distributions of progression-free and overall survival in the two groups were compared with the use of the log-rank test. P values were not adjusted for multiple interim analyses. All P values and confidence in-tervals reported are two-sided, and all analyses are of data for the intention-to-treat population unless otherwise noted. Adverse events and seri-ous adverse events were tabulated according to trial group and the Medical Dictionary for Regulatory Activities (Med DRA) System Organ Class catego-rization and preferred terms. For patients in the chemotherapy-alone group who crossed over to the iniparib group, safety data reported after the crossover were analyzed separately. Results Patients Between October 16, 2007, and March 9, 2009, 123 patients were randomly assigned to a treat-ment group: 62 to the chemotherapy-only group and 61 to the iniparib group. A total of 116 pa-tients (94%) received at least one dose of a study drug (Fig. 1): 57 patients in the iniparib group 123 Patients underwent randomization (intention-to-treat population) 61 Were assigned to receive gemcitabine and carboplatin plus iniparib62 Were assigned to receive gemcitabine and carboplatin 4 Did not receive the study drugs 2 Withdrew consent 2 Had unknown reason3 Did not receive the study drugs 2 Withdrew consent 1 Had a protocol violation 57 Received gemcitabine and carboplatin plus iniparib (safety population)59 Received gemcitabine and carboplatin (safety population) 51 Discontinued the study treat-ment 8 Had an adverse event 37 Had disease progression 3 Were withdrawn by physician 3 Had other reason55 Discontinued the study treat-ment 13 Had an adverse event 37 Had disease pro-gression (includes patients who crossed over to receive iniparib) 1 Did not comply 1 Was withdrawn by physician 3 Had other reason 6 Were included in the ongoing study 4 Were included in the ongoing study Figure 1. Enrollment, Randomization, and Follow-up of the Study Patients. The New England Journal of Medicine Downloaded from nejm. org on September 10, 2016. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved.

ID_1_Phase II_ OShaughnessy 2011.pdf

Iniparib plus Chemotherapy in Triple-Negative Breast Cancer n engl j med 364;3 nejm. org january 20, 2011 209and 59 patients in the chemotherapy-alone group. These 116 patients were included in the safety analysis. As of the date of data cutoff, November 16, 2009, a total of 6 of the 57 patients (11%) in the iniparib group and 4 of the 59 patients (7%) in the chemotherapy-alone group were still re-ceiving treatment. Thirty of 59 patients (51%) in the chemotherapy-alone group crossed over to receive iniparib in combination with gemcitabine and carboplatin. Table 1. Baseline Characteristics of the Study Patients, According to Treatment Group. Characteristic Gemcitabine-Carboplatin and Iniparib (N = 61)Gemcitabine-Carboplatin Alone (N = 62) Female sex — no. (%) 61 (100) 62 (100) Age — yr Median 56 53 Range 34-76 26-80 Race — no. (%)* White 48 (79) 48 (77) Black or African ancestry 9 (15) 12 (19) Asian 1 (2) 0 Unknown 3 (5) 2 (3) ECOG performance status — no. (%)† 0 42 (69) 42 (68) 1 18 (30) 20 (32) Missing data or unknown 1 (2) 0 No. of metastatic organ sites — no. (%) 1 7 (11) 7 (11) 2 19 (31) 12 (19) ≥3 35 (57) 43 (69) Metastatic site — no. (%) Bone 20 (33) 23 (37) Brain 2 (3) 6 (10) Chest wall or skin 18 (30) 12 (19) Liver 24 (39) 28 (45) Lung 38 (62) 32 (52) Lymph nodes 40 (66) 39 (63) Prior neoadjuvant or adjuvant chemotherapy — no. (%) 47 (77) 43 (69) No. of prior courses of chemotherapy for metastases — no. (%) 0 35 (57) 37 (60) 1 21 (34) 13 (21) 2 4 (7) 6 (10) 3 0 1 (2) Missing data 1 (2) 5 (8) Bevacizumab-containing regimen — no. (%) 9 (15) 8 (13) Taxane-containing regimen — no. (%) 51 (84) 44 (71) Anthracycline-containing regimen — no. (%) 45 (74) 40 (65) * Race was self-reported. † The Eastern Cooperative Oncology Group (ECOG) performance status reflects the daily-living abilities of the patient, on a scale of 0 (fully active without symptoms) to 5 (dead). The New England Journal of Medicine Downloaded from nejm. org on September 10, 2016. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved.

