A Phase I-II, Randomization, Open-Label Clinical Trial of Fulvestrant Versus the Combination of Fulvestrant, MK-0646, and Dasatinib as First-Line Therapy for Metastatic Hormone Receptor-Positive HER2-Negative Breast Cancer
Trial Snapshot
- Phase
- Phase 1
- Status
- Terminated
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 11
- Locations
- 1
- Primary Endpoint
- Phase I Maximum Tolerated Dose (MTD) for Dose Level 1
Study Overview
Brief Summary
The goals of this clinical research study are to learn the tolerable and effective doses of the drug MK-0646 that can be given in combination with Sprycel (dasatinib) and Faslodex (fulvestrant) to patients with hormone receptor-positive metastatic breast cancer. The safety of these drugs will be studied as well as markers in the tumors that may help researchers predict the tumors' reaction to the treatment.
Detailed Description
The Study Drugs:
Fulvestrant is designed to block estrogen from helping breast cancer tumor cells grow. By blocking estrogen, it may stop tumor growth.
Dasatinib is designed to change the function of genes. By changing the function of these genes, it may prevent cancer from growing and spreading.
MK-0646 is designed to block proteins that help breast cancer cells grow. By blocking these proteins, it may cause the cancer cells to die.
Study Procedures:
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- Female
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •For the Phase I: Patients with histologically or cytologically confirmed diagnosis of metastatic hormone receptor-positive HER2-negative breast cancer who have received up to one line of endocrine therapy for metastatic disease.
- •Measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST) or evaluable disease (e.g., bone metastasis, or lesions which do not fulfill RECIST criteria for metastatic disease)
- •Age >/= 18 years
- •Eastern Cooperative Oncology Group (ECOG) performance status of </= 2
- •Required laboratory values: Absolute neutrophil count (ANC)>/= 1500 cells/mm^3, platelet count >/= 100,000 cells/mm^3, hemoglobin >/= 9 gm/L; bilirubin </= 1.5 * upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) </= 2.5 * ULN; serum creatinine </= 2.0 * ULN
- •Ability to understand the requirements of the study, provided written informed consent and authorization of use and disclosure of protected health information, and agree to abide by the study restrictions and to return for the required assessments.
- •Patients must be postmenopausal (> 12 months of amenorrhea, bilateral oophorectomy).
- •Patients must have received prior anti-estrogen therapy in the adjuvant setting.
- •Patients may have easily accessible tumors for biopsy (confirmed by interventional radiology).
- •Patients must consent to biopsies.
- •For the Phase II: Patients with histologically or cytologically confirmed diagnosis of metastatic hormone receptor-positive, HER2-negative, breast cancer who have received up to one line of endocrine therapy for metastatic disease.
- •Measurable disease by RECIST or evaluable disease (e.g., bone metastasis, or lesions which do not fulfill RECIST criteria for metastatic disease)
- •Age >/= 18 years
- •ECOG performance status of </= 2
- •Required Laboratory Values: ANC >/= 1500 cells/mm^3, platelet count >/= 100,000 cells/mm^3, hemoglobin >/= 9 gm/L, Bilirubin </= 1.5 * ULN, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) </= 2.5 * ULN
- •Serum creatinine </= 2.0 * ULN
- •Ability to understand the requirements of the study, provide written informed consent and authorization of use and disclosure of protected health information, and agree to abide by the study restrictions and to return for the required assessments.
- •Patients must be postmenopausal (> 12 months of amenorrhea, bilateral oophorectomy).
- •Patients must have received prior anti-estrogen therapy in the adjuvant setting.
- •Patients may have easily accessible tumors for biopsy (confirmed by interventional radiology).
- •Patients must consent to biopsies.
Exclusion Criteria
- •For the Phase I: History of prior malignancies within the past 5 years with the exception of curatively treated basal or squamous cell carcinomas of the skin or carcinoma in situ of the cervix
- •Concurrent severe or uncontrolled medical disease (i.e., systemic infection, diabetes, hypertension, coronary artery disease, congestive heart failure, ongoing or recent gastrointestinal bleed, hepatic or cardiac compromise, hypocalcemia, or known platelet function abnormality).
