S0622, Dasatinib in Treating Patients With Stage IV Breast Cancer That Has Spread to the Bone

Study Overview
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Brief Summary
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RATIONALE: Dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. PURPOSE: This randomized phase II trial is studying two different schedules of dasatinib to compare how well they work in treating patients with stage IV breast cancer that has spread to the bone.

Detailed Description
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OBJECTIVES: Compare the progression-free survival of patients with stage IV bone metastasis-predominant breast cancer treated with 1 of 2 treatment schedules of dasatinib. Compare the response rate (complete and partial, confirmed and unconfirmed) in patients treated with these regimens. Compare the MUC-1 antigen response rate (CA 15-3 or CA 27-29) in patients treated with these regimens. Compare the circulating tumor cell response rate in patients treated with these regimens. Compare the anti-osteoclast activity, as measured by changes in bone turnover markers, in patients treated with these regimens. Compare the frequency and severity of toxicities of these regimens in these patients. Compare the pain profiles of these patients and explore changes over time. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to concurrent trastuzumab (Herceptin®) treatment (yes vs no). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive oral dasatinib once daily. Arm II: Patients receive oral dasatinib twice daily. In both treatment arms, treatment continues for at least 24 weeks in the absence of disease progression or unacceptable toxicity. Blood samples are acquired from patients once weekly in weeks 1, 4, 8, 16, and 24. Samples are analyzed for tumor markers, circulating tumor cells, and bone markers. Patients complete a self-reported brief pain inventory questionnaire at baseline and once in weeks 8, 16, and 24. After completion of study treatment, patients are followed every 3-6 months for up to 2 years. PROJECTED ACCRUAL: A total of 80 patients will be accrued for this study.

Official Title
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Phase II Studies of Two Different Schedules of Dasatinib (NSC-732517) in Bone Metastasis Predominant Metastatic Breast Cancer

Conditions
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Breast Cancer, Metastatic Cancer

Intervention / Treatment
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* Drug: dasatinib


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of breast carcinoma meeting the following criteria: Stage IV disease Bone metastasis-predominant disease, defined as the presence of ≥ 1 bone metastasis with or without nonbone (visceral or soft tissue) disease where the number of bone metastases is at least the number of measurable visceral target lesions Visceral disease that does not cause a reduction in ECOG performance status allowed Must meet 1 of the following criteria: Measurable disease within the past 28 days Nonmeasurable disease with rising serum CA 15-3, CA 27-29, CEA, or CA-125 documented by 2 consecutive measurements taken ≥ 14 days apart with the most recent measurement being within the past 42 days These measurements need not be consecutive, and the prior measurement could have been months to years prior to the current measurement if the marker is considered by the investigator to reflect disease progression The second serum marker value must be greater than the institution's upper limit of normal and show ≥ a 20% increase over the first measurement No symptomatic brain or CNS metastases Prior CNS or brain metastasis allowed provided it was treated with radiotherapy ≥ 8 weeks ago No pleural or pericardial effusion Hormone receptor status known Estrogen receptor- and/or progesterone receptor-positive disease must have progressed on ≥ 1 hormonal therapy in the metastatic setting PATIENT CHARACTERISTICS: Male or female Menopausal status not specified Zubrod performance status 0-2 QTc < 450 msec by EKG Ejection fraction ≥ 50% by MUGA or 2-dimensional echocardiogram with no significant abnormalities within the past 12 weeks for patients on trastuzumab No active infection requiring systemic therapy No uncontrolled concurrent condition that would preclude the ability to take oral medication, including the following: Nausea Vomiting Diarrhea Lack of physical integrity of the upper gastrointestinal tract Malabsorption syndrome No clinically significant cardiac disease, including the following: Congestive heart failure Symptomatic coronary artery disease Cardiac arrhythmias not well controlled Myocardial infarction within the past 12 months No concurrent active malignancy Prior malignancies allowed provided the patient is currently disease-free Not pregnant or nursing Fertile patients must use effective contraception during and for 3 months after completion of study therapy PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior RankL inhibitor therapy No more than 1 prior cytotoxic chemotherapy for metastatic disease At least 3 weeks since prior chemotherapy and recovered At least 1 week since prior radiotherapy to non-CNS disease and recovered At least 3 weeks since prior and no concurrent intravenous bisphosphates (e.g., zoledronate) At least 7 days since prior and no concurrent antiplatelet agents, including any of the following*: Anticoagulants (e.g., tirofiban, eptifibatide, ticlopidine) Aspirin or aspirin-containing combinations Dipyridamole Epoprostenol Clopidogrel Cilostazol Abciximab NOTE: *Nonsteroidal anti-inflammatory drugs and medically indicated platelet-inhibiting medication allowed At least 7 days since prior and no concurrent CYP3A4 inhibitors, including any of the following: HIV protease inhibitors (e.g., amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir) Select antibiotics (e.g., ciprofloxacin, clarithromycin, doxycycline, enoxacin, isoniazid, telithromycin) Azole antifungals (e.g., itraconazole, ketoconazole, miconazole, voriconazole) Select anesthetics (e.g., ketamine, propofol) Hypericum perforatum (St. John's wort) Nefazodone Nicardipine Diclofenac Quinidine Imatinib mesylate At least 7 days since prior and no concurrent medications that prolong the QTc interval, including any of the following: Antiarrhythmic agents (e.g., quinidine, procainamide, disopyramide phosphate, amiodarone, sotalol hydrochloride, ibutilide, dofetilide) Antipsychotic agents (e.g., chlorpromazine, mesoridazine, thioridazine, pimozide, haloperidol, droperidol) Select antibiotics (e.g., erythromycin, clarithromycin, sparfloxacin, pentamidine) Narcotic analgesics (e.g., levomethadyl, methadone, domperidone) Calcium channel blockers (e.g., bepridil, lidoflazine) Antimalarial agents (e.g., halofantrine, chloroquine) Parasympathomimetic agents (e.g., cisapride) Arsenic trioxide No other concurrent antineoplastic therapy for breast cancer, including any of the following: Radiotherapy Chemotherapy Immunotherapy Biologic therapy Hormonal therapy Gene therapy No concurrent grapefruit juice consumption No concurrent short-acting antacid agents within 2 hours of dasatinib administration Concurrent trastuzumab (Herceptin®) therapy for HER-2 positive patients allowed provided patients have been on continuous trastuzumab for ≥ 12 weeks