ID_1_Phase II_ OShaughnessy 2011.pdf

The new england journal of medicine n engl j med 364;3 nejm. org january 20, 2011 210Overall, the two treatment groups were well-balanced with regard to the baseline character-istics of the patients ( Table 1 ). A total of 60% and 57% of patients in the chemotherapy-alone and iniparib groups, respectively, received study treatment as first-line therapy for metastatic dis-ease. In all, 65% and 74% of patients, respective-ly, had received prior anthracycline-containing therapy, and 71% and 84% of patients, respec-tively, had received prior taxane-containing therapy. Efficacy In the intention-to-treat population, the rate of clinical benefit was 56% (34 of 61 patients) in the iniparib group and 34% (21 of 62 patients) in the chemotherapy-alone group (P = 0. 01). The overall rate of response was 52% (32 of 61 patients) in the iniparib group and 32% (20 of 62 patients) in the chemotherapy-alone group (P = 0. 02) (Table 2). For patients who received at least one cycle of therapy and underwent both baseline and post-treatment assessments of tumor size, the rate of clinical benefit was 62% (34 of 55 patients) in the iniparib group and 39% (21 of 54 patients) in the chemotherapy-alone group (P = 0. 02). The overall rate of response among these patients was 58% (32 of 55 patients) in the iniparib group and 37% (20 of 54 patients) in the chemotherapy-alone group (P = 0. 03). The median progression-free survival in the intention-to-treat population was 5. 9 months in the iniparib group and 3. 6 months in the che-motherapy-alone group (hazard ratio for disease progression with iniparib, 0. 59; 95% confidence interval [CI], 0. 39 to 0. 90; P = 0. 01) (Fig. 2A and Table 2 ). The median overall survival in the intention-to-treat population was 12. 3 months in the inipa-rib group and 7. 7 months in the chemotherapy-alone group (hazard ratio for death with iniparib, 0. 57; 95% CI, 0. 36 to 0. 90; P = 0. 01) ( Fig. 2B and Table 2 ). A total of 30 of 59 patients (51%) in the chemo-therapy-alone group crossed over to receive iniparib in combination with gemcitabine and carboplatin, after disease progression occurred. Patients who crossed over received a median of 1. 5 cycles of iniparib; 25 of the 30 patients (83%) discontinued treatment after one or two cycles. Table 2. Summary of Efficacy Measures in the Intention-to-Treat Population. * Outcome Gemcitabine-Carboplatin and Iniparib (N = 61)Gemcitabine-Carboplatin Alone (N = 62) P Value† Overall survival Months — median (95% CI) 12. 3 (9. 8-21. 5) 7. 7 (6. 5-13. 3) 0. 01 Hazard ratio (95% CI) 0. 57 (0. 36-0. 90) Progression-free survival Months — median (95% CI) 5. 9 (4. 5-7. 2) 3. 6 (2. 6-5. 2) 0. 01 Hazard ratio (95% CI) 0. 59 (0. 39-0. 90) Overall rate of response — no. (%) 32 (52) 20 (32) 0. 02 Best overall response — no. (%) Complete response 2 (3) 1 (2) Partial response 30 (49) 19 (31) Stable disease 11 (18) 13 (21) Stable disease for ≥6 mo 2 (3) 1 (2) Progressive disease 10 (16) 18 (29) Not able to be evaluated‡ 8 (13) 11 (18) Clinical benefit — no. (%)§ 34 (56) 21 (34) 0. 01 * CI denotes confidence interval. † P values were not adjusted for multiple interim analyses. ‡ Patients for whom best overall response could be evaluated had completed at least one cycle of treatment and had undergone both baseline and post-treatment assessment of tumor size. § The rate of clinical benefit was defined as the percentage of patients who had a complete response, a partial response, or stable disease for at least 6 months. The New England Journal of Medicine Downloaded from nejm. org on September 10, 2016. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved.

