Pancreatic Cancer Metastatic
Conditions
Keywords
Metastatic, Pancreatic Cancer, Adenocarcinoma
Brief summary
The purpose of this research study is to determine if the study drug, dasatinib, given in combination with 5-Fluorouracil, leucovorin and oxaliplatin (FOLFOX) will work against metastatic pancreatic cancer. Dasatinib is a Food and Drug Administration (FDA) approved drug for treating chronic myelogenous leukemia and acute lymphoblastic leukemia, however it is not currently approved for use in the treatment of pancreatic cancer.
Detailed description
Systemic control of pancreatic cancer remains a clinical unmet need. The recent superiority of 5-FU based combination therapies over the historical standard gemcitabine represents an opportunity to develop novel combinations of synergistic and effective cytotoxic and biologic targeted therapies. Src excess activity has been demonstrated in pancreatic cancer and is implicated in the invasive and metastatic phenotype clearly represented by this disease. Inhibition of Src activity is associated with numerous biologic modifications capable of positively modifying this phenotype and appears to have synergy with restoring inherent chemosensitivity. The addition of dasatinib to FOLFOX (FOLFOX-D) represents a novel therapeutic regimen in pancreatic cancer with safety and pharmacokinetic data already having been established in colorectal cancer. This protocol will test the safety and activity of this combination in pancreatic cancer where current clinical outcomes remain far from optimal.
Interventions
DRUGDasatinib
Dasatinib 150mg PO daily on days 1-14 of each 14 day cycle
DRUGmFOLFOX6
mFOLFOX6 (oxaliplatin 85mg/m2 IV, leucovorin 400mg/m2 IV, 5-Fluorouracil bolus 400mg/m2 IV, and 5-Fluorouracil 2400mg/m2 IV) on day 1 of each 14 day cycle
Sponsors
Bristol-Myers Squibb
University of Florida
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Pancreatic adenocarcinoma with evidence of metastatic disease on imaging * Measurable disease (per RECIST 1.1) * ECOG Performance Status 0-2 * No prior chemotherapy or radiotherapy for metastatic pancreatic cancer. Patients may have received prior treatment for non-metastatic disease; however the diagnosis of metastatic disease must have been made more than 6 months after completion of treatment. * Patients may have a history of other malignancies if there is no current evidence of persistent or recurrent disease and they are not undergoing any active therapy (including hormonal) * Patent biliary system * Patients receiving anti-coagulation treatment with an agent such as Coumadin or heparin may be allowed to participate, provided they are on stable anti-coagulation therapy with no active bleeding and have no condition that carries a high risk of bleeding * Adequate organ and marrow function * Ability to take oral medication (dasatinib must be swallowed whole) * Patient agrees to discontinue prohibited concomitant medications * Age \> 18 years * Women of childbearing potential (WOCBP) must be using an adequate method of contraception throughout the study and for at least 4 weeks after the last dose of study drug. * A male subject of fathering potential must use an adequate method of contraception throughout the study and for at least 4 weeks after the last dose of study drug.
