Pancreatic Cancer
Conditions
Keywords
Induction Chemotherapy, Stereotactic Body Radiotherapy (SBRT), Dose Escalation, Locally Advanced Pancreatic Cancer (LAPC), Maximum Tolerated Dose (MTD)
Brief summary
This is a dose escalation trial to evaluate the safety of stereotactic body radiotherapy (SBRT) delivered in 3 fractions for patients with locally advanced pancreatic cancer (LAPC) who have received induction chemotherapy (FOLFIRINOX or gemcitabine and nab-paclitaxel).
Detailed description
This is a phase I study, with an expansion cohort, of up to 34 patients to identify the maximum tolerated dose (MTD) of a 3-fraction regimen of stereotactic body radiotherapy (SBRT) for locally-advanced pancreatic cancer patients who have not developed distant progression following induction chemotherapy (FOLFIRINOX or gemcitabine and nab-paclitaxel) as per standard of care. After completion of induction chemotherapy, stereotactic body radiotherapy SBRT will be administered in 3 fractions, every other day, on an outpatient basis. Dose escalation will start with dose level 1 (9 Gy x 3 fractions) and increase by 1 Gy per fraction at each dose level, dose level 2 will be 10 Gy x 3 fractions and dose level 3 will be 11 Gy x 3 fractions.
Interventions
DRUGFOLFIRINOX or gemcitabine/abraxane
Patients will have received induction chemotherapy for 3+ months with either FOLFIRINOX or gemcitabine/abraxane with at least stable disease.
RADIATIONSBRT
After completion of induction chemotherapy, stereotactic body radiation therapy (SBRT) will be administered in 3 fractions, every other day, on an outpatient basis. Dose escalation will start with dose level 1 (9 Gy x 3 fractions) and increase by 1 Gy per fraction at each dose level, dose level 2 will be 10 Gy x 3 fractions and dose level 3 will be 11 Gy x 3 fractions.
Sponsors
University of Colorado, Denver
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Dose escalation will start with dose level 1 (9 Gy x 3 fractions) and increase by 1 Gy per fraction at each dose level, dose level 2 will be 10 Gy x 3 fractions and dose level 3 will be 11 Gy x 3 fractions.
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
1. Histologically or cytopathologically confirmed adenocarcinoma of the pancreas. 2. Locally advanced, unresectable pancreatic cancer as confirmed by the multidisciplinary input from a hepatobiliary surgeon and as defined on CT as having tumor abutment of \>180° (\> 50%) of the circumference of the superior mesenteric artery (SMA) or celiac axis, unreconstructable superior mesenteric vein (SMV) or portal vein (PV) involvement. 3. No evidence of distant metastasis either prior to or after induction chemotherapy. 4. Completion of at least 3 months, but no more than 6 months of standard induction chemotherapy for LAPC, which may include FOLFIRINOX or gemcitabine and nab-paclitaxel, preferably within 2-4 weeks but no longer than 8 weeks. 5. Pancreatic tumor size ≤ 5 cm. 6. Age ≥18 years. 7. ECOG 0-1. 8. Patients must have acceptable organ and marrow function as defined below: * Leukocytes \>3,000/µL * Absolute neutrophil count \>1,500/µL * Platelets \>70,000/µL * Total bilirubin Within 2 x upper limit of normal * AST (SGOT)/ALT (SGPT) \<2.5 x institutional upper limit of normal * Creatinine Within 1.5 x upper limit of normal OR * Creatinine clearance \>60 mL/min for patients with creatinine levels above institutional normal 9. Ability to understand and follow the breathing instructions involved in the respiratory gating procedure or to tolerate compression sufficient to reduce fiducial motion to \<= 5mm. 10. Ability to understand and the willingness to sign a written informed consent document. 11. Residual or on-going ≥ Grade 3 treatment-related toxicity from previous chemotherapy
Exclusion criteria
1. Patients who have had prior abdominal radiotherapy. 2. Patients receiving any investigational agents. 3. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. 4. Contraindication to IV contrast 5. Patients in which iodine contrast is contraindicated. 6. Pregnant and breastfeeding women are excluded. Women of child-bearing potential who are unwilling or unable to use an acceptable method of birth control to avoid pregnancy for the entire study period and for up to 4 weeks after the study are excluded. This applies to any woman who has experienced menarche and who has not undergone successful surgical sterilization or is not postmenopausal (defined as amenorrhea for at least 12 consecutive months, or women on hormone replacement therapy with serum FSH levels greater than 35 mIU/mL. A negative urine or serum pregnancy test must be obtained within 14 days prior to the start of study therapy in all women of child-bearing potential. Male subjects must also agree to use effective contraception for the same period as above.