Trastuzumab Deruxtecan With Nivolumab in Advanced Breast and Urothelial Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Breast Cancer, Urothelial Carcinoma

Intervention / Treatment
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* Drug: Trastuzumab deruxtecan
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>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<br>* The investigational product is a sterile lyophilized powder, which is made into solution for intravenous administration.<br>* Other names: Enhertu;Drug: Nivolumab<br>* 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.<br>* Other names: Opdivo;|
| Experimental: Dose Expansion - Cohort 1<br>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<br>* The investigational product is a sterile lyophilized powder, which is made into solution for intravenous administration.<br>* Other names: Enhertu;Drug: Nivolumab<br>* 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.<br>* Other names: Opdivo;|
| Experimental: Dose Expansion - Cohort 2<br>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<br>* The investigational product is a sterile lyophilized powder, which is made into solution for intravenous administration.<br>* Other names: Enhertu;Drug: Nivolumab<br>* 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.<br>* Other names: Opdivo;|
| Experimental: Dose Expansion - Cohort 3<br>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<br>* The investigational product is a sterile lyophilized powder, which is made into solution for intravenous administration.<br>* Other names: Enhertu;Drug: Nivolumab<br>* 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.<br>* Other names: Opdivo;|
| Experimental: Dose Expansion - Cohort 4<br>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<br>* The investigational product is a sterile lyophilized powder, which is made into solution for intravenous administration.<br>* Other names: Enhertu;Drug: Nivolumab<br>* 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.<br>* Other names: Opdivo;|

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Human epidermal growth factor receptor-2, Refractory, Metastatic, Urothelial cancer, Breast Cancer, HER2