Gemcitabine Hydrochloride With or Without Erlotinib Hydrochloride Followed By the Same Chemotherapy Regimen With or Without Radiation Therapy and Capecitabine or Fluorouracil in Treating Patients With Pancreatic Cancer That Has Been Removed By Surgery

Official Title: “A Phase III Trial Evaluating Both Erlotinib and Chemoradiation as Adjuvant Treatment for Patients With Resected Head of Pancreas Adenocarcinoma”

RATIONALE: Drugs used in chemotherapy, such as gemcitabine hydrochloride, capecitabine, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells. Giving chemotherapy together with or without erlotinib hydrochloride and/or radiation therapy after surgery may kill any tumor cells that remain after surgery. It is not yet known whether chemotherapy is more effective when given with or without erlotinib hydrochloride and/or radiation therapy in treating pancreatic cancer.

PURPOSE: This randomized phase III trial is studying gemcitabine hydrochloride and erlotinib hydrochloride to see how well they work compared with gemcitabine hydrochloride alone followed by the same chemotherapy regimen with or without radiation therapy and capecitabine or fluorouracil in treating patients with pancreatic cancer that was removed by surgery.

OBJECTIVES:

Primary - To determine whether the addition of erlotinib hydrochloride to adjuvant chemotherapy comprising gemcitabine hydrochloride improves survival as compared to gemcitabine hydrochloride alone following R0 or R1 resection in patients with pancreatic adenocarcinoma. - To determine whether the use of concurrent fluoropyrimidine and radiotherapy following adjuvant gemcitabine hydrochloride-based chemotherapy further enhances survival of patients who have no evidence of progressive disease after 5 courses of gemcitabine hydrochloride-based chemotherapy.

Secondary - To evaluate the disease-free survival of patients who are disease-free after 5 courses of adjuvant gemcitabine hydrochloride-based chemotherapy followed by fluoropyrimidine-based chemoradiotherapy. - To evaluate the disease-free survival of patients treated with adjuvant gemcitabine hydrochloride-based chemotherapy with vs without erlotinib hydrochloride. - To evaluate the disease-free and overall survival of patients stratified by wild-type and K-Ras status treated with adjuvant gemcitabine hydrochloride-based chemotherapy with vs without erlotinib hydrochloride. - To evaluate adverse events associated with adjuvant gemcitabine hydrochloride-based chemotherapy with vs without erlotinib hydrochloride in these patients. - To evaluate adverse events associated with adjuvant gemcitabine hydrochloride-based chemotherapy with vs without fluoropyrimidine-based chemoradiotherapy in patients who are disease-free after adjuvant gemcitabine hydrochloride-based chemotherapy. - To evaluate preoperative cross-sectional imaging of primary adenocarcinoma of the head of the pancreas in order to determine the frequency with which objective criteria of resectability are present. - To determine the predictive roles of K-Ras mutations and epithelial to mesenchymal transition phenotype in response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibition in early-stage pancreatic cancer. - To determine the frequency of EGFR-activated pathway and its influence on outcome. - To determine the association between developmental molecular markers and outcome. - To determine the phenotype and genotype of tumors in patients with recurrence after resection. - To determine if low baseline fatigue, as measured by the FACIT-Fatigue, predicts survival. - To explore correlations between baseline fatigue, as measured by PROMIS, and survival.

OUTLINE: This is a multicenter study. Patients are stratified according to nodal status (involved vs uninvolved), CA19-9 result (≤ 90 IU/L vs 91-180 IU/L), and surgical margins (positive [R1] vs negative [R0]). Patients are randomized to 1 of 2 treatment arms. - Arm I: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Treatment repeats every 28 days for 5 courses in the absence of disease progression or unacceptable toxicity. - Arm II: Patients receive gemcitabine hydrochloride as in arm I and oral erlotinib hydrochloride once daily on days 1-28. Treatment repeats every 28 days for 5 courses in the absence of disease progression or unacceptable toxicity.

Patients with no disease progression after treatment in arm I or II are then stratified according to their first randomization treatment arm (arm I vs arm II) and randomized to 1 of 2 additional treatment arms (arm III or IV). - Arm III: Patients receive 1 course of the same treatment that they receive in arm I or II. - Arm IV: Patients receive 1 course of the same treatment that they receive in arm I or II. Beginning within 7-21 days after completion of chemotherapy, patients undergo radiotherapy (3-dimensional conformal radiotherapy or intensity-modulated radiotherapy) 5 days per week for 5½ weeks (28 fractions). During radiotherapy, patients receive either oral capecitabine twice daily 5 days per week or fluorouracil IV continuously for 5½ weeks or until radiotherapy is completed.

Patients complete a quality-of-life questionnaires (FACIT-Fatigue and PROMIS) at baseline, after completion of treatment in arm I or II, and at 9, 12, and 24 months.

Tumor tissue and peripheral blood samples are collected for biomarker and other correlative laboratory studies. Urine samples may also be collected and studied in the laboratory.

After completion of study treatment, patients are followed up periodically.