ID_1_Phase II_ OShaughnessy 2011.pdf

Iniparib plus Chemotherapy in Triple-Negative Breast Cancer n engl j med 364;3 nejm. org january 20, 2011 211In 1 of the 30 patients (3%), there was an uncon-firmed partial response, and 4 of the 30 patients (13%) had stable disease. Safety Table 3 lists the most common adverse events in the safety population. The most frequent adverse events included grade 1 nausea, fatigue or asthe-nia, and constipation; grade 3 anemia; and grade 3 or 4 neutropenia. The incidence of grade 3 or 4 adverse events was 86% in the iniparib group and 81% in the chemotherapy-alone group; these events included neutropenia, thrombocytopenia, anemia, and leukopenia. The rates of both grade 3 or 4 anemia and thrombocytopenia were more than 5% higher in the iniparib group than in the chemotherapy-alone group, but no significant differences were observed in the frequency of any adverse event between the two treatment groups (P>0. 05 for any grade of adverse events and for grade 3 or 4 adverse events). The rate of serious adverse events was similar in the two groups (29% in the chemotherapy-alone group and 28% in the iniparib group). In AProgression-free Survival BOverall Survival Overall Survival (%)100 8090 70 60 40 30 1050 20 0 0 4 8 12 16 20 24 2 6 10 14 18 22 Months Hazard ratio for death with iniparib, 0. 57 (95% CI, 0. 3 6-0. 90) P=0. 01 No. at Risk Gemcitabine-carboplatin plus iniparib Gemcitabine-carboplatin alone61 6260 5954 4750 3846 2935 2224 1617 1212 911 46 10 03 0Gemcitabine-carboplatin plus iniparib Gemcitabine-carboplatin alone Progression-free Survival (%)100 8090 70 60 40 30 1050 20 0 0 4 8 12 16 20 2 6 10 14 18 22 Months Hazard ratio for progression with iniparib, 0. 59 (95% CI, 0. 3 9-0. 90) P=0. 01 No. at Risk Gemcitabine-carboplatin plus iniparib Gemcitabine-carboplatin alone61 6251 3838 2525 1216 69 47 45 23 12 01 00 0Gemcitabine-carboplatin plus iniparib Gemcitabine-carboplatin alone Figure 2. Kaplan-Meier Estimates of Progression-free and Overall Survival Rates, According to Treatment Group. Dots represent patients whose data were censored. The New England Journal of Medicine Downloaded from nejm. org on September 10, 2016. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved.

ID_1_Phase II_ OShaughnessy 2011.pdf

The new england journal of medicine n engl j med 364;3 nejm. org january 20, 2011 212Table 3. Common Adverse Events in the Safety Population. * Event Gemcitabine-Carboplatin and Iniparib (N = 57)Gemcitabine-Carboplatin Alone (N = 59) Any Grade 3 Grade 4 Any Grade 3 Grade 4 number of patients (percent) Any event 57 (100) 30 (53) 19 (33) 59 (100) 26 (44) 22 (37) Neutropenia 46 (81) 25 (44) 13 (23) 48 (81) 21 (36) 16 (27) Anemia 38 (67) 13 (23) 0 40 (68) 9 (15) 0 Thrombocytopenia 36 (63) 10 (18) 11 (19) 30 (51) 6 (10) 10 (17) Leukopenia 16 (28) 7 (12) 0 13 (22) 6 (10) 0 Fatigue or asthenia 40 (70) 4 (7) 0 43 (73) 10 (17) 1 (2) Nausea 38 (67) 0 0 39 (66) 1 (2) 0 Constipation 24 (42) 1 (2) 0 32 (54) 1 (2) 0 Vomiting 16 (28) 1 (2) 0 21 (36) 1 (2) 0 Dyspnea 16 (28) 2 (4) 0 19 (32) 2 (3) 0 Headache 14 (25) 0 0 18 (31) 0 0 Pyrexia 14 (25) 0 0 10 (17) 0 0 Diarrhea 11 (19) 1 (2) 0 18 (31) 1 (2) 0 Stomatitis 11 (19) 0 0 9 (15) 0 0 Peripheral edema 11 (19) 0 0 9 (15) 1 (2) 0 Cough 10 (18) 1 (2) 0 10 (17) 0 0 Increased ALT 10 (18) 3 (5) 0 9 (15) 1 (2) 0 Arthralgia 9 (16) 1 (2) 0 10 (17) 0 0 Peripheral neuropathy 9 (16) 0 0 7 (12) 0 0 Alopecia 9 (16) 0 0 7 (12) 0 0 Anorexia 8 (14) 0 0 10 (17) 1 (2) 0 Dizziness 8 (14) 0 0 7 (12) 0 0 Bone pain 8 (14) 1 (2) 0 5 (8) 1 (2) 0 Anxiety 8 (14) 0 0 11 (19) 0 0 Increased AST 7 (12) 1 (2) 0 9 (15) 2 (3) 0 Dyspepsia 6 (11) 0 0 7 (12) 0 0 Insomnia 6 (11) 1 (2) 0 7 (12) 0 0 Dehydration 6 (11) 1 (2) 0 4 (7) 0 0 Depression 6 (11) 0 0 7 (12) 1 (2) 0 Rash 5 (9) 0 0 10 (17) 0 0 Hyperglycemia 5 (9) 1 (2) 0 6 (10) 0 0 Abdominal pain 3 (5) 0 0 8 (14) 2 (3) 0 Decreased weight 1 (2) 0 0 6 (10) 0 0 * Patients could have more than one adverse event. The safety population included all patients who received at least one dose of a study drug. Other adverse events reported for at least 10% of patients included urinary tract infection, de-creased appetite, dysgeusia, exertional dyspnea, oropharyngeal pain, erythema, back pain, musculoskeletal chest pain, musculoskeletal pain, neck pain, and pain in an extremity. No significant differences were observed in the frequency of any adverse event between the two treatment groups (P>0. 05 for any grade of adverse events and for grade 3 or 4 ad-verse events. ) ALT denotes alanine aminotransferase, and AST aspartate aminotransferase. The New England Journal of Medicine Downloaded from nejm. org on September 10, 2016. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved.

