DS8201a and Pembrolizumab in Participants With Locally Advanced/Metastatic Breast or Non-Small Cell Lung Cancer

Sponsor

Daiichi Sankyo, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04042701

Collaborator

AstraZeneca UK Limited (Other), Merck Sharp & Dohme LLC (Industry)

115

Enrollment

Locations

Arms

38.6

Anticipated Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This two-part study will include a dose escalation part to determine the recommended dose for expansion of DS8201a and pembrolizumab and a dose expansion part to evaluate efficacy, safety, and tolerability of the combination.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer Non-small Cell Lung Carcinoma	Drug: Trastuzumab deruxtecan (DS-8201a) Drug: Trastuzumab deruxtecan (DS-8201a) Drug: Pembrolizumab	Phase 1

Detailed Description

This phase 1b, open-label, 2-part, multicenter, non-randomized, multiple-dose study will evaluate DS-8201a in combination with pembrolizumab in participants with advanced/metastatic breast cancer or non-small cell lung cancer (NSCLC).

In the dose escalation part of the study, escalating doses of DS-8201a in combination with pembrolizumab will be assessed. DS-8201a and pembrolizumab 200 mg will be administered on Day 1 of every 21-day cycle. The initial dose administered for DS8201a will be 3.2 mg/kg Q3W. Escalation to the next dose (5.4 mg/kg Q3W) will be based on acceptable safety signals based on the earlier dose cohort.

Upon completion of dose escalation with the recommended dose of escalation (RDE) established, the dose expansion part of the study will begin. The dose expansion part will include 4 cohorts: Human epidermal growth factor receptor 2 (HER2+) breast cancer participants with prior ado-trastuzumab emtansine (T-DM1), HER2 low breast cancer participants with prior failed standard treatments, HER2-expressing NSCLC participants who have not received any prior treatment with anti-PD-1, anti-PD-L1, or HER2 agents, and HER2-mutant NSCLC participants who have not received any prior treatment with anti-PD-1, anti-PD-L1, or HER2 agents.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

115 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Phase 1b, open-label, 2-part, multicenter, non-randomized, multiple-dose studyPhase 1b, open-label, 2-part, multicenter, non-randomized, multiple-dose study

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1b, Multicenter, Two-Part, Open-Label Study of Trastuzumab Deruxtecan (DS-8201a), An Anti-Human Epidermal Growth Factor Receptor-2 (HER2)-Antibody Drug Conjugate (ADC), In Combination With Pembrolizumab, An Anti-PD-1 Antibody, For Subjects With Locally Advanced/Metastatic Breast Or Non-Small Cell Lung Cancer (NSCLC)

Actual Study Start Date :

Feb 10, 2020

Anticipated Primary Completion Date :

Aug 1, 2022

Anticipated Study Completion Date :

May 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part 1 (Dose Escalation) HER2-positive breast cancer, HER2-low expressing breast cancer, HER2-expressing NSCLC, and HER2-mutant NSCLC participants who received escalating doses of DS8201a (initial dose 3.2 mg/kg Q3W) and pembrolizumab 200 mg.	Drug: Trastuzumab deruxtecan (DS-8201a) Part 1: Two dose levels of DS-8201a (3.2 mg/kg Q3W and 5.4 mg/kg Q3W via intravenous (IV) infusion will be administered for the dose escalation part of the study in combination with pembrolizumab. Part 2: Once Part 1 of the study is complete and a RDE for DS-8201a has been established, Part 2 will begin. Drug: Pembrolizumab All participants will receive pembrolizumab (200 mg Q3W) via intravenous (IV) infusion prior to DS-8201a in Parts 1 and 2 of the study.
Experimental: HER2-positive breast cancer (Part 2 Dose Expansion) HER2-positive breast cancer participants with prior ado-trastuzumab emtansine (T-DM1) with disease progression and who received DS8201a at the RDE in combination with pembrolizumab 200 mg.	Drug: Trastuzumab deruxtecan (DS-8201a) Part 1: Two dose levels of DS-8201a (3.2 mg/kg Q3W and 5.4 mg/kg Q3W via intravenous (IV) infusion will be administered for the dose escalation part of the study in combination with pembrolizumab. Part 2: Once Part 1 of the study is complete and a RDE for DS-8201a has been established, Part 2 will begin. All participants will receive DS-8201a at the RDE in combination with pembrolizumab. Drug: Pembrolizumab All participants will receive pembrolizumab (200 mg Q3W) via intravenous (IV) infusion prior to DS-8201a in Parts 1 and 2 of the study.
Experimental: HER2-low breast cancer (Part 2 Dose Expansion) HER2 low breast cancer participants with prior failed standard treatments who received DS8201a at the RDE in combination with pembrolizumab 200 mg.	Drug: Trastuzumab deruxtecan (DS-8201a) Part 1: Two dose levels of DS-8201a (3.2 mg/kg Q3W and 5.4 mg/kg Q3W via intravenous (IV) infusion will be administered for the dose escalation part of the study in combination with pembrolizumab. Part 2: Once Part 1 of the study is complete and a RDE for DS-8201a has been established, Part 2 will begin. All participants will receive DS-8201a at the RDE in combination with pembrolizumab. Drug: Pembrolizumab All participants will receive pembrolizumab (200 mg Q3W) via intravenous (IV) infusion prior to DS-8201a in Parts 1 and 2 of the study.
Experimental: HER2-expressing NSCLC (Part 2 Dose Expansion) HER2-expressing NSCLC participants who had not received any prior treatment with anti-PD-1, anti-PD-L1, or HER2 agents and received DS8201a at the RDE in combination with pembrolizumab 200 mg.	Drug: Trastuzumab deruxtecan (DS-8201a) Part 1: Two dose levels of DS-8201a (3.2 mg/kg Q3W and 5.4 mg/kg Q3W via intravenous (IV) infusion will be administered for the dose escalation part of the study in combination with pembrolizumab. Part 2: Once Part 1 of the study is complete and a RDE for DS-8201a has been established, Part 2 will begin. All participants will receive DS-8201a at the RDE in combination with pembrolizumab. Drug: Pembrolizumab All participants will receive pembrolizumab (200 mg Q3W) via intravenous (IV) infusion prior to DS-8201a in Parts 1 and 2 of the study.
Experimental: HER2-mutant NSCLC (Part 2 Dose Expansion) HER2-mutant NSCLC participants who had not received any prior treatment with anti-PD-1, anti-PD-L1, or HER2 agents and received DS8201a at the RDE in combination with pembrolizumab 200 mg.	Drug: Trastuzumab deruxtecan (DS-8201a) Part 1: Two dose levels of DS-8201a (3.2 mg/kg Q3W and 5.4 mg/kg Q3W via intravenous (IV) infusion will be administered for the dose escalation part of the study in combination with pembrolizumab. Part 2: Once Part 1 of the study is complete and a RDE for DS-8201a has been established, Part 2 will begin. All participants will receive DS-8201a at the RDE in combination with pembrolizumab. Drug: Pembrolizumab All participants will receive pembrolizumab (200 mg Q3W) via intravenous (IV) infusion prior to DS-8201a in Parts 1 and 2 of the study.

Outcome Measures

Primary Outcome Measures

Dose-limiting toxicities (DLTs), Part 1 [Within two 3-week cycles (6 weeks)]
Maximum Tolerated Dose (MTD) or recommended dose expansion (RDE) of DS-8201a (Part1) are based on the occurrence of DLTs.
Objective Response Rate (ORR), Confirmed by Independent Central Review, Part 2 [Within approximately 30 months]

Secondary Outcome Measures

Treatment-emergent adverse events [Within approximately 30 months]
Pharmacokinetic Parameter Maximum Serum Concentration (Cmax) [Cycle 1, Day 1: predose and postdose, Day 8, and Day 15; Cycle 2, Day 1 predose and postdose, and Cycle 3, Day 1 (each cycle is 21 days)]
Cmax of trastuzumab deruxtecan, MAAA-118A, and total anti-HER2 antibody will be assessed.
Pharmacokinetic Parameter Area Under the Concentration-time Curve (AUC) [Cycle 1, Day 1: predose and postdose, Day 8, and Day 15; Cycle 2, Day 1 predose and postdose, and Cycle 3, Day 1 (each cycle is 21 days)]
Area under the concentration-time curve of trastuzumab deruxtecan, MAAA-118A, and total anti-HER2 antibody will be assessed.
Duration of Response (DoR) [Within approximately 30 months]
Disease Control Rate (DCR) [Within approximately 30 months]
Progression-Free Survival (PFS), based on Independent Central Review using RECIST v1.1 [Within approximately 30 months]
Time to Response (TTR), based on Independent Central Review using RECIST v1.1 [Within approximately 30 months]
Overall survival (OS) [Within approximately 30 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Written informed consent
Adults ≥18 years
Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 1
Pathologically documented HER2-expressing locally advanced/metastatic breast cancer, and HER2-expressing or HER2-mutant locally advanced/metastatic NSCLC
Willing to provide a tumor biopsy during screening and during treatment
Have at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as assessed by the Investigator
Adequate cardiac function, as defined by left ventricular ejection fraction (LVEF) ≥50% within 28 days before enrollment.
Adequate organ function
Adequate treatment washout period before enrollment

Inclusion Criteria Specific to Part 1

Participants in Part 1 should meet the additional inclusion criteria listed for 1 of the 4 cohorts in Part 2.

