Clinical trial NCT01818063: Carboplatin and Combination Chemotherapy With or Without Veliparib in Treating Patients With Stage IIB-IIIC Breast Cancer
Official title: An Adaptive, Randomized Phase II Trial to Determine Pathologic Complete Response With the Addition of Carboplatin With and Without Veliparib to Standard Chemotherapy in the Neoadjuvant Treatment of Triple-Negative Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Estrogen Receptor-negative Breast Cancer
HER2-negative Breast Cancer
Progesterone Receptor-negative Breast Cancer
Stage II Breast Cancer
Stage IIIA Breast Cancer
Stage IIIB Breast Cancer
Stage IIIC Breast Cancer
Triple-negative Breast Cancer
Lead sponsor: Thomas Jefferson University
Sponsor class: OTHER
Collaborators: name: Susan G. Komen Breast Cancer Foundation
First posted: 2013-03-26
Enrollment: 9
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This randomized phase II trial studies how well carboplatin and combination chemotherapy with or without veliparib works in treating patients with stage IIB-IIIC breast cancer. Drugs used in chemotherapy, such as paclitaxel, carboplatin, doxorubicin hydrochloride, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving carboplatin and combination chemotherapy are more effective with or without veliparib is more effective in treating breast cancer.

Detailed description: PRIMARY OBJECTIVE:

1) To compare the pathologic complete response (path CR) in patients with stage IIB or stage III triple negative breast cancer treated with neoadjuvant paclitaxel and carboplatin to the path CR of patients treated with paclitaxel, carboplatin, and veliparib.

SECONDARY OBJECTIVES:

1. Relapse free survival (follow-up period of 36 months).
2. Overall clinical response to neoadjuvant therapy.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive paclitaxel intravenously (IV) and carboplatin IV on day 1 (course 1 only) or day 2 (courses 2-12). Treatment repeats every 7 days for 12 courses in the absence of disease progression or unacceptable toxicity. Beginning 21 days after the last course, patients receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive veliparib orally (PO) twice daily (BID) on days 1-5. Patients also receive paclitaxel IV and carboplatin IV on day 3 (course 1 only) or day 4 (courses 2-12). Treatment repeats every 7 days for 12 courses in the absence of disease progression or unacceptable toxicity. Beginning 21 days after the last course, patients receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 36 months.

Eligibility criteria: Inclusion Criteria:

1. Written informed consent must be obtained prior to any study-related procedures.
2. Histologically confirmed adenocarcinoma of the breast with the following markers: Estrogen receptor negative (\<1%), progesterone receptor negative (\<1%), and Her-2/neu negative (Her-2/neu 0-1+ IHC or FISH ratio \<1.8 or average HER2 gene copy number of \<four signal/nucleus for test systems without internal control probe).
3. Female ≥ 18 years old.
4. Clinical stage IIA (T2N0), IIB (T2N1, T3N0) or stage IIIA (T1N2, T2N2, T3N1, T3N2), IIIB, or IIIC breast cancer with no prior treatment.
5. Complete radiology or tumor assessment within 28 days prior to enrollment

   1. Breast MRI
   2. Unilateral Breast Ultrasound
   3. Distant metastatic work-up completed with PET/CT.
   4. If enlarged axillary lymph nodes are found during staging scans, FNA must be performed to determine whether the node is involved with cancer.
   5. If axillary lymph nodes are clinically negative during initial work-up, sentinel node biopsy will be performed prior to initiation of chemotherapy.
6. ECOG Performance Status of 0 or 1
7. Adequate organ and hematologic function as evidenced by the following laboratory studies within 4 weeks of study enrollment:

   1. Cardiac Ejection Fraction \>/= lower limit of normal as determined by 2-D echo or MUGA scan according to institutional standards.
   2. Hematologic function, as follows: Absolute neutrophil count ≥ 1.5 x 109/L, Platelet count ≥ 100 x 109/L and ≤ 850 x 109/L, Hemoglobin ≥ 9 g/dL, PTT and INR \< 1.5 x ULN.
   3. Renal function, as follows: Serum creatinine \</= 1.4 mg/dL).
   4. Hepatic function, as follows:Aspartate aminotransferase (AST) ≤ 2.5 x ULN, Alanine aminotransferase (ALT) ≤ 2.5 x ULN , Total bilirubin ≤ 2 x ULN (except for patients with UGT1A1 promoter polymorphism, i.e. Gilbert syndrome, confirmed by genotyping or Invader UGT1A1 molecular assay prior to study enrollment. Patients enrolled with Gilbert syndrome must have total bilirubin \< 3 ULN).
8. Patient must be willing and able to undergo MRI as outlined in protocol.

Exclusion Criteria:

1. Known hypersensitivity to doxorubicin, cyclophosphamide, paclitaxel, cremophor or medications containing cremophor(miconazole, docetaxel, sandimmune, nelfinavir mesylate, propofol, diazepam injection, vitamin K injection, ixabepilone, aci-jel) or carboplatin.
2. Known HIV or active Hepatitis B or C infection.
3. Prior treatment for the currently diagnosed breast cancer.
4. Prior treatment with doxorubicin up to 400 mg/m2.
5. Pre-existing Grade 3 or 4 sensory neuropathy.
6. History of bleeding diathesis or extensive bleeding requiring blood transfusion within 14 days of enrollment.
7. Major surgical procedure within 4 weeks (28 days) prior to enrollment (port placement is not considered a major surgical procedure).
8. Clinically significant cardiac disease within 12 months of study enrollment, including myocardial infarction, unstable angina, congestive heart failure, or ongoing arrhythmias requiring medication or pacemaker.
9. Non-healing wound, ulcer or fracture.
10. Ongoing or active infection.
11. Pregnant (i.e., positive beta-human chorionic gonadotropin test) or lactating
12. Not willing to use a highly effective method of birth control (i.e. those which result in low failure rates, less than 1% per year), defined as intrauterine devices, barrier methods (condoms, contraceptive sponges, diaphragms, vaginal rings used with spermicidal jellies or creams), oral contraceptive pills, or sexual abstinence. Contraception must be used during the study.
13. T0 tumors
14. Active dental infection

