Clinical trial NCT01921751: High or Standard Intensity Radiation Therapy After Gemcitabine Hydrochloride and Nab-paclitaxel in Treating Patients With Pancreatic Cancer That Cannot Be Removed by Surgery
Official title: A Phase II Randomized Trial Evaluating the Addition of High or Standard Intensity Radiation to Gemcitabine and Nab-paclitaxel for Locally Advanced Pancreatic Cancer
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Pancreatic Adenocarcinoma
Stage III Pancreatic Cancer
Keywords: SMAD4
IMRT
gemcitabine
high-dose radiotherapy
Lead sponsor: Radiation Therapy Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
name: NRG Oncology
First posted: 2013-08-13
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Overall Survival
timeFrame: 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 outcomes:
measure: Overall Survival Within SMAD4 Subsets
timeFrame: 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.
measure: Patterns of Failure (Local and Metastatic Failure)
timeFrame: From randomization until last follow-up. Maximum follow-up at time of study termination was 8.3 months.
measure: Correlation Between SMAD4 Status Determined by Immunohistochemistry (IHC) and Genetic SMAD4 Status
timeFrame: Baseline
Other outcomes:
Locations:
city: Oakland
country: United States
facility: Kaiser Permanente Oakland-Broadway
state: California
city: Santa Clara
country: United States
facility: Kaiser Permanente Medical Center - Santa Clara
state: California
city: South San Francisco
country: United States
facility: Kaiser Permanente Cancer Treatment Center
state: California
city: Atlanta
country: United States
facility: Emory University/Winship Cancer Institute
state: Georgia
city: Chicago
country: United States
facility: Saint Joseph Hospital
state: Illinois
city: Decatur
country: United States
facility: Decatur Memorial Hospital
state: Illinois
city: Peoria
country: United States
facility: OSF Saint Francis Medical Center Radiation Oncology Service at the Central Illinois Comprehensive CC
state: Illinois
city: Peoria
country: United States
facility: OSF Saint Francis Medical Center
state: Illinois
city: Fort Wayne
country: United States
facility: Radiation Oncology Associates PC
state: Indiana
city: Fort Wayne
country: United States
facility: Parkview Hospital Randallia
state: Indiana
city: Ames
country: United States
facility: McFarland Clinic PC-William R Bliss Cancer Center
state: Iowa
city: Des Moines
country: United States
facility: Iowa Methodist Medical Center
state: Iowa
city: New Orleans
country: United States
facility: Ochsner Medical Center Jefferson
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins University/Sidney Kimmel Cancer Center
state: Maryland
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: Saint Joseph Mercy Hospital
state: Michigan
city: Bemidji
country: United States
facility: Sanford Clinic North-Bemidgi
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Willmar
country: United States
facility: Rice Memorial Hospital
state: Minnesota
city: Saint Louis
country: United States
facility: Mercy Hospital Saint Louis
state: Missouri
city: Springfield
country: United States
facility: Mercy Hospital Springfield
state: Missouri
city: Springfield
country: United States
facility: CoxHealth South Hospital
state: Missouri
city: Mount Holly
country: United States
facility: Fox Chase Cancer Center at Virtua Memorial Hospital of Burlington County
state: New Jersey
city: Pennington
country: United States
facility: Capital Health Medical Center-Hopewell
state: New Jersey
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Bismarck
country: United States
facility: Sanford Bismarck Medical Center
state: North Dakota
city: Fargo
country: United States
facility: Roger Maris Cancer Center
state: North Dakota
city: Akron
country: United States
facility: Akron General Medical Center
state: Ohio
city: Bryn Mawr
country: United States
facility: Bryn Mawr Hospital
state: Pennsylvania
city: Paoli
country: United States
facility: Paoli Memorial Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania/Abramson Cancer Center
state: Pennsylvania
city: West Reading
country: United States
facility: Reading Hospital
state: Pennsylvania
city: Wynnewood
country: United States
facility: Lankenau Medical Center
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Sioux Falls
country: United States
facility: Sanford USD Medical Center - Sioux Falls
state: South Dakota
city: Knoxville
country: United States
facility: Thompson Cancer Survival Center
state: Tennessee
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
city: Murray
country: United States
facility: Intermountain Medical Center
state: Utah
city: Ogden
country: United States
facility: McKay-Dee Hospital Center
state: Utah
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute/University of Utah
state: Utah
city: Berlin
country: United States
facility: Central Vermont Medical Center/National Life Cancer Treatment
state: Vermont
city: Burlington
country: United States
facility: University of Vermont Medical Center
state: Vermont
city: Green Bay
country: United States
facility: Saint Vincent Hospital
state: Wisconsin
city: Green Bay
country: United States
facility: Saint Mary's Hospital
state: Wisconsin
city: Marinette
country: United States
facility: Bay Area Medical Center
state: Wisconsin
city: Sturgeon Bay
country: United States
facility: Door County Cancer Center
state: Wisconsin
Study officials:
affiliation: NRG Oncology
name: Edgar Ben-Josef
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.