Dysautonomia International

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

Purpose

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.

Condition

Gastric Cancer

Eligibility

Eligible Ages: Between 18 Years and 130 Years
Eligible Sex: All
Accepts Healthy Volunteers: No

Inclusion Criteria

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

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.

Study Design

Phase: Phase 2
Study Type: Interventional
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: The study will consist of 2 phases: a dose escalation phase (Part 1) and dose expansion phases (Part 2, Part 3, Part 4 and Part 5). 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, Part 4 and Part 5 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.
Primary Purpose: Treatment
Masking: None (Open Label)

Arm Groups

Arm	Description	Assigned Intervention
Experimental Arm 1A	T-DXd and 5-fluorouracil (5-FU)	Drug: Fluorouracil (5-FU) 5-FU: administered as an IV infusion Drug: Trastuzumab deruxtecan T-DXd: administered as an IV infusion Other names: DS-8201a, Enhertu
Experimental Arm 1B	T-DXd and capecitabine	Drug: Capecitabine Capecitabine: administered orally Drug: Trastuzumab deruxtecan T-DXd: administered as an IV infusion Other names: DS-8201a, Enhertu
Experimental Arm 1C	T-DXd and durvalumab	Biological: Durvalumab Durvalumab: administered as an IV infusion Other names: MEDI4736 Drug: Trastuzumab deruxtecan T-DXd: administered as an IV infusion Other names: DS-8201a, Enhertu
Experimental Arm 1D(b)	T-DXd, capecitabine, and oxaliplatin	Drug: Capecitabine Capecitabine: administered orally Drug: Oxaliplatin Oxaliplatin: administered as an IV infusion Drug: Trastuzumab deruxtecan T-DXd: administered as an IV infusion Other names: DS-8201a, Enhertu
Experimental Arm 1E(a)	T-DXd, 5-FU, and durvalumab	Drug: Fluorouracil (5-FU) 5-FU: administered as an IV infusion Biological: Durvalumab Durvalumab: administered as an IV infusion Other names: MEDI4736 Drug: Trastuzumab deruxtecan T-DXd: administered as an IV infusion Other names: DS-8201a, Enhertu
Experimental Arm 1E(b)	T-DXd, capecitabine, and durvalumab	Drug: Capecitabine Capecitabine: administered orally Biological: Durvalumab Durvalumab: administered as an IV infusion Other names: MEDI4736 Drug: Trastuzumab deruxtecan T-DXd: administered as an IV infusion Other names: DS-8201a, Enhertu
Active Comparator Arm 2A	Trastuzumab, 5-FU or capecitabine, and cisplatin or oxaliplatin	Drug: Fluorouracil (5-FU) 5-FU: administered as an IV infusion Drug: Capecitabine Capecitabine: administered orally Drug: Oxaliplatin Oxaliplatin: administered as an IV infusion Biological: Trastuzumab Trastuzumab: administered as an IV infusion Drug: Cisplatin Cisplatin: administered as an IV infusion
Experimental Arm 2B	T-DXd monotherapy	Drug: Trastuzumab deruxtecan T-DXd: administered as an IV infusion Other names: DS-8201a, Enhertu
Experimental Arm 2C	T-DXd, 5-FU or capecitabine	Drug: Fluorouracil (5-FU) 5-FU: administered as an IV infusion Drug: Capecitabine Capecitabine: administered orally Drug: Trastuzumab deruxtecan T-DXd: administered as an IV infusion Other names: DS-8201a, Enhertu
Experimental Arm 2D	T-DXd, pembrolizumab and 5-FU or capecitabine	Drug: Fluorouracil (5-FU) 5-FU: administered as an IV infusion Drug: Capecitabine Capecitabine: administered orally Drug: Trastuzumab deruxtecan T-DXd: administered as an IV infusion Other names: DS-8201a, Enhertu Biological: Pembrolizumab Pembrolizumab: administered as an IV infusion
Experimental Arm 2E	T-DXd and pembrolizumab	Drug: Trastuzumab deruxtecan T-DXd: administered as an IV infusion Other names: DS-8201a, Enhertu Biological: Pembrolizumab Pembrolizumab: administered as an IV infusion
Experimental Arm 2F	T-DXd, pembrolizumab and 5-FU or capecitabine	Drug: Fluorouracil (5-FU) 5-FU: administered as an IV infusion Drug: Capecitabine Capecitabine: administered orally Drug: Trastuzumab deruxtecan T-DXd: administered as an IV infusion Other names: DS-8201a, Enhertu Biological: Pembrolizumab Pembrolizumab: administered as an IV infusion
Experimental Arm 3A	T-DXd, Volrustomig and 5-FU or capecitabine	Drug: Fluorouracil (5-FU) 5-FU: administered as an IV infusion Drug: Capecitabine Capecitabine: administered orally Drug: Trastuzumab deruxtecan T-DXd: administered as an IV infusion Other names: DS-8201a, Enhertu Biological: Volrustomig Volrustomig: administered as an IV infusion Other names: MEDI5752
Experimental Arm 3B	T-DXd, Volrustomig and 5-FU or capecitabine	Drug: Fluorouracil (5-FU) 5-FU: administered as an IV infusion Drug: Capecitabine Capecitabine: administered orally Drug: Trastuzumab deruxtecan T-DXd: administered as an IV infusion Other names: DS-8201a, Enhertu Biological: Volrustomig Volrustomig: administered as an IV infusion Other names: MEDI5752
Experimental Arm 4A	T-DXd, Rilvegostomig and 5-FU or capecitabine	Drug: Fluorouracil (5-FU) 5-FU: administered as an IV infusion Drug: Capecitabine Capecitabine: administered orally Drug: Trastuzumab deruxtecan T-DXd: administered as an IV infusion Other names: DS-8201a, Enhertu Biological: Rilvegostomig Rilvegostomig: administered as an IV infusion Other names: AZD2936
Experimental Arm 4B	T-DXd, Rilvegostomig and 5-FU or capecitabine	Drug: Fluorouracil (5-FU) 5-FU: administered as an IV infusion Drug: Capecitabine Capecitabine: administered orally Drug: Trastuzumab deruxtecan T-DXd: administered as an IV infusion Other names: DS-8201a, Enhertu Biological: Rilvegostomig Rilvegostomig: administered as an IV infusion Other names: AZD2936
Experimental Part 5 Main Cohort	T-DXd, Volrustomig and 5-FU or capecitabine	Drug: Fluorouracil (5-FU) 5-FU: administered as an IV infusion Drug: Capecitabine Capecitabine: administered orally Drug: Trastuzumab deruxtecan T-DXd: administered as an IV infusion Other names: DS-8201a, Enhertu Biological: Volrustomig Volrustomig: administered as an IV infusion Other names: MEDI5752
Experimental Part 5 Cohort 2	T-DXd, Volrustomig and 5-FU or capecitabine	Drug: Fluorouracil (5-FU) 5-FU: administered as an IV infusion Drug: Capecitabine Capecitabine: administered orally Drug: Trastuzumab deruxtecan T-DXd: administered as an IV infusion Other names: DS-8201a, Enhertu Biological: Volrustomig Volrustomig: administered as an IV infusion Other names: MEDI5752

Recruiting Locations

Research Site
Baltimore, Maryland 21287

Research Site
Boston, Massachusetts 02215

Research Site
New York, New York 10065

Research Site
Houston, Texas 77090

More Details

Status: Recruiting
Sponsor: AstraZeneca

Study Contact

AstraZeneca Clinical Study Information Center
1-877-240-9479
information.center@astrazeneca.com

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.