Bile Duct Neoplasms, Pancreatic Neoplasms
Conditions
Keywords
advanced pancreatic and biliary tract carcinomas
Brief summary
This study involves the use of oxaliplatin, capecitabine, and sorafenib which are all drugs approved by the Food and Drug Administration (FDA) for use in the treatment of different cancers. Their use in this exact combination is considered experimental for the treatment of pancreas and biliary tract; however the combination has been tested in a preliminary trial. We are also testing a survey designed. The purpose of this research study is to investigate the chemotherapy drug sorafenib in combination with oxaliplatin and capecitabine chemotherapies for the treatment of pancreas and biliary tract cancers.to help patients report their side effects from chemotherapy treatments.
Detailed description
Primary Objectives * To assess the overall safety of sorafenib when administered with the 2DOC regimen capecitabine and oxaliplatin in patients with advanced or metastatic pancreas or biliary tract cancers. * To define the dose limiting toxicity and maximally tolerated dose of this combination. * To assess the clinical response rate (stable, partial and complete responses) of the combination in patients with advanced or metastatic pancreas or biliary tract cancers. Secondary Objectives * To define the time to progression and overall survival for patients treated with this regimen. * To evaluate the congruency of the Adverse Events Self-Report Survey in determining patient reported side effects of treatment
Interventions
DRUGOxaliplatin
On days 1 and 15 of each 28 day treatment cycle, patients receive oxaliplatin 85 mg/m2 as a 2-hour IV infusion. Following the infusion of oxaliplatin, the infusion line should be flushed with Dextrose 5% in Water.
DRUGCapecitabine
Each course of oral capecitabine administration will commence following administration of oxaliplatin. Capecitabine 2250 mg/m2 will be given every 8 hours for a total of 6 doses as above, commencing with each cycle of therapy. Because capecitabine is provided in fixed dose forms, rounding will be necessary. Rounding will be to the nearest 150 mg on a per dose basis.
DRUGSorafenib
Cohort 1 will receive 200 mg of sorafenib orally twice daily, cohort 2 will receive 400 mg orally twice daily, both beginning on the first day of the first cycle (see section 9.1). If needed, cohort -1 will be used, at 200 mg of sorafenib once daily. Sorafenib should be taken without food (at least 1 hour before or 2 hours after eating). Cohort I (Dose escalation phase) Agent Dose Route Day Cycle length Sorafenib 200 mg BID Oral Daily Every 28 days If 1/3 patients develop a DLT, enroll 3 patients at dose level -1 Sorafenib 200 mg po qd. Cohort II (Phase II studies at MTD) Agent Dose Route Day Cycle length Sorafenib 400 mg BID Oral Daily Every 28 days
Sponsors
Bayer
Sanofi
University of Wisconsin, Madison
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have histologically or cytologically confirmed locally advanced inoperable or metastatic adenocarcinoma of the pancreas or biliary tract who have not previously received more than one systemic treatment for their disease. * Age at least 18 years old * ECOG performance status 0-2. * Patients must have adequate organ and marrow function as defined below: * WBC at least 3,000 * ANC at least 1,500 * PLT at least 100,000 * total bilirubin must be less than 2.5 x institutional upper limit of norm * AST(SGOT)/ALT(SGPT) must be less than 5 X institutional upper limit of normal * creatinine clearance must be greater than 50 mL/min as calculated by the Cockroft-Gault formula * Patients with ≤ grade 2 (CTC 3.0) neuropathy. * At least one measurable lesion as defined by RECIST criteria * The effects of oxaliplatin, capecitabine and sorafenib on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because DNA alkylating agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. * Because the risk of toxicity in nursing infants secondary to oxaliplatin treatment of the mother is unknown but may be harmful, breastfeeding should be discontinued if the mother is treated with oxaliplatin. * Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
* No concomitant radiation therapy, or other systemic cancer therapies. * Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other toxicities. * History of allergy to platinum compounds, capecitabine, sorafenib or to antiemetics appropriate for administration in conjunction with protocol-directed chemotherapy. * Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection, thrombolic or embolic events such as cerebrovascular accident including transient ischemic attacks within the past 6 months, symptomatic congestive heart failure, unstable angina pectoris within 3 months prior to entry study, myocardial infarction within 6 months prior to study entry, ongoing cardiac arrhythmia (excluding atrial fibrillation), uncontrolled hypertension (systolic blood pressure \> 150 mmHg or diastolic blood pressure \> 90 mmHg, despite optimal medical management), pulmonary hemorrhage/bleeding event \> CTCAE Grade 2 within 4 weeks of first dose of study drug, or any other hemorrhage/bleeding event \> CTCAE Grade 3 within 4 weeks of first dose of study