Cetuximab and Bevacizumab With or Without Gemcitabine to Treat Metastatic Pancreatic Cancer

Study Overview
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Brief Summary
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Eligible patients with metastatic pancreatic cancer will be treated with dual agent monoclonal antibody consisting of cetuximab and bevacizumab alone or in combination with gemcitabine

Official Title
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A Phase II, Randomized, Open-Label Study of Cetuximab and Bevacizumab Alone or in Combination With Fixed-Dose Rate Gemcitabine as First-Line Therapy of Patients With Metastatic Adenocarcinoma of the Pancreas

Conditions
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Metastatic Pancreatic Cancer

Intervention / Treatment
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* Biological: cetuximab
* Biological: bevacizumab
* Drug: gemcitabine
* Biological: cetuximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient has provided signed written informed consent. The patient is ≥18 years of age. The patient has histologically or cytologically-confirmed pancreatic adenocarcinoma not amenable to curative treatment with surgery or has documented or suspected extrapancreatic metastases. The patient has either (a) measurable disease as defined by Response Evaluation Criteria in Solid Tumors Version 1.0 (RECIST) or (b) non-measurable disease with an elevated baseline CA19-9 level (≥2 x the upper limit of normal [ULN]). The patient's Eastern Cooperative Oncology Group (ECOG) performance status is ≤2. The patient has adequate hematologic function as defined by an absolute neutrophil count (ANC) ≥1500/mm3 and a platelet count ≥100,000/mm3 obtained within 2 weeks prior to the first dose of study medication. The patient has adequate hepatic function as defined by a total bilirubin ≤2.0 mg/dL and transaminases ≤5.0 x ULN obtained within 2 weeks prior to the first dose of study medication. The patient has adequate renal function as defined by serum creatinine ≤2.0 x ULN and urine dipstick for proteinuria ≤1+ obtained within 2 weeks prior to the first dose of study medication. If urine dipstick is ≥2+, then a 24-hour urine for protein must demonstrate < 1000 mg of protein in 24 hours to allow participation in the study. Urinalysis is also acceptable. If the patient is on full-dose anticoagulation therapy (eg, warfarin or low molecular weight [LMW] heparin), the following criteria must be met: The patient has an in-range International Normalized Ratio ([INR]usually between 2 and 3) on a stable dose of oral anticoagulant or be on a stable dose of LMW heparin The patient has no active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices) If the patient is not on full-dose anticoagulation therapy, the following criteria must be met: The patient has adequate coagulation function as defined by INR ≤1.5 The patient has a partial thromboplastin (PTT) ≤ULN obtained within 2 weeks prior to the first dose of study medication If a woman, the patient agrees to use an accepted and effective method of contraception (hormonal or barrier methods, abstinence) prior to study entry and for the duration of the study. If a male and sexually active, the patient agrees to use effective contraception. The patient is accessible for treatment and follow-up. Patients enrolled in this trial must be treated at the participating center. Exclusion Criteria: Endocrine tumors or lymphoma of the pancreas Known brain metastases Prior therapy with an epidermal growth factor receptor (EGFR) inhibitor or vascular endothelial growth factor (VEGF) inhibitor Prior chemotherapy, hormonal therapy, or radiation therapy for advanced pancreatic cancer, patients who received chemotherapy and/or radiation therapy in the adjuvant setting will be eligible as long as the adjuvant therapy was completed >6 months prior Concurrent malignancy other than non-melanomatous skin cancer or carcinoma in situ of the cervix Concurrent treatment with other anti-cancer therapy, including other chemotherapy, immunotherapy, hormonal therapy, radiotherapy, chemoembolization, or targeted therapy Ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations History of arterial thrombotic events within 9 months History of uncontrolled hypertension (>150/100 mmHg) not on a stable regimen of anti-hypertensive therapy History of significant bleeding events or upper or lower gastrointestinal bleeding within 9 months History of gastrointestinal perforation within 12 months Serious non-healing wound ulcer, bone fracture, or major surgical procedure with 28 days If a woman, is pregnant or lactating An employee of the investigator or study center as well as family members of the employees

