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Ph1b/2 Study of the Safety and Efficacy of T-DXd Combinations in Advanced HER2-expressing Gastric Cancer (DESTINY-Gastric03) (DG-03)

Primary Purpose

Gastric Cancer

Status

Recruiting

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Fluorouracil (5-FU)

Capecitabine

Durvalumab

Oxaliplatin

Trastuzumab

Trastuzumab deruxtecan

Cisplatin

Pembrolizumab

MEDI5752

About this trial

This is an interventional treatment trial for Gastric Cancer focused on measuring Gastric Cancer, Esophageal Cancer, Carcinoma, HER2, Trastuzumab, Deruxtecan, T-DXd, DS-8201a, Gastroesophageal Cancer

Eligibility Criteria

18 Years - 130 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria:

Male and female participants must be at least 18 years of age
Disease Characteristics:
Locally advanced, unresectable, or metastatic disease Pathologically documented adenocarcinoma of the stomach, GEJ or esophagus with HER2 overexpression (IHC 3+ or IHC 2+/ISH+)
For Part 1, progression on or after at least one prior trastuzumab containing Regimen.
For Part 2, previously untreated for unresectable or metastatic adenocarcinoma of the stomach, GEJ or esophagus with HER2 overexpression.
Has measurable target disease assessed by the Investigator based on RECIST version 1.1
Has protocol defined adequate organ function including cardiac, renal and hepatic function
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:

History of active primary immunodeficiency, known HIV, active HBV or HCV infection.
Uncontrolled intercurrent illness
History of non-infectious pneumonitis/ILD, current ILD, or where suspected ILD that cannot be ruled out by imaging at screening.
Lung-specific intercurrent clinically significant severe illnesses.
Uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals.
Pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART).
Has spinal cord compression or clinically active central nervous system metastases.

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm 10

Arm 11

Arm 12

Arm 13

Arm 14

Arm Type

Experimental

Active Comparator

Experimental

Arm Label

Arm 1A

Arm 1B

Arm 1C

Arm 1D(b)

Arm 1E(a)

Arm 1E(b)

Arm 2A

Arm 2B

Arm 2C

Arm 2D

Arm 2E

Arm 2F

Arm 3A

Arm 3B

Arm Description

T-DXd and 5-fluorouracil (5-FU)

T-DXd and capecitabine

T-DXd and durvalumab

T-DXd, capecitabine, and oxaliplatin

T-DXd, 5-FU, and durvalumab

T-DXd, capecitabine, and durvalumab

Trastuzumab, 5-FU or capecitabine, and cisplatin or oxaliplatin

T-DXd monotherapy

T-DXd, 5-FU or capecitabine

T-DXd, 5-FU or capecitabine, and pembrolizumab

T-DXd and pembrolizumab

T-DXd, chemotherapy (FP) and pembrolizumab

T-DXd, FP and BSP (MEDI5752)

Outcomes

Primary Outcome Measures

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

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

Occurrence of dose limiting toxicities

Part 1: Changes from baseline in laboratory parameters

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

Part 1: Changes from baseline in vital signs

Changes in vital signs results compared to baseline results.

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

Changes in ECG results compared to baseline results.

Part 2 and Part 3: 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.

Secondary Outcome Measures

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.

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

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

Part 2 and Part 3: Changes from baseline in laboratory parameters

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

Part 2 and Part 3: Changes from baseline in vital signs

Changes in vital signs results compared to baseline results.

Part 2 and Part 3: Changes from baseline in body weight

Changes in body weight in kilograms compared to baseline results.

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

Changes in ECG results compared to baseline results.

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

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)

Progression Free Survival (PFS)

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

Overall survival (OS)

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

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

Serum concentration of durvalumab in study arms including T-DXd in combination with durvalumab

Individual participant data and descriptive statistics will be provided for serum concentration data at each time point for durvalumab.

Presence of ADAs for T-DXd and durvalumab and MEDI5752 (in study arms including T-DXd and durvalumab, and T-DXd and MEDI5752, respectively)

Individual participant data and descriptive statistics will be provided for data at each time point for each dose level for T-DXd and durvalumab.

Serum concentrations of MEDI5752 in study arms including T-DXd in combination with MEDI5752,

Individual participant data and descriptive statistics will be provided for data at each time point for MEDI5752.

Comparison of ORR

Comparison of objective response rate between participants using local HER2 test results and central HER2 test results from tumor samples with evaluable results

Comparison of DCR

Comparison of disease control rate between participants using local HER2 test results and central HER2 test results from tumor samples with evaluable results

Comparison of DoR

Comparison of duration of response between participants using local HER2 test results and central HER2 test results from tumor samples with evaluable results

Comparison of PFS

Comparison of progression-free survival between participants using local HER2 test results and central HER2 test results from tumor samples with evaluable results

Comparison of OS

Comparison of overall survival between participants using local HER2 test results and central HER2 test results from tumor samples with evaluable results

Full Information

NCT ID

NCT04379596

First Posted

May 5, 2020

Last Updated

October 12, 2023

Sponsor

AstraZeneca

Collaborators

Daiichi Sankyo Company, Limited 3-5-1 Nihonbashihoncho, Chuo-ku, Tokyo

1. Study Identification

Unique Protocol Identification Number

NCT04379596

Brief Title

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

Acronym

DG-03

Official Title

A Phase 1b/2 Multicenter, Open-label, Dose-escalation and Dose-expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity, and Antitumor Activity of Trastuzumab Deruxtecan (T-DXd) Monotherapy and Combinations in Adult Participants With HER2-expressing Gastric Cancer (DESTINY-Gastric-03)

Study Type

Interventional

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Recruiting

Study Start Date

June 3, 2020 (Actual)

