Gastric-Esophageal Cancer
Conditions
Keywords
ctDNA, Circulating tumor DNA, Gastric-Esophageal Cancer, Signatera, Molecular residual disease, MRD, Biomarker-guided therapy, Durvalumab, Fluorouracil, Leucovorin, Oxaliplatin, Docetaxel, D-FLOT, Adjuvant therapy, Tumor-informed assay, Gastric Cancer, Esophageal Cancer, Gastric adenocarcinoma, ctDNA-guided
Brief summary
The goal of this clinical trial is to assess if circulating tumor DNA, as assessed by Signatera tumor-informed MRD assay, can guide de-escalation of adjuvant therapy in patients with resectable Stage II-IVa Gastric/Gastric-Esophageal Cancer. The main question it aims to answer is: • To demonstrate if 2-year disease-free survival (DFS) among participants with resectable clinical Stage II-IVa gastric/gastro-esophageal cancer who received neoadjuvant D-FLOT and are ctDNA negative after curative intent R0 surgery receiving adjuvant durvalumab monotherapy is non-inferior to standard of care D-FLOT. Researchers will compare post-operative ctDNA negative participants who are receiving adjuvant durvalumab monotherapy to those who receive standard of care (D-FLOT) to see if they have similar outcomes. Participants will be asked to: * Receive serial ctDNA testing * Visit their study doctor per their standard of care visits about every 3 months for first 2 years and then every 6 months for an additional 3 years * Answer 5 questionnaires about their well-being
Detailed description
This is a prospective, open-label, multi-center, ctDNA-guided study with a randomized, non-inferiority component designed to examine clinical outcomes in treatment of gastric/gastric-esophageal cancer. Specifically, a component of the study will evaluate an adjuvant treatment de-escalation strategy for participants with resectable clinical Stage II-IVa gastric/gastric-esophageal cancer who have completed neoadjuvant therapy with durvalumab plus fluorouracil, leucovorin, oxaliplatin, docetaxel (D-FLOT) and R0 curative intent surgery. Concurrently, participants with post-operative ctDNA positive results will receive standard of care (SOC) D-FLOT with blinded serial ctDNA testing. Following R0 curative intent surgery, participants will be consented for study participation. Eligible participants will undergo treatment assignment based on post-operative MRD status at 5 weeks (+/- 2 weeks), as determined by the Signatera assay. Participants with negative post-operative circulating tumor DNA (ctDNA) results and no radiographic evidence of disease (within 6 weeks prior to randomization) will be randomized (1:1) to either SOC vs ct-DNA guided treatment. Randomized participants will be stratified according to pathologic (yp) lymph node status and tumor staging (ypT1-3, N0 vs T4 or N+), Combined Positive Score (CPS, CPS ≥ 1 vs CPS \<1), and pathological complete response (yes vs no). Assigned adjuvant treatment must start no later than 12 weeks post surgery. * Arm A (SOC Arm): Durvalumab for 1 year plus four 2 week cycles of FLOT with unblinded serial ctDNA testing and patient-reported outcomes (PROs) assessments. * Arm B (ctDNA-guided Arm): Durvalumab monotherapy for 1 year with unblinded serial ctDNA testing and PROs assessments. Participants who become ctDNA positive up through Cycle 11 Day 1 (C11D1) will receive four 2 week cycles of FLOT added to Durvalumab. Once adjuvant therapy is completed, all randomized participants will continue with serial ctDNA testing until recurrence and followed for up to 5 years for overall survival (OS), disease-free survival (DFS), metastasis-free survival (MFS) and disease-specific survival (DSS). Participants with post-operative ctDNA positive results at 5 weeks (+/- 2 weeks) will not be randomized. They will continue on observation and receive SOC D-FLOT with blinded serial ctDNA testing.
Interventions
Signatera Genome is intended for use as a post-surgical risk stratification tool for patients with resectable clinical Stage II-IVa gastric/gastro-esophageal cancer who are ctDNA negative after R0 curative intent surgery. The test is used to identify patients with no evidence of MRD following definitive surgery.
