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

Pancreatic Adenocarcinoma Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01921751
• Other study ID #: RTOG 1201
• Secondary ID: NCI-2013-01280RT
• Status: Terminated
• Phase: Phase 2
• Start date: August 2013
• Est. completion date: June 2016

Study information

• Verified date: June 2018
• Source: Radiation Therapy Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 20
• Est. completion date: June 2016
• Est. primary completion date: June 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Adenocarcinoma
• Pancreatic Adenocarcinoma
• Pancreatic Neoplasms
• Stage III Pancreatic Cancer

Intervention

Radiation:
• low intensity radiation therapy
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

Drug:
• Capecitabine
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
1000 mg/m2 weekly as a 30 minute infusion after nab-Paclitaxel, three weeks on and 1 week off [1 cycle = 4 weeks]

Radiation:
• high intensity radiation therapy
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

Drug:
• nab-Paclitaxel
125 mg/m2 weekly as a 30-40 minute infusion, three weeks on and 1 week [1 cycle = 4 weeks]

Locations

Country	Name	City	State
United States	Akron General Medical Center	Akron	Ohio
United States	McFarland Clinic PC-William R Bliss Cancer Center	Ames	Iowa
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	Emory University/Winship Cancer Institute	Atlanta	Georgia
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Sanford Clinic North-Bemidgi	Bemidji	Minnesota
United States	Central Vermont Medical Center/National Life Cancer Treatment	Berlin	Vermont
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	Boston Medical Center	Boston	Massachusetts
United States	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania
United States	University of Vermont Medical Center	Burlington	Vermont
United States	Saint Joseph Hospital	Chicago	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Iowa Methodist Medical Center	Des Moines	Iowa
United States	Roger Maris Cancer Center	Fargo	North Dakota
United States	Parkview Hospital Randallia	Fort Wayne	Indiana
United States	Radiation Oncology Associates PC	Fort Wayne	Indiana
United States	Saint Mary's Hospital	Green Bay	Wisconsin
United States	Saint Vincent Hospital	Green Bay	Wisconsin
United States	M D Anderson Cancer Center	Houston	Texas
United States	Thompson Cancer Survival Center	Knoxville	Tennessee
United States	Bay Area Medical Center	Marinette	Wisconsin
United States	Fox Chase Cancer Center at Virtua Memorial Hospital of Burlington County	Mount Holly	New Jersey
United States	Intermountain Medical Center	Murray	Utah
United States	Ochsner Medical Center Jefferson	New Orleans	Louisiana
United States	Kaiser Permanente Oakland-Broadway	Oakland	California
United States	McKay-Dee Hospital Center	Ogden	Utah
United States	Paoli Memorial Hospital	Paoli	Pennsylvania
United States	Capital Health Medical Center-Hopewell	Pennington	New Jersey
United States	OSF Saint Francis Medical Center	Peoria	Illinois
United States	OSF Saint Francis Medical Center Radiation Oncology Service at the Central Illinois Comprehensive CC	Peoria	Illinois
United States	University of Pennsylvania/Abramson Cancer Center	Philadelphia	Pennsylvania
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	Kaiser Permanente Medical Center - Santa Clara	Santa Clara	California
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Kaiser Permanente Cancer Treatment Center	South San Francisco	California
United States	CoxHealth South Hospital	Springfield	Missouri
United States	Mercy Hospital Springfield	Springfield	Missouri
United States	Door County Cancer Center	Sturgeon Bay	Wisconsin
United States	Reading Hospital	West Reading	Pennsylvania
United States	Rice Memorial Hospital	Willmar	Minnesota
United States	Lankenau Medical Center	Wynnewood	Pennsylvania

Sponsors (3)

Lead Sponsor	Collaborator
Radiation Therapy Oncology Group	National Cancer Institute (NCI), NRG Oncology

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.
Secondary	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.
Secondary	Correlation Between SMAD4 Status Determined by Immunohistochemistry (IHC) and Genetic SMAD4 Status		Baseline