Gemcitabine Plus Albumin-bound Paclitaxel In Patients With Advanced Metastatic Pancreatic Cancer

Study Overview
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Brief Summary
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To determine the maximum tolerated dose and dose-limiting toxicity of Gemcitabine plus Albumin-bound paclitaxel (ABI-007) in patients with advanced metastatic pancreatic cancer.

Detailed Description
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Albumin-bound paclitaxel is a novel, solvent-free, albumin-bound, 130 nanometer particle form of paclitaxel designed to avoid the problems associated with solvents used in Taxol(Abraxane prescribing information 2005). Albumin has a number of properties that make it an attractive molecule to combine with paclitaxel. Albumin is a natural transporter of endogenous hydrophobic molecules such as water-insoluble vitamins and hormones (Vorum 1999)and albumin binding to the gp-60 receptor (albondin) initiates the caveolae-mediated endothelial transport of protein-bound and unbound plasma constituents (John et al 2003, Minshall et al 2003, Tiruppathi et al 1997). This study consisted of a Phase 1 dose escalation phase, a Phase 2 treatment phase and a 24-month follow-up phase.

Official Title
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A Phase I Trial of Gemcitabine (Gemzar) Plus ABI-007 (ABRAXANE) In Patients With Advanced Metastatic Pancreatic Cancer

Conditions
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Metastatic Pancreatic Cancer

Intervention / Treatment
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* Drug: Gemcitabine
* Drug: Albumin-bound paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient has histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas. Patients with islet cell neoplasms are excluded. Male or non-pregnant and non-lactating female, and age greater or equal to 18. If a female patient is of child-bearing potential, as evidenced by regular menstrual periods, she must have a negative serum pregnancy test beta-human chorionic gonadotropin (B-hCG) documented within 72 hours of the first administration of study drug. If sexually active, the patient must agree to use contraception considered adequate and appropriate by the investigator. Patient must have received no prior therapy for the treatment of metastatic disease. Prior treatment with 5-fluorouracil (5-FU) or gemcitabine administered as a radiation sensitizer during and up to 4 weeks after radiation therapy is allowed. If a patient received gemcitabine in the adjuvant setting, tumor recurrence must have occurred at least 6 months after completing the last dose of gemcitabine. Patient has the following blood counts at baseline Absolute neutrophil count (ANC) equal or greater to 1.5 x 10^9/L; Platelets equal or greater to 100 x 10^9/L Hemoglobin equal or greater to 9 g/dL. Patient has the following blood chemistry levels at baseline: Aspartate aminotransferase (SGOT), Alanine aminotransferase (SGPT) equal or less than 2.5 x upper limit of normal range (ULN) is allowed Bilirubin less than or equal to ULN Serum creatinine within normal limits or calculated clearance equal or greater to 60 mL/min/1.73M^2 patients with serum creatinine levels above the institutional normal value Patient has no clinically significant abnormalities in urinalysis results Patient has acceptable coagulation status as indicated by a prothrombin time (PT) within normal limits (plus or minus 15%) and partial thromboplastin time (PTT) within normal limits (plus or minus 15%). Patient has a Karnofsky performance status (KPS) greater or equal to 70 (Eastern Cooperative Oncology Group [ECOG] PS 0-1). Patient has one or more metastatic tumors measurable by computed tomography (CT) scan. Patient has been informed about the nature of study, and has agreed to participate in the study, and signed the Informed Consent form prior to participation in any study-related activities. Exclusion Criteria: Patient has known brain metastases unless previously treated and well controlled for at least 3 months (defined as stable clinically, no edema, no steroids and stable in two scans at least 4 weeks apart). Patient uses therapeutic coumadin for a history of pulmonary emboli and deep vein thrombosis (DVT). Patient has active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy. Patient has known infection with human immunodeficiency virus (HIV), hepatitis B, hepatitis C. Patient has undergone major surgery, other than diagnostic surgery i.e.-- done to obtain a biopsy for diagnosis without removal of an organ), with 4 weeks prior to Day 1 of treatment in this study. Patient received radiotherapy, surgery, chemotherapy, or an investigational therapy within 3 weeks prior to study entry weeks (6 weeks for nitrosureas or mitomycin C). Patient has a history of allergy or hypersensitivity to the study drug. Patient has serious medical risk factors involving any of the major organ systems such that the investigator considers it unsafe for the patient to receive an experimental research drug. Patient is unwilling or unable to comply with study procedures. Patient is enrolled in any other clinical protocol or investigational trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 100 mg/m^2<br>Participants received albumin-bound paclitaxel 100 mg/m^2 followed by gemcitabine 1000 mg/m^2 by intravenous infusion (IV) on Days 1, 8 and 15 of each 28 day cycle (dose level one). Treatment continued until progressive disease or unacceptable toxicity. | Drug: Gemcitabine<br>* Administered by intravenous infusion over 30 minutes.<br>* Other names: Gemzar®;Drug: Albumin-bound paclitaxel<br>* Administered by intravenous infusion over 30 minutes.<br>* Other names: ABRAXANE®;|
| Experimental: 125 mg/m^2<br>Participants received albumin-bound paclitaxel 125 mg/m^2 followed by gemcitabine 1000 mg/m^2 by intravenous infusion (IV) on Days 1, 8 and 15 of each 28 day cycle (dose level two). Treatment continued until progressive disease or unacceptable toxicity. | Drug: Gemcitabine<br>* Administered by intravenous infusion over 30 minutes.<br>* Other names: Gemzar®;Drug: Albumin-bound paclitaxel<br>* Administered by intravenous infusion over 30 minutes.<br>* Other names: ABRAXANE®;|
| Experimental: 150 mg/m^2<br>Participants received albumin-bound paclitaxel 150 mg/m^2 followed by gemcitabine 1000 mg/m^2 by intravenous infusion (IV) on Days 1, 8 and 15 of each 28 day cycle (dose level three). Treatment continued until progressive disease or unacceptable toxicity. | Drug: Gemcitabine<br>* Administered by intravenous infusion over 30 minutes.<br>* Other names: Gemzar®;Drug: Albumin-bound paclitaxel<br>* Administered by intravenous infusion over 30 minutes.<br>* Other names: ABRAXANE®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-limiting Toxicities | A dose-limiting toxicity (DLT) is defined as one or more of the following toxicities related to study drug during Cycle 1, according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE), Version 3: Grade 4 neutropenia lasting >3 days in the absence of growth factor support; Grade 4 neutropenia associated with fever >38.5°C; Any other Grade 4 hematological toxicity; Grade 3 thrombocytopenia with hemorrhage; Grade 3 or 4 nausea, vomiting or diarrhea despite prophylaxis or treatment with an optimal anti-emetic or anti-diarrhea regimen; Any other Grade 3 or higher non-hematological toxicity attributable to the study drug, excluding alopecia and fatigue. | Cycle 1 (Days 1-28) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AE) | An AE was any untoward medical occurrence, not necessarily having a causal relationship with the patient's treatment, that began or worsened in grade after the start of study drug through 30 days after the last dose. A serious AE (SAE) is any untoward medical occurrence that is fatal, life-threatening, results in persistent or significant disability or incapacity, requires or prolongs existing in-patient hospitalization, is a congenital anomaly/birth defect, or is a condition that may jeopardize the patient or may require intervention to prevent one of the outcomes listed above. Treatment-related AEs (TRAEs) include those assessed by the Investigator as possibly, probably, or definitely related to study treatment. Severity was graded according to the NCI CTCAE based on the following: Grade 1- Mild; Grade 2 -Moderate; Grade 3 - Severe; Grade 4 - Life-threatening or disabling; Grade 5 - Death related to AE. | Up to 25 months | 
| Percentage of Participants Who Achieved an Objective Confirmed Overall Response | Overall Response is defined as the percent of participants who achieve an objective confirmed complete (CR) or partial response (PR). Response was determined according to Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, assessed by an Independent Radiological Reviewer. CR: The disappearance of all known disease and no new sites or disease-related symptoms confirmed at least 4 weeks after initial documentation. All sites must be assessed, including non-measurable sites, such as effusions, or markers. PR: At least a 30% decrease in the sum of the longest diameters of target lesions, taking as a reference the baseline sum of the longest diameters confirmed at least 4 weeks after initial documentation and no new non-target lesions and/or unequivocal progression of existing non-target lesions. PR is also recorded when all measurable disease has completely disappeared, but a non-measurable component (i.e., ascites) is still present but not progressing. | Up to approximately 4 years | 
| Percentage of Participants With Disease Control | Disease control is defined as participants with Stable Disease for at least 16 weeks, or confirmed complete or partial overall response, based on RECIST guidelines and assessed by an Independent Radiological Reviewer. Stable disease is defined as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for Progressive Disease, and no new non-target lesions or unequivocal progression of existing non-target lesions. Progressive Disease is defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum of the longest diameters recorded since the treatment started; or the appearance of one or more new lesions; or the unequivocal progression of a non-target lesion. | Up to approximately 4 years | 
| Progression-free Survival | Progression-free survival is defined as the time from first dose of study drug to the start of disease progression or patient death, whichever occurs first, assessed by an Independent Radiological Reviewer. Participants who do not have disease progression or have not died were censored at the last known time that the participant was progression free. Progression-free survival was summarized using Kaplan-Meier methods. Progressive Disease is defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum of the longest diameters recorded since the treatment started; or the appearance of one or more new lesions; or the unequivocal progression of a non-target lesion. | Up to approximately 4 years | 
| Duration of Response | Duration of response was assessed by progression-free survival for participants who achieved a confirmed Complete Response or Partial Response, assessed by an Independent Radiological Reviewer. | Up to approximately 4 years | 
| Overall Survival | Overall survival was defined as the time from the date of first dose of study drug to the date of patient death from all causes. Participants who did not die were censored at the last known time the patient was alive. Patient survival was summarized using Kaplan-Meier methods. | Up to approximately 4 years | 
| Maximal Degree of Myelosuppression | The maximal degree of myelosuppression was assessed by the overall nadir of absolute neutrophil count (ANC), white blood cell count and platelet count based on clinical laboratory measurements. | During the treatment phase, up to a maximum of 24 months. | 
| Maximal Degree of Anemia | The maximal degree of anemia (and myelosuppression) was assessed by the overall (any time after first dose of study drug) nadir of hemoglobin levels based on clinical laboratory measurements. | During the treatment phase, up to a maximum of 24 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic Pancreatic Cancer, Abraxane, Gemcitabine