Clinical trial NCT06731478: Study of TDXd, Chemotherapy, Pembrolizumab, and Trastuzumab in First-Line Metastatic HER2-Positive Gastric or Gastroesophageal Junction Cancer
Official title: A Multicenter, Randomized, Open-Label, Phase 3 Trial of Trastuzumab Deruxtecan (Enhertu®) Plus Chemotherapy Plus or Minus Pembrolizumab Versus Chemotherapy Plus Trastuzumab Plus or Minus Pembrolizumab as First-Line Treatment in Participants With Unresectable, Locally Advanced or Metastatic HER2-Positive Gastric Or Gastroesophageal Junction (GEJ) Cancer (Destiny-Gastric05)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Gastric Cancer
Gastroesophageal Junction Cancer
Keywords: Enhertu
Trastuzumab Deruxtecan
Chemotherapy
DS-8201a
HER2 positive
Lead sponsor: Daiichi Sankyo
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2024-12-12
Enrollment: 726
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This clinical trial is designed to assess the efficacy and safety of the triplet combination of trastuzumab deruxtecan (ENHERTU, T-DXd, DS-8201a) plus a fluoropyrimidine plus pembrolizumab versus standard of care (SoC) chemotherapy plus trastuzumab plus pembrolizumab as first-line therapy in participants with unresectable, locally advanced or metastatic HER2-positive tumor PD-L1 CPS ≥1 gastric or GEJ cancer in the Main Cohort. An Exploratory Cohort will also be evaluated to assess the efficacy and safety of T-DXd plus a fluoropyrimidine versus SoC chemotherapy plus trastuzumab in participants with unresectable, locally advanced or metastatic HER2-positive tumor PD-L1 CPS \<1 gastric or GEJ cancer.


Eligibility criteria: Inclusion

1. Sign and date the Tissue Prescreening ICF, prior to HER2 and PD-L1 CPS central testing. Sign and date the Main Screening ICF, prior to the start of any trial-specific qualification procedures. Sign and date the Optional PGx ICF (included in the Main Screening ICF) prior to any PGx procedure.
2. Adults ≥18 years of age on the day of signing the ICF. Follow local regulatory requirements if the legal age of consent for trial participation is \>18 years old.
3. Previously untreated, unresectable, locally advanced or metastatic gastric or GEJ adenocarcinoma histologically confirmed by pathology report. Prior treatment in the perioperative and/or adjuvant setting is permissible, provided there is \>6 months between the end of perioperative or neoadjuvant treatment and the diagnosis of recurrent disease.

   Note: Prior use of IO (ie, anti-PD-1/PD-L1) therapy in the (neo)adjuvant setting is allowed as long as there is \>6 months between the end of IO therapy and the diagnosis of recurrent disease.
4. Centrally determined HER2-positive (IHC 3+ or IHC 2+/ISH-positive) gastric or GEJ cancer as classified by the American Society of Clinical Oncology-College of American Pathologists for GC on a tumor biopsy as detected by prospective central test on new (core, incisional, excisional biopsy) or existing tumor tissue taken at the time of diagnosis of locally advanced or metastatic disease.

   Note: Archival samples taken from a previous diagnostic or surgical biopsy not previously irradiated can be accepted. Details pertaining to tumor tissue submission can be found in the Study Laboratory Manual.
5. All participants must provide a tumor sample for tissue-based IHC staining to centrally determine HER2 expression, PD-L1 CPS, and other correlatives. The mandatory FFPE tumor sample can be from either the primary tumor or metastatic biopsy. Specimens with limited tumor content (as centrally determined) and cytology samples are inadequate for defining tumor HER2 and PD-L1 status.
6. At least 1 target measurable lesion on CT or MRI, assessed by the investigator based on RECIST v1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been shown in such lesions.
7. LVEF ≥50% within 28 days before randomization.

exclusion criteria

1. Prior exposure to other HER2-targeting therapies (including ADCs).
2. Lack of physiological integrity of the upper gastrointestinal tract (ie, severe Crohn disease that results in malabsorption) or malabsorption syndrome that would preclude feasibility of oral chemotherapy (ie, capecitabine).
3. Known DPD enzyme deficiency. Note: Screening for DPD enzyme deficiency is required only in regions/countries where DPD testing is SoC and with unknown DPD status. For regions/countries where DPD testing is not SoC, local practice should be followed.
4. Contraindications to trastuzumab, 5-FU, capecitabine, cisplatin, or oxaliplatin treatment as per local label.
5. Medical history of myocardial infarction within 6 months before randomization or symptomatic CHF (New York Heart Association Class II to IV). Participants with troponin levels above ULN at Screening (as defined by the manufacturer) and without any myocardial infarction -related symptoms should have a cardiologic consultation during the Screening Period to rule out myocardial infarction.
6. Has a corrected QT interval (QTcF) prolongation to \>470 ms (females) or \>450 ms (males) based on the average of the screening triplicate 12-lead ECG.
7. Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening
8. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of the trial randomization, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, etc).

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: From date of randomization to the date of radiographic disease progression or death due to any cause, up to 59 months
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: From date of randomization to the date of death due to any cause, up to 59 months
Other outcomes:
Locations:
city: Laval
country: Canada
facility: Cité de la Santé de Laval
city: Toronto
country: Canada
facility: Mount Sinai Hospital
city: Beijing
country: China
facility: Beijing Cancer Hospital
city: Beijing
country: China
facility: Peking University Third Hospital
city: Wuhan
country: China
facility: Hubei Cancer Hospital
city: Chuo-ku
country: Japan
facility: National Cancer Center Hospital
city: Gifu-shi
country: Japan
facility: Gifu University Hospital
city: Kashiwa-shi
country: Japan
facility: National Cancer Center Hospital East
city: Kitakyushu
country: Japan
facility: JCHO Kyushu Hospital
city: Kochi-shi
country: Japan
facility: Kochi Health Sciences Center
city: Koto-ku
country: Japan
facility: Cancer Institute Hospital of JFCR
city: Matsuyama-shi
country: Japan
facility: NHO Shikoku Cancer Center
city: Natori-shi
country: Japan
facility: Miyagi Cancer Center
city: Niigata-shi
country: Japan
facility: Niigata Cancer Center Hospital
city: Osaka-shi
country: Japan
facility: Osaka International Cancer Institute
city: Osakasayama-shi
country: Japan
facility: Kindai University Hospital
city: Sapporo-shi
country: Japan
facility: Hokkaido University Hospital
city: Suita-shi
country: Japan
facility: Osaka University Hospital
city: Yokohama-shi
country: Japan
facility: Kanagawa Cancer Center
city: Hwasun-gun
country: Korea, Republic of
facility: Chonnam National University Hwasun Hospital
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center
city: Jeonju-si
country: Korea, Republic of
facility: Jeonbuk national university hospital
city: Seongnam
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Tilburg
country: Netherlands
facility: ETZ Elisabeth
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taoyuan City
country: Taiwan
facility: Chang Gung Memorial Hospital,Linkou
Study officials:
References: