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

• Sponsor: Radiation Therapy Oncology Group (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01921751
• Collaborator: National Cancer Institute (NCI) (NIH), NRG Oncology (Other)
• Enrollment: 20
• Locations: 46
• Arms: 3
• Duration (Months): 34
• Patients Per Site: 0.4
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Pancreatic Adenocarcinoma; Stage III Pancreatic Cancer	Radiation: low intensity radiation therapy; Drug: Capecitabine; Drug: Gemcitabine; Radiation: high intensity radiation therapy; Drug: nab-Paclitaxel	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

• 1. 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.
• 1. 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:

• 1. To evaluate patterns of failure (local and systemic progression) by SMAD family member 4 (SMAD4) status and intensity of radiation therapy.
• 1. To evaluate the impact of radiochemotherapy on OS for the subset of SMAD4 intact patients.
• 1. To evaluate adverse events associated with the treatments.
• 1. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: Aug 1, 2013
• Actual Primary Completion Date: Jun 1, 2016
• Actual Study Completion Date: Jun 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Chemotherapy + high intensity radiation 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; 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.; Other Names: Ro 09-1978/000 Xeloda ; Drug: Gemcitabine; 1000 mg/m2 weekly as a 30 minute infusion after nab-Paclitaxel, three weeks on and 1 week off [1 cycle = 4 weeks]; Other Names: dFdCyd Difluorodeoxycytidine Hydrochloride GEMCITABINE HYDROCHLORIDE Gemzar LY-188011 ; 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; Other Names: IMRT Intensity Modulated RT intensity-modulated radiation therapy Intensity-Modulated Radiotherapy ; Drug: nab-Paclitaxel; 125 mg/m2 weekly as a 30-40 minute infusion, three weeks on and 1 week [1 cycle = 4 weeks]; Other Names: ABI 007 ABI-007 Abraxane Albumin-bound Paclitaxel Albumin-Stabilized Nanoparticle Paclitaxel Nanoparticle Albumin-bound Paclitaxel Nanoparticle Paclitaxel
Experimental: Chemotherapy + low intensity radiation 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; 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; Other Names: 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 ; 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.; Other Names: Ro 09-1978/000 Xeloda ; Drug: Gemcitabine; 1000 mg/m2 weekly as a 30 minute infusion after nab-Paclitaxel, three weeks on and 1 week off [1 cycle = 4 weeks]; Other Names: dFdCyd Difluorodeoxycytidine Hydrochloride GEMCITABINE HYDROCHLORIDE Gemzar LY-188011 ; Drug: nab-Paclitaxel; 125 mg/m2 weekly as a 30-40 minute infusion, three weeks on and 1 week [1 cycle = 4 weeks]; Other Names: ABI 007 ABI-007 Abraxane Albumin-bound Paclitaxel Albumin-Stabilized Nanoparticle Paclitaxel Nanoparticle Albumin-bound Paclitaxel Nanoparticle Paclitaxel
Active Comparator: Chemotherapy Gemcitabine and nab-paclitaxel until progression or unacceptable toxicity [randomized to this arm after 3rd cycle and no progression]	Drug: Gemcitabine; 1000 mg/m2 weekly as a 30 minute infusion after nab-Paclitaxel, three weeks on and 1 week off [1 cycle = 4 weeks]; Other Names: dFdCyd Difluorodeoxycytidine Hydrochloride GEMCITABINE HYDROCHLORIDE Gemzar LY-188011 ; Drug: nab-Paclitaxel; 125 mg/m2 weekly as a 30-40 minute infusion, three weeks on and 1 week [1 cycle = 4 weeks]; Other Names: ABI 007 ABI-007 Abraxane Albumin-bound Paclitaxel Albumin-Stabilized Nanoparticle Paclitaxel Nanoparticle Albumin-bound Paclitaxel Nanoparticle Paclitaxel

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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".

2. 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.

3. Correlation Between SMAD4 Status Determined by Immunohistochemistry (IHC) and Genetic SMAD4 Status [Baseline]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

1. Zubrod Performance Status 0-1 within 30 days prior to registration

2. Age ≥ 18;

3. 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)

1. 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)

1. Patient must provide study specific informed consent prior to study entry

2. Women of childbearing potential and male participants must practice adequate contraception during protocol treatment and for at least 6 months following treatment

3. 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

1. 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

2. Prior allergic reaction to the study drug(s) involved in this protocol

3. Pre-existing Grade 2 or greater neuropathy

4. Distant metastases

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Kaiser Permanente Oakland-Broadway	Oakland	California	United States	94611
2	Kaiser Permanente Medical Center - Santa Clara	Santa Clara	California	United States	95051
3	Kaiser Permanente Cancer Treatment Center	South San Francisco	California	United States	94080
4	Emory University/Winship Cancer Institute	Atlanta	Georgia	United States	30322
5	Saint Joseph Hospital	Chicago	Illinois	United States	60657
6	Decatur Memorial Hospital	Decatur	Illinois	United States	62526
7	OSF Saint Francis Medical Center Radiation Oncology Service at the Central Illinois Comprehensive CC	Peoria	Illinois	United States	61615-7827
8	OSF Saint Francis Medical Center	Peoria	Illinois	United States	61637
9	Radiation Oncology Associates PC	Fort Wayne	Indiana	United States	46804
10	Parkview Hospital Randallia	Fort Wayne	Indiana	United States	46805
11	McFarland Clinic PC-William R Bliss Cancer Center	Ames	Iowa	United States	50010
12	Iowa Methodist Medical Center	Des Moines	Iowa	United States	50309
13	Ochsner Medical Center Jefferson	New Orleans	Louisiana	United States	70121
14	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
15	Boston Medical Center	Boston	Massachusetts	United States	02118
16	Saint Joseph Mercy Hospital	Ann Arbor	Michigan	United States	48106-0995
17	Sanford Clinic North-Bemidgi	Bemidji	Minnesota	United States	56601
18	Mayo Clinic	Rochester	Minnesota	United States	55905
19	Rice Memorial Hospital	Willmar	Minnesota	United States	56201
20	Mercy Hospital Saint Louis	Saint Louis	Missouri	United States	63141
21	Mercy Hospital Springfield	Springfield	Missouri	United States	65804
22	CoxHealth South Hospital	Springfield	Missouri	United States	65807
23	Fox Chase Cancer Center at Virtua Memorial Hospital of Burlington County	Mount Holly	New Jersey	United States	08060
24	Capital Health Medical Center-Hopewell	Pennington	New Jersey	United States	08534
25	University of Rochester	Rochester	New York	United States	14642
26	Sanford Bismarck Medical Center	Bismarck	North Dakota	United States	58501
27	Roger Maris Cancer Center	Fargo	North Dakota	United States	58122
28	Akron General Medical Center	Akron	Ohio	United States	44307
29	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania	United States	19010
30	Paoli Memorial Hospital	Paoli	Pennsylvania	United States	19301
31	University of Pennsylvania/Abramson Cancer Center	Philadelphia	Pennsylvania	United States	19104
32	Reading Hospital	West Reading	Pennsylvania	United States	19611
33	Lankenau Medical Center	Wynnewood	Pennsylvania	United States	19096
34	Rhode Island Hospital	Providence	Rhode Island	United States	02903
35	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota	United States	57117-5134
36	Thompson Cancer Survival Center	Knoxville	Tennessee	United States	37916
37	M D Anderson Cancer Center	Houston	Texas	United States	77030
38	Intermountain Medical Center	Murray	Utah	United States	84157
39	McKay-Dee Hospital Center	Ogden	Utah	United States	84403
40	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah	United States	84112
41	Central Vermont Medical Center/National Life Cancer Treatment	Berlin	Vermont	United States	05602
42	University of Vermont Medical Center	Burlington	Vermont	United States	05401
43	Saint Vincent Hospital	Green Bay	Wisconsin	United States	54301
44	Saint Mary's Hospital	Green Bay	Wisconsin	United States	54303
45	Bay Area Medical Center	Marinette	Wisconsin	United States	54143
46	Door County Cancer Center	Sturgeon Bay	Wisconsin	United States	54235-1495

Sponsors and Collaborators

• Radiation Therapy Oncology Group
• National Cancer Institute (NCI)
• NRG Oncology

Investigators

• Principal Investigator: Edgar Ben-Josef, NRG Oncology

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Radiation Therapy Oncology Group
• ClinicalTrials.gov Identifier: NCT01921751
• Other Study ID Numbers: RTOG 1201; NCI-2013-01280; RTOG 1201; RTOG-1201; U10CA180868; U10CA021661
• First Posted: Aug 13, 2013
• Last Update Posted: Jul 13, 2018
• Last Verified: Jun 1, 2018

• Keywords provided by Radiation Therapy Oncology Group: SMAD4; IMRT; gemcitabine; high-dose radiotherapy
• Additional relevant MeSH terms: Pancreatic Neoplasms; Gemcitabine; Paclitaxel; Albumin-Bound Paclitaxel; Capecitabine

Study Results

Participant Flow

Pre-assignment Detail	Patients were registered and received 3 cycles of Gemcitabine/nab-Paclitaxel and then had central SMAD4 testing done. Patients then had a CT/MRI of their abdomen/pelvis for restaging. Only non-progressing patients were then randomized after being stratified by carbohydrate antigen 19-9 (CA19-9) and SMAD4.

Arm/Group Title	Chemotherapy + High Intensity Radiation	Chemotherapy + Low Intensity Radiation	Chemotherapy
Arm/Group Description	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	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	Gemcitabine and nab-paclitaxel until progression or unacceptable toxicity [randomized to this arm after 3rd cycle and no progression]
Period Title: Overall Study
STARTED	4	4	5
COMPLETED	4	4	5
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Chemotherapy + High Intensity Radiation	Chemotherapy + Low Intensity Radiation	Chemotherapy	Total
Arm/Group Description	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	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	Gemcitabine and nab-paclitaxel until progression or unacceptable toxicity [randomized to this arm after 3rd cycle and no progression]	Total of all reporting groups
Overall Participants	4	4	5	13
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	63.5	69	66	66
Sex: Female, Male (Count of Participants)
Female	4 100%	3 75%	2 40%	9 69.2%
Male	0 0%	1 25%	3 60%	4 30.8%

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

All randomized patients

Arm/Group Title	Chemotherapy + High Intensity Radiation	Chemotherapy + Low Intensity Radiation	Chemotherapy
Arm/Group Description	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	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	Gemcitabine and nab-paclitaxel until progression or unacceptable toxicity [randomized to this arm after 3rd cycle and no progression]
Measure Participants	4	4	5
Count of Participants [Participants]	4 100%	4 100%	5 100%

2. Secondary Outcome

Title	Overall Survival Within SMAD4 Subsets
Description	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".
Time Frame	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.

Outcome Measure Data

Analysis Population Description

All randomized patients

Arm/Group Title	Chemotherapy + High Intensity Radiation	Chemotherapy + Low Intensity Radiation	Chemotherapy
Arm/Group Description	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	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	Gemcitabine and nab-paclitaxel until progression or unacceptable toxicity [randomized to this arm after 3rd cycle and no progression]
Measure Participants	4	4	5
Intact	1 25%	1 25%	3 60%
Loss	3 75%	2 50%	1 20%
Undetermined	0 0%	1 25%	1 20%

3. Secondary Outcome

Title	Patterns of Failure (Local and Metastatic Failure)
Description	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.
Time Frame	From randomization until last follow-up. Maximum follow-up at time of study termination was 8.3 months.

Outcome Measure Data

Analysis Population Description

Randomized eligible patients with follow-up data.

Arm/Group Title	Chemotherapy + High Intensity Radiation	Chemotherapy + Low Intensity Radiation	Chemotherapy
Arm/Group Description	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	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	Gemcitabine and nab-paclitaxel until progression or unacceptable toxicity [randomized to this arm after 3rd cycle and no progression]
Measure Participants	1	2	0
Local Failure	0 0%	0 0%
Metastatic Failure	0 0%	1 25%

4. Secondary Outcome

Title	Correlation Between SMAD4 Status Determined by Immunohistochemistry (IHC) and Genetic SMAD4 Status
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Because the study was terminated early, genetic SMAD4 status was not determined and therefore this analysis will not occur.

Arm/Group Title	Chemotherapy + High Intensity Radiation	Chemotherapy + Low Intensity Radiation	Chemotherapy
Arm/Group Description	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	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	Gemcitabine and nab-paclitaxel until progression or unacceptable toxicity [randomized to this arm after 3rd cycle and no progression]
Measure Participants	0	0	0

Adverse Events

Adverse Event Reporting Description	Registered patients with adverse event data are included. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Arm/Group Title	Chemotherapy + High Intensity Radiation		Chemotherapy + Low Intensity Radiation		Chemotherapy		Chemotherapy - Not Randomized
Arm/Group Description	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		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		Gemcitabine and nab-paclitaxel until progression or unacceptable toxicity [randomized to this arm after 3rd cycle and no progression]		Induction chemotherapy with three cycles of gemcitabine and nab-paclitaxel [not randomized]
All Cause Mortality
	Chemotherapy + High Intensity Radiation		Chemotherapy + Low Intensity Radiation		Chemotherapy		Chemotherapy - Not Randomized
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Chemotherapy + High Intensity Radiation		Chemotherapy + Low Intensity Radiation		Chemotherapy		Chemotherapy - Not Randomized
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/4 (50%)		1/4 (25%)		1/5 (20%)		1/7 (14.3%)
Cardiac disorders
Atrial fibrillation	1/4 (25%)		0/4 (0%)		0/5 (0%)		0/7 (0%)
Gastrointestinal disorders
Diarrhea	0/4 (0%)		1/4 (25%)		0/5 (0%)		0/7 (0%)
Gastrointestinal disorders - Other, specify	0/4 (0%)		0/4 (0%)		0/5 (0%)		1/7 (14.3%)
Vomiting	0/4 (0%)		1/4 (25%)		0/5 (0%)		0/7 (0%)
General disorders
Edema limbs	0/4 (0%)		1/4 (25%)		0/5 (0%)		0/7 (0%)
Infections and infestations
Lung infection	1/4 (25%)		0/4 (0%)		0/5 (0%)		0/7 (0%)
Investigations
Neutrophil count decreased	1/4 (25%)		0/4 (0%)		1/5 (20%)		0/7 (0%)
Platelet count decreased	1/4 (25%)		0/4 (0%)		0/5 (0%)		0/7 (0%)
White blood cell decreased	1/4 (25%)		0/4 (0%)		0/5 (0%)		0/7 (0%)
Metabolism and nutrition disorders
Hyponatremia	0/4 (0%)		1/4 (25%)		0/5 (0%)		0/7 (0%)
Renal and urinary disorders
Acute kidney injury	0/4 (0%)		0/4 (0%)		1/5 (20%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	Chemotherapy + High Intensity Radiation		Chemotherapy + Low Intensity Radiation		Chemotherapy		Chemotherapy - Not Randomized
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		4/4 (100%)		5/5 (100%)		2/7 (28.6%)