- •Concomitant medication known to prolong QT interval, unless discontinued >/= 7 days of starting dasatinib therapy.
- •Newly diagnosed (within 3 months before enrollment) or poorly controlled (defined as a fasting serum glucose > 160 mg/dl or hemoglobin A1c > 8% at screening), type 1 or 2 diabetes mellitus.
- •Active or untreated brain metastasis
- •Pleural or pericardial effusion of any grade
- •Bone only metastases
- •Patients for whom endocrine therapy is not appropriate (i.e. life threatening metastatic disease).
- •Patients requiring therapeutic anticoagulation (Warfarin 1 mg for port maintenance is allowed).
- •For the Phase II: History of prior malignancies within the past 5 years with the exception of curatively treated basal or squamous cell carcinomas of the skin or carcinoma in situ of the cervix
- •Concurrent severe or uncontrolled medical disease (i.e., systemic infection, diabetes, hypertension, coronary artery disease, congestive heart failure, ongoing or recent gastrointestinal bleed, hepatic or cardiac compromise, hypocalcemia, or known platelet function abnormality).
- •Concomitant medication known to prolong QT interval, unless discontinued >/= 7 days of starting dasatinib therapy.
- •Newly diagnosed (within 3 months before enrollment) or poorly controlled (defined as a fasting serum glucose > 160 mg/dl or hemoglobin A1c > 8% at screening), type 1 or 2 diabetes mellitus.
- •Active or untreated brain metastasis
- •Pleural or pericardial effusion of any grade
- •Bone only metastases
- •Patients for whom endocrine therapy is not appropriate (i.e. life threatening metastatic disease).
- •Patients requiring therapeutic anticoagulation (Warfarin 1 mg for port maintenance is allowed).
Arms & Interventions
Group 1: Fulvestrant
Group 1 will receive Fulvestrant only.
Intervention: Fulvestrant (Drug)
Group 2: Fulvestrant + Dasatinib
Group 2 will receive Fulvestrant and Dasatinib.
Intervention: Fulvestrant (Drug)
Group 2: Fulvestrant + Dasatinib
Group 2 will receive Fulvestrant and Dasatinib.
Intervention: Dasatinib (Drug)
Group 3: Fulvestrant + MK-0646
Group 3 will receive Fulvestrant and MK-0646.
Intervention: Fulvestrant (Drug)
Group 3: Fulvestrant + MK-0646
Group 3 will receive Fulvestrant and MK-0646.
Intervention: MK-0646 (Drug)
Group 4: Fulvestrant, MK-0646 + Dasatinib
Group 4 will receive Fulvestrant, MK-0646, and Dasatinib.
Intervention: Fulvestrant (Drug)
Group 4: Fulvestrant, MK-0646 + Dasatinib
Group 4 will receive Fulvestrant, MK-0646, and Dasatinib.
Intervention: MK-0646 (Drug)
Group 4: Fulvestrant, MK-0646 + Dasatinib
Group 4 will receive Fulvestrant, MK-0646, and Dasatinib.
Intervention: Dasatinib (Drug)
Outcomes
Primary Outcomes
Phase I Maximum Tolerated Dose (MTD) for Dose Level 1
Time Frame: 28 day cycle
Maximum Tolerated Dose (MTD) defined as the dose or dose-combination that has the mean posterior toxicity rate closest to the target toxicity rate of 0.33. Dose levels reviewed with each 28 day cycle. Treatment dose levels: Fulvestrant will be given using a loading dose of 500 mg intramuscularly (IM) on day 1 as two 250 mg/5 ml injections, followed by 500 mg IM on day 15 and on day 1 of each subsequent 28- day (+/- 2 days) cycle. MK-0646 will be given intravenously on days 1,8, 15, and 22 for each cycle at one of the two dose levels: 1) 5 mg/kg or 2) 10 mg/kg (Dose level 1) Dasatinib will be given orally (PO) continuously on days 1 -28 for each cycle at one of two dose levels: 1) 70 mg po daily or 2) 100 mg po daily
Patient Response (+ Time to Disease Progression)
Time Frame: Baseline, after two 28 day cycles, until disease progression.
Secondary Outcomes
No secondary outcomes reported