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

AstraZeneca

Status and phase: Enrolling; Phase 2

Conditions: Gastric Cancer

Treatments: Drug: Fluorouracil (5-FU); Drug: Cisplatin; Biological: Durvalumab; Biological: Volrustomig; Drug: Capecitabine; Biological: Rilvegostomig; Drug: Trastuzumab deruxtecan; Biological: Pembrolizumab; Drug: Oxaliplatin; Biological: Trastuzumab

Study type: Interventional

Funder types: Industry

Identifiers

NCT04379596

2019-004483-22 (EudraCT Number)

D967LC00001

Details and patient eligibility

About

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.

Enrollment: 413 estimated patients

Sex: All

Ages: 18 to 130 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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413 participants in 18 patient groups

Arm 1A

Experimental group

Description:

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

Treatment:

Drug: Trastuzumab deruxtecan

Drug: Fluorouracil (5-FU)

Arm 1B

Experimental group

Description:

T-DXd and capecitabine

Treatment:

Drug: Trastuzumab deruxtecan

Drug: Capecitabine

Arm 1C

Experimental group

Description:

T-DXd and durvalumab

Treatment:

Drug: Trastuzumab deruxtecan

Biological: Durvalumab

Arm 1D(b)

Experimental group

Description:

T-DXd, capecitabine, and oxaliplatin

Treatment:

Drug: Oxaliplatin

Drug: Trastuzumab deruxtecan

Drug: Capecitabine

Arm 1E(a)

Experimental group

Description:

T-DXd, 5-FU, and durvalumab

Treatment:

Drug: Trastuzumab deruxtecan

Biological: Durvalumab

Drug: Fluorouracil (5-FU)

Arm 1E(b)

Experimental group

Description:

T-DXd, capecitabine, and durvalumab

Treatment:

Drug: Trastuzumab deruxtecan

Drug: Capecitabine

Biological: Durvalumab

Arm 2A

Active Comparator group

Description:

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

Treatment:

Biological: Trastuzumab

Drug: Oxaliplatin

Drug: Capecitabine

Drug: Cisplatin

Drug: Fluorouracil (5-FU)

Arm 2B

Experimental group

Description:

T-DXd monotherapy

Treatment:

Drug: Trastuzumab deruxtecan

Arm 2C

Experimental group

Description:

T-DXd, 5-FU or capecitabine

Treatment:

Drug: Trastuzumab deruxtecan

Drug: Capecitabine

Drug: Fluorouracil (5-FU)

Arm 2D

Experimental group

Description:

T-DXd, pembrolizumab and 5-FU or capecitabine

Treatment:

Biological: Pembrolizumab

Drug: Trastuzumab deruxtecan

Drug: Capecitabine

Drug: Fluorouracil (5-FU)

Arm 2E

Experimental group

Description:

T-DXd and pembrolizumab

Treatment:

Biological: Pembrolizumab

Drug: Trastuzumab deruxtecan

Arm 2F

Experimental group

Description:

T-DXd, pembrolizumab and 5-FU or capecitabine

Treatment:

Biological: Pembrolizumab

Drug: Trastuzumab deruxtecan

Drug: Capecitabine

Drug: Fluorouracil (5-FU)

Arm 3A

Experimental group

Description:

T-DXd, Volrustomig and 5-FU or capecitabine

Treatment:

Drug: Trastuzumab deruxtecan

Drug: Capecitabine

Biological: Volrustomig

Drug: Fluorouracil (5-FU)

Arm 3B

Experimental group

Description:

T-DXd, Volrustomig and 5-FU or capecitabine

Treatment:

Drug: Trastuzumab deruxtecan

Drug: Capecitabine

Biological: Volrustomig

Drug: Fluorouracil (5-FU)

Arm 4A

Experimental group

Description:

T-DXd, Rilvegostomig and 5-FU or capecitabine

Treatment:

Drug: Trastuzumab deruxtecan

Biological: Rilvegostomig

Drug: Capecitabine

Drug: Fluorouracil (5-FU)

Arm 4B

Experimental group

Description:

T-DXd, Rilvegostomig and 5-FU or capecitabine

Treatment:

Drug: Trastuzumab deruxtecan

Biological: Rilvegostomig

Drug: Capecitabine

Drug: Fluorouracil (5-FU)

Part 5 Main Cohort

Experimental group

Description:

T-DXd, Volrustomig and 5-FU or capecitabine

Treatment:

Drug: Trastuzumab deruxtecan

Drug: Capecitabine

Biological: Volrustomig

Drug: Fluorouracil (5-FU)

Part 5 Cohort 2

Experimental group

Description:

T-DXd, Volrustomig and 5-FU or capecitabine

Treatment:

Drug: Trastuzumab deruxtecan

Drug: Capecitabine

Biological: Volrustomig

Drug: Fluorouracil (5-FU)