ANZCTR - Registration

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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

29/08/2019

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]

ISRCTN98335443

Universal Trial Number (UTN)

Trial acronym

m-BEP

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Metastatic breast cancer

Condition category

Condition code

Cancer

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]

Treatment: Drugs

Comparator / control treatment

No control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

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]

Within the first 4 weeks of treatment with the combination of ABT-199 and tamoxifen

Secondary outcome [1]

Toxicities of the combination of ABT-199 and tamoxifen measured using CTCAE v4.0

Timepoint [1]

Continuous throughout the study

Secondary outcome [2]

Response rate, defined as Complete Response (CR) or Partial Response (PR) as defined by RECIST v1.1

Timepoint [2]

Within the first 24 weeks of treatment

Secondary outcome [3]

Progression-free survival measured from the date of commencement of treatment until disease progression or death prior to progression from any cause

Timepoint [3]

Disease progression or death prior to progression from any cause

Secondary outcome [4]

Overall survival measured from the date of commencement of treatment until death from any cause

Timepoint [4]

Death from any cause

Secondary outcome [5]

Clinical benefit rate, defined as CR, PR or Stable Disease (SD) measured according to RECIST v1.1

Timepoint [5]

Within the first 24 weeks of treatment

Secondary outcome [6]

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]

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?

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

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Royal Melbourne Hospital - City campus - Parkville

Recruitment hospital [2]

Peter MacCallum Cancer Institute - East Melbourne

Recruitment hospital [3]

Austin Health - Austin Hospital - Heidelberg

Recruitment postcode(s) [1]

3084 - Heidelberg

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

AbbVie

Address [1]

Level 7, 241 O'Riordan Street
Mascot NSW 2020

Country [1]

Australia

Funding source category [2]

Government body

Name [2]

Victorian Cancer Agency

Address [2]

GPO Box 4057
Melb VIC 3001

Country [2]

Australia

Primary sponsor type

Hospital

Name

Melbourne Health

Address

300 Grattan Street
Parkville 3050
VIC

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Nil

Address [1]

Nil

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Melbourne Health

Ethics committee address [1]

300 Grattan Street
Parkville 3050

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

16/12/2014

Ethics approval number [1]

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

Prof Geoff Lindeman

Address

Department of Medical Oncology
Royal Melbourne Hospital
300 Grattan St
Parkville 3050
VIC

Country

Australia

Phone

+61393427151

Fax

[email protected]

Contact person for public queries

Name

Ms Kirsten Hogg

Address

Royal Melbourne Hospital
300 Grattan St
Parkville St
VIC

Country

Australia

Phone

+61393452805

Fax

[email protected],.au

Contact person for scientific queries

Name

Dr Sheau Wen Lok

Address

Department of Medical Oncology
Royal Melbourne Hospital
300 Grattan St
Parkville 3050
VIC

Country

Australia

Phone

+61393452805

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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

Type	Is Peer Reviewed?	DOI	Citations or Other Details	Attachment
Study results article	Yes		Lok SW, Whittle JR, Vaillant F, The CE, Lo LL, Pol... [More Details]

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	PALVEN: Phase Ib trial of palbociclib, letrozole and venetoclax in estrogen receptor-and BCL2-positive advanced breast cancer.	2022	https://dx.doi.org/10.2217/fon-2021-1450
Embase	Venetoclax treatment in patients with cancer has limited impact on circulating T and NK cells.	2023	https://dx.doi.org/10.1182/bloodadvances.2022008221
Dimensions AI	Key Survival Factor, Mcl-1, Correlates with Sensitivity to Combined Bcl-2/Bcl-xL Blockade	2017	https://doi.org/10.1158/1541-7786.mcr-16-0280-t
Dimensions AI	A phase 1b dose-escalation and expansion study of the BCL-2 inhibitor venetoclax combined with tamoxifen in ER and BCL-2-positive metastatic breast cancer	2019	https://doi.org/10.1158/2159-8290.cd-18-1151

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically