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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

NCT01013649

Description:

This randomized phase II-R/III trial studies 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 was removed by surgery. 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, by stopping them from dividing, or by stopping them from spreading. 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.

Related Conditions:
  • Pancreatic Adenocarcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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 II-R and a Phase III Trial Evaluating Both Erlotinib (Ph II-R) and Chemoradiation (Ph III) as Adjuvant Treatment for Patients With Resected Head of Pancreas Adenocarcinoma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2011-01987
  • SECONDARY ID: NCI-2011-01987
  • SECONDARY ID: RTOG 0848
  • SECONDARY ID: CDR0000659092
  • SECONDARY ID: RTOG-0848
  • SECONDARY ID: RTOG-0848
  • SECONDARY ID: U10CA180830
  • SECONDARY ID: U10CA180868
  • SECONDARY ID: U10CA021661
  • NCT ID: NCT01013649

Conditions

  • Pancreatic Acinar Cell Carcinoma
  • Pancreatic Ductal Adenocarcinoma
  • Pancreatic Intraductal Papillary-Mucinous Neoplasm
  • Stage IA Pancreatic Cancer AJCC v6 and v7
  • Stage IB Pancreatic Cancer AJCC v6 and v7
  • Stage IIA Pancreatic Cancer AJCC v6 and v7
  • Stage IIB Pancreatic Cancer AJCC v6 and v7

Interventions

DrugSynonymsArms
CapecitabineRo 09-1978/000, XelodaArm IV (chemotherapy, chemoradiotherapy)
ChemotherapyChemo, Chemotherapy (NOS), Chemotherapy, Cancer, GeneralArm I (gemcitabine hydrochloride or combination chemotherapy)
Erlotinib HydrochlorideCp-358,774, OSI-774, TarcevaArm II (gemcitabine hydrochloride, erlotinib hydrochloride)
Fluorouracil5-Fluoro-2,4(1H, 3H)-pyrimidinedione, 5-Fluorouracil, 5-Fluracil, 5-FU, AccuSite, Carac, Fluoro Uracil, Fluouracil, Flurablastin, Fluracedyl, Fluracil, Fluril, Fluroblastin, Ribofluor, Ro 2-9757, Ro-2-9757Arm IV (chemotherapy, chemoradiotherapy)
Gemcitabine HydrochloridedFdCyd, Difluorodeoxycytidine Hydrochloride, Gemzar, LY-188011, LY188011Arm I (gemcitabine hydrochloride or combination chemotherapy)

Purpose

This randomized phase II-R/III trial studies 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 was removed by surgery. 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, by stopping them from dividing, or by stopping them from spreading. 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.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine whether the addition of erlotinib (erlotinib hydrochloride) to gemcitabine
      (gemcitabine hydrochloride) adjuvant chemotherapy shows a signal for improved survival as
      compared to gemcitabine alone following R0 or R1 resection of head of pancreas adenocarcinoma
      (including adenocarcinoma of the head, neck, and uncinate process). (Phase II-R) II. To
      determine whether the use of concurrent fluoropyrimidine and radiotherapy following adjuvant
      gemcitabine based chemotherapy or non-gemcitabine based chemotherapy such as modified
      fluorouracil-leucovorin-irinotecan-oxaliplatin regimen (FOLFIRINOX) further enhances survival
      for such patients who are without evidence of progressive disease after 5 months of adjuvant
      chemotherapy. (Phase III)

      SECONDARY OBJECTIVES:

      I. To evaluate disease-free survival of adjuvant chemotherapy followed by radiotherapy and
      concurrent fluoropyrimidine for patients with resected head of pancreas adenocarcinoma who
      are disease free after 5 months of adjuvant chemotherapy.

      II. To evaluate disease-free survival of standard adjuvant gemcitabine chemotherapy with and
      without erlotinib for patients with resected head of pancreas adenocarcinoma.

      III. To evaluate adverse events with and without erlotinib for patients with resected head of
      pancreas adenocarcinoma.

      IV. To evaluate adverse events of adjuvant chemotherapy with or without radiation therapy and
      concurrent fluoropyrimidine for patients with resected head of pancreas adenocarcinoma who
      are disease free after adjuvant chemotherapy.

      V. To evaluate preoperative cross-sectional imaging of the primary head of pancreas
      adenocarcinoma in order to determine the frequency with which objective criteria of
      resectability are present.

      VI. To determine if patients reporting low baseline fatigue, as measured by the Functional
      Assessment of Chronic Illness Therapy (FACIT)-Fatigue, predicts survival and to explore
      correlations between baseline fatigue, as measured by Patient-Reported Outcomes Measurement
      Information System (PROMIS), and survival.

      OUTLINE: Patients without disease progression after treatment in arm I or II are randomized
      to 1 of 2 additional treatment arms (arm III or IV).

      ARM I: Patients receive either gemcitabine hydrochloride or allowable combination
      chemotherapy per standard of care for 5 months.

      ARM II (closed to accrual 4/2/14): Patients receive gemcitabine hydrochloride intravenously
      (IV) over 30 minutes on days 1, 8, and 15 and erlotinib hydrochloride orally (PO) once daily
      on days 1-28. Treatment repeats every 28 days for up to 5 courses in the absence of disease
      progression or unacceptable toxicity.

      ARM III: Patients receive the same treatment as in arm I for 1 month.

      ARM IV: Patients receive the same treatment as in arm I for 1 month. 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 5.5 weeks (28
      fractions). During radiotherapy, patients receive either capecitabine PO twice daily (BID) 5
      days per week or fluorouracil IV continuously for 5.5 weeks or until radiotherapy is
      completed.

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

Trial Arms

NameTypeDescriptionInterventions
Arm I (gemcitabine hydrochloride or combination chemotherapy)Active ComparatorPatients receive either gemcitabine hydrochloride or allowable combination chemotherapy per standard of care for 5 months.
  • Chemotherapy
  • Gemcitabine Hydrochloride
Arm II (gemcitabine hydrochloride, erlotinib hydrochloride)ExperimentalPatients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 and erlotinib hydrochloride PO once daily on days 1-28. Treatment repeats every 28 days for up to 5 courses in the absence of disease progression or unacceptable toxicity. (closed to accrual 4/2/14)
  • Erlotinib Hydrochloride
  • Gemcitabine Hydrochloride
Arm III (chemotherapy)ExperimentalPatients receive the same treatment as in arm I for 1 month.
  • Chemotherapy
  • Gemcitabine Hydrochloride
Arm IV (chemotherapy, chemoradiotherapy)ExperimentalPatients receive the same treatment as in arm I for 1 month. 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 5.5 weeks (28 fractions). During radiotherapy, patients receive either capecitabine PO BID 5 days per week or fluorouracil IV continuously for 5.5 weeks or until radiotherapy is completed.
  • Capecitabine
  • Chemotherapy
  • Fluorouracil
  • Gemcitabine Hydrochloride

Eligibility Criteria

        Inclusion Criteria:

          -  Histologic proof of primary head of pancreas invasive adenocarcinoma managed with a
             potentially curative resection (i.e., removal of all gross tumor) involving a classic
             pancreaticoduodenectomy (Whipple) or a pylorus preserving pancreaticoduodenectomy;
             patients with invasive adenocarcinoma that also contains a component of intraductal
             papillary mucinous neoplasm (IPMN) are eligible

               -  The operating surgeon must document in the operative note that a complete gross
                  excision of the primary tumor was achieved; the pathology report must include
                  documentation of the margin status and the size of the tumor; the pathology
                  report must also include the status of the three major margins—bile duct,
                  pancreatic parenchyma, and retroperitoneal (uncinate)

          -  For patients who have not started their chemotherapy prior to registration, the
             interval between definitive tumor-related surgery and 1st step registration must be
             between 21-70 days; for patients entering on the study who have already received up to
             3 months of adjuvant chemotherapy as per the treating institution, the interval
             between definitive tumor-related surgery and day one of adjuvant chemotherapy must be
             between 21-77 days

          -  Patients will be staged according to the 6th edition American Joint Committee on
             Cancer (AJCC) staging system with pathologic stage T1-3, N0-1, M-0 being eligible

          -  Zubrod performance status 0 or 1

          -  Complete history and physical examination including weight and Zubrod status within 31
             days of study entry (or within 31 days prior to day 1 of chemotherapy post-surgery for
             those patients having started chemotherapy prior to first step registration)

          -  Before starting therapy the patient should be able to maintain adequate oral nutrition
             of >= 1500 calories estimated caloric intake per day and be free of significant nausea
             and vomiting

          -  Complete blood count (CBC)/differential obtained within 21 days of registration on
             study (or within 21 days prior to day 1 of chemotherapy post-surgery for those
             patients having started chemotherapy prior to first step registration)

          -  Absolute neutrophil count (ANC) >= 1,500/mm^3

          -  Platelets >= 100,000/mm^3

          -  Hemoglobin (Hgb) >= 8.0 g/dL (transfusion or other intervention to achieve Hgb >= 8.0
             g/dl is acceptable)

          -  Post resection serum cancer antigen (CA)19-9 =< 180 units/mL AND prior to any systemic
             treatment

          -  Serum total bilirubin =< twice the institutional upper limit of normal (ULN) within 21
             days of registration on study (or within 21 days prior to day 1 of chemotherapy
             post-surgery for those patients having started chemotherapy prior to first step
             registration)

          -  Creatinine levels =< twice the institutional upper limit of normal within 21 days of
             registration on study (or within 21 days prior to day 1 of chemotherapy post-surgery
             for those patients having started chemotherapy prior to first step registration)

