Study of Proton Therapy in Adjuvant Pancreatic Cancer

Phase 1

Completed

Conditions: Resected Pancreatic Adenocarcinoma

Interventions: Drug: mFOLFIRINOX
Radiation: Proton beam radiation

Registration Number: NCT03885284

Lead Sponsor: Georgetown University

Brief Summary: This trial aims to determine a safe schedule of short-course proton beam radiation therapy with adjuvant mFOLFIRINOX for patients with resected pancreatic adenocarcinoma.

Detailed Description: The investigators hypothesize that resected pancreatic cancer patients will benefit from enhanced local control with the addition of radiation therapy to adjuvant FFX. The recently reported PRODIGE 24 study, demonstrated that 12 cycles of adjuvant FFX without radiation therapy significantly improved survival and time to metastatic failure rates as compared to GEM alone. Excessive distant failures rates using prior adjuvant systemic therapies, may have limited the impact of radiation therapy; therefore, improvements in systemic control can increase the benefit of local control.

In this study, the investigators utilize 5 fraction PRT, delivered over 1 week, during adjuvant FFX (between cycles 6 and 7) to minimize the interruptions in chemotherapy as well as to reduce the length of time from surgical resection to initiating adjuvant radiation therapy. Conventional radiation therapy is typically delivered over 5 weeks and is commonly given after the completion of adjuvant chemotherapy. Conventional radiation therapy cannot be given concurrently with FFX due to the synergistic toxicities. In contrast, PRT significantly reduces the exposure of normal tissues to the effects of radiation therapy and has been safely delivered using a 5 fraction schedule with chemotherapy, as previously discussed.

Chemotherapy will consist of mFOLFIRINOX in 14-day cycles x 12 as used in the PRODIGE 24 study:

* Irinotecan 150 mg/m2 IV day 1

* Oxaliplatin 85 mg/m2 IV day 1

* Leucovorin 400 mg/m2 IV day 1

* 5-fluorouracil 2,400 mg/m2 IV days 1-3 (no bolus)

* Pegfilgrastim 6 mg SC on-body injector day 3 (optional, up to investigator's discretion, can alternatively do day 4 without on-body injector)

* Suggested supportive care medications: fosaprepitant 150 mg IV day 1, dexamethasone 12 mg IV day 1, ondansetron 16 mg IV day 1, dexamethasone 4 mg PO q AM days 2-3, ondansetron 8 mg PO BID days 2-3.

* Dose adjustments will be permitted at the discretion of the treating oncologist based on patients' prior tolerability to FFX

* Proton radiation will consistent of 5 daily doses of 5 GyE total, ideally administered Monday through Friday but can be administered within 7 business days, between cycles 6 and 7

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 9

Inclusion Criteria

Undergone pancreaticoduodenectomy with curative intent
Pathologically-confirmed pancreatic adenocarcinoma of the pancreatic head (adenocarcinoma must be the predominant component of the histology)
Completed 2 cycles of adjuvant chemotherapy composed of 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan
Complete resection (R0) or resection with microscopic positive magins (R1)
Adequate healing post-operatively
Bone marrow function: absolute neutrophil count (ANC) ≥ 1,500/mm3; Platelets ≥ 100 × 109/L; hemoglobin ≥ 9.0 g/dL. Patients may have a transfusion of red blood cells to meet the hemoglobin requirement.
Renal function: serum creatinine ≤ 1.5 × upper normal limit of institution's normal range or creatinine clearance ≥ 30 mL/min for subjects with creatinine levels above institutional normal
Hepatic function: AST and ALT ≤ 3.0 × the upper normal limit of institution's normal range. Total bilirubin ≤ 1.5 × the upper normal limit of institution's normal range.
Partial Thromboplastin Time (PTT) must be ≤ 1.5 × upper normal limit of institution's normal range and INR (International Normalized Ratio) < 1.5. Subjects on anticoagulant (such as warfarin) will be permitted to enroll as long as the INR is in the acceptable therapeutic range as determined by the investigator.
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0-1
Prior neoadjuvant chemotherapy is alllowed
Patients must have fully recovered from all effects of surgery. Patients must have had at least two weeks after minor surgery and four weeks after major surgery before starting therapy. Minor procedures requiring "Twilight" sedation such as endoscopies or mediport placement may only require a 24-hour waiting period, but this must be discussed with an investigator.
Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to initiation of treatment and/or postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential
Patient is capable of understanding and complying with parameters as outlined in the protocol and able to sign and date the informed consent, approved by the Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures

Exclusion Criteria

Ampullary adenocarcinoma
Women who are pregnant or breastfeeding
Macroscopic positive margins (R2) or evidence of residual local or metastatic disease
Resection not including pancreaticoduodenectomy
Known allergy or intolerance to leucovorin, 5-fluorouracil, oxaliplatin, or irinotecan
Prior radiation to the upper abdomen
Inability to swallow pills or bowel obstruction
Any invasive cancer in the previous 3 years requiring chemotherapy, radiation, or anticancer therapy following surgery
Insurance unwilling to pre-authorize PRT, FFX, and (if necessary) pegfilgrastim
Clinically significant liver disease (Patients with resolved hepatitis B infection are eligible if HBsAg testing is negative; Patients with resolved hepatitis C infection are eligible if viral RNA PCR is negative)
Uncontrolled HIV infection (CD4 count must be at least 200 and viral load undectable on a stable antiretroviral regimen to be eligible for enrollment)
Major surgery within 4 weeks prior to enrollment

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dose Level 1	mFOLFIRINOX	mFOLFIRINOX + Proton beam radiation Radiation given on days 8-12 of cycle 6
Dose Level 1	Proton beam radiation	mFOLFIRINOX + Proton beam radiation Radiation given on days 8-12 of cycle 6
Dose Level 2	mFOLFIRINOX	mFOLFIRINOX + Proton beam radiation Radiation given on days 15-19 of cycle 6
Dose Level 2	Proton beam radiation	mFOLFIRINOX + Proton beam radiation Radiation given on days 15-19 of cycle 6

Primary Outcome Measures

Name	Time	Method
Incidence of Dose Limiting Toxicites (DLTs)	6 months	Recommended phase II dose and schedule (RP2D) of short-course PRT integrated within adjuvant mFOLFIRINOX will be based on number of Dose limiting toxicities.
Safety (Adverse Events) of Short-course PRT Integrated Within Adjuvant mFOLFIRINOX	6 months	Dose Limiting Toxicities. Adverse Event data will be collected and presented as descriptive statistics using the CTCAE version 5.0
Feasibility (Rate of Successful Completion) of Short-course PRT Integrated Within Adjuvant mFOLFIRINOX	6 months	Success rate defined as # of patients that completed proton beam planning, proton beam treatment, and completion of adjuvant therapy

Secondary Outcome Measures

Name	Time	Method
Recurrence-free Survival (RFS)	12 months	Defined as time from surgery until evidence of disease recurrence.
Overall Survival (OS)	2 years	Defined as time from surgery until death from any cause or last follow-up.