High or Standard Intensity Radiation Therapy After Gemcitabine Hydrochloride and Nab-paclitaxel in Treating Patients With Pancreatic Cancer That Cannot Be Removed by Surgery

Study Overview
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Brief Summary
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This randomized phase II trial studies how well high or standard intensity radiochemotherapy after gemcitabine hydrochloride and paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel) work compared with gemcitabine hydrochloride and nab-paclitaxel alone in treating patients with pancreatic cancer that cannot be removed by surgery. Drugs used in chemotherapy, such as gemcitabine hydrochloride and nab-paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs, such as capecitabine, may make tumor cells more sensitive to radiation therapy. Giving radiation therapy in different ways and adding chemotherapy may kill more tumor cells. It is not yet known whether high intensity radiochemotherapy after gemcitabine hydrochloride and nab-paclitaxel is more effective than standard intensity radiochemotherapy after gemcitabine hydrochloride and nab-paclitaxel or gemcitabine hydrochloride and nab-paclitaxel alone in treating pancreatic cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine if intensified radiochemotherapy following gemcitabine and nab-paclitaxel in patients with unresectable pancreatic cancer will show a signal for improved 2-year overall survival (OS) from 10% to 22.5% as compared to chemotherapy with gemcitabine and nab-paclitaxel alone. II. To determine if standard radiochemotherapy, following gemcitabine and nab-paclitaxel, in patients with unresectable pancreatic cancer will show a signal for improved 2-year OS from 10% to 22.5% as compared to chemotherapy with gemcitabine and nab-paclitaxel alone. SECONDARY OBJECTIVES: I. To evaluate patterns of failure (local and systemic progression) by SMAD family member 4 (SMAD4) status and intensity of radiation therapy. II. To evaluate the impact of radiochemotherapy on OS for the subset of SMAD4 intact patients. III. To evaluate adverse events associated with the treatments. IV. To evaluate correlation between SMAD4 status determined by immunohistochemistry (IHC) and genetic SMAD4 status. Patients are randomized to 1 of 3 treatment arms. After completion of study treatment, patients are followed up at 1 month and then every 3 months.

Official Title
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A Phase II Randomized Trial Evaluating the Addition of High or Standard Intensity Radiation to Gemcitabine and Nab-paclitaxel for Locally Advanced Pancreatic Cancer

Conditions
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Pancreatic Adenocarcinoma, Stage III Pancreatic Cancer

Intervention / Treatment
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* Radiation: low intensity radiation therapy
* Drug: Capecitabine
* Drug: Gemcitabine
* Radiation: high intensity radiation therapy
* Drug: nab-Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically proven diagnosis of adenocarcinoma of the pancreas prior to registration Tumor diameter ≤ 7 cm Unresectable by radiographic criteria (pancreas protocol CT or MRI) or exploration within 30 days prior to registration. A cell block or core biopsy must be submitted for central review and analysis of SMAD4 status as soon as possible following step 1 registration. No distant metastases, based upon the following minimum diagnostic workup: History/physical examination within 30 days prior to registration Whole body fluorodeoxyglucose-positron emission tomography/computerized tomography (FDG-PET/CT) within 30 days prior to registration NOTE: If whole-body FDG-PET/CT is not performed, CT of the chest and CT (or MRI) of abdomen and pelvis must be obtained (imaging of abdomen and pelvis need not be repeated if already included in pancreas protocol study) Zubrod Performance Status 0-1 within 30 days prior to registration Age ≥ 18; Complete blood count (CBC)/differential obtained within 14 days prior to step 1 registration, with adequate bone marrow function defined as follows: Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3 Platelets ≥ 100,000 cells/mm3 Hemoglobin ≥ 8.0 g/dl (NOTE: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable) Additional laboratory studies within 14 days prior to registration: carbohydrate antigen 19-9 (CA19-9); NOTE: in the event that a stent has been placed and biliary obstruction has been relieved, the CA19-9 should be drawn post stent placement Creatinine < 2 mg/dl; Glomerular filtration rate (GFR) > 50 mL/min (Cockroft and Gault formula) Bilirubin < 1.5 x ULN Alanine aminotransferase (ALT) and aminotransferase (AST) ≤ 2.5 x ULN Activated partial thromboplastin time (aPTT), prothrombin time (PT) ≤1.2 x upper limit of normal (ULN) Patient must provide study specific informed consent prior to study entry Women of childbearing potential and male participants must practice adequate contraception during protocol treatment and for at least 6 months following treatment For females of child-bearing potential, negative serum pregnancy test within 30 days prior to registration Exclusion Criteria: More than one primary lesion Prior invasive malignancy (unless disease free for a minimum of 1095 days [3 years]); Non-melanomatous skin cancer and previous early prostate cancer that had a non-rising prostate-specific antigen (PSA) are eligible Prior systemic anti-cancer therapy for pancreatic cancer; note that prior chemotherapy for a different cancer is allowable Prior radiation therapy to the abdomen that would result in overlap of radiation therapy fields Severe, active co-morbidity, defined as follows: Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months Transmural myocardial infarction within the last 6 months 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 Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease Control (CDC) definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. Protocol-specific requirements may also exclude immuno-compromised patients Pregnancy or women of childbearing potential, women who cannot discontinue breastfeeding and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic Prior allergic reaction to the study drug(s) involved in this protocol Pre-existing Grade 2 or greater neuropathy Distant metastases

