Ganitumab and Gemcitabine Hydrochloride Followed by Radiation Therapy, Ganitumab, Capecitabine, and Maintenance Therapy in Treating Patients With Locally Advanced Cancer of the Pancreas

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Monoclonal antibodies, such as ganitumab, 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 cancer-killing substances to them. Drugs used in chemotherapy, such as gemcitabine hydrochloride and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Specialized radiation therapy, such as 3-dimensional conformal radiation therapy, that delivers a high-dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. PURPOSE: This phase I trial is studying the side effects and best dose of ganitumab when given together with gemcitabine hydrochloride followed by radiation therapy, ganitumab, capecitabine, and maintenance therapy in treating patients with locally advanced cancer of the pancreas.

Detailed Description
-----------------
OBJECTIVES: Primary To evaluate the maximum dose of ganitumab, up to a target dose of 20 mg/kg, given concurrently with capecitabine and radiotherapy following induction ganitumab and gemcitabine hydrochloride in patients with locally advanced pancreatic cancer. Secondary To evaluate the safety profile of induction therapy comprising ganitumab and gemcitabine hydrochloride, followed by ganitumab and concurrent chemoradiation, and subsequently by maintenance ganitumab and gemcitabine hydrochloride until disease progression in patients with locally advanced pancreatic cancer. To evaluate response and overall survival of patients treated at the maximum dose of ganitumab given concurrently with capecitabine and radiotherapy following induction ganitumab and subsequently followed by maintenance ganitumab and gemcitabine hydrochloride until disease progression. OUTLINE: This is a multicenter, dose-escalation study of ganitumab followed by an expanded cohort study. Induction therapy: Patients receive ganitumab IV over 1-2 hours on days 1 and 15 and gemcitabine hydrochloride IV over 30 minutes on days 1, 15, and 22. Treatment repeats every 28 days for 2 courses. Concurrent therapy: Beginning 10-28 days later, patients undergo 3-dimensional conformal radiotherapy once daily, 5 days a week for 5.5 weeks beginning on day 1. Patients also receive concurrent ganitumab IV over 1-2 hours on days 1, 15, and 29 and capecitabine orally (PO) twice daily on days 1-5 weekly for 5.5 weeks. Maintenance therapy: Beginning 21-42 days later, patients receive ganitumab IV over 1-2 hours on days 1 and 15 and gemcitabine hydrochloride IV over 30 minutes on days 1, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed up every 3 months for 2 years, every 4 months for 1 year, and then annually thereafter.

Official Title
-----------------
A Phase I Study of Induction AMG 479 and Gemcitabine, Followed by AMG 479, Capecitabine, and 3D-Conformal Radiation Therapy (3D-CRT) With Subsequent Maintenance Therapy for Locally Advanced Pancreatic Cancer