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Maximum Tolerated Dose (MTD) of Stereotactic Body Radiotherapy (SBRT) in Locally Advanced Pancreatic Cancer (LAPC) Patients Who Have Not Developed Distant Progression After Induction Chemotherapies. | Up to 3 months | This will be accomplished by the standard 3+3 dose escalation design. Dose limiting toxicities (DLT) are defined by ≥ Grade 3 treatment-related GI toxicity within 3 months of SBRT. These include: (1) Bowel (includes bowel perforation, obstruction, or hemorrhage) and (2) Stomach (bleeding ulcer, perforation) as determined by imaging or endoscopic evaluation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | Up to 5 years | Progression free survival (PFS) will be measured from completion of SBRT to the time of tumor progression or death due to any cause. PFS will be estimated using the method of Kaplan and Meier. |
| Overall Survival | Up to 5 years | Overall survival (OS) will be measured from completion of SBRT until death due to any cause. OS will be estimated using the method of Kaplan and Meier. |
| Local Control | Up to 5 years | Local control (LC) will be measured from completion of SBRT to the time of identification of any local progression by imaging or surgical exploration. The pattern of patients experiencing local, distant or local with distant failure will be estimated using competing risks method. |
| Vascular and Cellular Changes | 6 weeks after SBRT | Investigators will measure changes in diffusion and perfusion/permeability by using perfusion CT derived parameters that can predict treatment response and to assess any correlation between these perfusion CT derived parameters and local control and progression-free survival |
| Quality of Life (QOL) | 6 months after SBRT | The primary objective of the QOL study is to document the patient's experience of treatment for locally advanced pancreatic cancer by examining global QOL, physical symptoms, physical functioning and emotional well-being at baseline, during treatment, and after treatment. QOL measures including EORTC-QLQ-C30 questionnaire and the Pancreatic Cancer subscale (EORTC-PAN26) will be assessed 14 days prior to SBRT (Time 0), 10-12 weeks after SBRT (Time 1), and 6 months after SBRT (Time 2). The primary QOL endpoints include the EORTC global QOL, physical symptoms, physical functioning and emotional well-being. |
| Small Intestine Changes | 6 weeks after SBRT | Investigators will measure changes in the perfusion/permeability related parameters of peripancreatic small intestine before, during and after SBRT for patients using pCT and correlating these changes with the development of gastrointestinal toxicity such as duodenal ulcers, strictures, or enteritis. Patients will undergo baseline, post-first-fraction SBRT and post-treatment CT scans. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| FOLFIRINOX or Gemcitabine/Abraxane Followed by SBRT Dose Level 1 SBRT will be administered in 3 fractions, every other day, on an outpatient basis, following chemotherapy with either FOLFIRINOX or gemcitabine/abraxane. Dose level 1 - 9 Gy x 3 fractions.
FOLFIRINOX or gemcitabine/abraxane: Patients will have received induction chemotherapy for 3+ months with either FOLFIRINOX or gemcitabine/abraxane with at least stable disease.
SBRT: After completion of induction chemotherapy, stereotactic body radiation therapy (SBRT) will be administered in 3 fractions, every other day, on an outpatient basis. Dose escalation will start with dose level 1 (9 Gy x 3 fractions) and increase by 1 Gy per fraction at each dose level, dose level 2 will be 10 Gy x 3 fractions and dose level 3 will be 11 Gy x 3 fractions. | 5 |
| FOLFIRINOX or Gemcitabine/Abraxane Followed by SBRT Dose Level 2 SBRT will be administered in 3 fractions, every other day, on an outpatient basis, following chemotherapy with either FOLFIRINOX or gemcitabine/abraxane. Dose level 2 - 10 Gy x 3 fractions.
FOLFIRINOX or gemcitabine/abraxane: Patients will have received induction chemotherapy for 3+ months with either FOLFIRINOX or gemcitabine/abraxane with at least stable disease.
SBRT: After completion of induction chemotherapy, stereotactic body radiation therapy (SBRT) will be administered in 3 fractions, every other day, on an outpatient basis. Dose escalation will start with dose level 1 (9 Gy x 3 fractions) and increase by 1 Gy per fraction at each dose level, dose level 2 will be 10 Gy x 3 fractions and dose level 3 will be 11 Gy x 3 fractions. | 5 |
| FOLFIRINOX or Gemcitabine/Abraxane Followed by SBRT Dose Level 3 SBRT will be administered in 3 fractions, every other day, on an outpatient basis, following chemotherapy with either FOLFIRINOX or gemcitabine/abraxane. Dose level 3 - 11 Gy x 3 fractions.
