Clinical trial NCT04379596: Ph1b/2 Study of the Safety and Efficacy of T-DXd Combinations in Advanced HER2-expressing Gastric Cancer (DESTINY-Gastric03)
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
Overall status: RECRUITING
Phase: PHASE2
Conditions: Gastric Cancer
Keywords: Gastric Cancer
Esophageal Cancer
Carcinoma
HER2
Trastuzumab
Deruxtecan
T-DXd
DS-8201a
Gastroesophageal Cancer
Adenocarcinoma
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Daiichi Sankyo Company, Limited 3-5-1 Nihonbashihoncho, Chuo-ku, Tokyo
First posted: 2020-05-07
Enrollment: 413
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The study will consist of 2 phases: a dose escalation phase (Part 1) and dose expansion phases (Part 2, Part 3 and Part 4). 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 and Part 4 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

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.


Eligibility criteria: 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 and 4b, 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 and Part 4, 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 \[Arm 3B\] and Part 4 \[Arm 4B\])) 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. History of active primary immunodeficiency, known HIV, active chronic, or past hepatitis B infection, or hepatitis C 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.

Primary outcomes:
measure: Part 1: Occurrence of adverse events (AEs) and serious adverse events (SAEs), graded according to NCI CTCAE v5.0
timeFrame: Safety will be assessed up to the follow-up period, approximately 24 months.
measure: Part 1: Ocurrence of dose-limiting toxicities (DLTs)
timeFrame: Safety will be assessed up to the follow-up period, approximately 24 months.
measure: Part 1: Changes from baseline in laboratory parameters
timeFrame: Safety will be assessed up to the follow-up period, approximately 24 months.
measure: Part 1: Changes from baseline in vital signs
timeFrame: Safety will be assessed up to the follow-up period, approximately 24 months.
measure: Part 1: Changes from baseline in electrocardiogram (ECG) results
timeFrame: Safety will be assessed up to the follow-up period, approximately 24 months.
measure: Part 2, Part 3 and Part 4: Endpoint assessed by Investigator per RECIST v1.1: Confirmed Objective Response Rate (ORR)
timeFrame: (Endpoint: ORR) Efficacy will be assessed at an average of approximately 12 months
Secondary outcomes:
measure: Part 1: Objective Response Rate (ORR)
timeFrame: Efficacy will be assessed at an average of approximately 12 months
measure: Part 2, Part 3 and Part 4: Occurrence of adverse events (AEs) and serious adverse events (SAEs)
timeFrame: Safety will be assessed up to follow-up period, approximately 24 months
measure: Part 2, Part 3 and Part 4: Changes from baseline in laboratory parameters
timeFrame: Safety will be assessed up to follow-up period, approximately 24 months
measure: Part 2, Part 3 and Part 4: Changes from baseline in vital signs
timeFrame: Safety will be assessed up to follow-up period, approximately 24 months
measure: Part 2, Part 3 and Part 4: Changes from baseline in body weight
timeFrame: Safety will be assessed up to follow-up period, approximately 24 months
measure: Part 2, Part 3 and Part 4: Changes from baseline in electrocardiogram (ECG) results
timeFrame: Safety will be assessed up to follow-up period, approximately 24 months
measure: Duration of Response (DoR)
timeFrame: Until progression or death, efficacy (DoR) will be assessed up to approximately 24 months
measure: Disease Control Rate (DCR)
timeFrame: Efficacy will be assessed at an average of approximately 12 months
measure: Progression Free Survival (PFS)
timeFrame: Until progression or death, efficacy (PFS) will be assessed up to approximately 24 months
measure: Overall survival (OS)
timeFrame: Until death, efficacy (OS) will be assessed up to approximately 24 months
measure: Serum concentration of T-DXd, total anti-HER2 antibody, and MAAA-1181a in all arms
timeFrame: While on study drug up to study completion, approximately 24 months
measure: Serum concentration of durvalumab in study arms including T-DXd in combination with durvalumab
timeFrame: While on study drug up to study completion, approximately 24 months
measure: Presence of ADAs for T-DXD, durvalumab, volrustomig and rilvegostomig (in study arms including T-DXd and durvalumab, and T-DXd and volrustomig, and T-DXd and rilvegostomig respectively)
timeFrame: While on study drug up to study completion, approximately 24 months
measure: Serum concentrations of volrustomig and rilvegostomig in study arms including T-DXd in combination with volrustomig and T-DXd in combination with rilvegostomig
timeFrame: While on study drug up to study completion, approximately 24 months
measure: Comparison of ORR
timeFrame: While on study drug up to study completion, approximately 24 months
measure: Comparison of DCR
timeFrame: While on study drug up to study completion, approximately 24 months
measure: Comparison of DoR
timeFrame: While on study drug up to study completion, approximately 24 months
measure: Comparison of PFS
timeFrame: While on study drug up to study completion, approximately 24 months
measure: Comparison of OS
timeFrame: While on study drug up to study completion, approximately 24 months
Other outcomes:
Locations:
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country: Russian Federation
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country: Taiwan
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city: Tainan
country: Taiwan
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country: Taiwan
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city: Taipei
country: Taiwan
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country: Taiwan
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country: United Kingdom
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city: London
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city: Manchester
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city: Sutton
country: United Kingdom
facility: Research Site
Study officials:
References: