Clinical trial NCT03523572: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Breast Cancer
Urothelial Carcinoma
Keywords: Human epidermal growth factor receptor-2
HER2
Refractory
Metastatic
Urothelial cancer
Breast Cancer
Lead sponsor: Daiichi Sankyo
Sponsor class: INDUSTRY
Collaborators: name: Bristol-Myers Squibb
name: AstraZeneca
First posted: 2018-05-14
Enrollment: 86
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
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)
Primary purpose: TREATMENT

Brief summary: This is a study of trastuzumab deruxtecan 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 maximum tolerated dose/recommended dose for expansion, when used in combination with nivolumab
* Part 2 is to assess the efficacy and safety of this dose combination.

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 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

Primary outcomes:
measure: Number of Participants With Dose-Limiting Toxicities at 3.2 mg/kg and 5.4 mg/kg Dose Level in Participants With HER2-expressing Advanced Breast Cancer in Dose Escalation
timeFrame: Cycles 1 and 2 (each cycle is 21 days)
measure: Percentage of Participants With Objective Response Rate (ORR) Based on Independent Central Review in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer
timeFrame: Every 6 weeks in the first year after Day 1 of Cycle 1 and thereafter every 12 weeks until disease progression or initiation of additional anticancer therapy and survival, up to 2 years 11.5 months (each cycle is 21 days)
Secondary outcomes:
measure: Duration of Response (DoR) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer
timeFrame: Every 6 weeks in the first year after Day 1 of Cycle 1 and thereafter every 12 weeks until disease progression or initiation of additional anticancer therapy and survival, up to 5 years (each cycle is 21 days)
measure: Percentage of Participants With Disease Control Rate (DCR) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer
timeFrame: Every 6 weeks in the first year after Day 1 of Cycle 1 and thereafter every 12 weeks until disease progression or initiation of additional anticancer therapy and survival, up to 5 years (each cycle is 21 days)
measure: Progression-Free Survival (PFS) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer
timeFrame: Every 6 weeks in the first year after Day 1 of Cycle 1 and thereafter every 12 weeks until disease progression or initiation of additional anticancer therapy and survival, up to 5 years (each cycle is 21 days)
measure: Time to Response (TTR) Based on Independent Central Review in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer
timeFrame: Every 6 weeks in the first year after Day 1 of Cycle 1 and thereafter every 12 weeks until disease progression or initiation of additional anticancer therapy and survival, up to 5 years (each cycle is 21 days)
measure: Overall Survival (OS) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer
timeFrame: Date of first dose of study drug to the date of death due to any cause, up to 5 years
measure: Percentage of Participants With Objective Response Rate (ORR) Based on Investigator Assessment in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer
timeFrame: Every 6 weeks in the first year after Day 1 of Cycle 1 and thereafter every 12 weeks until disease progression or initiation of additional anticancer therapy and survival, up to 5 years (each cycle is 21 days)
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
timeFrame: Date of signing the informed consent form up to 100 days after last dose of study drug or start of a new anticancer drug (whichever occurs first), up to 5 years
Other outcomes:
Locations:
city: Santa Monica
country: United States
facility: UCLA - Medical Center
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Miami
country: United States
facility: University of Miami Hospital & Clinics/Sylvester Comprehensive Cancer Center
state: Florida
city: Louisville
country: United States
facility: Norton Cancer Institute
state: Kentucky
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute Carolinas Healthcare System
state: North Carolina
city: Canton
country: United States
facility: Gabrail Cancer Center Research
state: Ohio
city: Nashville
country: United States
facility: Tennessee Oncology - Sara Cannon Research Institute
state: Tennessee
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Kortrijk
country: Belgium
facility: AZ Groeninge
state: West-Vlaanderen
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Wilrijk
country: Belgium
facility: GZA Hospital Campus Sint-Augustinus
city: Angers
country: France
facility: Institut de Cancerologie de L'Ouest
city: Dijon
country: France
facility: Centre Georges Francois Leclerc
city: Saint-Herblain
country: France
facility: ICO Rene Gauducheau
city: Berlin
country: Germany
facility: Charite Campus Benjamin Franklin
state: Brandenburg
city: Frankfurt
country: Germany
facility: University Hospital Frankfurt
state: Hessen
city: Dresden
country: Germany
facility: University Cancer Center
state: Sachsen
city: Milano
country: Italy
facility: Ospedale San Raffaele
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
city: Siena
country: Italy
facility: Azienda Ospedaliera Universitaria Senese U.O.C. Immunoterapia Oncologica
city: Madrid
country: Spain
facility: Hospital Gregorio Maranon Madrid Spain
city: Madrid
country: Spain
facility: MD Anderson Cancer Center Madrid
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal Madrid
city: Madrid
country: Spain
facility: Fundacion Jimenez Diaz
city: Madrid
country: Spain
facility: START Madrid CIOCC
city: London
country: United Kingdom
facility: Sarah Cannon Research Institute UK
state: England
city: London Borough of Sutton
country: United Kingdom
facility: Royal Marsden Hospital (Surrey)
Study officials:
affiliation: Daiichi Sankyo
name: Global Team Leader
role: STUDY_DIRECTOR
References: