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Simple oral therapy with capecitabine (CAPE) and cyclophosphamide (CPA) for metastatic breast cancer (MBC). A Study by the Southwest Oncology Group (S0430)

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Presentation on theme: "Simple oral therapy with capecitabine (CAPE) and cyclophosphamide (CPA) for metastatic breast cancer (MBC). A Study by the Southwest Oncology Group (S0430)"— Presentation transcript:

1 Simple oral therapy with capecitabine (CAPE) and cyclophosphamide (CPA) for metastatic breast cancer (MBC). A Study by the Southwest Oncology Group (S0430) A. F. Schott, D. Lew, W. E. Barlow, K. S. Albain, H. K. Chew, J. L. Wade, K. S. Lanier, H. M. Linden, G. N. Hortobagyi, R. B. Livingston 1

2 Background Patients prefer oral regimens for treatment of MBC in general Caveats – Not willing to sacrifice efficacy – Toxicity cannot be higher Liu, G., et al., Journal of Clinical Oncology, 1997. 15(1): p. 110-115. Pfeiffer, P., et al., European Journal of Cancer, 2006. 42(16): p. 2738-43. 2

3 Single Agent Versus Combination Chemotherapy Regimens Combinations regimens: – Typically have higher response rates, time to progression, and progression free survival – Toxicity higher – Cost higher – Overall survival benefit not often achieved True synergistic interaction may have the potential to increase survival 3

4 Cyclophosphamide (CPA) Effect on Capecitabine Metabolism CPA 4

5 Copyright © 2000 The American Society for Clinical Investigation, Inc.2 Hanahan D; Bergers G; Bergsland E: Journal of Clinical Investigation. 105(8):1045-7, 2000 Apr. 5

6 Study Objectives To estimate the response rate to combination oral therapy with cyclophosphamide and capecitabine in the treatment of metastatic breast cancer. To estimate progression-free survival and overall survival in this population treated with this combination. To evaluate the toxicity of this drug combination in metastatic breast cancer. To explore the use of MUC-1 antigens (CA 27-29 or CA 15-3) as a surrogate for clinical benefit in patients with non- measurable disease. 6

7 Study Design One-stage, single arm Phase II trial Historical comparator: pivotal trial leading to FDA drug registration of capecitabine, with a documented response rate of 25% overall The combined oral therapy would be of interest if the response rate was increased to 42%. Assuming a significance level of α = 0.05 (1-sided) and 72 patients with measurable disease, the power to detect this difference would be 92% overall 7

8 Main Eligibility Criteria Metastatic breast cancer 0, 1, or 2 prior chemotherapies for metastatic disease No prior capecitabine or oral cyclophosphamide for metastatic disease If ER positive, must have progressed on at least one hormonal therapy in the metastatic setting 8

9 Main Eligibility Criteria Disease must satisfy a) or b): – a) RECIST measurable disease – b) non-measurable disease but with elevated MUC-1 antigen (CA 15-3 or CA 27-29), and documented increase prior to enrollment No concurrent antineoplastic therapy (no trastuzumab). Bisphosphonates allowed. Normal organ function, including creatinine clearance >40 ml/min. 9

10 Study Treatment Patients with CrCl 40-50 ml/min started at capecitabine dose -1 (1000 mg twice daily) 10

11 Patient Characteristics Number enrolled112 Number eligible96 Age, years Median Range 59 34-88 Reasons for ineligibles: No measurable disease, and MUC-1 antigen ineligible: 10 ER positive disease, but no prior endocrine Rx: 4 Too many prior chemotherapies: 2 11

12 Patient and Disease Characteristics CharacteristicNo. of Patients% Premenopausal Postmenopausal 18 78 19 81 ER positive ER negative ER unknown 56 39 1 58 41 1 HER-2/neu Negative HER-2/neu Positive Her-2 equivocal/unknown 79 6 11 82 6 11 No. of prior metastatic CT regimens 0 1 2 52 31 13 54 32 14 12

13 Patient and Disease Characteristics CharacteristicNo. of Patients% Metastatic sites* Bone Lung Liver Lymph nodes Pleura Other 53 44 38 26 11 48 55 46 40 27 11 50 No. of metastatic sites 1 2 >= 3 25 30 41 26 31 43 13

14 Adverse Event≤1234 Allergy/immunology93100 Blood/Bone Marrow5915173 Cardiac Arrhythmia93100 Constitutional symptoms731830 Dermatology/Skin671980 Endocrine92110 Gastrointestinal711930 Infection89410 Metabolic/Laboratory85540 Musculoskeletal/Soft Tissue93100 Neurology89500 Ocular/Visual93100 Pain88600 Pulmonary/Upper Respiratory93010 Renal/Genitourinary93100 Vascular92011 MAXIMUM GRADE ANY ADVERSE EVENT2335314 14

15 Efficacy Results-Response Efficacy MeasureNo. Evaluable Number Responding Percentage (95% CI) Overall Responses Complete Partial 80/9629 4 25 36% (26-48%) Response rate chemo subsets 0 prior chemo 1 prior chemo 2 prior chemo 44 25 11 14 10 5 32% 40% 45% Response rate receptor subsets ER or PR positive ER and PR negative 41 38 17 12 41% 32% Response rate age subsets < 65 years ≥ 65 years 54 26 25 4 46% 15% 15

