Trastuzumab Deruxtecan With Nivolumab in Advanced Breast and Urothelial Cancer
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| ClinicalTrials.gov Identifier: NCT03523572 |
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Recruitment Status :
Active, not recruiting
First Posted : May 14, 2018
Last Update Posted : August 12, 2021
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This is a study of trastuzumab deruxtecan, which was approved by the FDA (in December 2019) for the treatment of HER2-positive unresectable or metastatic breast cancer following two or more prior anti-HER2 based regimens.
Participants will receive this study drug along with a cancer drug, an immune checkpoint inhibitor, anti-PD1, called nivolumab.
The study will be done in two parts:
- Part 1 is to identify the recommended dose to use for treatment.
- Part 2 is to find out how well the combination works, and how safe and tolerable it is.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Breast Cancer Urothelial Carcinoma | Drug: Trastuzumab deruxtecan Drug: Nivolumab | Phase 1 |
The purpose of this phase 1b (Part 1, Part 2) study is to assess the combination of a test drug (trastuzumab deruxtecan) with nivolumab in participants with HER2-expressing breast and urothelial cancer who had disease progression during or after prior therapies, did not respond to standard therapies, or for whom no standard therapy is available.
The study will be performed in 2 parts.
- Part 1 is to test different doses of trastuzumab deruxtecan when given along with a fixed dose of nivolumab, and establish the most effective and the maximum/recommended tolerated dose, when used in combination with nivolumab
- Part 2 is to assess the efficacy and safety of this dose combination.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 99 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Sequential Assignment |
| Intervention Model Description: | Part 1 will be a sequential dose-finding (dose escalation) study, Part 2 will consist of a single group of four cohorts who receive the recommended dose (determined during Part 1) |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | A Phase 1b, Multicenter, Two-Part, Open-Label Study of Trastuzumab Deruxtecan, an Anti-Human Epidermal Growth Factor Receptor-2 (HER2)-Antibody Drug Conjugate (ADC), in Combination With Nivolumab, an Anti-PD-1 Antibody, for Subjects With HER2-expressing Advanced Breast and Urothelial Cancer |
| Actual Study Start Date : | June 20, 2018 |
| Actual Primary Completion Date : | July 22, 2021 |
| Estimated Study Completion Date : | July 2022 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Dose Escalation
Part 1 will enroll participants meeting the eligibility criteria set up for any of the 4 cohorts of Part 2 specified below using a 3 + 3 + 3 design. Escalating/de-escalating doses of trastuzumab deruxtecan in combination with a flat dose of nivolumab will be administered on Day 1 of each 21-day cycle. The recommended dose for expansion (RDE) will be calculated using data collected from this population in the first two cycles. These participants may continue to receive study treatment in subsequent cycles. |
Drug: Trastuzumab deruxtecan
The investigational product is a sterile lyophilized powder, which is made into solution for intravenous administration.
Other Name: Enhertu Drug: Nivolumab Nivolumab is an aqueous solution formulated at 10 mg/mL to be administered at a flat dose of 360 mg IV over 30 minutes. Protocol-defined thyroid testing is required while taking nivolumab.
Other Name: Opdivo |
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Experimental: Dose Expansion - Cohort 1
Cohort 1 (n=30): Participants with pathologically documented advanced/metastatic breast cancer that has centrally-determined positive HER2 expression (IHC 3+ or IHC 2+/ISH+) [as defined by American Society of Clinical Oncology/College of American Pathologists (ASCO-CAP) guidelines]. These participants have received prior ado-trastuzumab emtansine (T-DM1). Participants will receive the RDE of trastuzumab deruxtecan and the flat dose of nivolumab. |
Drug: Trastuzumab deruxtecan
The investigational product is a sterile lyophilized powder, which is made into solution for intravenous administration.
Other Name: Enhertu Drug: Nivolumab Nivolumab is an aqueous solution formulated at 10 mg/mL to be administered at a flat dose of 360 mg IV over 30 minutes. Protocol-defined thyroid testing is required while taking nivolumab.
Other Name: Opdivo |
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Experimental: Dose Expansion - Cohort 2
Cohort 2 (n=15): Participants with pathologically documented advanced/metastatic breast cancer that has centrally-determined low HER2 expression (IHC 1+ or IHC 2+/ISH-), who have exhausted treatments that can confer any clinically meaningful benefit (eg, other therapies such as hormonal therapy for patients who are hormone receptor positive). Participants will receive the RDE of trastuzumab deruxtecan and the flat dose of nivolumab. |
Drug: Trastuzumab deruxtecan
The investigational product is a sterile lyophilized powder, which is made into solution for intravenous administration.
Other Name: Enhertu Drug: Nivolumab Nivolumab is an aqueous solution formulated at 10 mg/mL to be administered at a flat dose of 360 mg IV over 30 minutes. Protocol-defined thyroid testing is required while taking nivolumab.
Other Name: Opdivo |
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Experimental: Dose Expansion - Cohort 3
Cohort 3 (n=30): Participants with pathologically documented advanced/metastatic urothelial carcinoma that has centrally-determined HER2 expression of IHC 2+ or 3+, who received prior platinum-based therapy with documented progression. Participants will receive the RDE of trastuzumab deruxtecan and the flat dose of nivolumab. |
Drug: Trastuzumab deruxtecan
The investigational product is a sterile lyophilized powder, which is made into solution for intravenous administration.
Other Name: Enhertu Drug: Nivolumab Nivolumab is an aqueous solution formulated at 10 mg/mL to be administered at a flat dose of 360 mg IV over 30 minutes. Protocol-defined thyroid testing is required while taking nivolumab.
