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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT04298918




Registration number
NCT04298918
Ethics application status
Date submitted
5/03/2020
Date registered
6/03/2020
Date last updated
8/11/2021

Titles & IDs
Public title
A Study Evaluating the Safety and Efficacy of Venetoclax in Combination With Trastuzumab Emtansine in Patients With Previously Treated HER2-Positive Locally Advanced or Metastatic Breast Cancer
Scientific title
A Phase lb/ll, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of Venetoclax in Combination With Trastuzumab Emtansine in Patients With Previously Treated HER2-Positive Locally Advanced or Metastatic Breast Cancer
Secondary ID [1] 0 0
2019-004200-35
Secondary ID [2] 0 0
CO41863
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Placebo
Treatment: Drugs - Venetoclax
Treatment: Drugs - Trastuzumab emtansine

Experimental: Dose Escalation Phase - Participants received venetoclax in combination with a fixed dose of trastuzumab emtansine.

Experimental: Dose Expansion Phase - Participants were to receive venetoclax at the Phase II Recommended Dose (RP2D) in combination with trastuzumab emtansine.

Experimental: Randomized Phase II Arm 1 - Participants were to receive trastuzumab emtansine + placebo.

Experimental: Randomized Phase II Arm 2 - Participants were to receive trastuzumab emtansine + venetoclax.


Treatment: Drugs: Placebo
Participants will receive oral placebo in combination with trastuzumab emtansine.

Treatment: Drugs: Venetoclax
Participants will receive oral venetoclax.

Treatment: Drugs: Trastuzumab emtansine
Participants will receive intravenous (IV) trastuzumab emtansine.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Dose Escalation: Number of Participants With Adverse Events
Timepoint [1] 0 0
Baseline up until 28 days after the last dose of study drug or until initiation of new systemic anti-cancer therapy, whichever occurs first (up to a maximum of 20 weeks).
Primary outcome [2] 0 0
Expansion Phase: Objective Response Rate (ORR)
Timepoint [2] 0 0
Up to 30 months
Primary outcome [3] 0 0
Phase II: ORR
Timepoint [3] 0 0
Up to 30 months
Primary outcome [4] 0 0
Phase II: Progression-Free Survival (PFS)
Timepoint [4] 0 0
Up to 30 months
Secondary outcome [1] 0 0
All Phases: Plasma Concentration of Venetoclax
Timepoint [1] 0 0
At pre-defined time points from Cycle 1 Day 8 and/or Cycle 2 Day 1 through Cycle 4 Day 1 (cycle = 21 days)
Secondary outcome [2] 0 0
Phase II: Serum Concentration of Trastuzumab Emtansine
Timepoint [2] 0 0
At pre-defined time points from Cycle 1 Day 1 through Cycle 4 Day 1 (cycle = 21 days)
Secondary outcome [3] 0 0
Expansion Phase and Phase II: Number of Participants With Adverse Events
Timepoint [3] 0 0
Baseline up until 28 days after the last dose of study drug or until initiation of new systemic anti-cancer therapy, whichever occurs first (up to a maximum of 20 weeks).
Secondary outcome [4] 0 0
Expansion Phase and Phase II: Duration of Response (DOR)
Timepoint [4] 0 0
Up to 30 months
Secondary outcome [5] 0 0
Phase II: Overall Survival (OS)
Timepoint [5] 0 0
Randomization to death from any cause (up to 30 months)
Secondary outcome [6] 0 0
Phase II: Number of Participants With Anti-Drug Antibodies (ADAs) to Trastuzumab Emtansine
Timepoint [6] 0 0
Up to 30 months

Eligibility
Key inclusion criteria
Inclusion Criteria

- Histologically or cytologically confirmed invasive metastatic breast cancer (MBC) or
locally advanced breast cancer (LABC) that is incurable, unresectable, and previously
treated with multimodality therapy

- Measurable disease that is evaluable per Response Evaluation Criteria in Solid Tumors
(RECIST) v1.1

- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

- Willing to provide tumor biopsy sample at the time of screening

- Local histological or cytological confirmation of estrogen receptor (ER) and/or
progesterone receptor status as defined by using immunohistochemistry (IHC) per
American Society of Clinical Oncology/College of American Pathologists criteria

- Percentage of ER and/or progesterone receptor positivity, if available

- Willing to provide blood samples at the time of screening, on-study, and at
progression for exploratory research on biomarkers

- HER2-positive BC as defined by an IHC score of 3+ or gene amplified by in situ
hybridization (ISH) as defined by a ratio of >/= 2.0 for the number of HER2 gene
copies to the number of chromosome 17 copies

- Adequate hematologic and end-organ function

- Screening left ventricular ejection fraction (LVEF) >/= 50% on echocardiogram (ECHO)
or multiple-gated acquisition (MUGA) scan

- Negative HIV test, hepatitis B surface antigen (HBsAg), total hepatitis B core
antibody (HBcAb) test at screening, or positive total HBcAb test followed by a
negative hepatitis B virus (HBV) DNA test at screening

- Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody
test followed by a negative HCV RNA test at screening

- For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive methods that result in a failure rate
of < 1% per year during the treatment period and for at least 30 days after the last
dose of venetoclax or 7 months after the last dose of trastuzumab emtansine

- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
contraceptive methods, and agreement to refrain from donating sperm during the
treatment period and for at least 30 days after the last dose of venetoclax or 7
months after the last dose of trastuzumab emtansine

Inclusion Criteria for Expansion Phase Only

In addition to the general inclusion criteria, participants in the expansion phase must
also meet the following criteria for study entry:

- Trastuzumab emtansine experienced cohort: Disease progression during or after
trastuzumab emtasine in the advanced/metastatic setting or disease recurrence in the
neoadjuvant/adjuvant setting; At least 50% of participants in the expansion cohort
must have a tumor that is Bcl-2 high (defined as >50% of tumor cells stained with an
intensity of immunohistochemistry (IHC) 2+ or 3+)

- Trastuzumab deruxtacan (DS-8201a) experienced cohort: Disease progression during or
after trastuzumab deruxtecan in the advanced/metastatic setting; Prior trastuzumab
emtansine in any setting is allowed; At least 50% of participants in the expansion
cohort must have a tumor that is Bcl-2 high
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria

- Receipt of any anticancer drug/biologic or investigational treatment 21 days prior to
Cycle 1, Day 1 except hormone therapy, which can be given up to 7 days prior to Cycle
1, Day 1

- Radiation therapy within 2 weeks prior to Cycle 1, Day 1

- History of exposure to the following cumulative doses of anthracyclines as specified:
Doxorubicin >500 mg/m2; Liposomal doxorubicin >500 mg/m2; Epirubucin >720 mg/m2;
Mitoxantrone >120 mg/m2; Idarubicin >90 mg/m2. If another anthracycline or more than
one anthracycline has been used, then the cumulative dose must not exceed the
equivalent of 500 mg/m2 doxorubicin.

- History of other malignancy within the previous 5 years

- Cardiopulmonary dysfunction

- Current severe, uncontrolled systemic disease

- Major surgical procedure or significant traumatic injury within 28 days prior to
randomization or anticipation of the need for major surgery during the course of study
treatment

- Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection
(excluding fungal infections of nail beds) at study enrollment, or any major episode
of infection requiring treatment with IV antibiotics or hospitalization (relating to
the completion of the course of antibiotics) within 4 weeks prior to Cycle 1, Day 1

- Clinically significant history of liver disease, including cirrhosis, current alcohol
abuse, autoimmune hepatic disorders, sclerosis cholangitis, or active infection with
HBV or HCV)

- Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia

- Known HIV infection or human T-cell leukemia virus 1 infection

- Spinal cord compression not definitively treated with surgery and/or radiation, or
previously diagnosed and treated spinal cord compression without evidence that disease
has been clinically stable for > 2 weeks prior to randomization

