Clinical Trials /

Trastuzumab Deruxtecan With Nivolumab in Advanced Breast and Urothelial Cancer

NCT03523572

Description:

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.

Related Conditions:
  • Breast Carcinoma
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Trastuzumab Deruxtecan With Nivolumab in Advanced Breast and Urothelial Cancer
  • 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

Clinical Trial IDs

  • ORG STUDY ID: DS8201-A-U105
  • SECONDARY ID: 2018-000371-32
  • NCT ID: NCT03523572

Conditions

  • Breast Cancer
  • Urothelial Carcinoma

Interventions

DrugSynonymsArms
Trastuzumab deruxtecanEnhertuDose Escalation
NivolumabOpdivoDose Escalation

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Dose EscalationExperimentalPart 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.
  • Trastuzumab deruxtecan
  • Nivolumab
Dose Expansion - Cohort 1ExperimentalCohort 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.
  • Trastuzumab deruxtecan
  • Nivolumab
Dose Expansion - Cohort 2ExperimentalCohort 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.
  • Trastuzumab deruxtecan
  • Nivolumab
Dose Expansion - Cohort 3ExperimentalCohort 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.
  • Trastuzumab deruxtecan
  • Nivolumab
Dose Expansion - Cohort 4ExperimentalCohort 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.
  • Trastuzumab deruxtecan
  • Nivolumab

Eligibility Criteria

        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 5
             months (females) or 7 months (males) after the last dose of study drug

          9. Agrees to avoid harvesting sperm or ova for any reason from screening to at least 5
             months (females) or 7 months (males) after the last dose of study drug

         10. Has a life expectancy of at least 3 months

         11. If eligible for Part 2, is eligible for Part 1

        Exclusion Criteria:

          1. Has received prior treatment with nivolumab or trastuzumab deruxtecan

          2. Has medical history of myocardial infarction within 6 months before enrollment,
             symptomatic congestive heart failure (CHF) (New York Heart Association classes II-IV),
             or troponin levels consistent with myocardial infarction 28 days before enrollment

          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) (that required
             steroids), has ILD 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part 1: Number of participants with dose-limiting toxicity at each dose level
Time Frame:2 cycles (within 2 months)
Safety Issue:
Description:Categories: Low Dose, High Dose

Secondary Outcome Measures

Measure:Duration of Response (DoR)
Time Frame:within 24 months
Safety Issue:
Description:
Measure:Disease Control Rate (DCR)
Time Frame:within 24 months
Safety Issue:
Description:
Measure:Progression Free Survival (PFS)
Time Frame:within 24 months
Safety Issue:
Description:PFS is defined as the time from randomization until objective tumor progression or death, whichever occurs first.
Measure:Time to Response based on central review
Time Frame:within 24 months
Safety Issue:
Description:
Measure:Overall Survival (OS)
Time Frame:within 24 months
Safety Issue:
Description:Overall survival is defined as the time from randomization until death from any cause and is measured in the intent-to-treat population.
Measure:ORR
Time Frame:within 24 months
Safety Issue:
Description:ORR, as assessed by the investigator based on RECIST Version 1.1.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Daiichi Sankyo, Inc.

Trial Keywords

  • Human epidermal growth factor receptor-2
  • HER2
  • Refractory
  • Metastatic
  • Urothelial cancer
  • Breast Cancer

Last Updated

February 5, 2020