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: cetuximab + bevacizumab + gemcitabine<br>Cetuximab 400 mg/m2 weekly (over 120 minutes) on day 1 of cycle 1 with subsequent weekly infusions of 250 mg/m2 (over 60 minutes), followed by bevacizumab 10 mg/kg (over 60 minutes) on day 1 and repeated every 2 weeks, and gemcitabine 1000 mg/m2/minute over 100 minutes weekly x 3 of 4 weeks. All medications will be administered by intravenous infusion on the same day. The order of study drug administration will be cetuximab, bevacizumab, and gemcitabine. On day 1 of cycle 1, one hour must elapse between administration of cetuximab and bevacizumab. | Biological: cetuximab<br>* I.V. infusion of 400 mg/m2 (over 120 minutes) on day 1 of cycle 1<br>* Other names: Erbitux®;Biological: bevacizumab<br>* 10 mg/kg (over 60 minutes) on day 1 and repeated every 2 weeks.<br>* Other names: Avastin®;Drug: gemcitabine<br>* 1000 mg/m2 administered intravenously at 10 mg/m2/minute over 100 minutes weekly x 3 of 4 weeks.<br>* Other names: Gemzar®;Biological: cetuximab<br>* I.V.infusions of 250 mg/m2 (over 60 minutes) weekly<br>* Other names: Erbitux®;|
| Active Comparator: cetuximab + bevacizumab<br>Cetuximab 400 mg/m2 weekly (over 120 minutes) on day 1 of cycle 1 with subsequent weekly infusions of 250 mg/m2 (over 60 minutes), followed by bevacizumab 10 mg/kg (over 60 minutes) on day 1 and repeated every 2 weeks. Both medications will be administered by intravenous infusion on the same day. The order of study drug administration will be cetuximab and bevacizumab. On day 1 of cycle 1, one hour must elapse between administration of cetuximab and bevacizumab. | Biological: cetuximab<br>* I.V. infusion of 400 mg/m2 (over 120 minutes) on day 1 of cycle 1<br>* Other names: Erbitux®;Biological: bevacizumab<br>* 10 mg/kg (over 60 minutes) on day 1 and repeated every 2 weeks.<br>* Other names: Avastin®;Biological: cetuximab<br>* I.V.infusions of 250 mg/m2 (over 60 minutes) weekly<br>* Other names: Erbitux®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Progression-free survival is the time from randomization until the date of progressive disease (PD) or death from any cause whichever is first reported. Patients who die without a reported prior progression were considered to have progresssed on the day of their death. Patients who did not progress were censored at the day of their last tumor assessment. | Time from randomization to disease progression or death from any cause (Range: 0 -10 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | This measure is defined as the time from randomization to the date of death due to any cause. Survival of living patients or those who lost to follow-up were censored on the last date the patients were known to be alive. | Survival information was collected continuously every 3 months after completion of therapy and/or follow-up (range: 1-19 months). | 
| The Number of Patients With a Best Overall Response of Either a Complete Response (CR) or Partial Response (PR) | The best overall response is the number of patients with a best overall response of CR or PR, as classifed by the investigator according to the RECIST guidelines. A CR is the disappearance of all target lesions and a PR is at least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum longest diameter. | Tumor evaluations were performed every 8 weeks while on cetuximab therapy until PD or recurrence. Patients with a PR or CR had a confirmatory tumor assessment no less than 4 weeks after the initial evaluation. | 
| Percentage of Patients With Carbohydrate Antigen 19-9 (CA19-9) Response at End of Cycle 2 in Patients With Elevated Baseline Values (Equal or Greater Than 2 x Upper Limit of Normal). | CA19-9 is a tumor marker for pancreatic cancer and the level usually increases as the disease is progressing. The CA19-9 response was the percentage of patients whose CA19-9 level was declining, stable or increasing < 10% compared with baseline, divided by the total patients with elevated baseline CA19-9 in that arm. | First day of treatment to the end of Cycle 2, Week 1 | 
| Time to Progression (TTP) | Time to progression was defined as the time from randomization until the date of objectively confirmed tumor progression was first reported. The censoring rule was consistent with PFS except death. Patients who died from any cause were censored at the time of death or at last tumor assessment date if the death date was missing. For patients lost to follow-up, they were censored at the last tumor assessment date. | Time from randomization until the date of objective tumor progression was first reported (range: 11 -38 months) | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Reported AEs per patient were coded according to the corresponding preferred term and system organ class in the Medical Dictionary for regulatory Activities dictionary. The National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 3.0 was used to grade all AEs. The collection of AEs began at the time the patient received the first cetuximab dose and continued during the study until 30 days after the last dose of cetuximab. All patients who were enrolled and treated with cetuximab were assessed for safety (mITT population, as treated). | An AE was included in the safety analysis if its onset date occurred anytime during cetuximab treatment or up to 30 days after the last dose of cetuximab. | 