Primary outcomes:
measure: Count of Participants That Achieve Pathologic Complete Response (PCR)
timeFrame: 36 months following surgery
Secondary outcomes:
measure: Overall Clinical Response
timeFrame: Up to 3 years
measure: Relapse Free Survival
timeFrame: Up to 3 years
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: Walter Reed National Military Medical Center
state: Maryland
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Reading
country: United States
facility: Reading Hospital
state: Pennsylvania
Study officials:
affiliation: Thomas Jefferson University
name: Edith Mitchell, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Perou CM. Molecular stratification of triple-negative breast cancers. Oncologist. 2011;16 Suppl 1:61-70. doi: 10.1634/theoncologist.2011-S1-61.
citation: Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, Lickley LA, Rawlinson E, Sun P, Narod SA. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res. 2007 Aug 1;13(15 Pt 1):4429-34. doi: 10.1158/1078-0432.CCR-06-3045.
citation: Bauer KR, Brown M, Cress RD, Parise CA, Caggiano V. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry. Cancer. 2007 May 1;109(9):1721-8. doi: 10.1002/cncr.22618.
citation: Lund MJ, Butler EN, Bumpers HL, Okoli J, Rizzo M, Hatchett N, Green VL, Brawley OW, Oprea-Ilies GM, Gabram SG. High prevalence of triple-negative tumors in an urban cancer center. Cancer. 2008 Aug 1;113(3):608-15. doi: 10.1002/cncr.23569.
citation: Bosch A, Eroles P, Zaragoza R, Vina JR, Lluch A. Triple-negative breast cancer: molecular features, pathogenesis, treatment and current lines of research. Cancer Treat Rev. 2010 May;36(3):206-15. doi: 10.1016/j.ctrv.2009.12.002. Epub 2010 Jan 8.
citation: NCCN. NCCN Clinical Practice Guidelines in Oncology, Version 2.2011. 2011.
citation: Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, Ingle JN, Cooper MR, Hayes DF, Tkaczuk KH, Fleming G, Holland JF, Duggan DB, Carpenter JT, Frei E 3rd, Schilsky RL, Wood WC, Muss HB, Norton L. Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol. 2003 Mar 15;21(6):976-83. doi: 10.1200/JCO.2003.02.063.
citation: Mamounas EP, Bryant J, Lembersky B, Fehrenbacher L, Sedlacek SM, Fisher B, Wickerham DL, Yothers G, Soran A, Wolmark N. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol. 2005 Jun 1;23(16):3686-96. doi: 10.1200/JCO.2005.10.517. Epub 2005 May 16.
citation: Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008 Apr 17;358(16):1663-71. doi: 10.1056/NEJMoa0707056.
citation: Liedtke C, Mazouni C, Hess KR, Andre F, Tordai A, Mejia JA, Symmans WF, Gonzalez-Angulo AM, Hennessy B, Green M, Cristofanilli M, Hortobagyi GN, Pusztai L. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008 Mar 10;26(8):1275-81. doi: 10.1200/JCO.2007.14.4147. Epub 2008 Feb 4.
citation: Rouzier R, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K, Hess KR, Stec J, Ayers M, Wagner P, Morandi P, Fan C, Rabiul I, Ross JS, Hortobagyi GN, Pusztai L. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res. 2005 Aug 15;11(16):5678-85. doi: 10.1158/1078-0432.CCR-04-2421.
citation: Wang S, Yang H, Tong F, Zhang J, Yang D, Liu H, Cao Y, Liu P, Zhou P, Cheng L, Liu M, Guo J. Response to neoadjuvant therapy and disease free survival in patients with triple-negative breast cancer. Gan To Kagaku Ryoho. 2009 Feb;36(2):255-8.
citation: Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, Ollila DW, Sartor CI, Graham ML, Perou CM. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res. 2007 Apr 15;13(8):2329-34. doi: 10.1158/1078-0432.CCR-06-1109.
citation: Perez EA, Moreno-Aspitia A, Aubrey Thompson E, Andorfer CA. Adjuvant therapy of triple negative breast cancer. Breast Cancer Res Treat. 2010 Apr;120(2):285-91. doi: 10.1007/s10549-010-0736-z. Epub 2010 Jan 22.
citation: Sirohi B, Arnedos M, Popat S, Ashley S, Nerurkar A, Walsh G, Johnston S, Smith IE. Platinum-based chemotherapy in triple-negative breast cancer. Ann Oncol. 2008 Nov;19(11):1847-52. doi: 10.1093/annonc/mdn395. Epub 2008 Jun 20.
citation: Roy V, Pockaj BA, Allred JB, Apsey H, Northfelt DW, Nikcevich D, Mattar B, Perez EA. A Phase II trial of docetaxel and carboplatin administered every 2 weeks as preoperative therapy for stage II or III breast cancer: NCCTG study N0338. Am J Clin Oncol. 2013 Dec;36(6):540-4. doi: 10.1097/COC.0b013e318256f619.
citation: Frasci G, Comella P, Rinaldo M, Iodice G, Di Bonito M, D'Aiuto M, Petrillo A, Lastoria S, Siani C, Comella G, D'Aiuto G. Preoperative weekly cisplatin-epirubicin-paclitaxel with G-CSF support in triple-negative large operable breast cancer. Ann Oncol. 2009 Jul;20(7):1185-92. doi: 10.1093/annonc/mdn748. Epub 2009 Feb 13.
citation: Anders CK, Winer EP, Ford JM, Dent R, Silver DP, Sledge GW, Carey LA. Poly(ADP-Ribose) polymerase inhibition: "targeted" therapy for triple-negative breast cancer. Clin Cancer Res. 2010 Oct 1;16(19):4702-10. doi: 10.1158/1078-0432.CCR-10-0939. Epub 2010 Sep 21.
citation: Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O'Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JH, de Bono JS. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009 Jul 9;361(2):123-34. doi: 10.1056/NEJMoa0900212. Epub 2009 Jun 24.
