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

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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.

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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)

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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

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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

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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

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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

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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?

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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

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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!