Metastatic breast cancer Cancer
Conditions
Interventions
The study will be conducted in 2 consecutive stages:
1. Dose Escalation Stage with a total of 5 dose cohorts of the interventional drug. Subjects will be treated in a standard 3+3 dose
Sponsors
Melbourne Health
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Subjects >18 years of age 2. Signed informed consent 3. Histological or cytological confirmation of metastatic carcinoma of the breast with the following tumour molecular characteristics: 3.1. ER positive (>1% positive stained carcinoma cells) 3.2. Bcl-2 positive (defined as >10% cells with at least moderate cytoplasmic staining; intensity 2-3 on 0-3 scale) 3.3. HER2 non-amplified 4. Subjects must nor have received tamoxifen within the last 3 months. 5. Subject must have evaluable or measurable disease (bone-only metastases are allowed). 6. Eastern Cooperative Oncology Group (ECOG) performance score of 1 or above. 7. Subjects of childbearing potential must have a negative serum pregnancy test. 8. Subject must have adequate organ and marrow function. 9. Life expectancy >6 months 10. Subjects must be suitable for oral drug administration.
Exclusion criteria
Exclusion criteria: 1. Subjects who have previously been exposed to ABT-199 2. Absolute contraindication to tamoxifen use 3. Subjects who are pregnant or lactating 4. Subjects with uncontrolled CNS metastases 5. Any anti-cancer therapy received within 21 days of study treatment including chemotherapy, radiotherapy or other investigational therapy 6. Subjects who are taking warfarin 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: 8.1. Steroid therapy for anti-neoplastic intent 8.2. CYP3A inhibitors such as fluconazole, ketoconazole, and clarithromycin 8.3. Potent CYP3A inducers such as rifampicin, carbamazepine, phenytoin and St John's Wort 9. Subjects with active uncontrolled infection 10. Known history of HIV infection, Hepatitis B or C 11. History of other malignancies within the past 5 years except for treated BCC, SCC, malignant melanoma <1mm, localised thyroid cancer or cervical carcinoma in situ 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 effective contraception during and for up to 30 days after study drug discontinuation 14. Subjects on contraception that is oestrogen or progestin based (Mirena accepted). 15. Subjects who are on hormone replacement therapy
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 1. Maximum tolerated dose (MTD) 2. Dose-limiting toxicities (DLTs) Both reported within the first 4 weeks of treatment with the combination of ABT-199 and tamoxifen. This will be measured by assessing side-effects experienced by subjects during the first 4 weeks of treatment. | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Toxicities measured using CTCAE v4.0 - ongoing throughout study treatment 2. Response as defined by RECIST v1.1 within the first 24 weeks of treatment 3. Progression-free survival (PFS) measured from the date of commencement of treatment with the combination of ABT-199 and tamoxifen until disease progression or death prior to progression from any cause 4. Overall survival measured from the date of commencement of treatment with the combination of ABT-199 and tamoxifen until death from any cause. 5. Clinical benefit rate as defined by: 5.1. Achievement of a complete or partial response during the first 24 weeks of treatment with the combination of ABT-199 and tamoxifen; or 5.2. Maintenance of stable disease until 24 weeks after commencement of treatment according to RECIST v1.1 guidelines 6. Biological response assessed using: 6.1. Change in Ki67 expression assessed by immunohistochemistry after 4 weeks of treatment at the MTD . This will be assessed using the MIB-1 antibody, with the percentage of positively immunostained nuclei in relation to quiescent non-proliferating cells calculated (known as the Ki67 index) 6.2. Change in activated caspase-3 (or TUNEL) expression after 4 weeks of combination treatment with ABT-199 and tamoxifen at the MTD | — |
Countries
Australia
Contacts
Public ContactKylie Shackleton
Outcome results
None listed