| Change From Baseline in Quality of Life (QoL) Assessment Using the Linear Analog Scale Assessment (LASA), Overall QoL at Cycle 2 Week 4 | Accrual on the trial was stopped earlier than planned due to insufficient efficacy on both arms. The primary analysis of pancreatic cancer symptoms was conducted using the LASA QoL questionnaire and was considered exploratory. The Overall QoL question change from baseline to Cycle 2 Week 4 is reported. The best overall score is 10 and the worst is 0. A negative score indicates worsening from baseline. | Screening, and then every 8 weeks while receiving study drug to 30-day follow-up | 
| Change From Baseline in QoL Assessment Using LASA, Overall Mental Well Being, at Cycle 2 Week 4 | Accrual on the trial was stopped earlier than planned due to insufficient efficacy on both arms. The primary analysis of pancreatic cancer symptoms was conducted using the LASA QoL questionnaire and was considered exploratory. The Overall Mental Well Being question change from baseline to Cycle 2 Week 4 is reported. The best overall score is 10 and the worst is 0. A negative score indicates worsening from baseline. | Screening, and then every 8 weeks while receiving study drug to 30-day follow-up | 
| Change From Baseline in QoL Assessment Using LASA, Overall Physical Well Being, at Cycle 2 Week 4 | Accrual on the trial was stopped earlier than planned due to insufficient efficacy on both arms. The primary analysis of pancreatic cancer symptoms was conducted using the LASA QoL questionnaire and was considered exploratory. The Overall Physical Well Being question change from baseline to Cycle 2 Week 4 is reported. The best overall score is 10 and the worst is 0. A negative score indicates worsening from baseline. | Screening, and then every 8 weeks while receiving study drug to 30-day follow-up | 
| Change From Baseline in QoL Assessment Using LASA, Overall Emotional Well Being, at Cycle 2 Week 4 | Accrual on the trial was stopped earlier than planned due to insufficient efficacy on both arms. The primary analysis of pancreatic cancer symptoms was conducted using the LASA QoL questionnaire and was considered exploratory. The Overall Emotional Well Being question change from baseline to Cycle 2 Week 4 is reported. The best overall score is 10 and the worst is 0. A negative score indicates worsening from baseline. | Screening, and then every 8 weeks while receiving study drug to 30-day follow-up | 
| Change From Baseline in QoL Assessment Using LASA, Level of Social Activity, at Cycle 2 Week 4 | Accrual on the trial was stopped earlier than planned due to insufficient efficacy on both arms. The primary analysis of pancreatic cancer symptoms was conducted using the LASA QoL questionnaire and was considered exploratory. The Level of Social Activity question change from baseline to Cycle 2 Week 4 is reported. The best overall score is 10 and the worst is 0. A negative score indicates worsening from baseline. | Screening, and then every 8 weeks while receiving study drug to 30-day follow-up | 
| Change From Baseline in QoL Assessment Using LASA, Overall Spiritual Well Being, at Cycle 2 Week 4 | Accrual on the trial was stopped earlier than planned due to insufficient efficacy on both arms. The primary analysis of pancreatic symptoms was conducted using the LASA QoL questionnaire and was considered exploratory. The Overall Spiritual Well Being question change from baseline to Cycle 2 Week 4 is reported. The best overall score is 10 and the worst is 0. A negative score indicates worsening from baseline. | Screening, and then every 8 weeks while receiving study drug to 30-day follow-up while receiving study drug | 
| Change From Baseline in QoL Assessment Using LASA, Frequency of Pain, at Cycle 2 Week 4 | Accrual on the trial was stopped earlier than planned due to insufficient efficacy on both arms. The primary analysis of pancreatic cancer symptoms was conducted using the LASA QoL questionnaire and was considered exploratory. The Frequency of Pain question change from baseline to Cycle 2 Week 4 is reported. The best overall score is 10 and the worst is 0. A negative score indicates improvement from baseline. | Screening, and then every 8 weeks while receiving study drug to 30-day follow-up | 
| Change From Baseline in QoL Assessment Using LASA, Severity of Pain, Average, at Cycle 2 Week 4 | Accrual on the trial was stopped earlier than planned due to insufficient efficacy on both arms. The primary analysis of pancreatic cancer symptoms was conducted using the LASA QoL questionnaire and was considered exploratory. The Severity of Pain question change from baseline to Cycle 2 Week 4 is reported. The best overall score is 10 and the worst is 0. A positive score indicates improvement from baseline. | Screening, and then every 8 weeks while receiving study drug to 30-day follow-up while receiving study drug | 
