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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

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ClinicalTrials.gov Identifier: NCT04298918
Recruitment Status : Terminated (Decision to discontinue the study based on broader development and strategic prioritisation. The Sponsor concludes there is no benefit-risk impact on the CO41863 study.)
First Posted : March 6, 2020
Last Update Posted : April 13, 2021
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

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.

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: Placebo Drug: Venetoclax Drug: Trastuzumab emtansine Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official 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
Actual Study Start Date : September 23, 2020
Actual Primary Completion Date : February 4, 2021
Actual Study Completion Date : February 4, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Dose Escalation Phase
Participants will receive venetoclax in combination with a fixed dose of trastuzumab emtansine.
Drug: Venetoclax
Participants will receive oral venetoclax.
Other Name: Venclexta

Drug: Trastuzumab emtansine
Participants will receive intravenous (IV) trastuzumab emtansine.
Other Name: Kadcyla

Experimental: Dose Expansion Phase
Participants will receive venetoclax at the Phase II Recommended Dose (RP2D) in combination with trastuzumab emtansine.
Drug: Venetoclax
Participants will receive oral venetoclax.
Other Name: Venclexta

Drug: Trastuzumab emtansine
Participants will receive intravenous (IV) trastuzumab emtansine.
Other Name: Kadcyla

Experimental: Randomized Phase II Arm 1
Participants will receive trastuzumab emtansine + placebo.
Drug: Placebo
Participants will receive oral placebo in combination with trastuzumab emtansine.

Drug: Trastuzumab emtansine
Participants will receive intravenous (IV) trastuzumab emtansine.
Other Name: Kadcyla

Experimental: Randomized Phase II Arm 2
Participants will receive trastuzumab emtansine + venetoclax.
Drug: Venetoclax
Participants will receive oral venetoclax.
Other Name: Venclexta

Drug: Trastuzumab emtansine
Participants will receive intravenous (IV) trastuzumab emtansine.
Other Name: Kadcyla




Primary Outcome Measures :
  1. Dose Escalation: Percentage of Participants with Adverse Events [ Time Frame: Up to 18 months ]
  2. Expansion Phase: Objective Response Rate (ORR) [ Time Frame: Up to 30 months ]
  3. Phase II: ORR [ Time Frame: Up to 30 months ]
  4. Phase II: Progression-Free Survival (PFS) [ Time Frame: Up to 30 months ]

Secondary Outcome Measures :
  1. All Phases: Plasma Concentration of Venetoclax [ Time Frame: At pre-defined time points from Cycle 1 Day 8 and/or Cycle 2 Day 1 through Cycle 4 Day 1 (cycle = 21 days) ]
  2. Phase II: Serum Concentration of Trastuzumab Emtansine [ Time Frame: At pre-defined time points from Cycle 1 Day 1 through Cycle 4 Day 1 (cycle = 21 days) ]
  3. Expansion Phase and Phase II: Percentage of Participants with Adverse Events [ Time Frame: Up to 30 months ]
  4. Expansion Phase and Phase II: Duration of Response (DOR) [ Time Frame: Up to 30 months ]
  5. Phase II: Overall Survival (OS) [ Time Frame: Randomization to death from any cause (up to 30 months) ]
  6. Phase II: Change from Baseline in Anti-Drug Antibodies to Trastuzumab Emtansine [ Time Frame: Up to 30 months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04298918


Locations
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United States, Texas
MD Anderson Cancer Center
Houston, Texas, United States, 77030
Australia, Victoria
Peter MacCallum Cancer Center
East Melbourne, Victoria, Australia, 3002
Hungary
Honvédelmi Minisztérium Állami Egészségügyi Központ; Onkológiai Osztály; Pharmacy
Budapest, Hungary, 1062
Szabolcs-Szatmar-Bereg Megyei Korhazak es Egyetemi Oktatokorhaz; Onkoradiológia
Nyíregyháza, Hungary, 4400
Pécsi Tudományegyetem; Klinikai Központ Onkoterápiás Intézet
Pécs, Hungary, 7623
Jasz-Nagykun-Szolnok Megyei Hetenyi Geza Korhaz-Rendelointezet; Megyei Onkologiai Kozpont
Szolnok, Hungary, 5004
Korea, Republic of
Samsung Medical Center
Seoul, Korea, Republic of, (0)6351
Asan Medical Center
Seoul, Korea, Republic of, 05505
Spain
Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia
Valencia, Spain, 46010
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche
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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT04298918    
Other Study ID Numbers: CO41863
2019-004200-35 ( EudraCT Number )
First Posted: March 6, 2020    Key Record Dates
Last Update Posted: April 13, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Trastuzumab
Ado-Trastuzumab Emtansine
Venetoclax
Maytansine
Antineoplastic Agents, Immunological
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action