Conditions
-----------------
Pancreatic Cancer

Intervention / Treatment
-----------------
* Biological: ganitumab
* Drug: capecitabine
* Drug: gemcitabine hydrochloride
* Radiation: 3-dimensional conformal radiation therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Pathologically confirmed (histologic or cytologic) locally advanced adenocarcinoma of the pancreas Patients must have unresectable disease based on institutional standardized criteria of unresectability or medical inoperability Patients with or without regional adenopathy are eligible No distant metastases based upon the following minimum diagnostic workup: History and/or physical examination, including collection of weight and vital signs, within 28 days prior to study entry Abdominal and/or pelvic CT scan with IV contrast or MRI scan within 21 days prior to study entry Chest CT scan or whole-body PET/CT within 21 days prior to study entry No second malignancy or peritoneal seeding PATIENT CHARACTERISTICS: Zubrod performance status 0-1 Absolute neutrophil count (ANC) ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Hemoglobin (Hgb) ≥ 10.0 g/dL (the use of transfusion or other intervention to achieve Hgb ≥ 10.0 g/dL is acceptable) Glycosylated hemoglobin (HgbA1c) ≤ 8% Serum creatinine ≤ 1.5 mg/dL Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 3 times upper limit of normal (ULN) Total bilirubin < 3.0 mg/dL Alkaline phosphatase < 3 times ULN Fasting blood glucose < 160 mg/dL Patients with a non-fasting blood glucose > 160 mg/dL (8.9 mmol/L) must have a fasting blood glucose ≤ 160 mg/dL (8.9 mmol/L) in order to be eligible No grade 2 or worse hearing impairment Negative serum pregnancy test (if applicable) Women of childbearing potential and men who are sexually active must be willing/able to use medically acceptable forms of contraception during the course of the study, and for 3 months (6 months for men) after the last study drug administration Not pregnant or nursing Ability to swallow oral medications At least 3 years since prior malignancy except non-melanomatous skin cancer or carcinoma in situ of the breast, oral cavity, or cervix No severe active co-morbidity, defined as any of the following: Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months Transmural myocardial infarction within 6 months prior to study entry Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization, or precluding study therapy within 30 days before registration Uncontrolled malabsorption syndrome significantly affecting gastrointestinal function Any unresolved bowel or bile duct obstruction Major resection of the stomach or small bowel that could affect the absorption of capecitabine Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition HIV testing is not required for entry into this protocol Existing venous thromboembolism requiring anti-coagulation therapy No prior allergic reaction to capecitabine or gemcitabine hydrochloride PRIOR CONCURRENT THERAPY: No prior systemic chemotherapy for pancreatic cancer Prior chemotherapy for malignancies other than pancreatic cancer is allowed provided chemotherapy was completed > 3 years prior to study entry No prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields More than 28 days since any prior major surgery Insertion of a vascular access device, insertion of a biliary stent, exploratory laparotomy, or laparoscopy are not considered major surgery No prior ganitumab Patients requiring concurrent oral anticoagulants (e.g., Coumadin, warfarin) are eligible provided there is increased vigilance with respect to monitoring international normalized ratio (INR) No concurrent participation in another clinical treatment trial No concurrent intensity-modulated radiotherapy No other concurrent therapy including the following: Other investigational or approved chemotherapeutic agents Other monoclonal antibody Sorivudine or brivudine A Cimetidine G-CSF agents

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Dose level -1A (Ganitumab 6 mg/kg, Capecitabine 825mg/m2) | Biological: ganitumab<br> <br> Drug: capecitabine<br> <br> Drug: gemcitabine hydrochloride<br> <br> Radiation: 3-dimensional conformal radiation therapy<br> <br> |
| Experimental: Arm B<br>Dose level 1A (Ganitumab 12 mg/kg, Capecitabine 825mg/m2) | Biological: ganitumab<br> <br> Drug: capecitabine<br> <br> Drug: gemcitabine hydrochloride<br> <br> Radiation: 3-dimensional conformal radiation therapy<br> <br> |
| Experimental: Arm C<br>Dose level 2A (Ganitumab 20 mg/kg, Capecitabine 825mg/m2) | Biological: ganitumab<br> <br> Drug: capecitabine<br> <br> Drug: gemcitabine hydrochloride<br> <br> Radiation: 3-dimensional conformal radiation therapy<br> <br> |
| Experimental: Arm D<br>Dose level -1B (Ganitumab 6 mg/kg, Capecitabine 625mg/m2) | Biological: ganitumab<br> <br> Drug: capecitabine<br> <br> Drug: gemcitabine hydrochloride<br> <br> Radiation: 3-dimensional conformal radiation therapy<br> <br> |
| Experimental: Arm E<br>Dose level 1B (Ganitumab 12 mg/kg, Capecitabine 625mg/m2) | Biological: ganitumab<br> <br> Drug: capecitabine<br> <br> Drug: gemcitabine hydrochloride<br> <br> Radiation: 3-dimensional conformal radiation therapy<br> <br> |
| Experimental: Arm F<br>Dose level 2B (Ganitumab 20 mg/kg, Capecitabine 625mg/m2) | Biological: ganitumab<br> <br> Drug: capecitabine<br> <br> Drug: gemcitabine hydrochloride<br> <br> Radiation: 3-dimensional conformal radiation therapy<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity of ganitumab and capecitabine given concurrently with radiotherapy |  | From start of chemoradiation to 21 days after the end of chemoradiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate (for patients treated at maximum-tolerated dose of ganitumab) |  | Analysis occurs after all patients have been potentially followed for 1 year | 
| Overall survival (for patients treated at maximum-tolerated dose of ganitumab) |  | Analysis occurs after all patients have been potentially followed for 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
adenocarcinoma of the pancreas, stage IIB pancreatic cancer, stage III pancreatic cancer