ID_1_Phase II_ OShaughnessy 2011.pdf

Iniparib plus Chemotherapy in Triple-Negative Breast Cancer n engl j med 364;3 nejm. org january 20, 2011 213the safety population, 8 of 57 patients (14%) in the iniparib group and 13 of 59 patients (22%) in the chemotherapy-alone group discontinued treatment because of adverse events. The dose of gemcitabine was reduced in 63% of patients (37 of 59) receiving chemotherapy alone and in 65% of patients (37 of 57) receiving iniparib. The dose of carboplatin was reduced in 78% of pa-tients (46 of 59) receiving chemotherapy alone and in 84% of patients (48 of 57) receiving ini-parib. The dose of iniparib was reduced in 26% of patients (15 of 57). The median number of treatment cycles administered was seven in the iniparib group and four in the chemotherapy-alone group. Fatal adverse events occurred in 2 of the 59 patients (3%) in the chemotherapy-alone group and 3 of 57 patients (5%) in the iniparib group, all attributable to disease progression within 30 days after receipt of study treatment. Discussion This open-label phase 2 trial showed that the ad-dition of iniparib to gemcitabine and carboplatin significantly improved all measures of efficacy, including the rate of clinical benefit, overall sur-vival, progression-free survival, and the rate of ob-jective (complete or partial) response, in patients with metastatic triple-negative breast cancer. The rate of clinical benefit, which encom-passes both objective responses and stable dis-ease for at least 6 months, was selected as the primary end point for this study, rather than the more commonly used phase 2 efficacy end point of overall rate of response. The rate of clinical benefit was selected on the basis of the hypothe-sis that iniparib may exert cytostatic effects rather than, or in addition to, cytotoxic effects when used in combination with chemotherapy, result-ing in disease stabilization in addition to tumor regression. For this reason, stable disease last-ing at least 6 months was regarded as clinically meaningful in assessing the antitumor activity of iniparib. The gemcitabine-carboplatin combination has been evaluated in several studies of metastatic breast cancer and has demonstrated activity at various doses and schedules. In our study, both chemotherapy agents were given on days 1 and 8, in close proximity to the doses of iniparib, to take advantage of possible synergy among the agents. The overall rate of response in the chemotherapy-alone group (32%) was similar to the rate de-scribed in previous studies of gemcitabine-plati-num therapy for metastatic breast cancer (range, 26 to 34). 21-23 The addition of iniparib to chemo-therapy significantly increased the overall rate of response to 52% (P = 0. 02), suggesting that ini-parib may overcome the intrinsic drug resistance of some triple-negative breast cancers. The fact that nearly all patients eventually had disease pro-gression while receiving iniparib plus chemother-apy suggests an acquired resistance to iniparib. Minimal antitumor activity of iniparib was observed in crossover patients whose disease had progressed on chemotherapy alone. These data are analogous to the decreased benefit of olapa-rib in patients with BRCA1/2-associated meta-static breast cancer whose disease was platinum-resistant. 28 Iniparib-gemcitabine-carboplatin therapy showed no significant increase in toxicity as com-pared with gemcitabine-carboplatin. The similar safety profiles in the two groups may be attrib-utable to specificity in the targeting of tumor cells deficient in homologous-recombination-dependent DNA repair, which spares normal, homologous-recombination-proficient cells. 29,30 Differences in the risk of adverse events between the two groups were minimal, despite the greater exposure to gemcitabine and carboplatin of pa-tients in the iniparib group than patients in the chemotherapy-alone group (seven vs. four cycles of treatment). Limitations of this open-label, phase 2 study include the small sample size, which limits our assessment of overall survival; potential investi-gator bias in assessing the rate of clinical benefit and progression-free survival; and the slight im-balance in prognostic factors, favoring the inipa-rib group over the chemotherapy-alone group — including the number of patients with three or more metastatic sites and the particular sites of metastases ( Table 1 ). Finally, multiple interim analyses were conducted to assess the need for and design of a subsequent phase 3 trial. In conclusion, despite its limitations, this phase 2 study provides proof of concept that the combination of iniparib with gemcitabine-carbo-platin provides significant clinical benefit with a favorable safety profile in patients with meta-static triple-negative breast cancer. On the basis of these results, a phase 3 trial of iniparib plus chemotherapy in patients with metastatic triple-The New England Journal of Medicine Downloaded from nejm. org on September 10, 2016. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved.

