| Eligibility |
Inclusion Criteria:
A participant will be eligible for inclusion in the study if the participant:
1. Has a newly diagnosed primary diagnosis of American Joint Committee of Cancer (AJCC)
8th Edition Stage IV esophageal or gastroesophageal adenocarcinoma, gastric
adenocarcinoma, pancreatic/ampullary adenocarcinoma, intrahepatic cholangiocarcinoma,
extrahepatic cholangiocarcinoma gallbladder adenocarcinoma, duodenal, and ampullary
adenocarcinoma.
1. All participants must have confirmed histologic diagnosis of the primary tumor
2. Excludes patients with bone and brain metastasis (See exclusion criteria)
2. Has a primary tumor that must be locally resectable or can be treated definitively
(see preferred intervention sequence). 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).
3. Has limited (2 sites) metastatic disease determined to be completely resectable or
treatable with curative intention (see treatment algorithm) at the time of diagnosis
(before induction chemotherapy). This includes:
1. Up to 5 pulmonary metastasis amenable to wedge resection (maximum of 3 wedge
resections) or lobectomy (single lobectomy) or consolidative radiation/ablative
therapy
2. Up to 5 hepatic metastasis amenable to hepatectomy (segmentectomy, sectionectomy,
sectorectomy, minor hepatectomy (not more than 3 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).
3. Lymphatic metastases that are resectable or intervenable (limited to only two
non-regional sites).
4. Resectable peritoneal disease with a PCI of <6 and the ability to obtain a CC0
cytoreduction.
5. Distant metastasis must be limited to two of the above-mentioned sites (a-d).
6. If both pulmonary and liver metastasis are present (a, b), then a total of 5
lesions will be considered oligometastatic.
4. 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.
5. Has adequate organ function, as described below (Appendix 4); all screening laboratory
tests should be performed within 30 days prior to the first study intervention.
Prior Therapy
6. Patients taking substrates, inhibitors, or inducers of Cytochrome P450 3A4 (CYP3A4)
should be encouraged to switch to alternative drugs whenever possible, given the
potential for drug-drug interactions.
Demographics
7. Is male or female, 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.
8. Has an Eastern Cooperative Oncology Group (ECOG) performance status score 0-1 at the
time of randomization.
Male Participants
9. 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.
Female Participants
10. 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) for at least 95 days following completion, corresponding to
time needed to eliminate any study intervention(s). Should a woman become pregnant or
suspect that she is pregnant while participating in this study, she should inform her
treating physician immediately.
Informed Consent
11. The participant (or legally acceptable representative if applicable) provides written
informed consent for the study. The participant may also provide consent for Future
Biomedical Research (FBR). However, the participant may participate in the main study
without participating in FBR.
Exclusion Criteria:
The participant must be excluded from the study if the participant:
Medical Conditions
1. 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.
2. Has hypoxia as defined by pulse oximeter reading <92% at rest or requires intermittent
or chronic supplemental oxygen.
3. 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.
4. Has known central nervous system (CNS) metastasis and/or carcinomatous meningitis.
5. Has known osseous metastasis.
6. 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.
7. Has poorly controlled hypertension defined as SBP =150mmHg and/or DBP =90mmHg.
8. Has moderate to severe hepatic impairment (Child-Pugh B or C).
9. Has a known psychiatric condition such as schizophrenia, mania, delirium, or a
substance abuse disorder that would interfere with the study-related procedures.
10. Is unable to swallow orally administered medication or has a gastrointestinal disorder
affecting absorption (severe dysphasia, bowel obstruction, malabsorption).
11. Has known malignant pleural effusion or previous malignant effusion previously treated
at the time of enrollment.
12. Has histologic subtypes not included in the inclusion criteria (including esophageal
squamous cell carcinoma, gastroenteropancreatic neuroendocrine tumors, hepatocellular
carcinoma, etc.).
13. Has ECOG performance status score 2 or greater.
14. Has a primary tumor that is not amenable to treatment.
15. Has weight loss = 20% from diagnosis despite appropriate nutritional support.
16. Has progressive disease following the first three months of chemotherapy.
17. Patients with detectable circulating tumor DNA (ctDNA) following three months of
induction chemotherapy.
Prior/Concomitant Therapy
18. Has previously treated metastatic disease with surgery, radiation, or ablative
procedures.
a. Patients can be enrolled if they have received systemic chemotherapy consistent
with the trial protocol, and they meet all of the inclusion criteria and none of the
remaining exclusion criteria.
19. Has had major surgery within 3 weeks prior to the first dose of the study
intervention. Participants must have recovered from all surgery-related complications.
20. Has received a live vaccine within 30 days prior to the first dose of study drug.
Examples of live vaccines include but are not limited to the following: measles,
mumps, rubella, varicella/zoster (chickenpox), yellow fever, rabies, BCG, and typhoid
vaccine. Seasonal influenza vaccine for injection are generally killed virus vaccines
and are allowed; however, intranasal influenza vaccine (eg. FluMist®) are live
attenuated vaccines and are not allowed.
Diagnostic Assessments
21. Has an active infection requiring systemic therapy
22. Has known active TB/ COVID infection
23. 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
24. Has a known history of HIV infection
25. Has a known history of HBV (defined as HBsAg reactive) or known active HCV (defined as
HCV RNA [qualitative] is detected) infection.
Note: Testing for HBV and HCV is only required if mandated by the local health
authority.
Other Exclusions
26. 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.
27. Inability to receive chemotherapy and/or surgery and/or radiotherapy and/or ablative
procedures due to medical/insurance reasons.
28. Has peritoneal metastases with a peritoneal carcinoma index (PCI) score of >6.
29. Requires emergency surgery due to bleeding, perforation, or obstruction.
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