Trastuzumab Deruxtecan With Nivolumab in Advanced Breast and Urothelial Cancer

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Breast Cancer; Urothelial Carcinoma
• Intervention / Treatment: Drug: Trastuzumab deruxtecan; Drug: Nivolumab

Detailed Description

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
• Enrollment (Anticipated): 99
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1200
    • Cliniques Universitaires Saint-Luc
  • Wilrijk, Belgium, 2610
    • GZA Hospital Campus Sint-Augustinus
  • West-Vlaanderen
    • Kortrijk, West-Vlaanderen, Belgium, 8500
      • Az Groeninge
• France
  • Angers, France, 49055
    • Institut de Cancérologie de l'Ouest
  • Dijon, France, 21079
    • Centre Georges François Leclerc
  • Saint-Herblain, France, 44805
    • ICO René Gauducheau
• Germany
  • Brandenburg
    • Berlin, Brandenburg, Germany, 12200
      • Charite Campus Benjamin Franklin
  • Hessen
    • Frankfurt, Hessen, Germany, 60590
      • University Hospital Frankfurt
  • Sachsen
    • Dresden, Sachsen, Germany, 01307
      • University Cancer Center
• Italy
  • Milano, Italy, 20132
    • Ospedale San Raffaele
  • Milano, Italy, 20133
    • Fondazione IRCCS Istituto Nazionale dei Tumori
  • Siena, Italy, 53100
    • Azienda Ospedaliera Universitaria Senese U.O.C. Immunoterapia Oncologica
• Spain
  • Madrid, Spain, 28040
    • Fundacion Jimenez Diaz
  • Madrid, Spain, 28033
    • MD Anderson Cancer Center Madrid
  • Madrid, Spain, 28007
    • Hospital Gregorio Maranon Madrid Spain
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal Madrid
  • Madrid, Spain, 28050
    • START Madrid CIOCC
• United Kingdom
  • London Borough of Sutton, United Kingdom, SM25PT
    • Royal Marsden Hospital (Surrey)
  • England
    • London, England, United Kingdom, W1G6AD
      • Sarah Cannon Research Institute UK
• United States
  • California
    • Santa Monica, California, United States, 90404-2125
      • UCLA - Medical Center
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Hospital & Clinics/Sylvester Comprehensive Cancer Center
  • Kentucky
    • Louisville, Kentucky, United States, 40202-3700
      • Norton Cancer Institute
  • New York
    • New York, New York, United States, 10029-6504
      • Icahn School of Medicine at Mount Sinai
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Institute Carolinas Healthcare System
  • Ohio
    • Canton, Ohio, United States, 44718-2566
      • Gabrail Cancer Center Research
  • Tennessee
    • Nashville, Tennessee, United States, 37203-1619
      • Tennessee Oncology - Sara Cannon Research Institute
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute
  • Washington
    • Seattle, Washington, United States, 98109
      • University of Washington Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Is the age of majority (adulthood) in their country
2. Has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1
3. 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
4. Has an adequate archival tumor sample available for the central laboratory to determine eligibility to participate
5. Has at least 1 measurable lesion per RECIST version 1.1
6. Has cardiac, bone marrow, kidney, liver, blood and clotting test results required per protocol
7. Has had an adequate washout period before enrollment since previous surgery and other treatment
8. 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
9. 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
10. Has a life expectancy of at least 3 months

Exclusion Criteria:

1. Has received prior treatment with nivolumab or trastuzumab deruxtecan
2. 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.
3. 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
4. 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
5. 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
6. Is pregnant or breastfeeding, or planning to become pregnant
7. 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
8. Has received a live vaccine within 30 days before the first dose of study drug
9. Is related to the investigator or another employee of the sponsor or the study site
10. Is pregnant, breastfeeding, or planning to become pregnant

11. 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:

    1. safety or well-being of the participant or offspring
    2. safety of study staff
    3. analysis of results

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: 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 Names: Opdivo
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 Names: 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 Names: Opdivo
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 Names: 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 Names: Opdivo
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 Names: 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 Names: 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 Names: 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 Names: Opdivo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Number of participants with dose-limiting toxicity at each dose level	Categories: Low Dose, High Dose	2 cycles (within 2 months; each cycle is 21 days)
Part 2: Dose expansion - Objective response rate (ORR) as assessed by Central Imaging Review	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.	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)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response (DoR)		within 24 months
Disease Control Rate (DCR)		within 24 months
Progression Free Survival (PFS)	PFS is defined as the time from randomization until objective tumor progression or death, whichever occurs first.	within 24 months
Time to Response based on central review		within 24 months
Overall Survival (OS)	Overall survival is defined as the time from randomization until death from any cause and is measured in the intent-to-treat population.	within 24 months
ORR	ORR, as assessed by the investigator based on RECIST Version 1.1.	within 24 months
Number of participants with treatment emergent adverse events (TEAEs) during the trial	Total number of participants in the safety analysis set with TEAEs collected during the trial (including follow-up periods), for inclusion in the database	at the time of final database lock (anticipated within three years)

Collaborators and Investigators

• Sponsor: Daiichi Sankyo, Inc.
• Collaborators: Bristol-Myers Squibb; AstraZeneca

Study record dates

Study Major Dates

• Study Start (Actual): June 20, 2018
• Primary Completion (Actual): July 22, 2021
• Study Completion (Anticipated): July 1, 2022

Study Registration Dates

• First Submitted: April 30, 2018
• First Submitted That Met QC Criteria: May 1, 2018
• First Posted (Actual): May 14, 2018

Study Record Updates

• Last Update Posted (Actual): August 12, 2021
• Last Update Submitted That Met QC Criteria: August 11, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Breast Cancer; HER2; Refractory; Metastatic; Urothelial cancer; Human epidermal growth factor receptor-2
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Carcinoma, Transitional Cell; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Trastuzumab; Nivolumab
• Other Study ID Numbers: DS8201-A-U105; 2018-000371-32 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD 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/
• IPD Sharing 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.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No