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

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

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.

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.

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