Trastuzumab Deruxtecan (DS-8201a) With Nivolumab in Advanced Breast and Urothelial Cancer

Study Description

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Brief Summary:

The purpose of this phase 1b study is to test the combination of an experimental drug known as DS-8201a given along with Nivolumab (a marketed drug) 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 look at different doses of DS-8201a when given along with a fixed dose of nivolumab, and establish the most effective and safe dose (maximum/recommended tolerated dose) when used in combination with nivolumab.
• Part 2 is to understand the positive or negative effects of this dose combination on the participant's body and disease.

The study will also determine the pharmacokinetics of DS-8201a when administered with nivolumab.

Condition or disease	Intervention/treatment	Phase
Breast Cancer; Urothelial Carcinoma	Drug: Trastuzumab deruxtecan (DS-8201a); Drug: Nivolumab	Phase 1

Study Design

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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 DS-8201a, 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
Estimated Primary Completion Date :	September 2020
Estimated Study Completion Date :	September 2020

Arms and Interventions

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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 doses of trastuzumab deruxtecan (DS-8201a) in combination with nivolumab will be assessed. DS-8201a and nivolumab will be administered on Day 1 of each 21-day cycle.	Drug: Trastuzumab deruxtecan (DS-8201a); The investigational product is a sterile lyophilized powder, which is made into solution for intravenous administration.; Other Name: Experimental product; 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; Other Name: 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 [as defined by American Society of Clinical Oncology/College of American Pathologists (ASCO-CAP) guidelines], who have previously received ado-trastuzumab emtansine (T-DM1). Participants will receive the Part 1 recommended dose of trastuzumab deruxtecan (DS-8201a) and the same dose of nivolumab as in Part 1.	Drug: Trastuzumab deruxtecan (DS-8201a); The investigational product is a sterile lyophilized powder, which is made into solution for intravenous administration.; Other Name: Experimental product; 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; Other Name: 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 Part 1 recommended dose of trastuzumab deruxtecan (DS-8201a) and the same dose of nivolumab as in Part 1.	Drug: Trastuzumab deruxtecan (DS-8201a); The investigational product is a sterile lyophilized powder, which is made into solution for intravenous administration.; Other Name: Experimental product; 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; Other Name: 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 Part 1 recommended dose of trastuzumab deruxtecan (DS-8201a) and the same dose of nivolumab as in Part 1.	Drug: Trastuzumab deruxtecan (DS-8201a); The investigational product is a sterile lyophilized powder, which is made into solution for intravenous administration.; Other Name: Experimental product; 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; 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 Part 1 recommended dose of trastuzumab deruxtecan (DS-8201a) and the same dose of nivolumab as in Part 1.	Drug: Trastuzumab deruxtecan (DS-8201a); The investigational product is a sterile lyophilized powder, which is made into solution for intravenous administration.; Other Name: Experimental product; 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; Other Name: Opdivo

Outcome Measures

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Primary Outcome Measures :

1. Number of participants with dose-limiting toxicity at each dose level [ Time Frame: 2 cycles (within 2 months) ]
   Categories: Low Dose, High Dose
2. Part 2: Dose expansion - Objective response rate (ORR) [ Time Frame: within 24 months ]
   ORR during the dose expansion part as assessed by the Independent Imaging Vendor (Central Imaging Review) based on RECIST Version 1.1

Secondary Outcome Measures :

1. Duration of Response (DoR) [ Time Frame: within 24 months ]
2. Disease Control Rate (DCR) [ Time Frame: within 24 months ]
3. Progression Free Survival (PFS) [ Time Frame: within 24 months ]
4. Time to Response based on central review [ Time Frame: within 24 months ]
5. Overall Survival (OS) [ Time Frame: within 24 months ]
6. ORR [ Time Frame: within 24 months ]
   ORR, as assessed by investigator and defined as the percentage of participants who achieved a confirmed response (CR or PR) during study treatment

Other Outcome Measures:

1. Maximum Concentration (Cmax) of Trastuzumab deruxtecan (DS-8201a) and metabollite (MAAA-1181a) [ Time Frame: 21-day Cycles 1 (Days 1, 8 and 15), 2 (Day 1) and 3 (Day 1) (within 3 months) ]
2. Serum Concentration of Total HER2 Antibody [ Time Frame: 21-day Cycles 1 (Days 1, 8 and 15), 2 (Day 1) and 3 (Day 1) (within 3 months) ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Is the age of majority in their country
• 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 at least 1 measurable lesion assessed by the investigator based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
• Meets the HER2 status in tumor tissue sample as confirmed by the central laboratory
• Is willing and able to provide an adequate archival tumor sample or is willing to undergo a tissue biopsy after the completion of the most recent treatment regimen
• Has Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1
• Demonstrates adequate organ functions: Required cardiac, bone marrow, kidney, liver and blood clotting functions as per protocol
• Has adequate washout period for previous surgery and other treatment before registration
• Agrees to use highly effective method of contraception starting with the first dose of study therapy through 7 months (for male) and 5 months (for female) after the last dose of study drug
• If a female of childbearing potential, has a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

Exclusion Criteria:

• Was previously treated with HER2-targeted therapy for HER2-positive breast cancer
• Was previously treated with medications such as anti-Programmed Death 1 PD-1 (or anti-PD-L1) or anti-Programmed Death Ligand 2 (anti-PD-L2), or anti-CTLA-4 antibody, or any other antibody or drug that specifically targets T-cell co-stimulation or checkpoint pathways.
• Has medical history of myocardial infarction, symptomatic congestive heart failure (CHF) (NYHA classes II-IV), unstable angina or serious cardiac arrhythmia
• Has a corrected QT (QTc) interval prolongation to > 450 millisecond (ms) in males and > 470 ms in females
• Has a medical history of clinically significant lung disease such as non-infectious interstitial lung disease or pneumonitis and require steroid treatment
• Requires treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immune suppression medications within 14 days of start of 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 history of any disease, 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

Contacts and Locations

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Locations

United States, California
UCLA - Medical Center	Recruiting
Santa Monica, California, United States, 90404-2125
Contact: Principal Investigator 310-829-5471 shurvitz@mednet.ucla.edu
United States, New York
Icahn School of Medicine at Mount Sinai	Recruiting
New York, New York, United States, 10029-6504
Contact: Principal Investigator 212-241-3131 charles.shapiro@mssm.edu
United States, Tennessee
Tennessee Oncology - Sara Cannon Research Institute	Recruiting
Nashville, Tennessee, United States, 37203-1619
Contact: Principal Investigator 615-329-7274 ehamilton@tnonc.com
Italy
Fondazione IRCCS Istituto Nazionale dei Tumori	Recruiting
Milano, Italy, 20133
Contact: Principal Investigator +39 223902402 andrea.necchi@istitutotumori.mi.it

Sponsors and Collaborators

Daiichi Sankyo, Inc.

Bristol-Myers Squibb

Investigators

Study Director:	Global Team Leader	Daiichi Sankyo, Inc.

More Information

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Responsible Party:	Daiichi Sankyo, Inc.
ClinicalTrials.gov Identifier:	NCT03523572 History of Changes
Other Study ID Numbers:	DS8201-A-U105; 2018-000371-32 ( EudraCT Number )
First Posted:	May 14, 2018
Last Update Posted:	February 12, 2019
Last Verified:	November 2018
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

Keywords provided by Daiichi Sankyo, Inc.:

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

Additional relevant MeSH terms:

Carcinoma, Transitional Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Nivolumab; Trastuzumab; Camptothecin; Antibodies, Monoclonal	Immunoconjugates; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antineoplastic Agents, Phytogenic; Topoisomerase I Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action