          -  Serum glutamic oxaloacetic transaminase (SGOT) must be =< 2.5 x institutional ULN
             within 21 days of registration on study (or within 21 days prior to day 1 of
             chemotherapy post-surgery for those patients having started chemotherapy prior to
             first step registration)

          -  Negative serum pregnancy test for women of childbearing potential within 14 days of
             study registration

          -  Abdominal/pelvic computed tomography (CT) scan with contrast is preferred; abdominal
             CT alone is acceptable only if insurance restrictions are experienced; chest CT/x-ray
             (CT of chest preferred) within 31 days of registration on study (or within 31 days
             prior to day 1 of chemo post-surgery for those patients having started chemotherapy
             prior to first step registration); patients allergic to intravenous (IV) contrast can
             have magnetic resonance imaging (MRI) of the abdomen/pelvis instead

          -  Signed study-specific informed consent

          -  Consultation, agreement, and documentation in the patient's chart by a radiation
             oncologist that patient is suitable to receive radiotherapy per this protocol

          -  Women of childbearing potential and male participants must practice adequate
             contraception

          -  Patients with active human immunodeficiency virus (HIV) infection are eligible if
             their cluster of differentiation (CD)4 count is > 499/cu mm and their viral load is <
             50 copies/ml; use of highly active antiretroviral treatment (HAART) is allowed

        Exclusion Criteria:

          -  Patients with non-adenocarcinomas, adenosquamous carcinomas, islet cell
             (neuroendocrine) tumors, cystadenomas, cystadenocarcinomas, carcinoid tumors, duodenal
             carcinomas, distal bile duct, and ampullary carcinomas; patients with tumors that are
             largely IPMN with a minimal or minor component of invasive carcinoma are not eligible;
             patients with acinar carcinomas are not eligible; patients with IPMN's that contain
             some secondary (minor) foci of adenocarcinoma are also not eligible

          -  Patients managed with a total pancreatectomy, a distal pancreatectomy, or central
             pancreatectomy

          -  Patients entering on the study after pancreaticoduodenectomy, who have not already
             started chemotherapy must not have had prior systemic chemotherapy for pancreas
             cancer; note that prior chemotherapy for a different cancer is allowable; for patients
             entering on the study who have already received up to 3 months of adjuvant
             chemotherapy as per the treating institution, patients must not have received adjuvant
             chemotherapy with agents other than gemcitabine, nab-paclitaxel, oxaliplatin,
             fluoropyrimidine, or irinotecan for the current pancreatic cancer; prior chemotherapy
             for a different cancer is allowable

          -  Prior radiotherapy to the region of the study cancer that would result in overlap of
             radiation therapy fields

          -  Previous history of invasive malignancy (except non-melanoma skin cancer) unless the
             patient has been disease free for at least 2 years prior to study entry (or first day
             of chemotherapy for patients having started chemotherapy prior to first step
             registration); patients with a previous history of carcinoma in situ are eligible

          -  Severe, active co-morbidity, defined as follows per time points indicated below (or
             per time points indicated below prior to the first day of chemotherapy for patients
             having started chemotherapy prior to first step registration):

               -  Unstable angina and/or congestive heart failure requiring hospitalization within
                  the last 6 months

               -  Transmural myocardial infarction within the 3 months of study registration

               -  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 at the time of registration

          -  Pregnant or lactating women

          -  Women of childbearing potential and men who are sexually active and not willing/able
             to use medically acceptable forms of contraception

          -  If surgical margin status cannot be determined after consultation with the operating
             surgeon and the institutional pathologist, the patient will be ineligible
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival (Phase II)
Time Frame:From the date of first randomization (gemcitabine vs. gemcitabine/erlotinib) to the date of death or last follow-up, assessed up to 11 years
Safety Issue:
Description:Overall survival will be estimated by the Kaplan-Meier method. The distribution of overall survival estimates between the two arms for both primary endpoint questions will be compared using the log rank test. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, that may be associated with overall survival.

Secondary Outcome Measures

Measure:Changes in fatigue as measured by the FACIT-F (primary) and the PROMIS derived short form (exploratory)
Time Frame:Baseline up to 24 months
Safety Issue:
Description:The primary HRQoL hypothesis will be tested using the log-rank statistic with a significance level of 0.05. Additionally, analyses of fatigue effect will be performed using the Cox proportional hazard model.
Measure:Disease-free survival
Time Frame:Up to 11 years
Safety Issue:
Description:Disease-free survival will be estimated by the Kaplan-Meier method.
Measure:Frequency of objective criteria of resectability as measured by preoperative imaging
Time Frame:Up to 11 years
Safety Issue:
Description:
Measure:Incidence of adverse events assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time Frame:Up to 11 years
Safety Issue:
Description:

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

October 17, 2017