Pancreatic Cancer
Conditions
Keywords
adenocarcinoma of the pancreas, stage IV pancreatic cancer, recurrent pancreatic cancer
Brief summary
RATIONALE: Monoclonal antibodies, such as RAV12, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving RAV12 together with gemcitabine may kill more tumor cells. PURPOSE: This phase II trial is studying the side effects and best dose of monoclonal antibody RAV12 when given together with gemcitabine in treating patients with metastatic pancreatic cancer.
Detailed description
OBJECTIVES: * To determine the maximum tolerated dose of monoclonal antibody RAV12 when administered with standard gemcitabine hydrochloride in patients with previously untreated metastatic pancreatic cancer. * To determine the proportion of these patients surviving at 8 months after initiation of this regimen. * To provide point estimates for response rate and duration of response in patients treated with this regimen. * To define the toxicity profile of this drug in these patients when administered with standard gemcitabine hydrochloride. * To estimate, preliminarily, the progression-free survival and overall survival of these patients after treatment with this regimen. * To explore the utility of the tumor marker, carbohydrate antigen 19-9 (CA19-9), in the assessment of these patients. OUTLINE: This is a dose-escalation study of monoclonal antibody RAV12, followed by an efficacy study. The study is conducted in two segments. * Segment 1 (dose escalation of RAV12): Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, 15, and 22 of course 1 and on days 1, 8, and 15 of each subsequent course. Patients also receive RAV12 IV once weekly on days 1, 8, and 15 or twice weekly on days 1, 4 or 5, 8, 11 or 12, 15, and 18 or 19 until the maximum tolerated dose (MTD) is reached. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. * Segment 2 (efficacy): Once the MTD has been determined, patients receive RAV12 at the MTD and gemcitabine hydrochloride as in segment 1. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Blood samples are obtained for pharmacokinetic sampling during the dose-escalation segment of the study. Samples are analyzed to determine plasma concentrations of RAV12, gemcitabine hydrochloride, and difluorodeoxyuridine. Blood samples are also examined periodically for expression of serum biomarkers (i.e., CA19-9, RAAG12, and HACA) and for DNA analysis of Fc-gamma receptor polymorphisms. Archival paraffin blocks or slides from biopsy of primary or metastatic deposit or fresh/frozen tissue may be obtained at baseline for additional correlative studies. Samples are analyzed by immunohistochemistry (IHC) for expression of RAAG12 and for development of a companion RAAG12 diagnostic assay. After completion of study therapy, patients are followed every 8 weeks for up to 3 years. PROJECTED ACCRUAL: This study will accrue a total of 18 patients in the dose-escalation segment and 63 patients in the efficacy segment of the trial.
Interventions
BIOLOGICALRAV12
RAV12 at 0.375 mg/kg weekly escalated to 0.75 mg/kg weekly, intravenously.
DRUGGemcitabine
1000 mg/m2 weekly, intravenously
Sponsors
MacroGenics
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
DISEASE CHARACTERISTICS: * Histologically or cytologically confirmed adenocarcinoma of the pancreas * Metastatic disease * No prior therapy for metastatic disease (except prior adjuvant chemotherapy and/or radiotherapy) * At least 1 radiographically measurable site of disease ≥ 2 cm in the largest dimension by traditional CT technique or ≥ 1 cm by spiral CT scan (per RECIST) * No known history of current or prior central nervous system (CNS) metastatic disease PATIENT CHARACTERISTICS: * Eastern Cooperative Oncology Group performance status 0-2 * Absolute neutrophil count ≥ 1,500/mm³ * Platelet count ≥ 100,000/mm³ * Hemoglobin ≥ 9.0 g/dL * alanine aminotransferase and aspartate aminotransferase ≤ 2.5 times upper limit of normal (ULN) * Alkaline phosphatase and γ-glutamyltransferase ≤ 2.5 times ULN * Amylase and lipase ≤ 1.5 times ULN * Total bilirubin ≤ 1.5 times ULN * Creatinine \< 1.5 mg/dL * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * Must be available for study-related treatments and assessments at the treating institution * No known hypersensitivity to any component of gemcitabine hydrochloride * No known hypersensitivity to murine or recombinant proteins, polysorbate 80, or any excipient contained in the drug formulation * No other primary malignancy that has been in remission for ≤ 3 years except treated nonmelanoma skin cancer, biopsy-confirmed carcinoma in situ of the cervix, squamous intraepithelial lesion on Papanicolaou smear, localized prostate cancer with Gleason score \< 6, or resected melanoma in situ * No other primary malignancy that has a generally accepted recurrence risk ≥ 10% * No active viral, bacterial, or systemic fungal infection requiring parenteral treatment within 4 weeks of enrollment * No history of chronic or recurrent infections that require continuous use of antiviral, antifungal, or antibacterial agents * No serious underlying