FDG-PET Directed Treatment in Improving Response in Patients With Locally Advanced Stomach or Gastroesophageal Junction Cancer

Study Overview
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Brief Summary
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This randomized phase II trial studies how well fludeoxyglucose F-18 (FDG)/positron emission tomography (PET) directed treatment improves response in patients with stomach or gastroesophageal junction cancer that has not spread past the stomach and is not responding to the usual treatment. PET scans are a different way to take pictures of cancer and can be used to look at how much energy (such as glucose) is being used by the cancer. Using PET scans early to monitor the success of treatment may allow doctors to measure response and change treatment accordingly.

Detailed Description
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Pre-registered patients receive standard pre-operative chemotherapy comprising epirubicin intravenously 50mg/m^2 (IV) on day 1; oxaliplatin 130 mg/m^2 IV or cisplatin 60 mg/m^2 IV on day 1; and capecitabine 625 mg/m^2 orally (PO) twice daily (BID) or fluorouracil 200 mg/m^2/day IV continuously on days 1-21; and undergo FDG-PET following course 1 (days 15-19). Patients defined as FDG-PET non-responders are registered and randomized to 1 of 2 treatment arms. Primary objective To assess and compare the overall survival (OS) of patients with locally advanced gastric cancer classified as FDG-PET non-responders after one cycle of pre-operative chemotherapy randomly assigned to receive either salvage chemotherapy before and after surgery or immediate surgery followed by fluorouracil sensitized radiotherapy. Secondary objectives To assess and compare progression-free survival (PFS) between the treatment arms (Arms A and B). To assess and compare R0 resection rate between the treatment arms (Arms A and B). To assess and compare pathologic complete response (pCR) rate between the treatment arms (Arms A and B). To assess the adverse events (AE) profile and safety of each treatment arm (Arms A and B), including post-operative mortality rate, 30-day post-operative targeted adverse events (i.e., dehiscence, significant infection, and re-operation rate). To examine the changes of FDG-PET SUV induced by pre-operative chemotherapy at different time points (from baseline to completion of one cycle of treatment before randomization, and 2 cycles of salvage treatment) in patients randomized to salvage treatment arm (Arm B). To collect measurement of fatigue and overall perception of QOL at registration of the study (Alliance registration QOL assessment study).

Official Title
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Impact of Early FDG-PET Directed Intervention on Preoperative Therapy for Locally Advanced Gastric Cancer: A Random Assignment Phase II Study

Conditions
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Adenocarcinoma of the Gastroesophageal Junction, Gastric Adenocarcinoma, Gastric Cancer

Intervention / Treatment
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* Procedure: FDG-PET
* Procedure: surgery
* Drug: 5-FU
* Drug: capecitabine
* Drug: docetaxel
* Drug: Irinotecan
* Radiation: 3D-CRT
* Radiation: IMRT


Participation Criteria
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Eligibility Criteria
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Pre-Registration Eligibility Criteria Documentation of Disease 1.1 Histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction (Siewert type II, III) 1.2 Pre-treatment clinical stage of T3-4N any M0 or T any N positive M0 as determined by laparoscopy, CT scan (or PET/CT), or endoscopic ultrasound (histologic confirmation of lymph involvement is not required). Therefore, patients can have measurable or non-measurable disease. 1.3 Patients with T1-2N0M0 tumors or patients with metastatic disease are NOT eligible. Patients must be eligible for curative intent surgical resection. FDG Avid malignancy - Patients must have an FDG avid tumor(s). FDG avid tumors are defined as a primary tumor with an increased uptake in the region of the tumor that has an SUV of > 5.0 or a tumor:liver SUV ratio of > 1.5. No prior history of congestive heart failure - NYHA class I to IV or known DPD deficiency No current grade 2, 3, or 4 of neuropathy. No known hypersensitivity to epirubicin, oxaliplatin and cisplatin, capecitabine and 5-flurouracil, docetaxel or irinotecan. Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. 7.1 Therefore, for women of childbearing potential only, a negative serum pregnancy test pregnancy test done ≤ 7 days prior to pre-registration is required. 7.2 A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months). Age ≥ 18 years ECOG Performance Status 0 or 1 Required Initial Laboratory Values: Absolute Neutrophil Count (ANC) ≥ 1,500/mm^3 Platelet Count ≥ 100,000/mm^3 Creatinine ≤ 1.5 x upper limit of normal (ULN) Total Bilirubin ≤ 1.5 x ULN, except in patients with Gilbert's disease AST and ALT ≤ 2.5 x ULN Alkaline Phosphatase ≤ 2.5 x ULN Registration Eligibility Criteria to Treatment Arms A or B Patient must continue to be eligible for curative intent surgical resection. Disease Progression: FDG avid malignancy that is classified as an FDG PET non- responder. PET non-responders are defined as having < 35% reduction in the FDG uptake of the primary tumor when compared to baseline. Concomitant Medications - 3.1 Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this trial. Patients on strong CYP3A4 inhibitors must discontinue the drug 14 days prior to the start of study treatment. 3.2 Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment. Patient must have received only one cycle of the following regimens during the pre-registration time period and no other therapy for gastric or gastroesophageal junction cancer: Epirubicin, Oxaliplatin, and Capecitabine Epirubicin, Oxaliplatin, and Fluorouracil Epirubicin, Cisplatin, and Capecitabine Epirubicin, Cisplatin, and Fluorouracil Toxicity recovery should include the following: Grade ≤ 2 neuropathy Grade ≤ 2 diarrhea Grade ≤ 2 mucositis Pre-registration chemotherapy given within 42 days of treatment (treatment meaning surgery if Arm A, chemotherapy if Arm B)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A - surgery, chemotherapy and radiation therapy<br>Patients undergo surgery within 42 days of completion of pre-registration chemotherapy. Beginning within 49 days of surgery, patients receive 5-FU IV continuously and capecitabine PO BID on days 1-7, and undergo 3D-CRT or IMRT QD on days 1-5. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity. | Procedure: surgery<br> <br> Drug: 5-FU<br>* 200 mg/m^2/day IV<br>Drug: capecitabine<br>* oral 800 mg/m^2 BID<br>Radiation: 3D-CRT<br> <br> Radiation: IMRT<br> <br> |
| Experimental: Arm B - surgery, chemotherapy and FDG-PET<br>Beginning within 28 days of day 1 of pre-registration chemotherapy, patients receive docetaxel IV and irinotecan IV on days 1 and 8. Treatment repeats every 3 weeks for 2 courses. Beginning within 42 days of completion of docetaxel and irinotecan, patients undergo surgery. Patients also undergo FDG-PET within 14 days of planned surgery. Beginning within 60 days after surgery, patients receive 3 additional courses of docetaxel and irinotecan hydrochloride courses in the absence of disease progression or unacceptable toxicity. | Procedure: FDG-PET<br> <br> Procedure: surgery<br> <br> Drug: docetaxel<br>* 30 mg/m^2 IV<br>Drug: Irinotecan<br>* 50 mg/m^2 IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival is defined as the time from date of randomization to death due to any cause. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator. | Up to 3 years | 
| Number of Patients Achieved R0 Resection During Surgery | The number of patients achieved R0 resection during surgery | At time of surgery | 
| Number of Patients Had Pathologic Complete Response | The number of patients had pathologic complete response (pCR). (pCR is defined as no gross or microscopic tumor identified with the surgical specimen. All lymph nodes should be free of tumor to document a PCR. If no gross tumor is visible, section around the area of inflammation (nodularity) should be made every 2-3 cm and specimens examined.) | Up to 3 years | 
| Number of Participants Who Reported Grade 3 or Higher Adverse Events | The number of patients who reported grade 3 or higher Adverse Events according to Common Terminology Criteria for Adverse Events version 4.0. | Up to 30 days after completion of protocol treatment |