Blood and lymphatic system disorders
Anemia	4/4 (100%)		2/4 (50%)		2/5 (40%)		2/7 (28.6%)
Febrile neutropenia	1/4 (25%)		1/4 (25%)		1/5 (20%)		0/7 (0%)
Eye disorders
Blurred vision	2/4 (50%)		0/4 (0%)		0/5 (0%)		1/7 (14.3%)
Eye disorders - Other, specify	0/4 (0%)		1/4 (25%)		0/5 (0%)		0/7 (0%)
Gastrointestinal disorders
Abdominal pain	2/4 (50%)		2/4 (50%)		2/5 (40%)		1/7 (14.3%)
Bloating	1/4 (25%)		0/4 (0%)		0/5 (0%)		0/7 (0%)
Constipation	2/4 (50%)		3/4 (75%)		1/5 (20%)		1/7 (14.3%)
Diarrhea	2/4 (50%)		2/4 (50%)		3/5 (60%)		2/7 (28.6%)
Dyspepsia	2/4 (50%)		0/4 (0%)		0/5 (0%)		0/7 (0%)
Flatulence	0/4 (0%)		1/4 (25%)		0/5 (0%)		0/7 (0%)
Mucositis oral	1/4 (25%)		1/4 (25%)		0/5 (0%)		0/7 (0%)
Nausea	3/4 (75%)		3/4 (75%)		2/5 (40%)		2/7 (28.6%)
Vomiting	0/4 (0%)		2/4 (50%)		1/5 (20%)		0/7 (0%)
General disorders
Chills	0/4 (0%)		1/4 (25%)		0/5 (0%)		1/7 (14.3%)
Edema limbs	1/4 (25%)		1/4 (25%)		0/5 (0%)		0/7 (0%)
Fatigue	4/4 (100%)		2/4 (50%)		5/5 (100%)		2/7 (28.6%)
Fever	1/4 (25%)		0/4 (0%)		0/5 (0%)		1/7 (14.3%)
Localized edema	0/4 (0%)		0/4 (0%)		1/5 (20%)		0/7 (0%)
Pain	1/4 (25%)		2/4 (50%)		0/5 (0%)		0/7 (0%)
Immune system disorders
Allergic reaction	0/4 (0%)		1/4 (25%)		0/5 (0%)		1/7 (14.3%)
Infections and infestations
Infections and infestations - Other, specify	0/4 (0%)		0/4 (0%)		1/5 (20%)		0/7 (0%)
Lung infection	1/4 (25%)		0/4 (0%)		0/5 (0%)		0/7 (0%)
Mucosal infection	1/4 (25%)		0/4 (0%)		0/5 (0%)		0/7 (0%)
Pharyngitis	1/4 (25%)		0/4 (0%)		0/5 (0%)		0/7 (0%)
Upper respiratory infection	0/4 (0%)		1/4 (25%)		0/5 (0%)		0/7 (0%)
Investigations
Alanine aminotransferase increased	1/4 (25%)		1/4 (25%)		2/5 (40%)		2/7 (28.6%)
Alkaline phosphatase increased	0/4 (0%)		2/4 (50%)		0/5 (0%)		1/7 (14.3%)
Aspartate aminotransferase increased	1/4 (25%)		1/4 (25%)		1/5 (20%)		2/7 (28.6%)
Lymphocyte count decreased	1/4 (25%)		2/4 (50%)		1/5 (20%)		0/7 (0%)
Neutrophil count decreased	3/4 (75%)		2/4 (50%)		3/5 (60%)		1/7 (14.3%)
Platelet count decreased	3/4 (75%)		1/4 (25%)		3/5 (60%)		2/7 (28.6%)
Weight gain	0/4 (0%)		1/4 (25%)		0/5 (0%)		0/7 (0%)
Weight loss	1/4 (25%)		1/4 (25%)		2/5 (40%)		1/7 (14.3%)
White blood cell decreased	4/4 (100%)		3/4 (75%)		4/5 (80%)		0/7 (0%)
Metabolism and nutrition disorders
Anorexia	4/4 (100%)		3/4 (75%)		3/5 (60%)		2/7 (28.6%)
Dehydration	1/4 (25%)		1/4 (25%)		0/5 (0%)		1/7 (14.3%)
Glucose intolerance	1/4 (25%)		0/4 (0%)		0/5 (0%)		0/7 (0%)
Hyperglycemia	0/4 (0%)		1/4 (25%)		0/5 (0%)		1/7 (14.3%)
Hyperkalemia	0/4 (0%)		1/4 (25%)		0/5 (0%)		0/7 (0%)