ID_1_Phase II_ OShaughnessy 2011.pdf

n engl j med 364;3 nejm. org january 20, 2011 214Iniparib plus Chemotherapy in Triple-Negative Breast Cancer negative breast cancer, adequately powered to study overall survival and progression-free sur-vival, is being conducted (Clinical Trials. gov num-ber, NCT00938652). Supported by Bi Par Sciences (now owned by Sanofi-Aventis). Presented in part at the annual meeting of the American Society of Clinical Oncology, Orlando, FL, May 31, 2009; the San Anto-nio Breast Cancer Symposium, San Antonio, TX, December 12, 2008, and December 11, 2009; and the annual meeting of the European Society for Medical Oncology, Milan, October 10, 2010. Dr. O'Shaughnessy reports receiving speaking fees and con-sulting fees from Sanofi-Aventis; Dr. Osborne, receiving travel support from Sanofi-Aventis; Dr. Yoffe, owning stock in Sanofi-Aventis; and Ms. Rocha and Drs. Koo, Sherman, and Bradley, being employees of and owning stock or stock options in Bi Par Sciences. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM. org. We thank Karla Burgos Polk and Joanne Brown for US Oncol-ogy project management, Stephan Herrera for critical review of a draft of the manuscript, and Alison Lovibond of Articulate-Science (paid by Sanofi-Aventis) for editorial assistance on a draft of the manuscript. References 1. Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 2006;295:2492-502. 2. Osborne CR, Kannan L, Ashfaq R, Ariyibi J, Frawley WH, Tripathy D. Clini-cal and pathological characterization of basal-like breast cancer. Presented at the San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2005. 3. Dent R, Hanna WM, Trudeau M, Raw-linson E, Sun P, Narod SA. Pattern of metastatic spread in triple-negative breast cancer. Breast Cancer Res Treat 2009;115: 423-8. 4. Rodríguez-Pinilla SM, Sarrío D, Hon-rado E, et al. Prognostic significance of basal-like phenotype and fascin expres-sion in node-negative invasive breast carci-nomas. Clin Cancer Res 2006;12:1533-9. 5. Rouzier R, Perou CM, Symmans WF, et al. Breast cancer molecular subtypes re-spond differently to preoperative chemo-therapy. Clin Cancer Res 2005;11:5678-85. 6. Parker JS, Mullins M, Cheang MC, et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol 2009;27:1160-7. 7. Kassam F, Enright K, Dent R, et al. Survival outcomes for patients with meta-static triple-negative breast cancer: impli-cations for clinical practice and trial de-sign. Clin Breast Cancer 2009;9:29-33. 8. Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of breast tumor sub-types in independent gene expression data sets. Proc Natl Acad Sci U S A 2003;100: 8418-23. 9. Swain SM. Triple-negative breast can-cer: metastatic risk and role of platinum agents. Presented at the American Society of Clinical Oncology Annual Meeting, Chicago, May 30-June 3, 2008. 10. Baldassarre G, Battista S, Belletti B, et al. Negative regulation of BRCA1 gene expression by HMGA1 proteins accounts for the reduced BRCA1 protein levels in sporadic breast carcinoma. Mol Cell Biol 2003;23:2225-38. 11. Beger C, Pierce LN, Kruger M, et al. Identification of Id4 as a regulator of BRCA1 expression by using a ribozyme-library-based inverse genomics approach. Proc Natl Acad Sci U S A 2001;98:130-5. 12. Esteller M, Silva JM, Dominguez G, et al. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst 2000;92:564-9. 