A 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

Phase 1

• Conditions: ocally advanced or metastatic breast cancer; MedDRA version: 20.0Level: LLTClassification code 10027475Term: Metastatic breast cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 23.0Level: PTClassification code 10065430Term: HER2 positive breast cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2019-004200-35-IT
• Lead Sponsor: F. HOFFMANN - LA ROCHE LTD.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2020-10-26
• Last Update Posted: 11 January 2021

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 244

Inclusion Criteria

- Age >= 18 years
- Ability to comply with the study protocol, in the investigator's judgment
- Histologically or cytologically confirmed invasive MBC or LABC that is incurable, unresectable, and previously treated with multimodality therapy
• Prior treatment for BC in the adjuvant, unresectable locally advanced, or metastatic settings, which must include a taxane, trastuzumab (alone or in combination with another agent), and pertuzumab
- Measurable disease that is evaluable per 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 ER and/or progesterone receptor status as defined by using 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 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 Dose-Escalation Phase Only
- Prior exposure to trastuzumab emtansine in any setting (advanced/metastatic or early breast cancer) is required

Inclusion Criteria for Expansion Phase Only
• Trastuzumab emtansine experienced cohort:
- Disease progression during or after trastuzumab emtansine treatment in the advanced/metastatic setting or disease recurrence in the neoadjuvant/adjuvant setting
- At least 50% patients in the expansion cohort (e.g., 10 out of 20) must have tumor that is Bcl-2 high
• Trastuzumab deruxtecan (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% patients in the expansion cohort (e.g., 10 out of 20) must have tumor that is Bcl-2 high

Inclusion Criteria for Randomized Phase II Stage
- Bcl-2 expression status by IHC either from fresh tissue or the most recent archival tissue by a central laboratory using the Ventana Bcl-2 IHC assay prior to randomization.
Are the trial subjects under 18? no
Number of subjects for th

Exclusion Criteria

- Receipt of any anticancer drug/biologic or investigational treatment 21 days prior to C1D1 except hormone therapy, which can be given up to 7 days prior to C1D1
- Radiation therapy within 2 weeks prior to C1D1
- History of exposure to the following cumulative doses of anthracyclines as specified below:
• 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/m 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 C1D1
- 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 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
- Malabsorption syndrome or other condition that would interfere with enteral absorption
- History of active inflammatory bowel disease requiring specific medication in the 12 months prior to randomization, or active and uncontrolled bowel inflammation 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 labo

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified