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

NCT04298918 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: CO418632019-004200-35
• Study Type: interventional
• Target: 1
• Locations: 2 countries
• Sites: 3

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.

Conditions

Breast Cancer

Outcome Measures

Primary Outcomes (4)

• Dose Escalation: Number of Participants With Adverse Events

  The study was terminated by the Sponsor. Only 1 participant was enrolled in this study. Based on the low enrolment number, no data is reported here in order to protect and maintain participant privacy/confidentiality.

  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).

• Expansion Phase: Objective Response Rate (ORR)

  The study was terminated by the Sponsor. Only 1 participant was enrolled in this study. Based on the low enrolment number, no data is reported here in order to protect and maintain participant privacy/confidentiality.

  Up to 30 months

• Phase II: ORR

  The study was terminated by the Sponsor. Only 1 participant was enrolled in this study. Based on the low enrolment number, no data is reported here in order to protect and maintain participant privacy/confidentiality.

  Up to 30 months

• Phase II: Progression-Free Survival (PFS)

  The study was terminated by the Sponsor. Only 1 participant was enrolled in this study. Based on the low enrolment number, no data is reported here in order to protect and maintain participant privacy/confidentiality.

  Up to 30 months

Secondary Outcomes (6)

• All Phases: Plasma Concentration of Venetoclax

  At pre-defined time points from Cycle 1 Day 8 and/or Cycle 2 Day 1 through Cycle 4 Day 1 (cycle = 21 days)

• Phase II: Serum Concentration of Trastuzumab Emtansine

  At pre-defined time points from Cycle 1 Day 1 through Cycle 4 Day 1 (cycle = 21 days)

• Expansion Phase and Phase II: Number of Participants With Adverse Events

  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).

• Expansion Phase and Phase II: Duration of Response (DOR)

  Up to 30 months

• Phase II: Overall Survival (OS)

  Randomization to death from any cause (up to 30 months)

Study Arms (4)

Dose Escalation Phase

EXPERIMENTAL

Participants received venetoclax in combination with a fixed dose of trastuzumab emtansine.

Drug: Venetoclax; Drug: Trastuzumab emtansine

Dose Expansion Phase

EXPERIMENTAL

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

Drug: Venetoclax; Drug: Trastuzumab emtansine

Randomized Phase II Arm 1

EXPERIMENTAL

Participants were to receive trastuzumab emtansine + placebo.

Drug: Placebo; Drug: Trastuzumab emtansine

Randomized Phase II Arm 2

EXPERIMENTAL

Participants were to receive trastuzumab emtansine + venetoclax.

Drug: Venetoclax; Drug: Trastuzumab emtansine

Interventions

Placebo DRUG

Participants will receive oral placebo in combination with trastuzumab emtansine.

Randomized Phase II Arm 1

Venetoclax DRUG

Participants will receive oral venetoclax.

Also known as: Venclexta

Dose Escalation Phase; Dose Expansion Phase; Randomized Phase II Arm 2

Trastuzumab emtansine DRUG

Participants will receive intravenous (IV) trastuzumab emtansine.

Also known as: Kadcyla

Dose Escalation Phase; Dose Expansion Phase; Randomized Phase II Arm 1; Randomized Phase II Arm 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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+)

You may not qualify if:

• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (3)

Peter MacCallum Cancer Center

East Melbourne, Victoria, 3002, Australia

Location

Asan Medical Center

Seoul, 05505, South Korea

Location

Samsung Medical Center

Seoul, 06351, South Korea

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

venetoclax; Ado-Trastuzumab Emtansine

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Maytansine; Macrolides; Lactones; Organic Chemicals; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Trastuzumab; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

The study was terminated by the Sponsor. Only 1 participant was enrolled in this study. Based on the low enrolment number, no data is reported here in order to protect and maintain participant privacy/confidentiality.

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800 821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 5, 2020
• First Posted: March 6, 2020
• Study Start: September 23, 2020
• Primary Completion: February 4, 2021
• Study Completion: February 4, 2021
• Last Updated: November 8, 2021
• Results First Posted: November 8, 2021

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will share

Locations

AU (1); KR (2)