Ph1b/2 Study of the Safety and Efficacy of T-DXd Combinations in Advanced HER2-expressing Gastric Cancer (DESTINY-Gastric03)

Phase 2RecruitingNCT04379596

AstraZeneca413 enrolled

Overview

DESTINY-Gastric03 will investigate the safety, tolerability, pharmacokinetics, immunogenicity, and preliminary antitumor activity of trastuzumab deruxtecan (T-DXd) alone or in combination with chemotherapy and/or immunotherapy in HER2-expressing advanced/metastatic gastric/gastroesophageal junction (GEJ) and esophageal adenocarcinoma patients. Study hypotheses: Combination of T-DXd with cytotoxic chemotherapy and/or immunotherapy administered to subjects at the recommended phase 2 dose will show manageable safety and tolerability and preliminary anti-tumor efficacy so as to permit further clinical testing. T-DXd in combination with cytotoxic chemotherapy or immune checkpoint inhibitor administered to HER2-expressing gastric, GEJ and esophageal cancer patients who have not received prior treatment for advanced/metastatic disease will show preliminary evidence of anti-tumour activity and the potential to become a therapeutic option for this patient population.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

413

Conditions

Gastric Cancer

Interventions

5-FU: administered as an IV infusion

CapecitabineDRUG

Capecitabine: administered orally

DurvalumabBIOLOGICAL

Durvalumab: administered as an IV infusion

OxaliplatinDRUG

Oxaliplatin: administered as an IV infusion

TrastuzumabBIOLOGICAL

Trastuzumab: administered as an IV infusion

Trastuzumab deruxtecanDRUG

T-DXd: administered as an IV infusion

CisplatinDRUG

Cisplatin: administered as an IV infusion

PembrolizumabBIOLOGICAL

Pembrolizumab: administered as an IV infusion

VolrustomigBIOLOGICAL

Volrustomig: administered as an IV infusion

RilvegostomigBIOLOGICAL

Rilvegostomig: administered as an IV infusion

Eligibility

Sex: ALLMin age: 18 YearsMax age: 130 Years

Medical Language ↔ Plain English

Inclusion criteria: 1. Male and female participants must be at least 18 years of age. Other age restrictions may apply as per local regulations 2. Disease Characteristics: 1. Locally advanced, unresectable, or metastatic disease based on most recent imaging 2. For Part 1, 2, 3a, 4a pathologically documented adenocarcinoma of the stomach/GEJ/esophagus, HER2-positive (IHC 3+ or IHC 2+/ISH+) based on local tissue testing results 3. For Part 3b,4b and Part 5, pathologically documented adenocarcinoma of the stomach/GEJ/esophagus, HER2-low (IHC 2+/ISH-negative or IHC 1+) based on local tissue testing results 3. For Part 1, progression on or after at least one prior trastuzumabcontaining regimen For Part 2, Part 3, Part 4 and Part 5, previously untreated for unresectable or metastatic adenocarcinoma of the stomach/GEJ/ esophagus with with HER2-positive (Part 2 and Part 3 \[Arm 3A\] and Part 4 \[Arm 4A\]) or HER2-low (Part 3 \[Arm 3B\], Part 4 \[Arm 4B\] and Part 5)) status 4. Has measurable target disease assessed by the Investigator based on RECIST version 1.1 5. Has protocol defined adequate bone marrow and organ function including cardiac, renal and hepatic function 6. If of reproductive potential, agrees to use a highly effective form of contraception or avoid intercourse during and upon completion of the study. Exclusion criteria: 1. Part 1 to 4: History of active primary immunodeficiency, known HIV, active chronic, or past hepatitis B infection, or hepatitis C infection. Part 5: evidence of active, uncontroled HIV, HBV or HCV infection. 2. Uncontrolled intercurrent illness. 3. History of non-infectious pneumonitis/ILD, current ILD, or where suspected ILD that cannot be ruled out by imaging at screening. 4. Lung-specific intercurrent clinically significant severe illnesses. 5. Uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals. 6. Pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART). 7. Has spinal cord compression or clinically active central nervous system metastases.

