Metastatic Pancreatic Cancer, Pancreatic Cancer
Conditions
Keywords
metastatic pancreatic cancer, locally advanced pancreatic cancer, FOLFIRINOX, phase II, progression free survival
Brief summary
The primary objective of this study was to determine the progression free survival in patients with metastatic pancreatic cancer and in patients with locally advanced unresectable non-metastatic pancreatic cancer treated with a dose-attenuated modification of folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX). Secondary endpoints included: determine objective response rate according to RECIST; determine overall survival; evaluate toxicity; determine rate of resection in locally advanced unresectable stratum; correlate time to progression, objective response, and overall survival with early changes in glucose metabolism using \[18F\]-fluorodeoxyglucose (FDG)-positron emission tomography (PET) scanning.
Detailed description
A phase II open label single arm multi-institutional study at Yale's Smilow Cancer Hospital (New Haven, CT, USA), the Smilow Cancer Hospital Care Centers (regional community-based clinics), the VA Connecticut Healthcare System West Haven Campus (West Haven, CT, USA) and Bridgeport Hospital (Bridgeport, CT, USA). The primary objective of this study was to determine the PFS in patients with MPC and LAPC treated with a dose attenuated modification of FOLFIRINOX. NOTE: Upon results reporting (2016), the registration record was reorganized to display MPC and LAPC groups in individual arms. The most meaningful comparison is between MPC/LAPC and historical controls. That is how results are reported in the published paper, see citations.
Interventions
DRUGFolfirinox
* Oxaliplatin 85 mg/m2 IV infused over two hours, followed by * Leucovorin 400 mg/m2 IV over two hours * Irinotecan 135 mg/m2 IV over 90 minutes (concurrent with leucovorin during the last 90 min of the leucovorin infusion) * 5-FU 300mg/m2 IV bolus, then 2400 mg/m2 continuous IV infusion over 46 hours FOLFIRINOX is a chemotherapy regimen. It is made up of the following four drugs: FOL - folinic acid (leucovorin), a vitamin B derivative that modulates/potentiates/reduces the side effects of fluorouracil; F - fluorouracil (5-FU), a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops DNA synthesis; IRIN - irinotecan (Camptosar), a topoisomerase inhibitor, which prevents DNA from uncoiling and duplicating; and OX - oxaliplatin (Eloxatin), a platinum-based antineoplastic agent, which inhibits DNA repair and/or DNA synthesis.
Sponsors
Yale 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
* Pathologic or cytologic documentation of pancreatic adenocarcinoma * Metastatic or locally advanced unresectable disease, including borderline unresectable disease * Patients with biliary or gastroduodenal obstruction must have drainage or surgical bypass prior to starting chemoradiation * Measurable or non-measurable assessable disease * No prior treatment (chemotherapy, biological therapy, or radiotherapy) for metastatic or non-metastatic locally advanced unresectable pancreatic cancer * 6 months since completion of any prior neoadjuvant or adjuvant therapy (chemotherapy or radiotherapy) for resected pancreatic cancer * No prior treatment with oxaliplatin or irinotecan * No prior treatment with fluoruouracil or capecitabine unless administered as a radiosensitizing drug during adjuvant/neoadjuvant chemoradiotherapy after/before resection of pancreatic cancer * Patients who received chemotherapy \> 2 years ago for malignancies other than pancreatic cancer are eligible, provided that chemotherapy was completed \> 2 years ago and there is no evidence of the second malignancy at the time of study entry * \> 4 weeks since major surgery * No other concurrent anticancer therapy * ECOG Performance Status: 0-1 * Age \> 18 * No other malignancy within past two years except basal cell carcinoma of the skin, cervical carcinoma in situ, or nonmetastatic prostate cancer * Paraffin block or slides must be available * Adequate organ function * No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung * No \> grade 1 sensory peripheral neuropathy * No uncontrolled seizure disorder, active neurological disease, or known CNS disease * No significant cardiac disease, including the following: unstable angina, New York Heart Association class II-IV congestive heart failure, myocardial infarction within six months prior to study enrollment * No history of chronic diarrhea * Not pregnant and not nursing * No other medical condition or reason that, in the opinion of the investigator, would preclude study participation * Laboratory parameters as follows: absolute neutrophil count ≥ 1,500/uL, platelet count ≥ 100,000/uL, hemoglobin ≥ 9 g,/dL, creatinine \< 1.5 X ULN or estimated GFR \> 30 ml/min, bilirubin \< 1.5 X ULN, AST and ALT \< 3 X ULN, negative pregnancy test in women of childbearing age
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | 24 weeks | The primary objective of this study is to determine the progression free survival in patients with metastatic pancreatic cancer and in patients with locally advanced unresectable non-metastatic pancreatic cancer treated with a dose-attenuated modification of FOLFIRINOX. Tumour response was determined according to RECIST 1.1 by independent radiology review. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | 24 weeks | Response will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST 1.1 by independent radiology review) at 8 week intervals in patients with metastatic disease and in patients with locally advanced disease. |
| Overall Survival | 24 weeks | Overall survival will be determined in patients with metastatic disease and in patients with locally advanced disease. |
| Toxicity | 24 weeks | Toxicities will be assessed according to Common Terminology Criteria for Adverse Events (CTCAE) 4.0. Rates of grade 3 and 4 toxicities will be compared to historical controls. MPC and LAPC are combined because they were given the exact same medication. The study aimed to compare this dosage with historical dosage, so this comparison is the most appropriate. |
| Rate of Resection in Patients With Locally Advanced Disease | 24 weeks | The rate of surgical resection in the cohort of patients with locally advanced disease will be determined. |
| Correlate Time to Progression, Objective Response, and Overall Survival With Early Changes in Glucose Metabolism Using FDG-positron Emission Tomography (PET) Scanning | 24 weeks | The time to progression, objective response rate, and overall survival will be correlated with early changes in glucose metabolism using FDG-positron emission tomography (PET) scanning in patients with metastatic disease and locally advanced disease. |
Countries
United States
Participant flow
Recruitment details
Patients with pathologically confirmed, measurable or non-measurable assessable MPC or LAPC (including unresectable and borderline resectable) were recruited from November 2011 through January 2014.
