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Trial registered on ANZCTR


Registration number
ACTRN12615000702516
Ethics application status
Approved
Date submitted
18/06/2015
Date registered
7/07/2015
Date last updated
10/12/2020
Date data sharing statement initially provided
29/08/2019
Date results information initially provided
10/12/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
An early phase study of ABT-199 in combination with tamoxifen in metastatic oestrogen receptor positive breast cancer
Scientific title
A Phase 1b Study of Bcl-2 inhibition with ABT-199 in combination with Tamoxifen in Metastatic ER-Positive Breast Cancer
Secondary ID [1] 286935 0
ISRCTN98335443
Universal Trial Number (UTN)
Trial acronym
m-BEP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic breast cancer 295361 0
Condition category
Condition code
Cancer 295628 295628 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 292129 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 295345 0
Maximum tolerated dose (MTD) - defined as the highest dose level at which the incidence of dose-limiting toxicity is less than 33% for a minimum of 6 patients
Timepoint [1] 295345 0
Within the first 4 weeks of treatment with the combination of ABT-199 and tamoxifen
Secondary outcome [1] 315395 0
Toxicities of the combination of ABT-199 and tamoxifen measured using CTCAE v4.0
Timepoint [1] 315395 0
Continuous throughout the study
Secondary outcome [2] 315504 0
Response rate, defined as Complete Response (CR) or Partial Response (PR) as defined by RECIST v1.1
Timepoint [2] 315504 0
Within the first 24 weeks of treatment
Secondary outcome [3] 315505 0
Progression-free survival measured from the date of commencement of treatment until disease progression or death prior to progression from any cause
Timepoint [3] 315505 0
Disease progression or death prior to progression from any cause
Secondary outcome [4] 315506 0
Overall survival measured from the date of commencement of treatment until death from any cause
Timepoint [4] 315506 0
Death from any cause
Secondary outcome [5] 315507 0
Clinical benefit rate, defined as CR, PR or Stable Disease (SD) measured according to RECIST v1.1
Timepoint [5] 315507 0
Within the first 24 weeks of treatment
Secondary outcome [6] 315508 0
Biological response of the combination of ABT-199 and tamoxifen in metastatic breast cancer using:
i. A change in Ki67 assay assessed using the MIB-1 antibody, with the percentage of positively immunostained nuclei in relation to quiescent non-proliferating cells calculated
ii. A change in activated caspase-3 (or TUNEL) expression
Timepoint [6] 315508 0
After 4 weeks of treatment

Eligibility
Key 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
28/07/2015
Actual
4/08/2015
Date of last participant enrolment
Anticipated
31/08/2018
Actual
4/09/2018
Date of last data collection
Anticipated
6/09/2021
Actual
30/06/2020
Sample size
Target
44
Accrual to date
Final
45
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 3945 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [2] 3946 0
Peter MacCallum Cancer Institute - East Melbourne
Recruitment hospital [3] 11680 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 23726 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 291499 0
Commercial sector/Industry
Name [1] 291499 0
AbbVie
Country [1] 291499 0
Australia
Funding source category [2] 291500 0
Government body
Name [2] 291500 0
Victorian Cancer Agency
Country [2] 291500 0
Australia
Primary sponsor type
Hospital
Name
Melbourne Health
Address
300 Grattan Street
Parkville 3050
VIC
Country
Australia
Secondary sponsor category [1] 290178 0
None
Name [1] 290178 0
Nil
Address [1] 290178 0
Nil
Country [1] 290178 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293039 0
Melbourne Health
Ethics committee address [1] 293039 0
300 Grattan Street
Parkville 3050
Ethics committee country [1] 293039 0
Australia
Date submitted for ethics approval [1] 293039 0
Approval date [1] 293039 0
16/12/2014
Ethics approval number [1] 293039 0
2014.226

Summary
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.
Trial website
https://www.transbcr.org.au/m-bep
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 58186 0
Prof Geoff Lindeman
Address 58186 0
Department of Medical Oncology
Royal Melbourne Hospital
300 Grattan St
Parkville 3050
VIC
Country 58186 0
Australia
Phone 58186 0
+61393427151
Fax 58186 0
Email 58186 0
[email protected]
Contact person for public queries
Name 58187 0
Kirsten Hogg
Address 58187 0
Royal Melbourne Hospital
300 Grattan St
Parkville St
VIC
Country 58187 0
Australia
Phone 58187 0
+61393452805
Fax 58187 0
Email 58187 0
[email protected],.au
Contact person for scientific queries
Name 58188 0
Sheau Wen Lok
Address 58188 0
Department of Medical Oncology
Royal Melbourne Hospital
300 Grattan St
Parkville 3050
VIC
Country 58188 0
Australia
Phone 58188 0
+61393452805
Fax 58188 0
Email 58188 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
The small sample size of this Phase1b study cannot ensure that collected participant data remain non-identifiable.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Study results articleYes Lok SW, Whittle JR, Vaillant F, The CE, Lo LL, Pol... [More Details]

Documents added automatically
SourceTitleYear of PublicationDOI
Dimensions AIKey Survival Factor, Mcl-1, Correlates with Sensitivity to Combined Bcl-2/Bcl-xL Blockade2017https://doi.org/10.1158/1541-7786.mcr-16-0280-t
Dimensions AIA phase 1b dose-escalation and expansion study of the BCL-2 inhibitor venetoclax combined with tamoxifen in ER and BCL-2-positive metastatic breast cancer2019https://doi.org/10.1158/2159-8290.cd-18-1151
EmbasePALVEN: Phase Ib trial of palbociclib, letrozole and venetoclax in estrogen receptor-and BCL2-positive advanced breast cancer.2022https://dx.doi.org/10.2217/fon-2021-1450
EmbaseVenetoclax treatment in patients with cancer has limited impact on circulating T and NK cells.2023https://dx.doi.org/10.1182/bloodadvances.2022008221
N.B. These documents automatically identified may not have been verified by the study sponsor.