Resected Pancreatic Adenocarcinoma
Conditions
Keywords
Pancreas, Radiation, mFOLFIRINOX
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
Interventions
DRUGmFOLFIRINOX
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.
RADIATIONProton 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
Sponsors
Georgetown University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 | 3 |
| 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 | 6 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Disease Progression | 1 | 3 |
| Overall Study | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | Dose Level 1 | Dose Level 2 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 4 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 6 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 5 Participants | 8 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 2 Participants | 4 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 2 / 6 |
| other Total, other adverse events | 3 / 3 | 6 / 6 |
| serious Total, serious adverse events | 0 / 3 | 1 / 6 |
Outcome results
Primary
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
Time frame: 6 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Level 1 | Feasibility (Rate of Successful Completion) of Short-course PRT Integrated Within Adjuvant mFOLFIRINOX | Completion PRT | 3 Participants |
| Dose Level 1 | Feasibility (Rate of Successful Completion) of Short-course PRT Integrated Within Adjuvant mFOLFIRINOX | completion of proton beam planning | 3 Participants |
| Dose Level 1 | Feasibility (Rate of Successful Completion) of Short-course PRT Integrated Within Adjuvant mFOLFIRINOX | completion of proton beam treatment | 3 Participants |
| Dose Level 1 | Feasibility (Rate of Successful Completion) of Short-course PRT Integrated Within Adjuvant mFOLFIRINOX | completion of adjuvant therapy | 2 Participants |
| Dose Level 2 | Feasibility (Rate of Successful Completion) of Short-course PRT Integrated Within Adjuvant mFOLFIRINOX | completion of adjuvant therapy | 2 Participants |
| Dose Level 2 | Feasibility (Rate of Successful Completion) of Short-course PRT Integrated Within Adjuvant mFOLFIRINOX | Completion PRT | 6 Participants |
| Dose Level 2 | Feasibility (Rate of Successful Completion) of Short-course PRT Integrated Within Adjuvant mFOLFIRINOX | completion of proton beam treatment | 6 Participants |
| Dose Level 2 | Feasibility (Rate of Successful Completion) of Short-course PRT Integrated Within Adjuvant mFOLFIRINOX | completion of proton beam planning | 6 Participants |
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.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Level 1 | Incidence of Dose Limiting Toxicites (DLTs) | 0 Dose limiting Toxicities |
| Dose Level 2 | Incidence of Dose Limiting Toxicites (DLTs) | 1 Dose limiting Toxicities |
Primary
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
Time frame: 6 months
Population: number of participants that had a dose limiting toxicity.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1 | Safety (Adverse Events) of Short-course PRT Integrated Within Adjuvant mFOLFIRINOX | 0 Participants |
| Dose Level 2 | Safety (Adverse Events) of Short-course PRT Integrated Within Adjuvant mFOLFIRINOX | 1 Participants |
Secondary
Overall Survival (OS)
Defined as time from surgery until death from any cause or last follow-up.
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1 | Overall Survival (OS) | 2 Participants |
| Dose Level 2 | Overall Survival (OS) | 4 Participants |
Secondary
Recurrence-free Survival (RFS)
Defined as time from surgery until evidence of disease recurrence.
Time frame: 12 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Level 1 | Recurrence-free Survival (RFS) | 12 months |
| Dose Level 2 | Recurrence-free Survival (RFS) | 12 months |