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

NCT ID: NCT01921751

Last Updated: 2018-07-13

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-08-31
• Study Completion Date: 2016-06-30

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.

Conditions

Pancreatic Adenocarcinoma; Stage III Pancreatic Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

Capecitabine

Intervention Type: DRUG

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

Intervention Type: DRUG

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

Intervention Type: RADIATION

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

Intervention Type: DRUG

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

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

Group Type: EXPERIMENTAL

low intensity radiation therapy

Intervention Type: RADIATION

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

Intervention Type: DRUG

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

Intervention Type: DRUG

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

nab-Paclitaxel

Intervention Type: DRUG

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

Chemotherapy

Gemcitabine and nab-paclitaxel until progression or unacceptable toxicity \[randomized to this arm after 3rd cycle and no progression\]

Group Type: ACTIVE_COMPARATOR

Gemcitabine

Intervention Type: DRUG

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

nab-Paclitaxel

Intervention Type: DRUG

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

Interventions

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

Intervention Type: RADIATION

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.

Intervention Type: DRUG

Gemcitabine

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

Intervention Type: DRUG

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

Intervention Type: RADIATION

nab-Paclitaxel

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

Intervention Type: DRUG

Other Intervention 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; Ro 09-1978/000; Xeloda; dFdCyd; Difluorodeoxycytidine Hydrochloride; GEMCITABINE HYDROCHLORIDE; Gemzar; LY-188011; IMRT; Intensity Modulated RT; intensity-modulated radiation therapy; Intensity-Modulated Radiotherapy; ABI 007; ABI-007; Abraxane; Albumin-bound Paclitaxel; Albumin-Stabilized Nanoparticle Paclitaxel; Nanoparticle Albumin-bound Paclitaxel; Nanoparticle Paclitaxel

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

NRG Oncology

OTHER

Sponsor Role: collaborator

Radiation Therapy Oncology Group

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Edgar Ben-Josef

Role: PRINCIPAL_INVESTIGATOR

NRG Oncology

Locations

Kaiser Permanente Oakland-Broadway

Oakland, California, United States

Kaiser Permanente Medical Center - Santa Clara

Santa Clara, California, United States

Kaiser Permanente Cancer Treatment Center

South San Francisco, California, United States

Emory University/Winship Cancer Institute

Atlanta, Georgia, United States

Saint Joseph Hospital

Chicago, Illinois, United States

Decatur Memorial Hospital

Decatur, Illinois, United States

OSF Saint Francis Medical Center Radiation Oncology Service at the Central Illinois Comprehensive CC

Peoria, Illinois, United States

OSF Saint Francis Medical Center

Peoria, Illinois, United States

Radiation Oncology Associates PC

Fort Wayne, Indiana, United States

Parkview Hospital Randallia

Fort Wayne, Indiana, United States

McFarland Clinic PC-William R Bliss Cancer Center

Ames, Iowa, United States

Iowa Methodist Medical Center

Des Moines, Iowa, United States

Ochsner Medical Center Jefferson

New Orleans, Louisiana, United States

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, United States

Boston Medical Center

Boston, Massachusetts, United States

Saint Joseph Mercy Hospital

Ann Arbor, Michigan, United States

Sanford Clinic North-Bemidgi

Bemidji, Minnesota, United States

Mayo Clinic

Rochester, Minnesota, United States

Rice Memorial Hospital

Willmar, Minnesota, United States

Mercy Hospital Springfield

Springfield, Missouri, United States

CoxHealth South Hospital

Springfield, Missouri, United States

Mercy Hospital Saint Louis

St Louis, Missouri, United States

Fox Chase Cancer Center at Virtua Memorial Hospital of Burlington County

Mount Holly, New Jersey, United States

Capital Health Medical Center-Hopewell

Pennington, New Jersey, United States

University of Rochester

Rochester, New York, United States

Sanford Bismarck Medical Center

Bismarck, North Dakota, United States

Roger Maris Cancer Center

Fargo, North Dakota, United States

Akron General Medical Center

Akron, Ohio, United States

Bryn Mawr Hospital

Bryn Mawr, Pennsylvania, United States

Paoli Memorial Hospital

Paoli, Pennsylvania, United States

University of Pennsylvania/Abramson Cancer Center

Philadelphia, Pennsylvania, United States

Reading Hospital

West Reading, Pennsylvania, United States

Lankenau Medical Center

Wynnewood, Pennsylvania, United States

Rhode Island Hospital

Providence, Rhode Island, United States

Sanford USD Medical Center - Sioux Falls

Sioux Falls, South Dakota, United States

Thompson Cancer Survival Center

Knoxville, Tennessee, United States

M D Anderson Cancer Center

Houston, Texas, United States

Intermountain Medical Center

Murray, Utah, United States

McKay-Dee Hospital Center

Ogden, Utah, United States

Huntsman Cancer Institute/University of Utah

Salt Lake City, Utah, United States

Central Vermont Medical Center/National Life Cancer Treatment

Berlin Corners, Vermont, United States

University of Vermont Medical Center

Burlington, Vermont, United States

Saint Vincent Hospital

Green Bay, Wisconsin, United States

Saint Mary's Hospital

Green Bay, Wisconsin, United States

Bay Area Medical Center

Marinette, Wisconsin, United States

Door County Cancer Center

Sturgeon Bay, Wisconsin, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 27701653 (View on PubMed)

Other Identifiers

NCI-2013-01280

Identifier Type: REGISTRY

Identifier Source: secondary_id

RTOG 1201

Identifier Type: OTHER

Identifier Source: secondary_id

RTOG-1201

Identifier Type: OTHER

Identifier Source: secondary_id

U10CA180868

Identifier Type: NIH

Identifier Source: secondary_id

View Link

U10CA021661

Identifier Type: NIH

Identifier Source: secondary_id

View Link

RTOG 1201

Identifier Type: -

Identifier Source: org_study_id