Exclusion criteria
* WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 4 weeks after the last dose of study drug. Women who are pregnant or breastfeeding and sexually active fertile men not using effective birth control if their partners are WOCBP are also excluded. * History of known brain metastases or carcinomatous meningitis * Recent major surgery (within 4 weeks) or minor surgery (within 2 weeks), excluding placement of a vascular access device or biliary stent * Uncontrolled diabetes * Any sensory neuropathy \> grade 1 at baseline * Serious active or uncontrolled infection * Concurrent medical condition which may increase the risk of toxicity including clinically significant pleural or pericardial effusion, patients with known DPD deficiency or patients with a history of allergic reactions attributed to oxaliplatin, 5-FU or leucovorin. * Cardiac Symptoms including unstable angina or stable angina markedly limiting ordinary physical activity, NYHA class III or IV congestive heart failure, myocardial infarction or stroke within 6 months of study enrollment, diagnosed congenital long QT syndrome, any history of clinically significant ventricular arrhythmias, prolonged QTc interval on pre-entry ECG or clinically significant peripheral vascular disease. * Subjects with hypokalemia or hypomagnesemia if it cannot be corrected prior to dasatinib administration * History of significant bleeding disorder unrelated to cancer, including diagnosed congenital bleeding disorders, diagnosed acquired bleeding disorder within one year or ongoing or recent (≤ 3 months) significant gastrointestinal bleeding. * History of any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of protocol therapy, might affect the interpretation of the results of the study, or that puts the subject at high risk for treatment complications. * Use of category I drugs that are generally accepted to have a risk of causing Torsades de Pointes * Use of potent CYP3A4 inhibitors that significantly increase dasatinib exposure * Prisoners or subjects who are involuntarily incarcerated * Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness * Inability to comply with study and/or follow-up procedures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | 3 years | Determine activity of 5-Fluorouracil, leucovorin, and oxaliplatin (FOLFOX) plus dasatinib on progression free survival (PFS) in patients with metastatic pancreatic adenocarcinoma |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Freedom From Metastasis | 3 years | To determine the rate of freedom from metastasis (FFM), which is defined as the percentage of subjects with documented progressive disease (by RECIST 1.1 criteria) who had no new lesions. RECIST 1.1 criteria defines progressive disease as the appearance of one or more new lesions and/or the increase of the sum of the largest diameter of the target lesions by at least 20% from the smallest sum collected (the sum must also have increased by at least 5 mm). |
| Median Time To Progression | 3 years | To determine the median time to progression (TTP). TTP is defined as the time (in months) from when a subject achieves either a complete or partial response by RECIST 1.1 criteria until progressive disease (by RECIST 1.1 criteria) or death occurs. |
| Median Overall Survival | 4 years | To determine median overall survival (OS) in months |
| Clinical Benefit Rate | 3 years | To determine the clinical benefit rate (CBR). The CBR is defined as the percentage of subjects who achieved either a complete or partial response or stable disease by RECIST 1.1 criteria. RECIST 1.1 criteria defines a partial response as a decrease of the sum of the largest diameter each target lesion by at least 30%. A complete response is defined as the disappearance of all target lesions (except lymph nodes, whose short axis must measure 10 mm or less). By RECIST 1.1 criteria, a subject is considered to have stable disease when the sum of the largest diameter of the target lesions has neither decreased enough to qualify as a partial response not increased enough to qualify as progressive disease. |
| Response Rate | 3 years | To determine the response rate (RR) by RECIST 1.1 criteria. The response rate is the number of subjects who had either a complete or partial response by RECIST 1.1 criteria. RECIST 1.1 criteria defines a partial response as a decrease of the sum of the largest diameter each target lesion by at least 30%. A complete response is defined as the disappearance of all target lesions (except lymph nodes, whose short axis must measure 10 mm or less). The imaging modality used for all RECIST assessments in this study was CT. |
| Safety and Tolerability | 3 years | To determine the safety profile and tolerability of this regimen in this population by evaluating acute treatment related toxicities using CTCAE v4.0 criteria. Using the CTCAE v4.0, the severity of each adverse event reported was graded on a scale of 1 (mild severity) to 5 (fatal). For this outcome measure the percentage of subjects experiencing any adverse event of each CTCAE grade was tabulated. |
| Drug Compliance | 3 years | To determine patient compliance with oral therapy. For this outcome measure, compliance with oral therapy is defined as the percentage of subjects that took dasatinib for at least one cycle. Compliance with oral therapy was documented with a medication diary that subjects were asked to complete to document whether each dose of dasatinib was taken. |
