None listed
Conditions
Brief summary
This is a study exploring the safety and efficacy of the combination of ABT-199 and tamoxifen in patients with metastatic ER-positive breast cancer. Who is it for? You may be eligible to take part in this study if you are aged over 18 and have metastatic breast cancer that is oestrogen receptor positive. Study Details Participants are recruited into either the dose escalation phase or dose expansion phase of the study depending upon when they decide to enrol. Before the study starts, they are asked to sign a consent form. Each participant then goes through a series of tests to see whether the study is suitable for them. These tests include reviewing the participants medical and medication history, a physical examination, an electrocardiogram (ECG), CT and bone scans (to locate and measure tumours), taking urine and blood samples for testing and asking about how able they are to do their usual daily activities. If a participant's test results are satisfactory, they are enrolled into the study. They are asked to visit the study hospital once a week for the first 4 weeks, and then at least once a month after that. Both the study medications (ABT-199 and tamoxifen) are tablets to be taken once a day by mouth with breakfast and a glass of water. Participants are given their first dose of both study medications in the hospital clinic. Subsequently, both tablets are provided for the participants to take at home every day with clear instructions on how to take the tablets. During the visits to the hospital, each participant has blood tests, CT scans and bone scans (if applicable) to determine if they are responding to treatment and to ensure that they are not having major side-effects as a result of the treatment. They are also asked if they are happy to have tissue biopsies of their cancer about a month after treatment. This is optional but strongly encouraged as it provides valuable information about how the drug affects the cancer. Each participant continues to take the study tablets as long as they are able to tolerate them, and if their cancer continues to respond. Each participant is monitored for side-effects after they have completed the study. Participants can, of course, choose to withdraw their participation from the study at any time.
Interventions
ABT-199 will be taken from a starting dose of 200mg once daily in oral tablet form for patients in Dose Escalation Stage (final dose for Dose Expansion Stage to be determined).
This will continue until the patient develops disease progression. In order to monitor compliance, a patient medication diary will be used and all unused tablets will be returned.
Tamoxifen will be taken at a dose of 20mg once a day in oral tablet form and will also continue until the patient develops disease progression
ABT-199 will be taken from a starting dose of 200mg once daily in oral tablet form for patients in Dose Escalation Stage (final dose for Dose Expansion Stage to be determined). This will continue until the patient develops disease progression. In order to monitor compliance, a patient medication diary will be used and all unused tablets will be returned. Tamoxifen will be taken at a dose of 20mg once a day in oral tablet form and will also continue until the patient develops disease progression.In order to monitor compliance, a patient medication diary will be used and all unused tablets will be returned.
Sponsors
Melbourne Health
Study design
Allocation
Non-randomised trial
Primary purpose
Treatment
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Subjects greater than or equal to 18 years of age 2. Signed informed consent 3. Histological or cytological confirmation* of metastatic carcinoma of the breast with the following tumor molecular characteristics: a) ER positive (>1% positive stained carcinoma cells) b) Bcl-2 positive (defined as >10% cells with at least moderate cytoplasmic staining; intensity 2-3 on 0-3 scale) c) HER2 non-amplified *Biopsy of a metastatic site is strongly encouraged in the Dose Expansion Stage and will be essential in at least 10 patients with visceral metastases. 4. A tumor paraffin tissue block or at least 15 unstained slides from the tumor tissue block from either the primary tumor or a metastatic site (in addition to the initial 6 slides sent for Pre-Screening) must be available for biomarker analyses. * In the event that this is not available, permission to be enrolled on the study must be obtained from the Principal Investigator 5. For the dose expansion phase, subject must not have received more than 3 lines in total of chemotherapy and/or endocrine therapy in the metastatic setting. 6. Subjects must not have received tamoxifen within the last 3 months. 7. Subject must have evaluable or measurable disease (bone-only metastases are allowed). *For the Dose Expansion Stage, only bony lesions clearly measurable on CT or MRI will be allowed if bone is the only site of disease 8. Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to 1 9. Subjects of childbearing potential (ie. Not postmenopausal for at least 2 years or surgically sterile) must have negative results for pregnancy test performed at screening with a serum sample obtained within 14 days prior to the first study drug administration. 10. Subject must have adequate organ and marrow function as defined below: a) Hemoglobin >9 g/dL b) Absolute neutrophil count > 1.5 x 109/L c) Platelet count > 100 x 109/L d) ALT and AST less than or equal to 2.5 x upper limit of normal (ULN), or less than or equal to 5 x ULN if liver metastases are present e) Total serum bilirubin less than or equal to 1.5 x ULN. Subjects with Gilbert’s syndrome may have a bilirubin >1.5 x ULN, per discussion with the investigator. f) Serum creatinine less than or equal to 1.5 xULN 11. Life expectancy > 6 months 12. Subjects must be suitable for oral drug administration
Exclusion criteria
1. Subjects who have previously been exposed to ABT-199 2. Absolute contraindication to tamoxifen use (e.g. life-threatening thromboembolic complications) 3. Subjects who are pregnant or lactating 4. Subjects with uncontrolled CNS metastases. Subjects who have had previous treatment of brain metastases with surgery or radiotherapy may be eligible if: a) Treatment was administered > 4 weeks prior to study entry; b) Subject is asymptomatic from CNS metastases; and c) If subject is on steroid medication for the purpose of controlling CNS metastases, this must be stable (i.e. no change in dose for at least 2 weeks from the date of first dose of ABT-199). 5. Any anti-cancer therapy received within 21 days of the first dose of study drug including chemotherapy, radiotherapy or other investigational therapy. Exceptions: a) Bisphosphonate therapy or denosumab is allowed for subjects with bone metastases. b) Radiotherapy with palliative intent to non-target sites is allowed. 6. Subjects who are taking warfarin. The use of alternative anticoagulation therapy such as systemic low-molecular weight heparin should be discussed with the investigator. 7. Subjects who have had major surgery within 21 days of the first dose of study drug. 8. Subject has received the following agents within 7 days prior to the first dose of study drug: a) Steroid therapy for anti-neoplastic intent; b) CYP3A inhibitors such as fluconazole, ketoconazole, and clarithromycin; c) Potent CYP3A inducers such as rifampicin, carbamazepine, phenytoin and St. John’s Wort. 9. Subjects with active uncontrolled infection. 10. Known history of human immunodeficiency virus (HIV) infection, chronic Hepatitis B or C. 11. History of other malignancies within the past 5 years except for treated skin basal cell carcinoma (BCC), squamous cell carcinoma (SCC), malignant melanoma less than or equal to 1.0 mm without ulceration, localised thyroid cancer, or cervical carcinoma in situ. Other malignancies considered to be at low risk of recurrence may also be included according to the discretion of the Chief Investigator. 12. Other history of medical or psychiatric condition that may interfere with the subject’s participation in the study. 13. Subjects with childbearing potential who refuse to use at least one of the following methods of contraception during and for a period of 30 days after study drug discontinuation: a) Total abstinence from sexual intercourse as the preferred lifestyle of the subject; periodic abstinence is not acceptable; b) Surgically sterile partner(s) e.g. vasectomy c) Intrauterine device (IUD) or Mirena d) Double-barrier method (contraceptive sponge, diaphragm or cervical cap with spermicidal jellies or cream AND a condom) 14. Subjects on contraception that is estrogen or progestin based (Mirena accepted) 15. Subjects who are on Hormone Replacement Therapy
Outcome results
None listed