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
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
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
Cyclophosphamide (CPA) Effect on Capecitabine Metabolism
CPA
4
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
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
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
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
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
Study Treatment
0 7 14 21 28 35 42
Days
Cyclophosphamide100 mg daily
Capecitabine 1500 mgtwice daily
Patients with CrCl 40-50 ml/min started at capecitabine dose -1 (1000 mg twice daily)
10
Patient Characteristics
Number enrolled 112Number eligible 96Age, years Median Range
5934-88
Reasons for ineligibles:
No measurable disease, and MUC-1 antigen ineligible : 10ER positive disease, but no prior endocrine Rx: 4Too many prior chemotherapies: 2
11
Patient and Disease CharacteristicsCharacteristic No. of Patients %PremenopausalPostmenopausal
1878
1981
ER positiveER negativeER unknown
56391
58411
HER-2/neu NegativeHER-2/neu PositiveHer-2 equivocal/unknown
796
11
826
11No. of prior metastatic CT regimens 0 1 2
523113
543214
12
Patient and Disease Characteristics
Characteristic No. of Patients %Metastatic sites* Bone Lung Liver Lymph nodes Pleura Other
534438261148
554640271150
No. of metastatic sites 1 2 >= 3
253041
263143
13
Adverse Event ≤1 2 3 4Allergy/immunology 93 1 0 0Blood/Bone Marrow 59 15 17 3Cardiac Arrhythmia 93 1 0 0Constitutional symptoms 73 18 3 0Dermatology/Skin 67 19 8 0Endocrine 92 1 1 0Gastrointestinal 71 19 3 0Infection 89 4 1 0Metabolic/Laboratory 85 5 4 0Musculoskeletal/Soft Tissue 93 1 0 0Neurology 89 5 0 0Ocular/Visual 93 1 0 0Pain 88 6 0 0Pulmonary/Upper Respiratory 93 0 1 0Renal/Genitourinary 93 1 0 0Vascular 92 0 1 1MAXIMUM GRADE ANY ADVERSE EVENT 23 35 31 4 14
Efficacy Results-ResponseEfficacy Measure No.
EvaluableNumber Responding
Percentage (95% CI)
Overall ResponsesCompletePartial
80/96 294
25
36% (26-48%)
Response rate chemo subsets0 prior chemo1 prior chemo2 prior chemo
442511
14105
32%40%45%
Response rate receptor subsetsER or PR positiveER and PR negative
4138
1712
41%32%
Response rate age subsets< 65 years≥ 65 years
5426
254
46%15% 15
Efficacy Results-PFS/OSEfficacy Measure No. Evaluable Median PFS
(months)Median OS (months)
Survival 96 5.9 19.6
Survival chemo subsets0 prior chemo1 prior chemo2 prior chemo
523113
7.16.64.1
24.717.38.6
Survival receptor subsetsER or PR positiveER and PR negative
5639
6.64.1
21.112.7
Survival age subsets< 65 years≥ 65 years
6531
7.12.9
20.417.8
16
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
Context: Other CAPE StudiesRIBBON-1
( NJ Robert, ASCO 2009)
RIBBON-2(Brufsky,
SABCS 2009)
SOLTI(Baselga,
SABCS 2009)
S0430 (1st and 2nd line only)
CAPE Combinator
Placebo/Bevacizumab
Placebo/Bevacizumab
Placebo/Sorafenib
CPA
# of pts 206/409 47/97 114/115 83
Prior chemos012
100%ExcludedExcluded
Excluded100%
Excluded
54%/43%45%/57%Excluded
54% (63%)32% (37%)14% (0%)
ER or PR +ER-Unknown
NR NR 68%/77%29%/17%
3%/6%
60%39%1%
Response 23.6%/35.4% NR 30.7%/38.3% 24/69 = 34.8%
PFS (months) 5.7/8.6 4.1/6.9 4.1/6.4 6.9 18
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
Acknowledgements
• Patients and families• CTEP of the NCI• Enrolling SWOG investigators and their
institutions
Investigator InstitutionAnderson, Jeanne E. Virginia Mason CCOP
Anderson, Tom Montana 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, Louis Davis, 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 Ann Southeast 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, Kasra Columbia River CCOP
Keogh, George P. Southeast CCC CCOP
Khilanani, Prem Beaumont CCOP
Klix, Mary M. St Louis CCOP
Kolevska, Tatjana Davis, 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 Lin Davis, U of CA Kaiser
Reddy, Gayatri Davis, U of CA Kaiser
Richman, Carol M. Davis, U of CA
Russell, Christy Ann So Calif, U
Salacz, Michael E. Kansas City CCOP
Sanchez, Ines J. BAMC/WHMC
Sanz-Altamira, Pedro M. Davis, U of CA
Sattar, Tanvir Davis, U of CA Kaiser
Schmulbach, Edmond L. Davis, U of CA Kaiser,
Seligman, Mark Columbia 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, Joseph Bay Area CCOP
Truica, Cristina San 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, Melissa Davis, U of CA Kaiser
Wicha, Max S. Michigan, U of
Yavorkovsky, Leonid Davis, U of CA Kaiser
Thank You!
Top Related