Breast Cancer
Conditions
Keywords
Dasatinib, Metastatic Breast Cancer, Sprycel, BMS-354825, Genetic testing, AZD6244, Selumetinib
Brief summary
The goal of this clinical research study is to learn if researchers can use genetic tests to predict who may benefit from treatment with SprycelTM (dasatinib) or selumetinib (AZD6244).
Detailed description
The Study Drug: Dasatinib blocks several different enzymes called protein kinases that are found in cancer cells. These enzymes are important to cancer cell growth. Blocking these kinases may stop or slow cancer growth. AZD6244 is designed to block the growth of cancer cells by interfering with specific targeted molecules needed for tumor growth, rather than by simply interfering with rapidly dividing cells (like in traditional chemotherapy). Study Drug Administration: If you are found to be eligible to take part in this study, you will take either dasatinib or AZD6244. The drug you take will be decided by your doctor based on the findings of the tumor biopsy. * If you take dasatinib, you will take 2 dasatinib tablets by mouth once every day. The dasatinib tablets will need to be swallowed whole and can be taken with or without a meal. * If you take AZD6244, you will take 3 tablets by mouth twice every day. The AZD6244 tablet will need to be taken with 8 ounces of water on an empty stomach (1 hour before or 2 hours after a meal) about 12 hours apart. If you have side effects, the study doctor may decrease your dose or you may stop receiving the study drug for up to 21 days. While you receive treatment with dasatinib or AZD6244, you may not receive other anti-cancer treatment such as chemotherapy or hormonal therapy. If you are receiving treatment with a bisphosphonate that is given by vein (such as Aredia or Zometa), you will not be able to receive the drug during the first 8 weeks of this study. This is done in order to avoid low calcium levels in the blood. You may be able to continue to receive the study drug after the first 8 weeks. Study Visits: Every 4 weeks while on study, you will have a complete physical exam. Blood (about 3-4 teaspoons) will be drawn for routine tests. * If you are taking dasatinib, at Week 4, you will have an ECG. * If you are taking AZD6244, at Week 8, and experience heart-related side effects suggestive of cardiac problems, you will have an ECHO or multiple gated acquisition scan (MUGA). Every 8 weeks, the scans (such as MRIs, CTs, and bone scans) and x-rays that were performed at screening will be repeated. If you experience visual disturbances while receiving AZD6244, you will have an eye exam. Length of Study: You may continue taking the study drug daily for as long as you are benefitting. You will be taken off study if the disease gets worse or intolerable side effects occur. End-of-Study Visit: If you are taken off study because of side effects, you will have CT scans or x-rays to check the status of the disease. This is an investigational study. Dasatinib is FDA approved to treat chronic myeloid leukemia. It is not yet FDA approved for the treatment of patients with breast cancer. At this time, the use of dasatinib in breast cancer patients is investigational. AZD6244 is not FDA approved or commercially available. Its use in this study is investigational. The tests that will be used to find out if you can receive treatment with dasatinib or AZD6244 are also investigational. Up to 769 patients will take part in this study. All will be enrolled at MD Anderson.
Interventions
DRUGDasatinib
100 mg tablet by mouth daily
DRUGAZD6244
75 mg by mouth twice daily.
Sponsors
Bristol-Myers Squibb
AstraZeneca
M.D. Anderson Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. (Turnstile One - Applies only to inclusion criteria 1 - 4): Histologically confirmed breast cancer and evidence of metastatic disease that can be biopsied with acceptable risk. Patients must agree to mandatory fine needle aspiration of the cancer for response marker determination. Patient must have a positive gene expression profile. Positive gene expression signature obtained separately on trial LAB11-0337 will also be acceptable for eligibility. 2. Patients must have measurable or evaluable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. 3. Subject, age \> 18 years (the safety and efficacy of dasatinib and the appropriate dose has not been established for children). 4. Signed written informed consent including a HIPAA form according to institutional guidelines. 5. (Turnstile Two Applies Only to Inclusion Criteria 5 -17) - Therapy with Dasatinib - Patient must have a positive gene expression profile. Positive gene expression obtained separately on trial LAB11-0337 will also be acceptable for eligibility. 6. Performance status Zubrod scale 0-2 (Appendix B) within 8 days of starting therapy. 7. Full physical examination and history including documentation of weight, height, and vital signs within 8 days of starting therapy. 8. Patients may have received any number of previous therapies for metastatic breast cancer. Patients must have received, had a contraindication to, or declined treatment with an anthracycline and taxane (and Herceptin if HER-2 positive) in either the adjuvant or metastatic setting. 