Participants by arm
| Arm | Count |
|---|---|
| MPC Modified FOLFIRINOX Patients with metastatic pancreatic cancer (MPC) were treated with modified FOLFIRINOX every 2 weeks as follows: oxaliplatin 85 mg m 2 infused over 120 min, immediately followed by folinic acid 400 mg m 2 infused over 120 min with the addition, after 30 min, of irinotecan 135 mg m 2 infused over 90 min, followed by 5FU 300 mg m 2 IV bolus, followed by 2400 mg m 2 continuous infusion for 46 h (25% reduction in bolus 5FU and irinotecan doses). All patients received pegylated filgrastim with each cycle on day 3 or 4 in the absence of severe leukocytosis. All patients routinely received palonosetron, aprepitant and dexamethasone for emesis prophylaxis. | 37 |
| LAPC Modified FOLFIRINOX Patients with locally advanced pancreatic cancer (LAPC) were treated with modified FOLFIRINOX every 2 weeks as follows: oxaliplatin 85 mg m 2 infused over 120 min, immediately followed by folinic acid 400 mg m 2 infused over 120 min with the addition, after 30 min, of irinotecan 135 mg m 2 infused over 90 min, followed by 5FU 300 mg m 2 IV bolus, followed by 2400 mg m 2 continuous infusion for 46 h (25% reduction in bolus 5FU and irinotecan doses). All patients received pegylated filgrastim with each cycle on day 3 or 4 in the absence of severe leukocytosis. All patients routinely received palonosetron, aprepitant and dexamethasone for emesis prophylaxis. | 31 |
| Total | 68 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 7 | 2 |
Baseline characteristics
| Characteristic | MPC Modified FOLFIRINOX | LAPC Modified FOLFIRINOX | Total |
|---|---|---|---|
| Age, Customized Age | 62 years | 63 years | 62 years |
| Biliary stent No | 28 participants | 14 participants | 42 participants |
| Biliary stent Yes | 9 participants | 17 participants | 26 participants |
| ECOG Performance Status 0: Fully active | 17 participants | 15 participants | 32 participants |
| ECOG Performance Status 1: Restricted in physically strenuous activity | 20 participants | 16 participants | 36 participants |
| Level of CA19.9 Elevated, <59 Upper Limits of Normal | 18 participants | 24 participants | 42 participants |
| Level of CA19.9 Elevated, >=59 Upper Limits of Normal | 15 participants | 4 participants | 19 participants |
| Level of CA19.9 Normal | 4 participants | 3 participants | 7 participants |
| Pancreatic tumour location Body | 14 participants | 4 participants | 18 participants |
| Pancreatic tumour location Head | 17 participants | 27 participants | 44 participants |
| Pancreatic tumour location Tumour Resection | 6 participants | 0 participants | 6 participants |
| Sex: Female, Male Female | 16 Participants | 11 Participants | 27 Participants |
| Sex: Female, Male Male | 21 Participants | 20 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 44 | 0 / 31 |
| other Total, other adverse events | 20 / 43 | 11 / 31 |
| serious Total, serious adverse events | 0 / 44 | 0 / 31 |
Outcome results
Primary
Progression Free Survival
The primary objective of this study is to determine the progression free survival in patients with metastatic pancreatic cancer and in patients with locally advanced unresectable non-metastatic pancreatic cancer treated with a dose-attenuated modification of FOLFIRINOX. Tumour response was determined according to RECIST 1.1 by independent radiology review.