Intervention(s) in this Clinical Trial

• Drug: capecitabine
  • Given orally
• Drug: erlotinib hydrochloride
  • Given orally
• Drug: fluorouracil
  • Given IV
• Drug: gemcitabine hydrochloride
  • Given IV
• Radiation: 3-dimensional conformal radiation therapy
  • Given for 5½ weeks (28 fractions)
• Radiation: intensity-modulated radiation therapy
  • Given for 5½ weeks (28 fractions)

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: Arm I
  • Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Treatment repeats every 28 days for 5 courses in the absence of disease progression or unacceptable toxicity.
• Experimental: Arm II
  • Patients receive gemcitabine hydrochloride as in arm I and oral erlotinib hydrochloride once daily on days 1-28. Treatment repeats every 28 days for 5 courses in the absence of disease progression or unacceptable toxicity.
• Experimental: Arm III
  • Patients receive 1 course of the same treatment that they receive in arm I or II.
• Experimental: Arm IV
  • Patients receive 1 course of the same treatment that they receive in arm I or II. Beginning within 7-21 days after completion of chemotherapy, patients undergo radiotherapy (3-dimensional conformal radiotherapy or intensity-modulated radiotherapy) 5 days per week for 5½ weeks (28 fractions). During radiotherapy, patients receive either oral capecitabine twice daily 5 days per week or fluorouracil IV continuously for 5½ weeks or until radiotherapy is completed.

Primary Measures

• Overall survival of patients treated with gemcitabine hydrochloride with vs without erlotinib hydrochloride (first randomization)
  • Safety Issue?: No
• Overall survival of patients treated with chemotherapy with vs without radiotherapy (second randomization)
  • Safety Issue?: No

Secondary Measures

• Disease-free survival
  • Safety Issue?: No
• Adverse events
  • Safety Issue?: Yes
• Frequency of objective criteria of resectability as measured by preoperative imaging
  • Safety Issue?: No
• Quality of life as measured by fatigue (FACIT-Fatigue and PROMIS-derived short form)
  • Safety Issue?: No
• Laboratory correlative studies related to K-Ras in patients treated with gemcitabine hydrochloride with vs without erlotinib hydrochloride (first randomization)
  • Safety Issue?: No

DISEASE CHARACTERISTICS:

• Histologically confirmed primary adenocarcinoma of the pancreatic head, neck, or uncinate process
• Intraductal papillary mucinous neoplasm or invasive adenocarcinoma allowed
• No non-adenocarcinoma, adenosquamous carcinoma, islet cell (neuroendocrine) tumor, cystadenoma, cystadenocarcinoma, carcinoid tumor, duodenal carcinoma, distal bile duct tumor, or ampullary carcinoma
• Pathologic stage T1-3, N0-1, M0 disease according to AJCC 6th edition
• Has undergone a potentially curative resection (i.e., removal of all gross tumor) involving a classic (Whipple) or a pylorus preserving pancreaticoduodenectomy within the past 21-56 days
• Operative report must contain a statement from the surgeon explicitly detailing that a total gross excision of the primary tumor was achieved
• Pathology report must include documentation of margin status, size of the tumor, and status of the 3 major surgical margins (bile duct, pancreatic parenchyma, and retroperitoneal [uncinate])
• Post-resection serum CA19-9 ≤ 180 IU/L
• Tumor tissue block and peripheral blood samples must be submitted to the study's central tumor bank for correlative studies
• No recurrent pancreatic cancer

PATIENT CHARACTERISTICS:

• Zubrod performance status 0-1
• ANC ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 8.0 g/dL (transfusion or other intervention allowed)
• Serum total bilirubin ≤ 2 times upper limit of normal (ULN)
• Creatinine ≤ 2 times ULN
• SGOT ≤ 2.5 times ULN
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Suitable to receive study radiotherapy, as documented by a radiation oncologist
• Active HIV infection allowed provided the CD4 count is ≥ 499/mm^3 and the viral load is ≤ 50 copies/mL
• Total oral caloric intake ≥ 1,500 calories/day
• No significant nausea and vomiting
• None of the following severe active comorbidities that would preclude study therapy:
• Unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months
• Transmural myocardial infarction within the past 3 months
• Acute bacterial or fungal infection requiring IV antibiotics
• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy
• No other invasive malignancies within the past 2 years except for nonmelanomatous skin cancer or carcinoma in situ

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior systemic chemotherapy for pancreatic cancer
• Prior chemotherapy for a different cancer allowed
• No prior total pancreatectomy, distal pancreatectomy, or central pancreatectomy
• No prior radiotherapy to the region of the study cancer that would result in overlap of radiotherapy fields
• Concurrent highly active antiretroviral treatment (HAART) allowed

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Radiation Therapy Oncology Group Other

Overall Clinical Trial Officials and Contacts

Ross A. Abrams, MD Study Chair Rush University Medical Center  

Information obtained from ClinicalTrials.gov on February 09, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT01013649

Study ID Number: CDR0000659092

ClinicalTrials.gov Identifier: NCT01013649

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database