13. Turner NC, Reis-Filho JS, Russell AM, et al. BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene 2007;26: 2126-32. 14. Bartkova J, Tommiska J, Oplustilova L, et al. Aberrations of the MRE11-RAD50-NBS1 DNA damage sensor complex in hu-man breast cancer: MRE11 as a candidate familial cancer-predisposing gene. Mol Oncol 2008;2:296-316. 15. Heikkinen T, Kärkkäinen H, Aaltonen K, et al. The breast cancer susceptibility mutation PALB2 1592del T is associated with an aggressive tumor phenotype. Clin Cancer Res 2009;15:3214-22. 16. Sørlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carci-nomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001;98:10869-74. 17. Tommiska J, Bartkova J, Heinonen M, et al. The DNA damage signalling ki-nase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ ERBB2-triple-negative breast cancer. On-cogene 2008;27:2501-6. 18. Alli E, Sharma VB, Sunderesakumar P, Ford JM. Defective repair of oxidative DNA damage in triple-negative breast cancer confers sensitivity to inhibition of poly(ADP-ribose) polymerase. Cancer Res 2009;69:3589-96. 19. Ossovskaya V, Li L, Broude EV, et al. BSI-201 enhances the activity of multiple classes of cytotoxic agents and irradiation in triple negative breast cancer. In: Program and abstracts of the American Associa-tion for Cancer Research Annual Meeting, Denver, April 18-22, 2009:5552. abstract. 20. Hastak K, Alli E, Ford JM. Synergistic chemosensitivity of triple-negative breast cancer cell lines to poly(ADP-Ribose) polymerase inhibition, gemcitabine, and cisplatin. Cancer Res 2010;70:7970-80. 21. Loesch D, Asmar L, Mc Intyre K, et al. Phase II trial of gemcitabine/carboplatin (plus trastuzumab in HER2-positive dis-ease) in patients with metastatic breast cancer. Clin Breast Cancer 2008;8:178-86. 22. Yardley DA, Burris HA III, Simons L, et al. A phase II trial of gemcitabine/car-boplatin with or without trastuzumab in the first-line treatment of patients with metastatic breast cancer. Clin Breast Can-cer 2008;8:425-31. 23. Chew HK, Doroshow JH, Frankel P, et al. Phase II studies of gemcitabine and cisplatin in heavily and minimally pre-treated metastatic breast cancer. J Clin Oncol 2009;27:2163-9. 24. Kopetz S, Mita MM, Mok I, et al. First in human phase I study of BSI-201, a small molecule inhibitor of poly ADP-ribose poly-merase (PARP) in subjects with advanced solid tumors. J Clin Oncol 2008;26:Suppl: 172S. abstract. 25. Mahany JJ, Lewis N, Heath EI, et al. A phase IB study evaluating BSI-201 in combination with chemotherapy in sub-jects with advanced solid tumors. J Clin Oncol 2008;26:Suppl:172s. abstract. 26. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-55. 27. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the re-sponse to treatment in solid tumors. J Natl Cancer Inst 2000;92:205-16. 28. Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibi-tor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 2010;376:235-44. 29. Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP- ribose) polymerase. Nature 2005;434:913-7. 30. Farmer H, Mc Cabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Na-ture 2005;434:917-21. Copyright © 2011 Massachusetts Medical Society. The New England Journal of Medicine Downloaded from nejm. org on September 10, 2016. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved.

ID_1_Phase II_ OShaughnessy 2011.pdf