- Known central nervous system (CNS) disease

- Leptomeningeal disease

- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures

- Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of
bisphosphonate therapy

- Current Grade >/= 3 peripheral neuropathy

- History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies, excipients of any drugs formulated in polysorbate 80
or 20 or fusion proteins

- Prior allogeneic stem cell or solid organ transplantation

- Pregnant or breastfeeding, or intending to become pregnant during the study or within
30 days after the last dose of venetoclax or 7 months after the last dose of
trastuzumab emtansine after the final dose of study treatment, whichever is later

- Consumption of grapefruit, grapefruit products, Seville oranges, or starfruit within 3
days before anticipated first dose of study drug until the last dose of study drug

- Administration of a live, attenuated vaccine within 4 weeks prior to initiation of
study treatment or anticipation of need for such a vaccine during the study

- Illicit drug or alcohol abuse within 12 months prior to screening, in the
investigator's judgment

- Malabsorption syndrome or other condition that would interfere with enteral absorption

- History of active inflammatory bowel disease (e.g., Crohn's disease or ulcerative
colitis) requiring specific medication in the 12 months prior to randomization, or
active and uncontrolled bowel inflammation (e.g., diverticulitis) at time of
randomization

- Inability or unwillingness to swallow a large number of tablets

- Known hypersensitivity to venetoclax or trastuzumab emtansine or to any of their
excipients

- Any serious medical condition or abnormality in clinical laboratory tests that, in the
investigator's judgment, precludes the patient's safe participation in and completion
of the study

- Other medical or psychiatric conditions that, in the opinion of the investigator, may
interfere with the patient's participation in the study

- Blood transfusions if performed within 2 weeks prior to screening

Exclusion Criteria for Randomized Phase II Stage

In addition to the general exclusion criteria, participants in the randomized Phase II
stage who meet the following criteria will be excluded:

- Prior treatment with trastuzumab emtansine in any setting (neoadjuvant/adjuvant or
advanced/metastatic setting)

- Prior treatment with venetoclax in any setting

- Prior treatment with anti-HER2 antibody drug conjugates (e.g. trastuzumab deruxtecan
[DS-8201a]), margetuximab, pyrotinib, or tucatinib)

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled 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
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1/Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Terminated
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
23/09/2020
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
4/02/2021
Sample size
Target
Accrual to date
Final
1
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
Peter MacCallum Cancer Center - East Melbourne
Recruitment postcode(s) [1] 0 0
3002 - East Melbourne
Recruitment outside Australia
Country [1] 0 0
Korea, Republic of
State/province [1] 0 0
Seoul

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Hoffmann-La Roche
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This two-part study is composed of two stages: a Phase Ib stage consisting of a
dose-escalation phase and an expansion phase; and a Phase II, randomized, placebo-controlled,
double-blind, multicenter stage. The Phase Ib stage will assess the safety and tolerability,
determine the maximum tolerated dose (MTD) and the recommended Phase II dose (RP2D), and
evaluate the preliminary efficacy of trastuzumab emtansine in combination with venetoclax in
participants with previously treated human epidermal growth factor receptor 2 (HER2) positive
unresectable locally advanced breast cancer (LABC) or metastatic breast cancer (MBC).
Additional patients may be enrolled in an expansion phase to evaluate the safety,
tolerability, and efficacy of trastuzumab emtansine in combination with venetoclax at RP2D in
patients with previously treated HER2-positive LABC or MBC who have previously received
either trastuzumab emtansine or trastuzumab deruxtecan (DS-8201a). The Phase II randomized
stage will evaluate the safety, efficacy, tolerability, and pharmacokinetics of trastuzumab
emtansine in combination with venetoclax at RP2D compared with trastuzumab emtansine plus
placebo in participants with previously treated HER2-positive LABC or MBC who have not
received prior trastuzumab emtansine therapy, either alone or in combination with other
anti-cancer therapies.
Trial website
https://clinicaltrials.gov/ct2/show/NCT04298918
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Clinical Trials
Address 0 0
Hoffmann-La Roche
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT04298918