Study of Proton Therapy in Adjuvant Pancreatic Cancer | NCT03885284

NCT03885284

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

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Derived Section

Miscellaneous Info Module

Status Module

Description Module

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

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Dose Level 1	Experimental	mFOLFIRINOX + Proton beam radiation Radiation given on days 8-12 of cycle 6	Drug: mFOLFIRINOX Radiation: Proton beam radiation
Dose Level 2	Experimental	mFOLFIRINOX + Proton beam radiation Radiation given on days 15-19 of cycle 6	Drug: mFOLFIRINOX Radiation: Proton beam radiation

Interventions

Name	Type	Description	Arm Group Labels	Other Names
mFOLFIRINOX	Drug	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.

Outcomes Module

Primary Outcomes

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

Secondary Outcomes

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

Eligibility Module

Eligibility Criteria

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

Name	Affiliation	Role
Benjamin Weinberg, MD	Georgetown University	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Georgetown University Medical Center - Lombardi Comprehensive Cancer Center		Washington D.C.	District of Columbia	20007	United States

PubMed Identifier	Type	Citation	Retractions
37717786	Derived	Weinberg BA, Wang H, Noel MS, He AR, Marshall JL, Weiner LM, Fishbein TM, Hodgins NE, Winslow ER, Jackson PG, Guerra JF, Aguila F, Unger KR. Phase 1 Study of Hypofractionated Proton Beam Radiation Therapy in Adjuvant Pancreatic Cancer (PROTON-PANC). Int J Radiat Oncol Biol Phys. 2024 Feb 1;118(2):362-367. doi: 10.1016/j.ijrobp.2023.09.015. Epub 2023 Sep 16.

Arm/Group Information

ID	Title	Description
FG000	Dose Level 1	mFOLFIRINOX + Proton beam radiation Radiation given on days 8-12 of cycle 6 mFOLFIRINOX: 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. Proton beam radiation: Proton beam radiation will consist 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
FG001	Dose Level 2	mFOLFIRINOX + Proton beam radiation Radiation given on days 15-19 of cycle 6 mFOLFIRINOX: 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. Proton beam radiation: Proton beam radiation will consist 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

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Dose Level 1	mFOLFIRINOX + Proton beam radiation Radiation given on days 8-12 of cycle 6 mFOLFIRINOX: 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. Proton beam radiation: Proton beam radiation will consist 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

Units	Counts
Participants	BG000

Baseline Measures

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Categorical			Count of Participants

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Incidence of Dose Limiting Toxicites (DLTs)

Recommended phase II dose and schedule (RP2D) of short-course PRT integrated within adjuvant mFOLFIRINOX will be based on number of Dose limiting toxicities.

Posted

Number

Dose limiting Toxicities

6 months

ID	Title	Description
OG000	Dose Level 1	mFOLFIRINOX + Proton beam radiation Radiation given on days 8-12 of cycle 6 mFOLFIRINOX: 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. Proton beam radiation: Proton beam radiation will consist 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

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Dose Level 1	mFOLFIRINOX + Proton beam radiation Radiation given on days 8-12 of cycle 6 mFOLFIRINOX: 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. Proton beam radiation: Proton beam radiation will consist 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

ID	Term
D063193	Heavy Ion Radiotherapy
D011878	Radiotherapy
D013812	Therapeutics