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: Chemotherapy + high intensity radiation<br>Induction chemotherapy with four cycles of gemcitabine and nab-paclitaxel [randomized to this arm after 3rd cycle and no progression]; followed by concurrent high intensity radiation therapy and capecitabine; followed by consolidation chemotherapy with gemcitabine and nab-paclitaxel until progression or unacceptable toxicity | Drug: Capecitabine<br>* 825 mg/m2 PO twice daily, 5 days/week, beginning on the first day of radiation therapy and ending on the last day of radiation therapy.<br>* Other names: Xeloda;Drug: Gemcitabine<br>* 1000 mg/m2 weekly as a 30 minute infusion after nab-Paclitaxel, three weeks on and 1 week off [1 cycle = 4 weeks]<br>* Other names: LY-188011;Radiation: high intensity radiation therapy<br>* 63 Gy intensity-modulated radiation therapy (IMRT) in 28 2.25 Gy fractions, 5 days/week, starts 3-5 weeks after the last dose of induction chemotherapy<br>* Other names: Intensity-Modulated Radiotherapy;Drug: nab-Paclitaxel<br>* 125 mg/m2 weekly as a 30-40 minute infusion, three weeks on and 1 week [1 cycle = 4 weeks]<br>* Other names: Nanoparticle Paclitaxel;|
| Experimental: Chemotherapy + low intensity radiation<br>Induction chemotherapy with four cycles of gemcitabine and nab-paclitaxel [randomized to this arm after 3rd cycle and no progression]; followed by concurrent low intensity radiation therapy and capecitabine; followed by consolidation chemotherapy with gemcitabine and nab-paclitaxel until progression or unacceptable toxicity | Radiation: low intensity radiation therapy<br>* 50.4 Gy in 28 1.8 Gy fractions (IMRT or 3D-CRT), 5 days/week, starting 3-5 weeks after the last dose of induction chemotherapy<br>* Other names: Intensity Modulated RT;Drug: Capecitabine<br>* 825 mg/m2 PO twice daily, 5 days/week, beginning on the first day of radiation therapy and ending on the last day of radiation therapy.<br>* Other names: Xeloda;Drug: Gemcitabine<br>* 1000 mg/m2 weekly as a 30 minute infusion after nab-Paclitaxel, three weeks on and 1 week off [1 cycle = 4 weeks]<br>* Other names: LY-188011;Drug: nab-Paclitaxel<br>* 125 mg/m2 weekly as a 30-40 minute infusion, three weeks on and 1 week [1 cycle = 4 weeks]<br>* Other names: Nanoparticle Paclitaxel;|
| Active Comparator: Chemotherapy<br>Gemcitabine and nab-paclitaxel until progression or unacceptable toxicity [randomized to this arm after 3rd cycle and no progression] | Drug: Gemcitabine<br>* 1000 mg/m2 weekly as a 30 minute infusion after nab-Paclitaxel, three weeks on and 1 week off [1 cycle = 4 weeks]<br>* Other names: LY-188011;Drug: nab-Paclitaxel<br>* 125 mg/m2 weekly as a 30-40 minute infusion, three weeks on and 1 week [1 cycle = 4 weeks]<br>* Other names: Nanoparticle Paclitaxel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Survival time is defined as time from randomization to date of death from any cause and was to be estimated by the Kaplan-Meier method. Given the limited follow-up due to early closure and termination of data collection, only the number of patients last reported to be alive at time of study termination is reported. | From randomization until last follow-up. Analysis was to occur after a total of 140 deaths were reported within the pairing of each radiation arm with the chemotherapy alone arm. Maximum follow-up at time of study termination was 8.3 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival Within SMAD4 Subsets | Survival time is defined as time from randomization to date of death from any cause and was to be estimated by the Kaplan-Meier method. Given the limited follow-up due to early closure and termination of data collection, only the number of patients last reported to be alive at time of study termination is reported. Patients are categorized by SMAD4 status of intact (positive nuclear labeling is observed of the neoplastic cells ), loss (no labeling observed of the neoplastic cells) , or undetermined (insufficient material for immunostaining or results are equivocal). This study terminated early with only 20 registered (346 planned) and 13 randomized (288 planned). There are no proven results as to which category has better incomes, but this study hypothesizes that intact is highly correlated with local failures and loss is highly correlated with widespread metastasis, in which case intact would correspond with positive results relative to loss. | From randomization until last follow-up. Analysis was to occur after a total of 140 deaths were reported within the pairing of each radiation arm with the chemotherapy alone arm. Maximum follow-up at time of study termination was 8.3 months. | 
| Patterns of Failure (Local and Metastatic Failure) | Local progression is defined as least a 20% increase in the sum of diameters of the primary, taking as reference the baseline sum. Given the inherent inaccuracy in determining size of a primary pancreatic carcinoma, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm and progression must be demonstrated on at least two sequential scans. Metastatic failure is defined as metastatic disease. Local and distant failure were to be estimated by the cumulative incidence method. Given the limited follow-up due to early closure and termination of data collection, only the number of patients with failure is reported. | From randomization until last follow-up. Maximum follow-up at time of study termination was 8.3 months. | 
| Correlation Between SMAD4 Status Determined by Immunohistochemistry (IHC) and Genetic SMAD4 Status |  | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SMAD4, IMRT, gemcitabine, high-dose radiotherapy