Study Comparing Standard of Care Chemotherapy With/ Without Sequential Cytoreductive Surgery for Patients With Metastatic Foregut Cancer and Undetectable Circulating Tumor-Deoxyribose Nucleic Acid Levels

Phase 2

Withdrawn

• Conditions: Gastric Adenocarcinoma; Lung Cancer; Metastatic Cancer; Foregut Carcinoid Tumor; Gallbladder Adenocarcinoma; GI Cancer; GI Carcinoma; Liver Cancer
• Interventions: Procedure: Video-Assisted Thoracic Surgery (VATS); Drug: Standard of Care Chemotherapy; Procedure: Lobectomy; Radiation: Consolidative Radiation; Radiation: Ablation Treatment; Procedure: Resection or Excision; Procedure: Peritonectomy; Other: Transarterial Radioembolization

• Registration Number: NCT04931420
• Lead Sponsor: University of Chicago

Brief Summary

This study is designed for participants who have cancer of the upper gastrointestinal (GI) tract such as cancer of the esophagus, stomach, duodenum (the initial portion of your small intestine), pancreas, bile duct (Cholangiocarcinoma), ampulla, or gall bladder with limited sites of spread (metastases). Doctors leading this study are looking to see if treating the disease using sequential procedures (more than one procedure given one after another) such as surgeries or radiation can lead to better survival and if these surgeries, combined with standard of care treatment, are safe for the treatment of upper GI cancers.

Detailed Description

This study is designed for participants who have cancer of the upper gastrointestinal (GI) tract such as cancer of the esophagus, stomach, duodenum (the initial portion of your small intestine), pancreas, bile duct (Cholangiocarcinoma), ampulla, or gall bladder with limited sites of spread (metastases).

Doctors leading this study are looking to see if treating the disease using sequential procedures (more than one procedure given one after another) such as surgeries or radiation can lead to better survival and if it is safe for the treatment of upper GI cancers.

The purpose of the proposed study is to identify a group of patients with metastatic cancer of the upper GI and biliary tract that may benefit from sequential procedures such as surgeries or radiation compared to the current standard of care chemotherapy treatment alone.

Study Timeline

• Study First Submitted: 2021-06-08
• Study First Submitted QC: 2021-06-15
• Study First Posted: 2021-06-18
• Study Start: 2022-05-19
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-29
• Last Update Posted: 2024-07-31
• Primary Completion: 2026-05-01
• Study Completion: 2027-11-01

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Arm A - Participants Who Receive Sequential Procedures	Video-Assisted Thoracic Surgery (VATS)	If you are assigned to this arm, study doctors will sequentially remove and treat all visible cancer spots with surgery, radiation, ablation, or other procedures. These interventions might include surgical removal of the diseased part of your lung, liver, lymph nodes, and/or the lining of your belly. In addition, if surgery could not be done, we could treat these diseased spots with other modalities such as radiation and/or radiofrequency/microwave ablation. If you're selected to be in this arm, the type of procedure you receive will vary based on your cancer and what the study doctor recommends for treatment.
Arm A - Participants Who Receive Sequential Procedures	Lobectomy	If you are assigned to this arm, study doctors will sequentially remove and treat all visible cancer spots with surgery, radiation, ablation, or other procedures. These interventions might include surgical removal of the diseased part of your lung, liver, lymph nodes, and/or the lining of your belly. In addition, if surgery could not be done, we could treat these diseased spots with other modalities such as radiation and/or radiofrequency/microwave ablation. If you're selected to be in this arm, the type of procedure you receive will vary based on your cancer and what the study doctor recommends for treatment.
Arm A - Participants Who Receive Sequential Procedures	Consolidative Radiation	If you are assigned to this arm, study doctors will sequentially remove and treat all visible cancer spots with surgery, radiation, ablation, or other procedures. These interventions might include surgical removal of the diseased part of your lung, liver, lymph nodes, and/or the lining of your belly. In addition, if surgery could not be done, we could treat these diseased spots with other modalities such as radiation and/or radiofrequency/microwave ablation. If you're selected to be in this arm, the type of procedure you receive will vary based on your cancer and what the study doctor recommends for treatment.
Arm A - Participants Who Receive Sequential Procedures	Ablation Treatment	If you are assigned to this arm, study doctors will sequentially remove and treat all visible cancer spots with surgery, radiation, ablation, or other procedures. These interventions might include surgical removal of the diseased part of your lung, liver, lymph nodes, and/or the lining of your belly. In addition, if surgery could not be done, we could treat these diseased spots with other modalities such as radiation and/or radiofrequency/microwave ablation. If you're selected to be in this arm, the type of procedure you receive will vary based on your cancer and what the study doctor recommends for treatment.
Arm A - Participants Who Receive Sequential Procedures	Resection or Excision	If you are assigned to this arm, study doctors will sequentially remove and treat all visible cancer spots with surgery, radiation, ablation, or other procedures. These interventions might include surgical removal of the diseased part of your lung, liver, lymph nodes, and/or the lining of your belly. In addition, if surgery could not be done, we could treat these diseased spots with other modalities such as radiation and/or radiofrequency/microwave ablation. If you're selected to be in this arm, the type of procedure you receive will vary based on your cancer and what the study doctor recommends for treatment.
Arm A - Participants Who Receive Sequential Procedures	Peritonectomy	If you are assigned to this arm, study doctors will sequentially remove and treat all visible cancer spots with surgery, radiation, ablation, or other procedures. These interventions might include surgical removal of the diseased part of your lung, liver, lymph nodes, and/or the lining of your belly. In addition, if surgery could not be done, we could treat these diseased spots with other modalities such as radiation and/or radiofrequency/microwave ablation. If you're selected to be in this arm, the type of procedure you receive will vary based on your cancer and what the study doctor recommends for treatment.
Arm A - Participants Who Receive Sequential Procedures	Transarterial Radioembolization	If you are assigned to this arm, study doctors will sequentially remove and treat all visible cancer spots with surgery, radiation, ablation, or other procedures. These interventions might include surgical removal of the diseased part of your lung, liver, lymph nodes, and/or the lining of your belly. In addition, if surgery could not be done, we could treat these diseased spots with other modalities such as radiation and/or radiofrequency/microwave ablation. If you're selected to be in this arm, the type of procedure you receive will vary based on your cancer and what the study doctor recommends for treatment.
Arm B (Control) - Participants Who Receive Standard of Care Chemotherapy	Standard of Care Chemotherapy	Participants in this arm receive the current standard of care chemotherapy for their specific type of gastrointestinal cancer. This treatment may include the continuation of chemotherapy and a few procedures which may improve your quality of life.

Primary Outcome Measures

Name	Time	Method
Progression Free Survival	12 months	The progression free survival (PFS) of participants undergoing sequential procedures (Arm A of study) vs standard of care chemotherapy (participants in Arm B - control group) as assessed by clinical records. Progression free survival will be defined as the time from randomization to first documented disease progression or death as assessed by clinical records.

Secondary Outcome Measures

Name	Time	Method
6 Month Progression Free Survival	6 months	The percentage of participants in each arm without disease progression/death at 6 months as assessed by clinical records.
Progression Free Survival 2	12 months	The percentage of participants in each arm without disease progression/death from randomization to progression on second line therapy, which includes repeat interventions.
Median Overall Survival	12 months	The median overall survival of participants undergoing sequential procedures (Arm A) vs standard of care therapy (Arm B) as assessed by clinical records. Median overall survival will be defined as the time from randomization to death from any cause.
Financial Toxicity	12 months	The financial burden and its consequences faced by participants undergoing sequential procedures vs. the financial burden experienced by participants receiving standard of care treatment (Arm B). This financial burden/toxicity will be assessed by the Comprehensive Score for Financial Toxicity (COST) questionnaire, a standardized participant-friendly questionnaire used to measure financial toxicity/burden of treatment.
Post-Procedure Morbidity of Participants in Arm A	12 months	The morbidity (the state of having a particular illness) of participants after undergoing sequential cytoreductive procedures (procedures used to remove tumors) as assessed by clinical records.
The Effect of Interventions on Circulating Tumor DNA (ctDNA)	2 years after randomization	The effect of interventions on circulating tumor DNA (ctDNA) levels in participants who receive aggressive interventions (Arm A) versus standard of care treatments (Arm B). The effect of interventions on ctDNA will be assessed based on recorded ctDNA levels measured using liquid biopsies at baseline and after treatment.
12 Month Progression Free Survival	12 months	The percentage of participants in each arm without disease progression/death at 12 months as assessed by clinical records.
Health-Related Quality of Life	12 months	Health-related quality of life (HRQoL) for participants undergoing sequential procedures (Arm A) vs. the HRQoL for participants receiving standard of care treatment (Arm B). This will be assessed by quality of questionnaires completed by participants at baseline and after treatment.
Post-Procedure Mortality of Participants in Arm A	12 months	The mortality (the number of deaths) of participants after undergoing sequential cytoreductive procedures (procedures used to remove tumors) as assessed by clinical records.
Incidence of Adverse Events Reported Among Participants in Arm B (Standard of Care Group)	12 months	The safety/ tolerability of standard of care treatment as assessed by reported adverse events from participants in Arm B. Adverse Events will be measured using the Common Terminology Criteria for Adverse Events (CTCAE) v.5.
Circulating Tumor DNA (ctDNA) Progression Free survival	2 years after randomization	The median circulating tumor DNA (ctDNA) progression free survival, which will be defined as the time from randomization to first documented disease progression, positive ctDNA detection, or death as assessed by the radiology team in participants with undetectable ctDNA. ctDNA levels in participants will be tested/assessed using liquid biopsies.