| Quality of Life, as Measured by the Cancer Therapy Satisfaction Questionnaire (CTSQ), 2007 | 3 years | To determine the quality of life (QOL) of patients receiving this therapy using the CTSQ questionnaire. The CTSQ consists of 16 questions where subjects respond with a score on a scale of 0 (worst)-4 (best). The responses to the questions are used to calculate 3 subscores: Expectations of Therapy (ET), Feelings about Side Effects (FSE), and Satisfaction with Therapy (SWT). Each subscore is calculated by multiplying the mean response value for the questions used to calculate that subscore by 25. The maximum value is 100 and the minimum value is 0 for all 3 subscores. A higher subscore indicates better QOL in that area. The mean difference in each of the 3 subscores from baseline and 95% confidence interval for the entire study population is reported here. A negative mean difference indicates a decrease from baseline in QOL for that area. |
| Quality of Life, as Measured by the Functional Assessment of Chronic Illness Therapy; Hepatobiliary Cancer (FACT-Hep) Questionnaire (Version 4.0) | 3 years | The FACT-Hep consists of 45 questions where subjects respond with a score on a scale of 0 (worst)-4 (best). The responses to the questions are summed to calculate 5 subscores: Physical Well-Being (PWB), Social Well-Being (SWB), Emotional Well-Being (EWB), Functional Well-Being (FWB), and Hepatobiliary Cancer Subscale (HCS). The mean difference in each of the 5 subscores from baseline, as well as the total score of the 5 subscores (the FACT-Hep Total Score) for the entire study population is reported here. The mean difference in the FACT-G Total Score (calculated by summing the PWB, SWB, EWB, and FWB subscores) is also reported here. A negative mean difference indicates a decrease from baseline in QOL. Score ranges- PWB subscore: 0-28, SWB subscore: 0-28, EWB subscore: 0-24, FWB subscore: 0-28, HCS subscore: 0-72, FACT-G Total Score: 0-108, and FACT-Hep Total Score: 0-180. A higher value for each subscore or total score indicates better QOL. |
| Site of Failure | 3 years | To determine the site of failure of this regimen in this population. The site of failure is the anatomical site(s) where disease progression by RECIST 1.1 criteria was noted on imaging. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment Arm Dasatinib and mFOLFOX6
Dasatinib: Dasatinib 150mg PO daily on days 1-14 of each 14 day cycle
mFOLFOX6: mFOLFOX6 (oxaliplatin 85mg/m2 IV, leucovorin 400mg/m2 IV, 5-Fluorouracil bolus 400mg/m2 IV, and 5-Fluorouracil 2400mg/m2 IV) on day 1 of each 14 day cycle | 44 |
| Total | 44 |
Baseline characteristics
| Characteristic | Treatment Arm |
|---|---|
| Age, Continuous | 65 years |
| ECOG Performance status Performance Status Unknown | 1 Participants |
| ECOG Performance status Status = 0 | 22 Participants |
| ECOG Performance status Status = 1 | 19 Participants |
| ECOG Performance status Status = 2 | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 38 Participants |
| Region of Enrollment United States | 44 Participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 42 / 44 |
| other Total, other adverse events | 44 / 44 |
| serious Total, serious adverse events | 24 / 44 |
Outcome results
Primary
Progression Free Survival (PFS)
Determine activity of 5-Fluorouracil, leucovorin, and oxaliplatin (FOLFOX) plus dasatinib on progression free survival (PFS) in patients with metastatic pancreatic adenocarcinoma
Time frame: 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasatinib and mFOLFOX6 | Progression Free Survival (PFS) | 4 months |
Secondary
Clinical Benefit Rate
To determine the clinical benefit rate (CBR). The CBR is defined as the percentage of subjects who achieved either a complete or partial response or stable disease by RECIST 1.1 criteria. RECIST 1.1 criteria defines a partial response as a decrease of the sum of the largest diameter each target lesion by at least 30%. A complete response is defined as the disappearance of all target lesions (except lymph nodes, whose short axis must measure 10 mm or less). By RECIST 1.1 criteria, a subject is considered to have stable disease when the sum of the largest diameter of the target lesions has neither decreased enough to qualify as a partial response not increased enough to qualify as progressive disease.
Time frame: 3 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dasatinib and mFOLFOX6 | Clinical Benefit Rate | 56.82 percentage of subjects |
Secondary
Drug Compliance
To determine patient compliance with oral therapy. For this outcome measure, compliance with oral therapy is defined as the percentage of subjects that took dasatinib for at least one cycle. Compliance with oral therapy was documented with a medication diary that subjects were asked to complete to document whether each dose of dasatinib was taken.
Time frame: 3 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dasatinib and mFOLFOX6 | Drug Compliance | 93.2 percentage of subjects |
Secondary
Freedom From Metastasis
To determine the rate of freedom from metastasis (FFM), which is defined as the percentage of subjects with documented progressive disease (by RECIST 1.1 criteria) who had no new lesions. RECIST 1.1 criteria defines progressive disease as the appearance of one or more new lesions and/or the increase of the sum of the largest diameter of the target lesions by at least 20% from the smallest sum collected (the sum must also have increased by at least 5 mm).
Time frame: 3 years
Population: The number of participants analyzed for this outcome measure only includes the 29 participants who had documented disease progression (by RECIST 1.1 criteria) during study participation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dasatinib and mFOLFOX6 | Freedom From Metastasis | 65.5 percentage of subjects |
Secondary
Median Overall Survival
To determine median overall survival (OS) in months
Time frame: 4 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasatinib and mFOLFOX6 | Median Overall Survival | 10.6 months |
Secondary
Median Time To Progression
To determine the median time to progression (TTP). TTP is defined as the time (in months) from when a subject achieves either a complete or partial response by RECIST 1.1 criteria until progressive disease (by RECIST 1.1 criteria) or death occurs.
Time frame: 3 years
Population: The number of participants analyzed for this outcome measure includes only the 11 participants who achieved either a complete or partial response by RECIST 1.1 criteria during study participation.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasatinib and mFOLFOX6 | Median Time To Progression | 9.8 months |
Secondary
Quality of Life, as Measured by the Cancer Therapy Satisfaction Questionnaire (CTSQ), 2007
To determine the quality of life (QOL) of patients receiving this therapy using the CTSQ questionnaire. The CTSQ consists of 16 questions where subjects respond with a score on a scale of 0 (worst)-4 (best). The responses to the questions are used to calculate 3 subscores: Expectations of Therapy (ET), Feelings about Side Effects (FSE), and Satisfaction with Therapy (SWT). Each subscore is calculated by multiplying the mean response value for the questions used to calculate that subscore by 25. The maximum value is 100 and the minimum value is 0 for all 3 subscores. A higher subscore indicates better QOL in that area. The mean difference in each of the 3 subscores from baseline and 95% confidence interval for the entire study population is reported here. A negative mean difference indicates a decrease from baseline in QOL for that area.
Time frame: 3 years
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Dasatinib and mFOLFOX6 | Quality of Life, as Measured by the Cancer Therapy Satisfaction Questionnaire (CTSQ), 2007 | Subscore difference for ET | -8.4 score on a scale |
| Dasatinib and mFOLFOX6 | Quality of Life, as Measured by the Cancer Therapy Satisfaction Questionnaire (CTSQ), 2007 | Subscore difference for FSE | 2.1 score on a scale |
| Dasatinib and mFOLFOX6 | Quality of Life, as Measured by the Cancer Therapy Satisfaction Questionnaire (CTSQ), 2007 | Subscore difference for SWT | -0.5 score on a scale |
Secondary
Quality of Life, as Measured by the Functional Assessment of Chronic Illness Therapy; Hepatobiliary Cancer (FACT-Hep) Questionnaire (Version 4.0)
The FACT-Hep consists of 45 questions where subjects respond with a score on a scale of 0 (worst)-4 (best). The responses to the questions are summed to calculate 5 subscores: Physical Well-Being (PWB), Social Well-Being (SWB), Emotional Well-Being (EWB), Functional Well-Being (FWB), and Hepatobiliary Cancer Subscale (HCS). The mean difference in each of the 5 subscores from baseline, as well as the total score of the 5 subscores (the FACT-Hep Total Score) for the entire study population is reported here. The mean difference in the FACT-G Total Score (calculated by summing the PWB, SWB, EWB, and FWB subscores) is also reported here. A negative mean difference indicates a decrease from baseline in QOL. Score ranges- PWB subscore: 0-28, SWB subscore: 0-28, EWB subscore: 0-24, FWB subscore: 0-28, HCS subscore: 0-72, FACT-G Total Score: 0-108, and FACT-Hep Total Score: 0-180. A higher value for each subscore or total score indicates better QOL.