Time frame: 24 weeks
Population: Two of 31 patients with LAPC were excluded from efficacy analysis because they did not complete four cycles to reach the first efficacy assessment (one due to cholecystitis with abscess and one due to cerebrovascular accident).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MPC Modified FOLFIRINOX | Progression Free Survival | 54 percentage of participants |
| LAPC Modified FOLFIRINOX | Progression Free Survival | 97 percentage of participants |
Secondary
Correlate Time to Progression, Objective Response, and Overall Survival With Early Changes in Glucose Metabolism Using FDG-positron Emission Tomography (PET) Scanning
The time to progression, objective response rate, and overall survival will be correlated with early changes in glucose metabolism using FDG-positron emission tomography (PET) scanning in patients with metastatic disease and locally advanced disease.
Time frame: 24 weeks
Population: This outcome was included in the 2012 protocol registration and actually describes a series of analyses that were not fully conducted, and will not be. The outcome measures described in the outcome description are presented as separated outcome measures elsewhere in this results record.
Secondary
Objective Response Rate
Response will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST 1.1 by independent radiology review) at 8 week intervals in patients with metastatic disease and in patients with locally advanced disease.
Time frame: 24 weeks
Population: Two of 31 patients with LAPC were excluded from efficacy analysis because they did not complete four cycles to reach the first efficacy assessment (one due to cholecystitis with abscess and one due to cerebrovascular accident).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MPC Modified FOLFIRINOX | Objective Response Rate | 35.1 percentage of participants |
| LAPC Modified FOLFIRINOX | Objective Response Rate | 17.2 percentage of participants |
Secondary
Overall Survival
Overall survival will be determined in patients with metastatic disease and in patients with locally advanced disease.
Time frame: 24 weeks
Population: Two of 31 patients with LAPC were excluded from efficacy analysis because they did not complete four cycles to reach the first efficacy assessment (one due to cholecystitis with abscess and one due to cerebrovascular accident).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MPC Modified FOLFIRINOX | Overall Survival | 81 percentage of participants |
| LAPC Modified FOLFIRINOX | Overall Survival | 100 percentage of participants |
Secondary
Rate of Resection in Patients With Locally Advanced Disease
The rate of surgical resection in the cohort of patients with locally advanced disease will be determined.
Time frame: 24 weeks
Population: Only LAPC patients were considered in the analysis. 13 patients in the LAPC group had surgical resection. The definition of locally unresectable and borderline were clarified in the protocol.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LAPC Modified FOLFIRINOX | Rate of Resection in Patients With Locally Advanced Disease | Total | 13 participants |
| LAPC Modified FOLFIRINOX | Rate of Resection in Patients With Locally Advanced Disease | Unresectable | 6 participants |
| LAPC Modified FOLFIRINOX | Rate of Resection in Patients With Locally Advanced Disease | Borderline | 7 participants |
Secondary
Toxicity
Toxicities will be assessed according to Common Terminology Criteria for Adverse Events (CTCAE) 4.0. Rates of grade 3 and 4 toxicities will be compared to historical controls. MPC and LAPC are combined because they were given the exact same medication. The study aimed to compare this dosage with historical dosage, so this comparison is the most appropriate.
Time frame: 24 weeks
Population: One of the total 75 patients did not receive treatment and was excluded from toxicity analysis. Treatment-related grade 3 and 4 adverse events observed in our study and in the historical control group treated with standard FOLFIRINOX.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MPC Modified FOLFIRINOX | Toxicity | Neutropenia | 4 participants |
| MPC Modified FOLFIRINOX | Toxicity | Thrombocytopenia | 5 participants |
| MPC Modified FOLFIRINOX | Toxicity | Anaemia | 2 participants |
| MPC Modified FOLFIRINOX | Toxicity | Febrile neutropenia | 1 participants |
| MPC Modified FOLFIRINOX | Toxicity | Diarrhea | 8 participants |
| MPC Modified FOLFIRINOX | Toxicity | Fatigue | 5 participants |
| MPC Modified FOLFIRINOX | Toxicity | Alanine aminotransferase (ALT) increased | 3 participants |
| MPC Modified FOLFIRINOX | Toxicity | Thromboembolic event | 3 participants |
| MPC Modified FOLFIRINOX | Toxicity | Peripheral sensory neuropathy | 2 participants |
| MPC Modified FOLFIRINOX | Toxicity | Vomiting | 1 participants |
| LAPC Modified FOLFIRINOX | Toxicity | Thromboembolic event | 0 participants |
| LAPC Modified FOLFIRINOX | Toxicity | Neutropenia | 5 participants |
| LAPC Modified FOLFIRINOX | Toxicity | Fatigue | 4 participants |
| LAPC Modified FOLFIRINOX | Toxicity | Thrombocytopenia | 2 participants |
| LAPC Modified FOLFIRINOX | Toxicity | Vomiting | 1 participants |
| LAPC Modified FOLFIRINOX | Toxicity | Anaemia | 2 participants |
| LAPC Modified FOLFIRINOX | Toxicity | Alanine aminotransferase (ALT) increased | 0 participants |
| LAPC Modified FOLFIRINOX | Toxicity | Febrile neutropenia | 2 participants |
| LAPC Modified FOLFIRINOX | Toxicity | Peripheral sensory neuropathy | 0 participants |
| LAPC Modified FOLFIRINOX | Toxicity | Diarrhea | 4 participants |