Sponsors
Natera, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed and dated informed consent form (ICF) obtained prior to any trial-specific enrollment procedure. 2. Age is ≥ 18 years-old at the time of ICF signature. 3. Able to submit adequate archival tumor tissue (eg, 6 to 10 unstained slides at 10 microns (μm) each or 12-19 unstained slides at 5-microns (μm) plus one hematoxylin and eosin slide (see study lab manual) obtained per standard of care procedures for submission to a central laboratory for Signatera testing OR prior commercial Signatera Genome test results. 4. Histologically confirmed adenocarcinoma of the stomach, esophagus and/or gastroesophageal junction (GEJ), resectable clinical Stage II-IVa per AJCC 9th edition. 5. Completion of full or modified course (based on Dosing and Modification Guidelines) of neoadjuvant D-FLOT therapy (ie, two 4-week cycles of durvalumab, four 2-week cycles of FLOT) . 6. Has undergone complete surgical resection of the gastric/GEJ tumor with pathologically confirmed negative margins (R0 resection). 7. Eligible to receive adjuvant D-FLOT treatment within 12 weeks postoperative per standard of care (SOC) as assessed by the treating clinician. 8. Known statuses pertaining to randomization stratification factors: 1. Post neoadjuvant, post-operative (yp) lymph node status and tumor staging (ypT1-3, N0 vs T4 or N+) 2. Combined Positive Score ( ≥ 1 vs \<1)Tumor PD-L1 status confirmed by immunohistochemistry/CPS score. 3. Post neoadjuvant, post-operative major pathological response (MPR): Yes/No 9. ECOG performance status 0-1. 10. No evidence of disease by radiographic imaging. 11. Must be willing to and able to comply with adjuvant treatment plans based on ctDNA results and other trial-mandated procedures. 12. Women of child bearing potential must have a confirmed negative pregnancy test within 14 days of enrollment per institutional standards.
Exclusion criteria
1. Histologic presence of adenosquamous cell carcinoma, squamous cell carcinoma, gastrointestinal stromal tumor, or neuroendocrine tumors. 2. Radiographic evidence of unresectable metastatic disease (ie, IVb). 3. Presence of peritoneal dissemination. 4. Any prior therapy (eg, radiation, chemoradiation, chemotherapy) for gastric or gastroesophageal cancer other than neoadjuvant D-FLOT and R0 curative intent surgery. 5. Known contradiction or hypersensitivity to durvalumab per the prescribing information; known contraindication or hypersensitivity to Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel or any of the drug excipients. 6. Known history of active primary immunodeficiency (eg, HIV), other contraindications of immunotherapy or receiving immunosuppressive medication per approved label. 7. Female participants who are pregnant or breastfeeding. 8. Concurrent enrollment in another clinical trial unless the study is observational, non-interventional. 9. Use of any commercial ctDNA or liquid biopsy monitoring outside of the study protocol during the primary 36-month monitoring period. 10. Concurrent invasive malignancy or a prior invasive malignancy whose treatment was completed within 5 years before ICF signature. Note: Participants with prior or concurrent in situ malignancies are eligible provided that adequate curative treatment is completed prior to enrollment. 11. Any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator's judgment, cause unacceptable safety risks, contraindicate participant participation in the clinical trial or compromise compliance with the protocol (e.g., chronic pancreatitis, chronic active hepatitis, liver cirrhosis or any other significant liver disease, active untreated or uncontrolled fungal, bacterial or viral infections, active infection requiring systemic antibacterial therapy, etc.)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease Free Survival (DFS) | 2 years from randomization to the first occurrence of disease recurrence or death from any cause, whichever occurs first | The primary objective of this study is to evaluate if disease free survival (DFS) among patients with resectable clinical stage II-IVa gastric/gastro-esophageal cancer who are ctDNA-negative after surgery undergoing ctDNA-guided observation is non-inferior to adjuvant D-FLOT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomization to Year 3 and randomization to Year 5 | Comparison of overall survival (OS) among Arm A (SOC) and Arm B (ctDNA guided) patients and assess whether adjuvant durvalumab monotherapy is non-inferior to standard of care adjuvant D-FLOT |
| Molecular Recurrence | From time of surgery up to 3 years | Compare Arm A(SOC) relative to Arm B (ctDNA guided) time from surgery (or first ctDNA negative assessment) to the detection of ctDNA positivity by the Signatera assay. |
| Metastasis-Free Survival (MFS) | From randomization at Year 2, Year 3, and Year 5 | To compare Arm A (SOC) relative to Arm B (ctDNA guided) on metastasis-free survival (MFS). |
| Disease-Specific Survival (DFS) | From randomization at Year 2, Year 3, and Year 5 | To compare Arm A (SOC) relative to Arm B (ctDNA guided) on disease-specific survival (DFS). |
| Discontinuation due to Adverse Events | From enrollment to Year 2 | Comparison of Arm A (SOC) relative to Arm B (ctDNA guided) on treatment discontinuation due to adverse events. |
| Quality of Life Outcomes | From enrollment to Year 2 | Comparison of Arm A (SOC) relative to Arm B (ctDNA guided) on quality of life and disease-related symptoms using patient-reported outcomes (PROs) from European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30). |
| Patient Reported Treatment Tolerability | From enrollment to Year 2 | To compare Arm A (SOC) relative to Arm B (ctDNA guided) to the patient-reported tolerability of treatment using Patient Reported Outcomes of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). |
Contacts
CONTACTSIGNAL-GEC 101 Study Team
STUDY_DIRECTORAdham Jurdi, MD
Natera, Inc.
Outcome results
None listed