medical condition that would impair the patient's ability to receive or tolerate the planned treatment at the investigational site, including significant pulmonary compromise or heart disease of New York Heart Association class III or IV * No dementia or altered mental status that would preclude sufficient understanding to provide informed consent PRIOR CONCURRENT THERAPY: * See Disease Characteristics * More than 4 weeks since prior major surgery * More than 4 weeks since prior and no other concurrent investigational agents * More than 1 week since prior oral antiviral, antifungal, or antibacterial therapy * No concurrent immunosuppressive medications, steroids (except steroid inhaler, ophthalmic solution, nasal spray, or a stable dose of ≤ 10 mg/day of oral prednisone or equivalent), other antineoplastic therapy, or antitumor vaccinations * Monoclonal antibody treatment for non-cancer indications must be completed at least 3 half lives from study entry * No concurrent prophylactic hematologic growth factors * No concurrent megavitamin therapy * No concurrent bisphosphonates
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Patients Alive at 8 Months | 8 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Partial Response and Complete Response Rates | 8 months | Based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.0; partial response = 30% decrease in sum of longest diameter. complete response = 100% decrease in sum of longest diameter. Rate of response = proportion of complete or partial responses based on number of patients evaluated. |
| Median Progression-free Survival | up to 11 months | Time from the first dose date to the date of first documented progression or death from any cause, whichever occurs first. |
| Number of Patients Alive at 12 Months | 12 months | — |
| Participants With Adverse Events | Throughout the study, up to 11 months | Frequency of adverse events and serious adverse events |
| Cmax | 29 days | RAV12 and gemcitabine cmax |
| Median Overall Survival | up to 11 months | Time from the first dose date to the date of death from any cause |
Countries
United States
Participant flow
Recruitment details
Patient recruitment was conducted by two cancer institutes between April and July 2008.
Participants by arm
| Arm | Count |
|---|---|
| RAV12 Plus Gemcitabine Escalating doses of RAV12, plus standard gemcitabine at 1000 mg/m2 iv over 30 min., weekly days 1, 8, 15, 22 of the first cycle and 1000 mg/m2 iv over 30 min., weekly days 1, 8, and 15 of each subsequent cycle of 28 days | 2 |
| Total | 2 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Progressive disease | 1 |
Baseline characteristics
| Characteristic | RAV12 Plus Gemcitabine |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants |
| Age, Continuous | 61 years |
| Region of Enrollment United States | 2 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 2 |
| other Total, other adverse events | 2 / 2 |
| serious Total, serious adverse events | 1 / 2 |
Outcome results
Primary
Number of Patients Alive at 8 Months
Time frame: 8 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RAV12 Plus Gemcitabine | Number of Patients Alive at 8 Months | 1 participants |
Secondary
Cmax
RAV12 and gemcitabine cmax
Time frame: 29 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| RAV12 Plus Gemcitabine | Cmax | NA mcg/mL |
Secondary
Median Overall Survival
Time from the first dose date to the date of death from any cause
Time frame: up to 11 months
Population: Survival data is only available for 1 patient. The second patient was known to be alive at 9 months but lost to follow up. Median overall survival cannot be calculated.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RAV12 Plus Gemcitabine | Median Overall Survival | NA months |
Secondary
Median Progression-free Survival
Time from the first dose date to the date of first documented progression or death from any cause, whichever occurs first.
Time frame: up to 11 months
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| RAV12 Plus Gemcitabine | Median Progression-free Survival | 4.5 months | Standard Deviation 4.94 |
Secondary
Number of Patients Alive at 12 Months
Time frame: 12 months
Population: The study was terminated at 11 months. There is no 12 month data.
Secondary
Partial Response and Complete Response Rates
Based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.0; partial response = 30% decrease in sum of longest diameter. complete response = 100% decrease in sum of longest diameter. Rate of response = proportion of complete or partial responses based on number of patients evaluated.
Time frame: 8 months
Population: Only 1 patient was evaluable for response assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RAV12 Plus Gemcitabine | Partial Response and Complete Response Rates | 0 participants |
Secondary
Participants With Adverse Events
Frequency of adverse events and serious adverse events
Time frame: Throughout the study, up to 11 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RAV12 Plus Gemcitabine | Participants With Adverse Events | 2 participants |