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

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.

• low intensity radiation therapy (Radiation), also known as 3-dimensional conformal radiation therapy, 3-dimensional radiation therapy, 3D-CRT, Conformal Therapy, Radiation Conformal Therapy, IMRT, intensity modulated radiation therapy, intensity-modulated radiation therapy, Intensity-Modulated Radiotherapy, Intensity Modulated RT: 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
• Capecitabine (Drug), also known as Ro 09-1978/000, Xeloda: 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.
• Gemcitabine (Drug), also known as dFdCyd, Difluorodeoxycytidine Hydrochloride, GEMCITABINE HYDROCHLORIDE, Gemzar, LY-188011: 1000 mg/m2 weekly as a 30 minute infusion after nab-Paclitaxel, three weeks on and 1 week off \[1 cycle = 4 weeks\]
• high intensity radiation therapy (Radiation), also known as IMRT, Intensity Modulated RT, intensity-modulated radiation therapy, Intensity-Modulated Radiotherapy: 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
• nab-Paclitaxel (Drug), also known as ABI 007, ABI-007, Abraxane, Albumin-bound Paclitaxel, Albumin-Stabilized Nanoparticle Paclitaxel, Nanoparticle Albumin-bound Paclitaxel, Nanoparticle Paclitaxel: 125 mg/m2 weekly as a 30-40 minute infusion, three weeks on and 1 week \[1 cycle = 4 weeks\]

Primary outcomes

• Overall Survival [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.]: 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.

Secondary outcomes

• Overall Survival Within SMAD4 Subsets [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.]: 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".
• Patterns of Failure (Local and Metastatic Failure) [From randomization until last follow-up. Maximum follow-up at time of study termination was 8.3 months.]: 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.
• Correlation Between SMAD4 Status Determined by Immunohistochemistry (IHC) and Genetic SMAD4 Status [Baseline]

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Histologically or cytologically proven diagnosis of adenocarcinoma of the pancreas prior to registration
2. Tumor diameter ≤ 7 cm
3. Unresectable by radiographic criteria (pancreas protocol CT or MRI) or exploration within 30 days prior to registration.
4. 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.
5. 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)
6. Zubrod Performance Status 0-1 within 30 days prior to registration
7. Age ≥ 18;
8. 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)
9. 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)
10. Patient must provide study specific informed consent prior to study entry
11. Women of childbearing potential and male participants must practice adequate contraception during protocol treatment and for at least 6 months following treatment
12. For females of child-bearing potential, negative serum pregnancy test within 30 days prior to registration

Exclusion Criteria:

1. More than one primary lesion
2. 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
3. Prior systemic anti-cancer therapy for pancreatic cancer; note that prior chemotherapy for a different cancer is allowable
4. Prior radiation therapy to the abdomen that would result in overlap of radiation therapy fields
5. 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
6. 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
7. Prior allergic reaction to the study drug(s) involved in this protocol
8. Pre-existing Grade 2 or greater neuropathy
9. Distant metastases

Participant flow

Outcome results

• Overall Survival (Primary), Count of participants, Participants: Chemotherapy + High Intensity Radiation 4; Chemotherapy + Low Intensity Radiation 4; Chemotherapy 5
• Overall Survival Within SMAD4 Subsets (Secondary), Count of participants, Participants: Chemotherapy + High Intensity Radiation 1; Chemotherapy + Low Intensity Radiation 1; Chemotherapy 3
• Patterns of Failure (Local and Metastatic Failure) (Secondary), Count of participants, Participants: Chemotherapy + High Intensity Radiation 0; Chemotherapy + Low Intensity Radiation 0; Chemotherapy
• Correlation Between SMAD4 Status Determined by Immunohistochemistry (IHC) and Genetic SMAD4 Status (Secondary)

Adverse events

Serious adverse events by term

Other adverse events by term

15 more terms not shown.

Limitations and caveats: This study terminated early with only 20 registered (346 planned) and 13 randomized (288 planned). Follow-up forms were collected on only 3 patients.

• Results publication: Jani A, Horowitz DP. Radiation Therapy Deviations in Trial of Locally Advanced Pancreatic Cancer [corrected]. JAMA. 2016 Oct 4;316(13):1409. doi: 10.1001/jama.2016.9778. No abstract available. PMID 27701653

• Edgar Ben-Josef, Principal investigator, NRG Oncology

NIH grants: U10CA180868, U10CA021661