Locations (100)

Research Site

Santa Monica, California, United States

WITHDRAWN

Research Site

Westwood, Kansas, United States

WITHDRAWN

Research Site

Baltimore, Maryland, United States

RECRUITING

Research Site

Boston, Massachusetts, United States

WITHDRAWN

Outcomes

Primary Outcomes

Part 1: Occurrence of adverse events (AEs) and serious adverse events (SAEs), graded according to NCI CTCAE v5.0

Occurrence of AEs and SAEs graded according to NCI CTCAE v5.0

Time frame: Safety will be assessed up to the follow-up period, approximately 24 months.

Part 1: Ocurrence of dose-limiting toxicities (DLTs)

Occurrence of dose limiting toxicities

Time frame: Safety will be assessed up to the follow-up period, approximately 24 months.

Part 1: Changes from baseline in laboratory parameters

Changes in laboratory parameters (every in appropriate units) compared to baseline results.

Time frame: Safety will be assessed up to the follow-up period, approximately 24 months.

Part 1: Changes from baseline in vital signs

Changes in vital signs results compared to baseline results.

Time frame: Safety will be assessed up to the follow-up period, approximately 24 months.

Part 1: Changes from baseline in electrocardiogram (ECG) results

Changes in ECG results compared to baseline results.

Time frame: Safety will be assessed up to the follow-up period, approximately 24 months.

Part 2, Part 3, Part 4 and Part 5: Endpoint assessed by Investigator per RECIST v1.1: Confirmed Objective Response Rate (ORR)

Confirmed ORR per RECIST 1.1 is the percentage of patients with Complete Response or Partial Response that is subsequently confirmed.

Time frame: (Endpoint: ORR) Efficacy will be assessed at an average of approximately 12 months

Secondary Outcomes

Part 1: Objective Response Rate (ORR)

Confirmed ORR per RECIST 1.1 is the percentage of patients with Complete Response or Partial Response that is subsequently confirmed.

Time frame: Efficacy will be assessed at an average of approximately 12 months

Part 2, Part 3, Part 4 and Part 5: Occurrence of adverse events (AEs) and serious adverse events (SAEs)

Occurrence of AEs and SAEs graded according to NCI CTCAE v5.0

Time frame: Safety will be assessed up to follow-up period, approximately 24 months

Part 2, Part 3, Part 4 and Part 5: Changes from baseline in laboratory parameters

Changes in laboratory parameters (every in appropriate units) compared to baseline results.

Time frame: Safety will be assessed up to follow-up period, approximately 24 months

Part 2, Part 3, Part 4 and Part 5: Changes from baseline in vital signs

Changes in vital signs results compared to baseline results.

Time frame: Safety will be assessed up to follow-up period, approximately 24 months

Part 2, Part 3 , Part 4 and Part 5: Changes from baseline in body weight

Changes in body weight in kilograms compared to baseline results.

Time frame: Safety will be assessed up to follow-up period, approximately 24 months

Part 2, Part 3, Part 4 and Part 5: Changes from baseline in electrocardiogram (ECG) results

Changes in ECG results compared to baseline results.

Time frame: Safety will be assessed up to follow-up period, approximately 24 months

Duration of Response (DoR)

DOR is defined as the time from the date of first documented response until the date of documented progression or death

Time frame: Until progression or death, efficacy (DoR) will be assessed up to approximately 24 months

Disease Control Rate (DCR)

DCR is the percentage of subjects who have a best overall response of complete response (CR) or partial response (PR) or stable disease (SD)

Time frame: Efficacy will be assessed at an average of approximately 12 months

Progression Free Survival (PFS)

PFS is the time from date of first dose until the date of objective disease progression or death

Time frame: Until progression or death, efficacy (PFS) will be assessed up to approximately 24 months

Overall survival (OS)

OS is the time from date of first dose until death due to any cause

Time frame: Until death, efficacy (OS) will be assessed up to approximately 24 months

Serum concentration of T-DXd, total anti-HER2 antibody, and MAAA-1181a in all arms

Individual participant data and descriptive statistics will be provided for serum concentration data at each time point for each dose level for T-DXd, total anti-HER2 antibody, MAAA-1181a