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral dasatinib once daily. | Drug: dasatinib<br>* given orally<br>|
| Experimental: Arm II<br>Patients receive oral dasatinib twice daily. | Drug: dasatinib<br>* given orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | RECIST progression defined as 20% increase in the sum of longest diameters of target measurable lesions over the smallest sum observed, unequivocal progression of non-measurable disease, the appearance of any new lesion/site, death due to disease without prior documentation of progression and without symptomatic deterioration, development of one or more new bone lesions from baseline, or symptomatic deterioration related to disease progression. Time from date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause. Patients last known to be alive and progression-free are censored at last date of contact. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (Complete and Partial, Confirmed and Unconfirmed) | Complete Response (CR) is complete disappearance of all measurable and non-measurable disease. No new lesions, no disease related symptoms, normalization of markers and other abnormal lab values. Partial Response (PR) is greater than or equal to 30% decrease under baseline of the sum of longest diameters of all target measurable lesions. No unequivocal progression of non-measurable disease. No new lesions. Confirmation of CR or PR means a repeat scan at least 4 weeks apart documented before progression or symptomatic deterioration. Progression is 20% increase in sum of longest diameters of target measurable lesions over smallest sum observed, unequivocal progression of non-measurable disease, appearance of any new lesion/site, death due to disease without prior documentation of progression and without symptomatic deterioration. Symptomatic deterioration is global deterioration of health status requiring discontinuation of treatment without objective evidence of progression. | Up to 2 years | 
| MUC-1 Antigen Response | MUC-1 Complete Response is reduction in MUC-1 such that MUC-1 <= ULN. MUC-1 Partial Response is greater than or equal to a 50% reduction in MUC-1 from baseline, but not qualifying as a CR. MUC-1 Progression is greater than or equal to a 50% increase in MUC-1 from baseline. MUC-1 Stable Disease is MUC-1 response not qualifying as CR, PR, or Progression. | at 4, 8, 16, and 24 weeks | 
| Circulating Tumor Cells (CTC) Response Rate | CTC response at 4 weeks is defined as the number of patients with initially elevated CTCs (>= 5 cells/7.5 ml), whose CTC level drops to < 5. | Up to 4 weeks | 
| Change in Serum Bone Turnover Markers Over Time -- NTx | Analysis included mean values of the serum biomarker NTx at baseline, 4, and 8 weeks. | at baseline, 4, and 8 weeks | 
| Change in Serum Bone Turnover Markers Over Time -- BAP | Analysis included mean values of the serum biomarker BAP at baseline, 4, and 8 weeks. | at baseline, 4, and 8 weeks | 
| Change in Serum Bone Turnover Markers Over Time | Analysis included mean values of the serum biomarkers sRANKL, IL-6, DKK, VEGF at baseline, 4, and 8 weeks. | at baseline, 4, and 8 weeks | 
| Change in Serum Bone Turnover Markers Over Time -- OC | Analysis included mean values of the serum biomarker OC at baseline, 4, and 8 weeks. | at baseline, 4, and 8 weeks | 
| Change in Serum Bone Turnover Markers Over Time -- OPG | Analysis included mean values of the serum biomarker OPG at baseline, 4, and 8 weeks. | at baseline, 4, and 8 weeks | 
| Change in Serum Bone Turnover Markers Over Time -- TRAP | Analysis included mean values of the serum biomarker TRAP at baseline, 4, and 8 weeks. | at baseline, 4, and 8 weeks | 
| Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Only adverse events that are possibly, probably or definitely related to study drug are reported. | Up to 2 years | 
| Mean Patient-reported Pain | Patient's rating of worst pain experienced between prestudy and week 24. Changes of >=2 points on the Brief Pain Inventory (BPI) are of interest. Pain is self-reported on the Brief Pain Inventory Short Form, on a 0-10 response scale, with higher scores reflecting more pain and more interference with functioning. | Baseline, 8, 16, and 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IV breast cancer, male breast cancer, recurrent breast cancer, bone metastases