Inclusion Criteria Specific to Part 2

Inclusion Criteria for Cohort 1

Pathologically documented, locally advanced/metastatic breast cancer that has centrally determined HER2-positive expression as per American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) Guidelines
Received prior trastuzumab emtansine (T-DM1) therapy with documented progression

Inclusion Criteria for Cohort 2

Pathologically documented, locally advanced/metastatic breast cancer that has centrally determined HER2-low expression (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization [ISH-])
Participants must have exhausted treatments that can confer any clinically meaningful benefit (eg, other therapies such as hormonal therapy for participants who are hormone receptor positive)

Inclusion Criteria for Cohort 3

Pathologically documented, locally advanced/metastatic NSCLC that has centrally determined HER2-expression (IHC 1+, 2+, or 3+)
Participants who have known epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK), BRAF V600E mutation, or ROS1 fusion should have disease progression after treatment with at least one genomically-targeted therapy for metastatic disease that are known to confer clinical benefit, or are intolerant to treatment, or refuse standard treatment

Inclusion Criteria for Cohort 4

Pathologically documented, locally advanced/metastatic HER2-mutant NSCLC
Participants who have known EGFR mutation, ALK, BRAF V600E mutation, or ROS1 fusion should have disease progression after treatment with at least one genomically-targeted therapy for metastatic disease that are known to confer clinical benefit, or are intolerant to treatment, or refuse standard treatment

Exclusion Criteria:

Prior treatment with pembrolizumab or DS-8201a
Medical history of myocardial infarction (MI) within 6 months before enrollment, symptomatic congestive heart failure (New York Heart Association Class II to IV). Participants with troponin levels above the upper limit of normal at Screening (as defined by the manufacturer), and without any MI-related symptoms, should have a cardiologic consultation before enrollment to rule out MI
Corrected QT interval (QTc) prolongation to >470 ms (females) or >450 ms (males)
History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
Spinal cord compression or clinically active central nervous system metastases
Active, known or suspected autoimmune disease
Condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of study treatment
Prior therapy with an anti-PD-1 or anti-PD-L1 agent
Prior therapy with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137) and was discontinued from that treatment due to a Grade 3 or higher immune-related adverse event (irAE)
Prior anti-HER2 therapy is not allowed for participants with HER2 low-expressing breast cancer or participants with NSCLC (Cohorts 2, 3, or 4). Prior treatment with pan-HER tyrosine kinase inhibitor is allowed.
Prior systemic anticancer therapy, including investigational agents within 2 to 6 weeks prior to treatment
Unresolved toxicities from previous anticancer therapy
Live vaccine within 30 days prior to the first dose of study drug
Currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment
Multiple primary malignancies within 3 years, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, other solid tumors curatively treated, or contralateral breast cancer
History of severe hypersensitivity reactions to other monoclonal antibodies and/or any of the study drug components
Active infection requiring systemic therapy
Known history of human immunodeficiency virus (HIV) infection
Active hepatitis B or C virus infection
History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, or any other reason the participant is found not appropriate to participate in the opinion of the treating Investigator
Known psychiatric or substance abuse disorders
Prior organ transplantation, including allogeneic stem cell transplantation
Pregnant, breastfeeding, or planning to become pregnant
Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses
Uncontrolled infection requiring IV antibiotics, anti-virals, or anti-fungals

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California San Francisco Medical Center	San Francisco	California	United States	94143
2	Moffit Cancer Center	Tampa	Florida	United States	33612
3	Center for Cancer & Blood Disorders	Bethesda	Maryland	United States	20817
4	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
5	Siteman Cancer Center-Washington University	Saint Louis	Missouri	United States	63110
6	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
7	Hope Cancer Center of East Texas	Tyler	Texas	United States	75701
8	Institut Bergonie	Bordeaux		France	33000
9	Centre Hospitalier Intercommunal de Créteil	Créteil		France	94000
10	CHU Timone	Marseille		France	13385
11	Institut PAOLI-CALMETTES	Marsielle		France	13273
12	University Cancer Institute Toulouse	Toulouse		France	31100
13	Gustave Roussy	Villejuif		France	94800
14	Institute Oncologico Baselga Hospital Quiron	Barcelona		Spain	08023
15	Hospital de la Santa Creu i de Sant Pau	Barcelona		Spain	08025
16	Hospital General Universitario Gregorio Marañon	Madrid		Spain	28009
17	MD Anderson Cancer Center	Madrid		Spain	28033
18	Hospital Universitario Miguel Servet	Zaragoza		Spain	50009
19	The Royal Marsden NHS Foundation Trust	London		United Kingdom	SW3 6JJ
20	Sarah Cannon Research Institute (SCRI)	London		United Kingdom	W1G 6AD
21	The Christie NHS Foundation Trust	Manchester		United Kingdom	M20 4BX
22	Royal Marsden Hospital	Sutton		United Kingdom	SM2 5PT
23	Clatterbridge Cancer Centre	Wirral		United Kingdom	CH63 4JY