FOLFIRINOX or gemcitabine/abraxane: Patients will have received induction chemotherapy for 3+ months with either FOLFIRINOX or gemcitabine/abraxane with at least stable disease.
SBRT: After completion of induction chemotherapy, stereotactic body radiation therapy (SBRT) will be administered in 3 fractions, every other day, on an outpatient basis. Dose escalation will start with dose level 1 (9 Gy x 3 fractions) and increase by 1 Gy per fraction at each dose level, dose level 2 will be 10 Gy x 3 fractions and dose level 3 will be 11 Gy x 3 fractions. | 4 |
| Total | 14 |
Baseline characteristics
| Characteristic | FOLFIRINOX or Gemcitabine/Abraxane Followed by SBRT Dose Level 1 | FOLFIRINOX or Gemcitabine/Abraxane Followed by SBRT Dose Level 2 | FOLFIRINOX or Gemcitabine/Abraxane Followed by SBRT Dose Level 3 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 4 Participants | 2 Participants | 9 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 1 Participants | 2 Participants | 5 Participants |
| Age, Continuous | 67 years | 68 years | 55 years | 67 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 5 Participants | 4 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 5 Participants | 4 Participants | 14 Participants |
| Region of Enrollment United States | 5 participants | 5 participants | 4 participants | 14 participants |
| Sex: Female, Male Female | 3 Participants | 5 Participants | 2 Participants | 10 Participants |
| Sex: Female, Male Male | 2 Participants | 0 Participants | 2 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 5 | 3 / 5 | 4 / 4 |
| other Total, other adverse events | 4 / 5 | 3 / 5 | 4 / 4 |
| serious Total, serious adverse events | 0 / 5 | 1 / 5 | 1 / 4 |
Outcome results
Primary
The Maximum Tolerated Dose (MTD) of Stereotactic Body Radiotherapy (SBRT) in Locally Advanced Pancreatic Cancer (LAPC) Patients Who Have Not Developed Distant Progression After Induction Chemotherapies.
This will be accomplished by the standard 3+3 dose escalation design. Dose limiting toxicities (DLT) are defined by ≥ Grade 3 treatment-related GI toxicity within 3 months of SBRT. These include: (1) Bowel (includes bowel perforation, obstruction, or hemorrhage) and (2) Stomach (bleeding ulcer, perforation) as determined by imaging or endoscopic evaluation.
Time frame: Up to 3 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FOLFIRINOX or Gemcitabine/Abraxane Followed by SBRT | The Maximum Tolerated Dose (MTD) of Stereotactic Body Radiotherapy (SBRT) in Locally Advanced Pancreatic Cancer (LAPC) Patients Who Have Not Developed Distant Progression After Induction Chemotherapies. | 33 grey |
Secondary
Local Control
Local control (LC) will be measured from completion of SBRT to the time of identification of any local progression by imaging or surgical exploration. The pattern of patients experiencing local, distant or local with distant failure will be estimated using competing risks method.
Time frame: Up to 5 years
Secondary
Overall Survival
Overall survival (OS) will be measured from completion of SBRT until death due to any cause. OS will be estimated using the method of Kaplan and Meier.
Time frame: Up to 5 years
Secondary
Progression Free Survival
Progression free survival (PFS) will be measured from completion of SBRT to the time of tumor progression or death due to any cause. PFS will be estimated using the method of Kaplan and Meier.
Time frame: Up to 5 years
Secondary
Quality of Life (QOL)
The primary objective of the QOL study is to document the patient's experience of treatment for locally advanced pancreatic cancer by examining global QOL, physical symptoms, physical functioning and emotional well-being at baseline, during treatment, and after treatment. QOL measures including EORTC-QLQ-C30 questionnaire and the Pancreatic Cancer subscale (EORTC-PAN26) will be assessed 14 days prior to SBRT (Time 0), 10-12 weeks after SBRT (Time 1), and 6 months after SBRT (Time 2). The primary QOL endpoints include the EORTC global QOL, physical symptoms, physical functioning and emotional well-being.
Time frame: 6 months after SBRT
Secondary
Small Intestine Changes
Investigators will measure changes in the perfusion/permeability related parameters of peripancreatic small intestine before, during and after SBRT for patients using pCT and correlating these changes with the development of gastrointestinal toxicity such as duodenal ulcers, strictures, or enteritis. Patients will undergo baseline, post-first-fraction SBRT and post-treatment CT scans.
Time frame: 6 weeks after SBRT
Secondary
Vascular and Cellular Changes
Investigators will measure changes in diffusion and perfusion/permeability by using perfusion CT derived parameters that can predict treatment response and to assess any correlation between these perfusion CT derived parameters and local control and progression-free survival
Time frame: 6 weeks after SBRT