16 Efficacy Results-PFS/OS Efficacy MeasureNo. EvaluableMedian PFS (months) Median OS (months) Survival965.919.6 Survival chemo subsets 0 prior chemo 1 prior chemo 2 prior chemo 52 31 13 7.1 6.6 4.1 24.7 17.3 8.6 Survival receptor subsets ER or PR positive ER and PR negative 56 39 6.6 4.1 21.1 12.7 Survival age subsets < 65 years ≥ 65 years 65 31 7.1 2.9 20.4 17.8 16

17 Summary This therapy did not meet the pre-specified criteria of interest, a 42% RR Did we set the bar too high? What other studies are available for comparison? 17

18 Context: Other CAPE Studies RIBBON-1 ( NJ Robert, ASCO 2009) RIBBON-2 (Brufsky, SABCS 2009) SOLTI (Baselga, SABCS 2009) S0430 (1 st and 2 nd line only) CAPE Combinator Placebo/ Bevacizumab Placebo/ Bevacizumab Placebo/ Sorafenib CPA # of pts206/40947/97114/11583 Prior chemos 0 1 2 100% Excluded 100% Excluded 54%/43% 45%/57% Excluded 54% (63%) 32% (37%) 14% (0%) ER or PR + ER- Unknown NR 68%/77% 29%/17% 3%/6% 60% 39% 1% Response23.6%/35.4%NR30.7%/38.3%24/69 = 34.8% PFS (months)5.7/8.64.1/6.94.1/6.46.9 18

19 Conclusions CPA/CAPE did not meet the pre-specified criteria RR and PFS of CPA/CAPE appear roughly comparable to combinations of CAPE with bevacizumab and sorafenib CPA/CAPE therapy not expected to improve OS compared to single-agent sequential therapy. Comparative effectiveness studies warranted – Toxicity – Cost – Patient preferences for IV versus oral treatment 19

20 Acknowledgements Patients and families CTEP of the NCI Enrolling SWOG investigators and their institutions

21 InvestigatorInstitution Anderson, Jeanne E.Virginia Mason CCOP Anderson, TomMontana CCOP Atkins, James N.Southeast CCC CCOP Burdakin, John H.Beaumont CCOP Chen, Eric Y.Puget Sound Christensen, Scott D.Davis, U of CA Colman, Lauren K.Northwest CCOP Corcoran, Melissa C.Utah, U of Elias, Anthony D.Colorado, U of Fehrenbacher, LouisDavis, U of CA Kaiser Feldman, Eric M.Puget Sound Gaynor, Ellen R.Loyola University Geils, George F.Southeast CCC CCOP Ginsberg, Steven S.Puget Sound Grennan, Tim W.Davis, U of CA Kaiser Grimm, Ruby AnnSoutheast CCC CCOP Hiner, Sharon L.Davis, U of CA Hoelzer, Karen L.Central IL CCOP Hoffman, Mark M.Rochester, Univ of Adirondack Ca Care Karamlou, KasraColumbia River CCOP Keogh, George P.Southeast CCC CCOP Khilanani, PremBeaumont CCOP Klix, Mary M.St Louis CCOP Kolevska, TatjanaDavis, U of CA Kaiser Lanzotti, Victor J.Central IL CCOP Lebos, Harvey C.Southeast CCC CCOP Lewis, Brian J.Davis, U of CA Kaiser Lo, Shelly S.Loyola University Mandell, Gilbert L.Davis, U of CA Kaiser Moore, Halle C. F.Cleveland Clinic Musci, Michael A.Davis, U of CA Kaiser Needles, Burton M.St Louis CCOP Okazaki, Ian J.Hawaii MBCCOP Owyong, Lay LinDavis, U of CA Kaiser Reddy, GayatriDavis, U of CA Kaiser Richman, Carol M.Davis, U of CA Russell, Christy AnnSo Calif, U Salacz, Michael E.Kansas City CCOP Sanchez, Ines J.BAMC/WHMC Sanz-Altamira, Pedro M.Davis, U of CA Sattar, TanvirDavis, U of CA Kaiser Schmulbach, Edmond L.Davis, U of CA Kaiser, Seligman, MarkColumbia River CCOP Simmons, John F.Davis, U of CA Kaiser Smerage, Jeffrey B.Michigan, U of Soule, Sharon E.Kansas City CCOP Specht, Jennifer M.Puget Sound Szumowski, JosephBay Area CCOP Truica, CristinaSan Antonio, U of TX Urba, Walter J.Columbia River CCOP Urquhart, Alexander T.Colorado, U of Velasco, Mario R.Central IL CCOP Vogel, Stanley J.Kansas, U of Stormont-Vail Health Webb, Dale I.Virginia Mason CCOP Weick, James K.Cleveland Clinic Whitney, MelissaDavis, U of CA Kaiser Wicha, Max S.Michigan, U of Yavorkovsky, LeonidDavis, U of CA Kaiser

22 Thank You!

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