Sequential Cytoreductive Interventions for the Treatment of Patients with Metastatic Digestive System Adenocarcinoma with Undetectable ctDNA
This phase II trial tests how well sequential cytoreduction interventions such as surgery, radiation, or ablation work, compared to standard of care, for the treatment of patients with digestive system adenocarcinoma that has spread from where it first started (primary site) to other places in the body (metastatic) and that has undetectable tumor cells found in the blood (ctDNA). Surgery includes a variety of procedures used to remove or replace diseased organs or tissues. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Ablation is the removal or destruction of tumor tissue and may be performed by surgery, hormones, drugs, radiofrequency, heat, or other methods. Sequential delivery of these types of cytoreductive interventions may be effective for the treatment of metastatic digestive system adenocarcinoma with undetectable ctDNA.
Inclusion Criteria
- Has a primary diagnosis of American Joint Committee on Cancer (AJCC) 8th Edition stage IV esophageal or gastroesophageal adenocarcinoma, gastric adenocarcinoma, pancreatic adenocarcinoma, intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder adenocarcinoma, duodenal, and ampullary adenocarcinoma. * All participants must have confirmed histologic diagnosis of the primary tumor, which may be confirmed retrospectively by a radiologist if necessary
- Has a primary tumor that must be locally resectable or can be treated definitively. Primary tumors included are esophageal, gastric, duodenal, ampullary, pancreatic, cholangiocarcinoma, and gall bladder carcinoma. Primary tumors should be resectable or treatable with consolidative radiotherapy or ablative therapy such as microwave ablation or trans-arterial chemo/radioembolization (cholangiocarcinomas)
- Has limited (2 sites) metastatic disease determined to be completely resectable or treatable with curative intention at the time of diagnosis. This includes: * Up to five pulmonary metastases amenable to wedge resection (maximum of three wedge resections) or lobectomy (single lobectomy) or consolidative radiation/ablative therapy * Up to five hepatic metastases amenable to hepatectomy (segmentectomy, sectionectomy, sectorectomy, minor hepatectomy, not more than three segments), wedge resection requiring a minimum of 40% of liver parenchyma following resection based on future liver remnant or a combination of partial hepatectomy and microwave ablation or trans-arterial radioembolization (TARE). * Lymphatic metastases that are resectable or intervenable (limited to only two nonregional sites). * Resectable peritoneal disease with a peritoneal carcinoma index (PCI) of ≤ 6 and the ability to obtain a completeness of cytoreduction (CC0) cytoreduction. * Distant metastasis must be limited to two of the above-mentioned sites. * If both pulmonary and liver metastasis are present, then a total of five lesions will be considered oligometastatic
- Patients with resected primary tumors can be included if they present with oligometastases at least six months after the completion of treatment of primary tumor with curative intent
- Patients must have had two concordant negative tissue informed ctDNA tests measured at different timepoints and with the second being within 45 days prior to enrollment
- Patients must have at least 4 months of prior effective systemic therapy
- Has hemoglobin ≥ 8 g/dL (within 30 days prior to the first study intervention)
- Has absolute neutrophil count (ANC) ≥ 1500/uL (within 30 days prior to the first study intervention)
- Has platelet count ≥ 75000/uL (within 30 days prior to the first study intervention)
- Has total bilirubin ≤ 1.5 times the upper limit of normal (ULN) (within 30 days prior to the first study intervention)
- Has aspartate aminotransferase (AST) & alanine aminotransferase (ALT) ≤ 5 times ULN (within 30 days prior to the first study intervention)
- Has creatinine clearance ≥ 50 mL/min (within 30 days prior to the first study intervention)
- Patient who is at least 18 years of age at the time of signing informed consent and less than 81 years of age at the time of signing informed consent
- Has an Eastern Cooperative Oncology Group (ECOG) performance status score 0-1 at the time of randomization
- A male participant must agree to use contraception (barrier birth control, abstinence) during the treatment period and for at least 95 days following completion, corresponding to time needed to eliminate any study intervention(s), and refrain from donating sperm during this period
- A female participant of childbearing age is eligible to participate if she is not pregnant, not breastfeeding, and agrees to use contraception (hormonal, barrier birth control, or abstinence) during the treatment period and for at least 95 days following completion. Should a woman become pregnant or suspect that she is pregnant while participating in this study, she should inform her treating physician immediately
- The participant (or legally acceptable representative if applicable) provides written informed consent for the study. The participant may also provide consent for the Foundation for Blood Research (FBR). However, the participant may participate in the main study without participating in the FBR
Exclusion Criteria
- Has a positive urine pregnancy test within 3 days prior to randomization or treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. * Note: In the event that 3 days have elapsed between the screening pregnancy test and the first dose of study intervention, another pregnancy test (urine or serum) must be performed and must be negative for the participant to start receiving study medication
- Has hypoxia as defined by pulse oximeter reading < 92% at rest or requires intermittent or chronic supplemental oxygen
- Has developed progressive disease on current line of systemic therapy
- Has a known additional malignancy that is progressing or has required active treatment within the past three years. * Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded
- Has known central nervous system (CNS) metastasis and/or carcinomatous meningitis
- Has known osseous metastasis
- Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months from treatment initiation, or New York Heart Association Class III or IV congestive heart failure. Medially controlled arrhythmia stable on medication is permitted
- Has poorly controlled hypertension defined as systolic blood pressure (SBP) ≥ 150mmHg and/or diastolic blood pressure (DBP) ≥ 90mmHg
- Has moderate to severe hepatic impairment (Child-Pugh B or C)
- Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study
- Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (severe dysphasia, bowel obstruction, malabsorption)
- Has known malignant pleural effusion or previous malignant effusion previously treated at the time of enrollment
- Has histologic subtypes not included in the inclusion criteria (including esophageal squamous cell carcinoma, gastroenteropancreatic neuroendocrine tumors, hepatocellular carcinoma, etc.)