Other Name: Opdivo |
|
Experimental: Dose Expansion - Cohort 4
Cohort 4 (n=15): Participants with pathologically documented advanced/metastatic urothelial carcinoma that has centrally-determined HER2 expression of IHC 1+, who received prior platinum-based therapy with documented progression. Participants will receive the RDE of trastuzumab deruxtecan and the flat dose of nivolumab. |
Drug: Trastuzumab deruxtecan
The investigational product is a sterile lyophilized powder, which is made into solution for intravenous administration.
Other Name: Enhertu Drug: Nivolumab Nivolumab is an aqueous solution formulated at 10 mg/mL to be administered at a flat dose of 360 mg IV over 30 minutes. Protocol-defined thyroid testing is required while taking nivolumab.
Other Name: Opdivo |
- Part 1: Number of participants with dose-limiting toxicity at each dose level [ Time Frame: 2 cycles (within 2 months; each cycle is 21 days) ]Categories: Low Dose, High Dose
- Part 2: Dose expansion - Objective response rate (ORR) as assessed by Central Imaging Review [ Time Frame: 6 months after the last participant is enrolled, or when 80% of participants have experienced disease progression or discontinued study treatment, whichever occurs first (within 24 months) ]ORR is defined as the percentage of participants with tumor size reduction of a predefined amount and for a minimum time period. ORR includes partial response (PR) and complete response (CR). ORR will be assessed by Central Imaging Review based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
- Duration of Response (DoR) [ Time Frame: within 24 months ]
- Disease Control Rate (DCR) [ Time Frame: within 24 months ]
- Progression Free Survival (PFS) [ Time Frame: within 24 months ]PFS is defined as the time from randomization until objective tumor progression or death, whichever occurs first.
- Time to Response based on central review [ Time Frame: within 24 months ]
- Overall Survival (OS) [ Time Frame: within 24 months ]Overall survival is defined as the time from randomization until death from any cause and is measured in the intent-to-treat population.
- ORR [ Time Frame: within 24 months ]ORR, as assessed by the investigator based on RECIST Version 1.1.
- Number of participants with treatment emergent adverse events (TEAEs) during the trial [ Time Frame: at the time of final database lock (anticipated within three years) ]Total number of participants in the safety analysis set with TEAEs collected during the trial (including follow-up periods), for inclusion in the database
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Is the age of majority (adulthood) in their country
- Has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1
- Has pathologically documented breast cancer or urothelial cancer that is unresectable or metastatic, and refractory to or intolerant of existing therapy(ies) known to provide clinical benefit, and as specified in each study cohort
- Has an adequate archival tumor sample available for the central laboratory to determine eligibility to participate
- Has at least 1 measurable lesion per RECIST version 1.1
- Has cardiac, bone marrow, kidney, liver, blood and clotting test results required per protocol
- Has had an adequate washout period before enrollment since previous surgery and other treatment
- If reproduction is possible, agrees to use protocol-defined methods of contraception (or completely abstain from heterosexual intercourse) from screening to at least 7 months for females and males after the last dose of study drug
- Agrees to avoid harvesting sperm or ova for any reason from screening to at least 7 months for females and males after the last dose of study drug
- Has a life expectancy of at least 3 months
Exclusion Criteria:
- Has received prior treatment with nivolumab or trastuzumab deruxtecan
- Has medical history of myocardial infarction (MI) within 6 months before enrollment, symptomatic congestive heart failure (CHF) (New York Heart Association classes II-IV). Troponin levels above upper limit of normal (ULN) at screening (as defined by the manufacturer) and without any MI-related symptoms should have a cardiologic consultation before enrollment to rule out MI.
- Has a corrected QT interval by Fredericia (QTcF) prolongation to > 470 ms (females) or > 450 ms (males) based on an average of the screening triplicate 12-lead electrocardiogram
- Has history of non-infectious interstitial lung disease (ILD/pneumonitis) (that required steroids), has ILD/pneumonitis currently, or it cannot be ruled out by imaging at screening
- Has a condition (other than active autoimmune disease) that requires systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of starting study treatment
- Is pregnant or breastfeeding, or planning to become pregnant
- Is suspected to have certain other protocol-defined diseases based on past medical history, physical exam, blood tests, eye test and imaging at screening period
- Has received a live vaccine within 30 days before the first dose of study drug
- Is related to the investigator or another employee of the sponsor or the study site
- Is pregnant, breastfeeding, or planning to become pregnant
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Has or had any disease, psychiatric or medical condition, metastatic condition, drug/medication use or other condition that might, per protocol or in the opinion of the investigator, compromise:
- safety or well-being of the participant or offspring
- safety of study staff
- analysis of results
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): NCT03523572
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| Study Director: | Global Team Leader | Daiichi Sankyo, Inc. |
| Responsible Party: | Daiichi Sankyo, Inc. |
| ClinicalTrials.gov Identifier: | NCT03523572 |
| Other Study ID Numbers: |
DS8201-A-U105 2018-000371-32 ( EudraCT Number ) |
| First Posted: | May 14, 2018 Key Record Dates |
| Last Update Posted: | August 12, 2021 |
| Last Verified: | August 2021 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/ |
| Supporting Materials: |
Study Protocol Statistical Analysis Plan (SAP) Clinical Study Report (CSR) |
| Time Frame: | Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication. |
| Access Criteria: | Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent. |
| URL: | https://vivli.org/ourmember/daiichi-sankyo/ |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Human epidermal growth factor receptor-2 HER2 Refractory |
Metastatic Urothelial cancer Breast Cancer |
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Carcinoma, Transitional Cell Neoplasms Carcinoma Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Nivolumab |
Trastuzumab Antineoplastic Agents, Immunological Antineoplastic Agents Immune Checkpoint Inhibitors Molecular Mechanisms of Pharmacological Action |