citation: O'Shaughnessy J, Osborne C, Pippen JE, Yoffe M, Patt D, Rocha C, Koo IC, Sherman BM, Bradley C. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011 Jan 20;364(3):205-14. doi: 10.1056/NEJMoa1011418. Epub 2011 Jan 5.
citation: O'Shaughnessy J, Schwartzberg S, Danso M, Rugo H, Miller K, Yardley D. A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple-negative breast cancer (TNBC). J Clin Oncol 2011;29 (suppl; abstr 1007).
citation: Liu X, Shi Y, Maag DX, Palma JP, Patterson MJ, Ellis PA, Surber BW, Ready DB, Soni NB, Ladror US, Xu AJ, Iyer R, Harlan JE, Solomon LR, Donawho CK, Penning TD, Johnson EF, Shoemaker AR. Iniparib nonselectively modifies cysteine-containing proteins in tumor cells and is not a bona fide PARP inhibitor. Clin Cancer Res. 2012 Jan 15;18(2):510-23. doi: 10.1158/1078-0432.CCR-11-1973. Epub 2011 Nov 29.
citation: Patel AG, De Lorenzo SB, Flatten KS, Poirier GG, Kaufmann SH. Failure of iniparib to inhibit poly(ADP-Ribose) polymerase in vitro. Clin Cancer Res. 2012 Mar 15;18(6):1655-62. doi: 10.1158/1078-0432.CCR-11-2890. Epub 2012 Jan 30.
citation: Comen EA, Robson M. Poly(ADP-ribose) polymerase inhibitors in triple-negative breast cancer. Cancer J. 2010 Jan-Feb;16(1):48-52. doi: 10.1097/PPO.0b013e3181cf01eb.
citation: Chen XS, Nie XQ, Chen CM, Wu JY, Wu J, Lu JS, Shao ZM, Shen ZZ, Shen KW. Weekly paclitaxel plus carboplatin is an effective nonanthracycline-containing regimen as neoadjuvant chemotherapy for breast cancer. Ann Oncol. 2010 May;21(5):961-7. doi: 10.1093/annonc/mdq041. Epub 2010 Mar 8.
citation: Betensky RA, Louis DN, Cairncross JG. Influence of unrecognized molecular heterogeneity on randomized clinical trials. J Clin Oncol. 2002 May 15;20(10):2495-9. doi: 10.1200/JCO.2002.06.140.
citation: Berry DA. Bayesian clinical trials. Nat Rev Drug Discov. 2006 Jan;5(1):27-36. doi: 10.1038/nrd1927.
citation: Barker AD, Sigman CC, Kelloff GJ, Hylton NM, Berry DA, Esserman LJ. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin Pharmacol Ther. 2009 Jul;86(1):97-100. doi: 10.1038/clpt.2009.68. Epub 2009 May 13.
citation: Heagerty PJ, Zheng Y. Survival model predictive accuracy and ROC curves. Biometrics. 2005 Mar;61(1):92-105. doi: 10.1111/j.0006-341X.2005.030814.x.
citation: Ivanova A, Qaqish BF, Schell MJ. Continuous toxicity monitoring in phase II trials in oncology. Biometrics. 2005 Jun;61(2):540-5. doi: 10.1111/j.1541-0420.2005.00311.x.
citation: Chen JQ, Russo J. ERalpha-negative and triple negative breast cancer: molecular features and potential therapeutic approaches. Biochim Biophys Acta. 2009 Dec;1796(2):162-75. doi: 10.1016/j.bbcan.2009.06.003. Epub 2009 Jun 13.
citation: Hergueta-Redondo M, Palacios J, Cano A, Moreno-Bueno G. "New" molecular taxonomy in breast cancer. Clin Transl Oncol. 2008 Dec;10(12):777-85. doi: 10.1007/s12094-008-0290-x.
citation: Rakha EA, Reis-Filho JS, Ellis IO. Basal-like breast cancer: a critical review. J Clin Oncol. 2008 May 20;26(15):2568-81. doi: 10.1200/JCO.2007.13.1748.
citation: Holstege H, Joosse SA, van Oostrom CT, Nederlof PM, de Vries A, Jonkers J. High incidence of protein-truncating TP53 mutations in BRCA1-related breast cancer. Cancer Res. 2009 Apr 15;69(8):3625-33. doi: 10.1158/0008-5472.CAN-08-3426. Epub 2009 Mar 31.
citation: Lakhani SR, Reis-Filho JS, Fulford L, Penault-Llorca F, van der Vijver M, Parry S, Bishop T, Benitez J, Rivas C, Bignon YJ, Chang-Claude J, Hamann U, Cornelisse CJ, Devilee P, Beckmann MW, Nestle-Kramling C, Daly PA, Haites N, Varley J, Lalloo F, Evans G, Maugard C, Meijers-Heijboer H, Klijn JG, Olah E, Gusterson BA, Pilotti S, Radice P, Scherneck S, Sobol H, Jacquemier J, Wagner T, Peto J, Stratton MR, McGuffog L, Easton DF; Breast Cancer Linkage Consortium. Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin Cancer Res. 2005 Jul 15;11(14):5175-80. doi: 10.1158/1078-0432.CCR-04-2424.
citation: Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009 Nov 25;139(5):871-90. doi: 10.1016/j.cell.2009.11.007.
citation: Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, Pietenpol JA. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011 Jul;121(7):2750-67. doi: 10.1172/JCI45014.
citation: Ruckhaberle E, Karn T, Engels K, Turley H, Hanker L, Muller V, Schmidt M, Ahr A, Gaetje R, Holtrich U, Kaufmann M, Rody A. Prognostic impact of thymidine phosphorylase expression in breast cancer--comparison of microarray and immunohistochemical data. Eur J Cancer. 2010 Feb;46(3):549-57. doi: 10.1016/j.ejca.2009.11.020. Epub 2009 Dec 18.
citation: Palacios J, Honrado E, Osorio A, Cazorla A, Sarrio D, Barroso A, Rodriguez S, Cigudosa JC, Diez O, Alonso C, Lerma E, Dopazo J, Rivas C, Benitez J. Phenotypic characterization of BRCA1 and BRCA2 tumors based in a tissue microarray study with 37 immunohistochemical markers. Breast Cancer Res Treat. 2005 Mar;90(1):5-14. doi: 10.1007/s10549-004-1536-0.
citation: Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, Wittliff JL, Wolff AC. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. Arch Pathol Lab Med. 2010 Jun;134(6):907-22. doi: 10.5858/134.6.907.
citation: Vance GH, Barry TS, Bloom KJ, Fitzgibbons PL, Hicks DG, Jenkins RB, Persons DL, Tubbs RR, Hammond ME; College of American Pathologists. Genetic heterogeneity in HER2 testing in breast cancer: panel summary and guidelines. Arch Pathol Lab Med. 2009 Apr;133(4):611-2. doi: 10.5858/133.4.611.