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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Gastric Cancer

Intervention / Treatment
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* Drug: Fluorouracil (5-FU)
* Drug: Capecitabine
* Biological: Durvalumab
* Drug: Oxaliplatin
* Biological: Trastuzumab
* Drug: Trastuzumab deruxtecan
* Drug: Cisplatin
* Biological: Pembrolizumab
* Biological: MEDI5752


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male and female participants must be at least 18 years of age. Other age restrictions may apply as per local regulations Disease Characteristics: Locally advanced, unresectable, or metastatic disease based on most recent imaging For Part 1, 2, 3a, pathologically documented adenocarcinoma of the stomach/GEJ/esophagus, HER2-positive (IHC 3+ or IHC 2+/ISH+) based on local tissue testing results For Part 3b, pathologically documented adenocarcinoma of the stomach/GEJ/esophagus, HER2-low (IHC 2+/ISH-negative or IHC 1+) based on local tissue testing results For Part 1, progression on or after at least one prior trastuzumabcontaining regimen For Part 2 and Part 3, previously untreated for unresectable or metastatic adenocarcinoma of the stomach/GEJ/ esophagus with with HER2-positive (Part 2 and Part 3, Arm 3A) or HER2-low (Part 3, Arm 3B) status 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1A<br>T-DXd and 5-fluorouracil (5-FU) | Drug: Fluorouracil (5-FU)<br>* 5-FU: administered as an IV infusion<br>Drug: Trastuzumab deruxtecan<br>* T-DXd: administered as an IV infusion<br>* Other names: DS-8201a;|
| Experimental: Arm 1B<br>T-DXd and capecitabine | Drug: Capecitabine<br>* Capecitabine: administered orally<br>Drug: Trastuzumab deruxtecan<br>* T-DXd: administered as an IV infusion<br>* Other names: DS-8201a;|
| Experimental: Arm 1C<br>T-DXd and durvalumab | Biological: Durvalumab<br>* Durvalumab: administered as an IV infusion<br>* Other names: MEDI4736;Drug: Trastuzumab deruxtecan<br>* T-DXd: administered as an IV infusion<br>* Other names: DS-8201a;|
| Experimental: Arm 1D(b)<br>T-DXd, capecitabine, and oxaliplatin | Drug: Capecitabine<br>* Capecitabine: administered orally<br>Drug: Oxaliplatin<br>* Oxaliplatin: administered as an IV infusion<br>Drug: Trastuzumab deruxtecan<br>* T-DXd: administered as an IV infusion<br>* Other names: DS-8201a;|
| Experimental: Arm 1E(a)<br>T-DXd, 5-FU, and durvalumab | Drug: Fluorouracil (5-FU)<br>* 5-FU: administered as an IV infusion<br>Biological: Durvalumab<br>* Durvalumab: administered as an IV infusion<br>* Other names: MEDI4736;Drug: Trastuzumab deruxtecan<br>* T-DXd: administered as an IV infusion<br>* Other names: DS-8201a;|
| Experimental: Arm 1E(b)<br>T-DXd, capecitabine, and durvalumab | Drug: Capecitabine<br>* Capecitabine: administered orally<br>Biological: Durvalumab<br>* Durvalumab: administered as an IV infusion<br>* Other names: MEDI4736;Drug: Trastuzumab deruxtecan<br>* T-DXd: administered as an IV infusion<br>* Other names: DS-8201a;|
| Active Comparator: Arm 2A<br>Trastuzumab, 5-FU or capecitabine, and cisplatin or oxaliplatin | Drug: Fluorouracil (5-FU)<br>* 5-FU: administered as an IV infusion<br>Drug: Capecitabine<br>* Capecitabine: administered orally<br>Drug: Oxaliplatin<br>* Oxaliplatin: administered as an IV infusion<br>Biological: Trastuzumab<br>* Trastuzumab: administered as an IV infusion<br>Drug: Cisplatin<br>* Cisplatin: administered as an IV infusion<br>|
| Experimental: Arm 2B<br>T-DXd monotherapy | Drug: Trastuzumab deruxtecan<br>* T-DXd: administered as an IV infusion<br>* Other names: DS-8201a;|
| Experimental: Arm 2C<br>T-DXd, 5-FU or capecitabine | Drug: Fluorouracil (5-FU)<br>* 5-FU: administered as an IV infusion<br>Drug: Capecitabine<br>* Capecitabine: administered orally<br>Drug: Trastuzumab deruxtecan<br>* T-DXd: administered as an IV infusion<br>* Other names: DS-8201a;|
| Experimental: Arm 2D<br>T-DXd, 5-FU or capecitabine, and pembrolizumab | Drug: Fluorouracil (5-FU)<br>* 5-FU: administered as an IV infusion<br>Drug: Capecitabine<br>* Capecitabine: administered orally<br>Drug: Trastuzumab deruxtecan<br>* T-DXd: administered as an IV infusion<br>* Other names: DS-8201a;Biological: Pembrolizumab<br>* Pembrolizumab: administered as an IV infusion<br>|