Time frame: 3 years
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Dasatinib and mFOLFOX6 | Quality of Life, as Measured by the Functional Assessment of Chronic Illness Therapy; Hepatobiliary Cancer (FACT-Hep) Questionnaire (Version 4.0) | Subscore difference for PWB | -4.4 score on a scale |
| Dasatinib and mFOLFOX6 | Quality of Life, as Measured by the Functional Assessment of Chronic Illness Therapy; Hepatobiliary Cancer (FACT-Hep) Questionnaire (Version 4.0) | Subscore difference for SWB | -0.9 score on a scale |
| Dasatinib and mFOLFOX6 | Quality of Life, as Measured by the Functional Assessment of Chronic Illness Therapy; Hepatobiliary Cancer (FACT-Hep) Questionnaire (Version 4.0) | Subscore difference for EWB | 0.6 score on a scale |
| Dasatinib and mFOLFOX6 | Quality of Life, as Measured by the Functional Assessment of Chronic Illness Therapy; Hepatobiliary Cancer (FACT-Hep) Questionnaire (Version 4.0) | Subscore difference for FWB | -2.8 score on a scale |
| Dasatinib and mFOLFOX6 | Quality of Life, as Measured by the Functional Assessment of Chronic Illness Therapy; Hepatobiliary Cancer (FACT-Hep) Questionnaire (Version 4.0) | Subscore difference for HCS | -6.3 score on a scale |
| Dasatinib and mFOLFOX6 | Quality of Life, as Measured by the Functional Assessment of Chronic Illness Therapy; Hepatobiliary Cancer (FACT-Hep) Questionnaire (Version 4.0) | Difference in FACT-G Total Score | -7.4 score on a scale |
| Dasatinib and mFOLFOX6 | Quality of Life, as Measured by the Functional Assessment of Chronic Illness Therapy; Hepatobiliary Cancer (FACT-Hep) Questionnaire (Version 4.0) | Difference in FACT-Hep Total Score | -13.7 score on a scale |
Secondary
Response Rate
To determine the response rate (RR) by RECIST 1.1 criteria. The response rate is the number of subjects who had either a complete or partial response by RECIST 1.1 criteria. RECIST 1.1 criteria defines a partial response as a decrease of the sum of the largest diameter each target lesion by at least 30%. A complete response is defined as the disappearance of all target lesions (except lymph nodes, whose short axis must measure 10 mm or less). The imaging modality used for all RECIST assessments in this study was CT.
Time frame: 3 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dasatinib and mFOLFOX6 | Response Rate | 25 percentage of subjects |
Secondary
Safety and Tolerability
To determine the safety profile and tolerability of this regimen in this population by evaluating acute treatment related toxicities using CTCAE v4.0 criteria. Using the CTCAE v4.0, the severity of each adverse event reported was graded on a scale of 1 (mild severity) to 5 (fatal). For this outcome measure the percentage of subjects experiencing any adverse event of each CTCAE grade was tabulated.
Time frame: 3 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib and mFOLFOX6 | Safety and Tolerability | Percent of subjects experiencing a Grade 4 event | 22.7 percentage of subjects |
| Dasatinib and mFOLFOX6 | Safety and Tolerability | Percent of subjects experiencing a grade 5 event | 9.1 percentage of subjects |
| Dasatinib and mFOLFOX6 | Safety and Tolerability | Percent of subjects experiencing a Grade 1 event | 88.6 percentage of subjects |
| Dasatinib and mFOLFOX6 | Safety and Tolerability | Percent of subjects experiencing a grade 2 event | 90.9 percentage of subjects |
| Dasatinib and mFOLFOX6 | Safety and Tolerability | Percent of subjects experiencing a Grade 3 event | 86.4 percentage of subjects |
Secondary
Site of Failure
To determine the site of failure of this regimen in this population. The site of failure is the anatomical site(s) where disease progression by RECIST 1.1 criteria was noted on imaging.
Time frame: 3 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dasatinib and mFOLFOX6 | Site of Failure | Left pleural effusion | 1 Participants |
| Dasatinib and mFOLFOX6 | Site of Failure | Liver | 12 Participants |
| Dasatinib and mFOLFOX6 | Site of Failure | Lungs | 3 Participants |
| Dasatinib and mFOLFOX6 | Site of Failure | Pancreas/liver | 4 Participants |
| Dasatinib and mFOLFOX6 | Site of Failure | Peritoneal carcinomatosis | 1 Participants |
| Dasatinib and mFOLFOX6 | Site of Failure | peritoneal carcinomatosis/liver | 1 Participants |
| Dasatinib and mFOLFOX6 | Site of Failure | Spleen/liver | 1 Participants |