9. Adequate organ function assessed within 14 days of study therapy, defined as: (a)Total bilirubin \</= 2.0 times the institutional Upper Limit of Normal (ULN); (b) Hepatic enzymes (AST, ALT ) \</= 2.5 times the institutional ULN; (c) Serum Na, K+, Mg2+, Phosphate and Ca2+ \>/= lower limit of normal (LLN); (d) Serum Creatinine \< 1.5 time the institutional ULN; and (e) Hemoglobin, Neutrophil count, Platelets, PT, PTT all Grade 0-1. 10. A baseline EKG within 14 days of starting therapy, with a QTc interval not \> 460 msec in women, or \> 450 in men. 11. Ability to take oral medication (dasatinib must be swallowed whole). 12. Patient must agree to discontinue St. Johns Wort while receiving dasatinib therapy if previously taken. 13. Patient must agree that IV bisphosphonate therapy will be withheld for the first 8 weeks of dasatinib therapy due to risk of hypocalcemia. (After the need for Ca2+ supplementation has been assessed and levels documented to be \>LLN, subjects on prior bisphosphonate may be restarted with caution at the investigator's discretion). 14. Females of childbearing potential must have a negative serum pregnancy test within 7 days of starting therapy. 15. Persons of reproductive potential must agree to use and utilize a barrier method of contraception throughout treatment and for at least 4 weeks after study drug is stopped. 16. Concurrent medications must be assessed, and patient must agree to discontinue all restricted medications within 7 days of starting therapy. 17. Stable brain metastasis for at least 3 months
Exclusion criteria
1. (Only turnstile II applies to
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit (CB) Rate (CB = Participants With Objective Tumor Response or Stable Disease > 6 Months) | Tumor status assessed every 8 weeks during therapy, up to 6 months | Rate of participants with response complete, partial response or stable disease categorized by Response Evaluation Criteria In Solid Tumors (RECIST) criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. Radiological response assessments must be repeated every 8 weeks during therapy. |
Countries
United States
Participant flow
Recruitment details
Recruitment Period: June 10, 2009 to July 25, 2012. All recruitment performed at The University of Texas MD Anderson Cancer Center.
Pre-assignment details
Of the 97 participants recruited, 67 were excluded from the trial before assignment to groups. No participants were assigned to MEK Pathway Activity Predictor Positive and MEK Pathway Predictor Negative Arms/Groups.
Participants by arm
| Arm | Count |
|---|---|
| Dasatinib Sensitivity Signature Participants predicted to respond to Dasatinib (Sprycel) by predictive gene signature receive dasatinib 100 mg by mouth daily. | 9 |
| SRC Pathway Activity Signature Participants predicted to respond to Dasatinib (Sprycel) by predictive gene signature receive dasatinib 100 mg by mouth daily. | 8 |
| Dasatinib Target Index Participants predicted to respond to Dasatinib (Sprycel) by predictive gene signature receive dasatinib 100 mg by mouth daily. | 13 |
| MEK Pathway Activity Predictor Positive Participants predicted to respond to selumetinib/AZD6244 by predictive gene signature (either MEK pathway activity predictor positive or MEK pathway predictor negative) receive selumetinib 75 mg by mouth twice daily (BID). | 0 |
| MEK Pathway Predictor Negative Participants predicted to respond to selumetinib/AZD6244 by predictive gene signature (MEK pathway predictor negative) receive selumetinib 75 mg by mouth twice daily (BID). | 0 |
| Total | 30 |
Baseline characteristics
| Characteristic | Dasatinib Sensitivity Signature | SRC Pathway Activity Signature | Dasatinib Target Index | Total |
|---|---|---|---|---|
| Age, Continuous | 46.5 years | 51.6 years | 54.3 years | 51 years |
| Region of Enrollment United States | 9 participants | 8 participants | 13 participants | 30 participants |
| Sex: Female, Male Female | 9 Participants | 8 Participants | 13 Participants | 30 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 27 / 30 |
| serious Total, serious adverse events | 3 / 30 |
Outcome results
Primary
Clinical Benefit (CB) Rate (CB = Participants With Objective Tumor Response or Stable Disease > 6 Months)
Rate of participants with response complete, partial response or stable disease categorized by Response Evaluation Criteria In Solid Tumors (RECIST) criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. Radiological response assessments must be repeated every 8 weeks during therapy.
Time frame: Tumor status assessed every 8 weeks during therapy, up to 6 months
Population: Selumetinib pathway predictor groups (both MEK pathway activity predictor positive and MEK pathway predictor negative) had no patients assigned to either group, and only treated participants (30) included in analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dasatinib Sensitivity Signature | Clinical Benefit (CB) Rate (CB = Participants With Objective Tumor Response or Stable Disease > 6 Months) | 0 Percentage of Participants |
| SRC Pathway Activity Signature | Clinical Benefit (CB) Rate (CB = Participants With Objective Tumor Response or Stable Disease > 6 Months) | 0 Percentage of Participants |
| Dasatinib Target Index | Clinical Benefit (CB) Rate (CB = Participants With Objective Tumor Response or Stable Disease > 6 Months) | 7.7 Percentage of Participants |