Primary Completion Date

September 29, 2025 (Anticipated)

Study Completion Date

September 29, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

AstraZeneca

Collaborators

Daiichi Sankyo Company, Limited 3-5-1 Nihonbashihoncho, Chuo-ku, Tokyo

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Gastric Cancer

Keywords

Gastric Cancer, Esophageal Cancer, Carcinoma, HER2, Trastuzumab, Deruxtecan, T-DXd, DS-8201a, Gastroesophageal Cancer

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Model Description

The study will consist of 2 phases: a dose escalation phase (Part 1) and dose expansion phases (Part 2 and Part 3). Part 1 will enroll HER2-overexpressing (IHC 3+ or IHC 2+/ISH+), previously treated gastric, gastro-esophageal junction (GEJ) or esophageal cancer patients, and Part 2 will enroll HER2-overexpressing patients who have not received prior treatment for metastatic or unresectable disease. Part 3 will enroll HER2-expressing patients who have not received prior treatment for metastatic or unresectable disease. In addition to safety and tolerability, this study will also assess ORR, DoR, DCR, OS, PFS and other measures of antitumor activity among treatment groups. Tumor evaluation using RECIST v1.1 will be conducted at screening and every 6 weeks until RECIST 1.1 objective disease progression or withdrawal of consent.

Masking

None (Open Label)

Allocation

Randomized

Enrollment

357 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Arm 1A

Arm Type

Experimental

Arm Description

T-DXd and 5-fluorouracil (5-FU)

Arm Title

Arm 1B

Arm Type

Experimental

Arm Description

T-DXd and capecitabine

Arm Title

Arm 1C

Arm Type

Experimental

Arm Description

T-DXd and durvalumab

Arm Title

Arm 1D(b)

Arm Type

Experimental

Arm Description

T-DXd, capecitabine, and oxaliplatin

Arm Title

Arm 1E(a)

Arm Type

Experimental

Arm Description

T-DXd, 5-FU, and durvalumab

Arm Title

Arm 1E(b)

Arm Type

Experimental

Arm Description

T-DXd, capecitabine, and durvalumab

Arm Title

Arm 2A

Arm Type

Active Comparator

Arm Description

Trastuzumab, 5-FU or capecitabine, and cisplatin or oxaliplatin

Arm Title

Arm 2B

Arm Type

Experimental

Arm Description

T-DXd monotherapy

Arm Title

Arm 2C

Arm Type

Experimental

Arm Description

T-DXd, 5-FU or capecitabine

Arm Title

Arm 2D

Arm Type

Experimental

Arm Description

T-DXd, 5-FU or capecitabine, and pembrolizumab

Arm Title

Arm 2E

Arm Type

Experimental

Arm Description

T-DXd and pembrolizumab

Arm Title

Arm 2F

Arm Type

Experimental

Arm Description

T-DXd, chemotherapy (FP) and pembrolizumab

Arm Title

Arm 3A

Arm Type

Experimental

Arm Description

T-DXd, FP and BSP (MEDI5752)

Arm Title

Arm 3B

Arm Type

Experimental

Arm Description

T-DXd, FP and BSP (MEDI5752)

Intervention Type

Drug

Intervention Name(s)

Fluorouracil (5-FU)

Intervention Description

5-FU: administered as an IV infusion

Intervention Type

Drug

Intervention Name(s)

Capecitabine

Intervention Description

Capecitabine: administered orally

Intervention Type

Biological

Intervention Name(s)

Durvalumab

Other Intervention Name(s)

MEDI4736

Intervention Description

Durvalumab: administered as an IV infusion

Intervention Type

Drug

Intervention Name(s)

Oxaliplatin

Intervention Description

Oxaliplatin: administered as an IV infusion

Intervention Type

Biological

Intervention Name(s)

Trastuzumab

Intervention Description

Trastuzumab: administered as an IV infusion

Intervention Type

Drug

Intervention Name(s)

Trastuzumab deruxtecan

Other Intervention Name(s)

DS-8201a

Intervention Description

T-DXd: administered as an IV infusion

Intervention Type

Drug

Intervention Name(s)

Cisplatin

Intervention Description

Cisplatin: administered as an IV infusion

Intervention Type

Biological

Intervention Name(s)

Pembrolizumab

Intervention Description

Pembrolizumab: administered as an IV infusion

Intervention Type

Biological

Intervention Name(s)

MEDI5752

Intervention Description

MEDI5752: administered as an IV infusion

Primary Outcome Measure Information:

Title

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

Description

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.

Title

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

Description

Occurrence of dose limiting toxicities

Time Frame

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

Title

Part 1: Changes from baseline in laboratory parameters

Description

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.

Title

Part 1: Changes from baseline in vital signs

Description

Changes in vital signs results compared to baseline results.

Time Frame

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

Title

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

Description

Changes in ECG results compared to baseline results.

Time Frame

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

Title

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

Description

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 Outcome Measure Information:

Title

Part 1: Objective Response Rate (ORR)

Description

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

Title

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

Description

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

Title

Part 2 and Part 3: Changes from baseline in laboratory parameters

Description

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

Title

Part 2 and Part 3: Changes from baseline in vital signs

Description

Changes in vital signs results compared to baseline results.

Time Frame

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

Title

Part 2 and Part 3: Changes from baseline in body weight

Description

Changes in body weight in kilograms compared to baseline results.

Time Frame

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

Title

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

Description

Changes in ECG results compared to baseline results.

Time Frame

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

Title

Duration of Response (DoR)

Description

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

Title

Disease Control Rate (DCR)

Description

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

Title

Progression Free Survival (PFS)

Description

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

Title

Overall survival (OS)

Description

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

Title

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

Description

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

Time Frame