drug, serious non-healing wound, ulcer, or bone fracture, evidence or history of bleeding diathesis or coagulopathy. * Pregnant or nursing women are excluded from this study because oxaliplatin, capecitabine and sorafenib is a DNA alkylating agent with the potential for teratogenic or abortifacient effects. Female patients of reproductive potential must have a negative urine or serum pregnancy test within two weeks prior to enrolling. * Major surgery, open biopsy or significant traumatic injury within 4 weeks of first study drug. * Because of drug interactions with sorafenib, use of St. John's Wort or rifampin (rifampicin) is contraindicated. Patients may discontinue the use of these drugs to become eligible for the study * Any condition that impairs patient's ability to swallow whole pills. * HIV-positive patients receiving anti-retroviral therapy (HAART) are excluded from the study because of possible pharmacokinetic interactions. * Second malignancy within the past 3 years (excluding nonmelanoma skin cancer and in situ cancers) that has not been treated with curative intent and is not currently without evidence of disease, * Patients with known gastrointestinal malabsorption syndromes are excluded as this concurrent illness will affect absorption of the oral medications.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | Up to 18 months | Response rate of participant to treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Up to 18 months | Time to progression, defined as number of days from day of first study drug administration to the day the patient experiences an event of disease progression or death; summarized using point estimates of the median time to progression and associated 95% confidence intervals for each stratum separately. |
| Overall Survival | Up to 18 months | Overall survival, defined as number of days from the day of first study drug administration to the day the patient dies, summarized using point estimates of the median time to progression, and associated 95% confidence intervals |
Countries
United States
Participant flow
Recruitment details
This study accrued through the Wisconsin Oncology Network (WON), a network of academic and private practice institutions across the state of Wisconsin and the upper Midwest.
Participants by arm
| Arm | Count |
|---|---|
| Phase I: 200mg Sorafenib+2DOC Cohort 1: 200mg Sorafenib+2DOC
Oxaliplatin + Oral Capecitabine + Sorafenib
Oxaliplatin: Days 1 and 15 of each 28 day treatment cycle, patients receive oxaliplatin 85 mg/m2 as a 2-hour IV infusion. Next, the infusion line should be flushed with Dextrose 5% in Water.
Capecitabine: Oral capecitabine administration will start after administration of oxaliplatin. Capecitabine 2250 mg/m2 will be given every 8 hours for a total of 6 doses, commencing with each cycle of therapy. Capecitabine is provided in fixed dose forms, and rounding will be to the nearest 150 mg on a per dose basis.
Sorafenib: 200 mg of sorafenib orally twice daily, beginning on the first day of the first cycle. If needed, cohort -1 will be used, at 200 mg of sorafenib once daily.
Cohort I
Sorafenib 200 mg BID Oral Daily Every 28 days
If 1/3 patients develop a DLT, enroll 3 patients at dose level -1 Sorafenib 200 mg po qd. | 9 |
| Phase I: 400mg Sorafenib BID+2DOC Cohort 2: 400mg Sorafenib+2DOC
Oxaliplatin + Oral Capecitabine + Sorafenib
Oxaliplatin: Days 1 and 15 of each 28 day treatment cycle, patients receive oxaliplatin 85 mg/m2 as a 2-hour IV infusion. Next, the infusion line should be flushed with Dextrose 5% in Water.
Capecitabine: Oral capecitabine administration will start after administration of oxaliplatin. Capecitabine 2250 mg/m2 will be given every 8 hours for a total of 6 doses, commencing with each cycle of therapy. Capecitabine is provided in fixed dose forms, and rounding will be to the nearest 150 mg on a per dose basis.
Sorafenib: 400 mg of sorafenib orally twice daily, both beginning on the first day of the first cycle (see section 9.1). If needed, cohort -1 will be used, at 200 mg of sorafenib once daily.
Cohort II (Phase II studies at MTD) Agent Dose Route Day Cycle length
Sorafenib 400 mg BID Oral Daily Every 28 days | 7 |
| Phase II: Pancreatic Cancer Oxaliplatin + Oral Capecitabine + Sorafeni
Oxaliplatin: Days 1 and 15 of each 28 day treatment cycle, patients receive oxaliplatin 85 mg/m2 as a 2-hour IV infusion. Next, the infusion line should be flushed with Dextrose 5% in Water.
Capecitabine: Oral capecitabine administration will start after administration of oxaliplatin. Capecitabine 2250 mg/m2 will be given every 8 hours for a total of 6 doses, commencing with each cycle of therapy. Capecitabine is provided in fixed dose forms, and rounding will be to the nearest 150 mg on a per dose basis.
Sorafenib: 400 mg of sorafenib orally twice daily, both beginning on the first day of the first cycle (see section 9.1). If needed, cohort -1 will be used, at 200 mg of sorafenib once daily. | 24 |
| Phase II: Biliary Tract Cancer Oxaliplatin + Oral Capecitabine + Sorafeni
Oxaliplatin: Days 1 and 15 of each 28 day treatment cycle, patients receive oxaliplatin 85 mg/m2 as a 2-hour IV infusion. Next, the infusion line should be flushed with Dextrose 5% in Water.
Capecitabine: Oral capecitabine administration will start after administration of oxaliplatin. Capecitabine 2250 mg/m2 will be given every 8 hours for a total of 6 doses, commencing with each cycle of therapy. Capecitabine is provided in fixed dose forms, and rounding will be to the nearest 150 mg on a per dose basis.
Sorafenib: 400 mg of sorafenib orally twice daily, both beginning on the first day of the first cycle (see section 9.1). If needed, cohort -1 will be used, at 200 mg of sorafenib once daily. | 8 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Pancreatic and Bilial Tract Cancer | Death | 0 | 0 | 1 | 1 |
| Phase I: 200mg Sorafenib+2DOC | Death | 1 | 0 | 0 | 0 |
| Phase I: 400mg Sorafenib BID+2DOC | Death | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Phase I: 200mg Sorafenib+2DOC | Phase I: 400mg Sorafenib BID+2DOC | Phase II: Pancreatic Cancer | Phase II: Biliary Tract Cancer |
|---|---|---|---|---|---|
| Age, Customized 50-59 years of age | 13 Participants | 1 Participants | 2 Participants | 8 Participants | 2 Participants |
| Age, Customized =< 50 years of age | 5 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants |
| Age, Customized 60-69 years of age | 16 Participants | 3 Participants | 4 Participants | 7 Participants | 2 Participants |
| Age, Customized 70-79 years of age | 12 Participants | 3 Participants | 0 Participants | 7 Participants | 2 Participants |
| Age, Customized >= 80 years of age | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 41 Participants | 8 Participants | 7 Participants | 21 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 1 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 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 | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 46 Participants | 9 Participants | 6 Participants | 24 Participants | 7 Participants |
| Region of Enrollment United States | 48 participants | 9 participants | 7 participants | 24 participants | 8 participants |
| Sex: Female, Male Female | 22 Participants | 5 Participants | 3 Participants | 11 Participants | 3 Participants |
| Sex: Female, Male Male | 26 Participants | 4 Participants | 4 Participants | 13 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 9 | 7 / 7 | 24 / 24 | 8 / 8 |
| serious Total, serious adverse events | 4 / 9 | 3 / 7 | 14 / 24 | 7 / 8 |
Outcome results
Primary
Overall Response Rate
Response rate of participant to treatment
Time frame: Up to 18 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I: 200mg Sorafenib+2DOC | Overall Response Rate | Progressive Disease | 1 participants |
| Phase I: 200mg Sorafenib+2DOC | Overall Response Rate | Partial Response | 1 participants |
| Phase I: 200mg Sorafenib+2DOC | Overall Response Rate | Stable Disease | 5 participants |
| Phase I: 400mg Sorafenib BID+2DOC | Overall Response Rate | Stable Disease | 2 participants |
| Phase I: 400mg Sorafenib BID+2DOC | Overall Response Rate | Partial Response | 1 participants |
| Phase I: 400mg Sorafenib BID+2DOC | Overall Response Rate | Progressive Disease | 0 participants |
| Phase II: Pancreatic Cancer | Overall Response Rate | Progressive Disease | 6 participants |
| Phase II: Pancreatic Cancer | Overall Response Rate | Partial Response | 3 participants |
| Phase II: Pancreatic Cancer | Overall Response Rate | Stable Disease | 11 participants |
| Phase II: Biliary Tract Cancer | Overall Response Rate | Stable Disease | 5 participants |
| Phase II: Biliary Tract Cancer | Overall Response Rate | Partial Response | 1 participants |
| Phase II: Biliary Tract Cancer | Overall Response Rate | Progressive Disease | 1 participants |
Secondary
Overall Survival
Overall survival, defined as number of days from the day of first study drug administration to the day the patient dies, summarized using point estimates of the median time to progression, and associated 95% confidence intervals
Time frame: Up to 18 months
Population: Overall survival was not a pre-specified Phase I outcome, and no data was collected or analyzed. No data was collected for Phase II biliary tract participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase II: Pancreatic Cancer | Overall Survival | 8.1 Months |
Secondary
Progression-free Survival (PFS)
Time to progression, defined as number of days from day of first study drug administration to the day the patient experiences an event of disease progression or death; summarized using point estimates of the median time to progression and associated 95% confidence intervals for each stratum separately.
Time frame: Up to 18 months
Population: PFS was not a pre-specified Phase I outcome, and no data was collected or analyzed. No data was collected for Phase II biliary tract participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase II: Pancreatic Cancer | Progression-free Survival (PFS) | 6.0 Months |