Hypoalbuminemia	2/4 (50%)		1/4 (25%)		1/5 (20%)		2/7 (28.6%)
Hypocalcemia	1/4 (25%)		1/4 (25%)		1/5 (20%)		0/7 (0%)
Hypoglycemia	0/4 (0%)		0/4 (0%)		1/5 (20%)		0/7 (0%)
Hypokalemia	2/4 (50%)		2/4 (50%)		0/5 (0%)		1/7 (14.3%)
Hypomagnesemia	3/4 (75%)		0/4 (0%)		0/5 (0%)		0/7 (0%)
Hyponatremia	1/4 (25%)		2/4 (50%)		0/5 (0%)		1/7 (14.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/4 (0%)		1/4 (25%)		0/5 (0%)		1/7 (14.3%)
Back pain	0/4 (0%)		1/4 (25%)		0/5 (0%)		1/7 (14.3%)
Generalized muscle weakness	1/4 (25%)		1/4 (25%)		0/5 (0%)		1/7 (14.3%)
Myalgia	0/4 (0%)		0/4 (0%)		1/5 (20%)		1/7 (14.3%)
Nervous system disorders
Dizziness	1/4 (25%)		1/4 (25%)		1/5 (20%)		1/7 (14.3%)
Dysesthesia	1/4 (25%)		0/4 (0%)		0/5 (0%)		0/7 (0%)
Dysgeusia	1/4 (25%)		0/4 (0%)		0/5 (0%)		1/7 (14.3%)
Paresthesia	1/4 (25%)		0/4 (0%)		0/5 (0%)		0/7 (0%)
Peripheral motor neuropathy	0/4 (0%)		0/4 (0%)		1/5 (20%)		0/7 (0%)
Peripheral sensory neuropathy	1/4 (25%)		2/4 (50%)		2/5 (40%)		0/7 (0%)
Psychiatric disorders
Anxiety	2/4 (50%)		0/4 (0%)		0/5 (0%)		1/7 (14.3%)
Depression	0/4 (0%)		0/4 (0%)		1/5 (20%)		1/7 (14.3%)
Insomnia	0/4 (0%)		0/4 (0%)		1/5 (20%)		0/7 (0%)
Renal and urinary disorders
Renal and urinary disorders - Other, specify	0/4 (0%)		1/4 (25%)		0/5 (0%)		0/7 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/4 (0%)		1/4 (25%)		1/5 (20%)		0/7 (0%)
Epistaxis	1/4 (25%)		0/4 (0%)		0/5 (0%)		1/7 (14.3%)
Hoarseness	1/4 (25%)		0/4 (0%)		0/5 (0%)		0/7 (0%)
Laryngeal inflammation	0/4 (0%)		0/4 (0%)		1/5 (20%)		0/7 (0%)
Postnasal drip	0/4 (0%)		0/4 (0%)		1/5 (20%)		0/7 (0%)
Sore throat	0/4 (0%)		0/4 (0%)		1/5 (20%)		0/7 (0%)
Skin and subcutaneous tissue disorders
Alopecia	2/4 (50%)		3/4 (75%)		2/5 (40%)		1/7 (14.3%)
Erythema multiforme	1/4 (25%)		0/4 (0%)		0/5 (0%)		0/7 (0%)
Palmar-plantar erythrodysesthesia syndrome	0/4 (0%)		1/4 (25%)		0/5 (0%)		0/7 (0%)
Pruritus	0/4 (0%)		1/4 (25%)		0/5 (0%)		0/7 (0%)
Rash acneiform	0/4 (0%)		0/4 (0%)		1/5 (20%)		0/7 (0%)
Rash maculo-papular	1/4 (25%)		0/4 (0%)		1/5 (20%)		1/7 (14.3%)
Vascular disorders
Hot flashes	0/4 (0%)		1/4 (25%)		0/5 (0%)		0/7 (0%)
Hypertension	0/4 (0%)		3/4 (75%)		0/5 (0%)		1/7 (14.3%)
Hypotension	1/4 (25%)		1/4 (25%)		0/5 (0%)		0/7 (0%)
Lymphedema	0/4 (0%)		0/4 (0%)		1/5 (20%)		0/7 (0%)

Limitations/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.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

PI's are required to abide by the sponsor's publication guidelines which require review by coauthors and subsequent review and approval by the sponsor.