| Change From Baseline in QoL Assessment Using LASA, Level of Fatigue, Average, at Cycle 2 Week 4 | Accrual on the trial was stopped earlier than planned due to insufficient efficacy on both arms. The primary analysis of pancreatic cancer symptoms was conducted using the LASA QoL questionnaire and was considered exploratory. The Level of Fatigue question change from baseline to Cycle 2 Week 4 is reported. The best overall score is 10 and the worst is 0. A positive score indicates improvement from baseline. | Screening, and then every 8 weeks while receiving study drug to 30-day follow-up | 
| Change From Baseline in QoL Assessment Using LASA, Level of Support, Friends and Family, at Cycle 2 Week 4 | Accrual on the trial was stopped earlier than planned due to insufficient efficacy on both arms. The primary analysis of pancreatic cancer symptoms was conducted using the LASA QoL questionnaire and was considered exploratory. The Level of Support, Friends and Family question change from baseline to Cycle 2 Week 4 is reported. The best overall score is 10 and the worst is 0. A negative score indicates worsening from baseline. | Screening, and then every 8 weeks while receiving study drug to 30-day follow-up | 
| Change From Baseline in QoL Assessment Using LASA, Financial Concerns, at Cycle 2 Week 4 | Accrual on the trial was stopped earlier than planned due to insufficient efficacy on both arms. The primary analysis of pancreatic cancer symptoms was conducted using the LASA QoL questionnaire and was considered exploratory. The Financial Concerns Question question change from baseline to Cycle 2 Week 4 is reported. The best overall score is 10 and the worst is 0. A negative score indicates worsening from baseline. | Screening, and then every 8 weeks while receiving study drug to 30-day follow-up | 
| Change From Baseline in QoL Assessment Using LASA, Legal Concerns, at Cycle 2 Week 4 | Accrual on the trial was stopped earlier than planned due to insufficient efficacy on both arms. The primary analysis of pancreatic cancer symptoms was conducted using the LASA QoL questionnaire and was considered exploratory. The Legal Concerns question change from baseline to Cycle 2 Week 4 is reported. The best overall score is 10 and the worst is 0. A negative score indicates worsening from baseline. | Screening, and then every 8 weeks while receiving study drug to 30-day follow-up | 
| Change From Baseline in Assessment of Pain Using the Brief Pain Inventory (BPI) Short Form, Worst Pain, at Cycle 2 Week 4 | Accrual on the trial was stopped earlier than planned due to insufficient efficacy on both arms. Analysis of pain using the BPI was considered exploratory. The Worst Pain (change from baseline) to Cycle 2 Week 4 is reported. The worst pain is 10 and no pain is 0. A negative score indicates improvement from baseline. | Screening, and then every 8 weeks while receiving study drug to 30-day follow-up | 
| Change From Baseline in Assessment of Pain Using BPI Short Form, Least Pain, at Cycle 2 Week 4 | Accrual on the trial was stopped earlier than planned due to insufficient efficacy on both arms. Analysis of pain using the BPI was considered exploratory. The Least Pain (change from baseline) to Cycle 2 Week 4 is reported. The worst pain is 10 and no pain is 0. A negative score indicates improvement from baseline. | Screening, and then every 8 weeks while receiving study drug to 30-day follow-up | 
| Change From Baseline in Assessment of Pain Using BPI Short Form, Average Pain, at Cycle 2 Week 4 | Accrual on the trial was stopped earlier than planned due to insufficient efficacy on both arms. Analysis of pain using the BPI was considered exploratory. The Average Pain (change from baseline) to Cycle 2 Week 4 is reported. The worst pain was 10 and no pain is 0. A negative score indicates improvement from baseline. | Screening, and then every 8 weeks while receiving study drug to 30-day follow-up | 
| Change From Baseline in Assessment of Pain Using BPI Short Form, Pain Right Now, at Cycle 2 Week 4 | Accrual on the trial was stopped earlier than planned due to insufficient efficacy on both arms. Analysis of pain using the BPI was considered exploratory. The Pain Right Now question (change from baseline) to Cycle 2 Week 4 is reported. The worst pain is 10 and no pain is 0. A negative score indicates improvement from baseline. | Screening, and then every 8 weeks while receiving study drug to 30-day follow-up | 
| Change From Baseline in Assessment of Pain Using BPI Short Form, Interference, at Cycle 2 Week 4 | Accrual on the trial was stopped earlier than planned due to insufficient efficacy on both arms. Analysis of pain using the BPI was considered exploratory. The Interference question (change from baseline) to Cycle 2 Week 4 is reported. Complete interference is scored as 10 and no interference is scored as 0. A negative score indicates improvement from baseline. | Screening, and then every 8 weeks while receiving study drug to 30-day follow-up |