| Experimental: Arm 2E<br>T-DXd and pembrolizumab | Drug: Trastuzumab deruxtecan<br>* T-DXd: administered as an IV infusion<br>* Other names: DS-8201a;Biological: Pembrolizumab<br>* Pembrolizumab: administered as an IV infusion<br>|
| Experimental: Arm 2F<br>T-DXd, chemotherapy (FP) and pembrolizumab | Drug: Fluorouracil (5-FU)<br>* 5-FU: administered as an IV infusion<br>Drug: Capecitabine<br>* Capecitabine: administered orally<br>Drug: Trastuzumab deruxtecan<br>* T-DXd: administered as an IV infusion<br>* Other names: DS-8201a;Biological: Pembrolizumab<br>* Pembrolizumab: administered as an IV infusion<br>|
| Experimental: Arm 3A<br>T-DXd, FP and BSP (MEDI5752) | Drug: Fluorouracil (5-FU)<br>* 5-FU: administered as an IV infusion<br>Drug: Capecitabine<br>* Capecitabine: administered orally<br>Drug: Trastuzumab deruxtecan<br>* T-DXd: administered as an IV infusion<br>* Other names: DS-8201a;Biological: MEDI5752<br>* MEDI5752: administered as an IV infusion<br>|
| Experimental: Arm 3B<br>T-DXd, FP and BSP (MEDI5752) | Drug: Fluorouracil (5-FU)<br>* 5-FU: administered as an IV infusion<br>Drug: Capecitabine<br>* Capecitabine: administered orally<br>Drug: Trastuzumab deruxtecan<br>* T-DXd: administered as an IV infusion<br>* Other names: DS-8201a;Biological: MEDI5752<br>* MEDI5752: administered as an IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 | 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. | 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. | 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. | Safety will be assessed up to the follow-up period, approximately 24 months. | 
| 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. | (Endpoint: ORR) Efficacy will be assessed at an average of approximately 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Efficacy will be assessed at an average of approximately 12 months | 
| 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 | Safety will be assessed up to follow-up period, approximately 24 months | 
| Part 2 and Part 3: Changes from baseline in laboratory parameters | Changes in laboratory parameters (every in appropriate units) compared to baseline results. | Safety will be assessed up to follow-up period, approximately 24 months | 
| Part 2 and Part 3: Changes from baseline in vital signs | Changes in vital signs results compared to baseline results. | Safety will be assessed up to follow-up period, approximately 24 months | 
| Part 2 and Part 3: Changes from baseline in body weight | Changes in body weight in kilograms compared to baseline results. | Safety will be assessed up to follow-up period, approximately 24 months | 
| Part 2 and Part 3: Changes from baseline in electrocardiogram (ECG) results | Changes in ECG results compared to baseline results. | 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 | 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) | 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 | 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 | 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 | While on study drug up to study completion, approximately 24 months | 
| 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. | While on study drug up to study completion, approximately 24 months | 
| 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. | While on study drug up to study completion, approximately 24 months | 
| 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. | While on study drug up to study completion, approximately 24 months | 
| 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 | While on study drug up to study completion, approximately 24 months | 
| 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 | While on study drug up to study completion, approximately 24 months | 
| 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 | While on study drug up to study completion, approximately 24 months | 
| 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 | While on study drug up to study completion, approximately 24 months | 
| 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 | While on study drug up to study completion, approximately 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gastric Cancer, Esophageal Cancer, Carcinoma, HER2, Trastuzumab, Deruxtecan, T-DXd, DS-8201a, Gastroesophageal Cancer