- Has a primary tumor that is not amenable to the treatment modalities
- Has albumin level less than 3.0 g/dL despite appropriate nutritional support
- Has detectable ctDNA at the time of enrollment
- Has an active infection requiring systemic therapy
- Has known active tuberculosis (TB)/COVID infection
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (dosing exceeding 10mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of the study intervention
- Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 95 days after the last study intervention
- Inability to receive chemotherapy and/or surgery and/or radiotherapy and/or ablative procedures due to medical/insurance reasons
- Requires emergency surgery due to bleeding, perforation, or obstruction
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT07282912.
Locations matching your search criteria
United States
Connecticut
New Haven
PRIMARY OBJECTIVE:
I. To compare the progression free survival (PFS) of patients undergoing sequential cytoreductive interventions (investigational group) versus (vs) standard of care therapy (control group).
SECONDARY OBJECTIVE:
I. To compare one year survival rate of patients undergoing sequential cytoreductive interventions vs standard of care therapy.
II. To compare health related quality of life (HRQoL) for patients undergoing sequential cytoreductive interventions vs standard of care therapy.
III. To compare the financial burden and its consequences faced by the patients for patients undergoing sequential cytoreductive interventions vs standard of care therapies.
IV. To evaluate post-procedure morbidity and mortality of patients in both arms.
V. To evaluate the safety and tolerability of standard of care therapy.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients with esophageal, gastroesophageal junction, gastric, duodenal or ampullary adenocarcinoma undergo sequential cytoreductive intervention(s) to the metastatic site(s) and primary tumor in the order described below within three months.
LUNG: Patients undergo video-assisted thoracoscopic (VATS) or open thoracotomy wedge resection or lobectomy or consolidative radiation or ablation.
NON-REGIONAL LYMPH NODES: Patients undergo excision of gross positive node or consolidative radiation.
LIVER: Patients undergo wedge resection or segmentectomy or sectionectomy or microwave ablation or transarterial radioembolization (TARE).
PRIMARY TUMOR: Patients undergo resection or consolidative radiation or definitive chemoradiotherapy (can be performed with liver intervention).
PERITONEUM: Patients undergo segmental peritonectomy (can be performed with primary tumor treatment).
Patients with pancreatic or gall bladder adenocarcinoma or cholangiocarcinoma undergo sequential cytoreductive intervention(s) to the metastatic site(s) and primary tumor in the order described below within months.
LUNG: Patients undergo VATS or open thoracotomy wedge resection or lobectomy or consolidative radiation or ablation.
NON-REGIONAL LYMPH NODES: Patients undergo excision of gross positive node or consolidative radiation.
LIVER: Patients undergo wedge resection or segmentectomy or sectionectomy or microwave ablation or TARE.
PRIMARY TUMOR: Patients undergo resection or consolidative radiation or definitive chemoradiotherapy or radiofrequency ablations or TARE (can be performed with liver intervention).
PERITONEUM: Patients undergo segmental peritonectomy (can be performed with primary tumor treatment).
After completion of sequential cytoreductive therapy, patients will continue on the standard of care therapy until progression or at the discretion of the treating physician. Patients undergo positron emission tomography (PET) scan, computed tomography (CT) scan and blood sample collection throughout the study.
ARM B: Patients continue to receive standard of care therapy in the absence of disease progression or unacceptable toxicity. Patients undergo PET scan, CT scan and blood sample collection throughout the study.
After completion of study treatment, patients are followed up every 3 months for 1 year.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationYale University
Principal InvestigatorKiran K. Turaga
- Primary ID2000038216
- Secondary IDsNCI-2026-03014
- ClinicalTrials.gov IDNCT07282912