Clinical Trials /

Neoadjuvant Chemotherapy Followed by Radiation Therapy and Gemcitabine/Sorafenib/Vorinostat in Pancreatic Cancer

NCT02349867

Description:

This is a phase 1 study of concurrent chemoradiation using a regimen of sorafenib and vorinostat with gemcitabine and radiation following chemotherapy in patients with pancreatic cancer to find the RP2D of the concurrent chemoradiation combination. A traditional 3+3 dose-escalation design will be conducted for the sorafenib and vorinostat dose escalation. Adenocarcinoma of the pancreas without distant metastasis that has been treated with ≥ 1 prior therapy (not including radiation) encompassing at least 2 months. Adequate hematologic, hepatic, and renal function. Ability to take oral medication. To determine the doses and schedule appropriate for phase 2 study of sorafenib and vorinostat with concurrent gemcitabine and radiation therapy (RT) as neoadjuvant treatment of pancreatic cancer following chemotherapy.

Related Conditions:
  • Pancreatic Adenocarcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Neoadjuvant Chemotherapy Followed by Radiation Therapy and Gemcitabine/Sorafenib/Vorinostat in Pancreatic Cancer
  • Official Title: A Phase 1 Study of Neoadjuvant Chemotherapy, Followed by Concurrent Chemoradiation With Gemcitabine, Sorafenib, and Vorinostat in Pancreatic Cancer

Clinical Trial IDs

  • ORG STUDY ID: MCC-12-07328
  • SECONDARY ID: NCI-2015-00017
  • SECONDARY ID: MCC-12-07328
  • SECONDARY ID: P30CA016059
  • NCT ID: NCT02349867

Conditions

  • Pancreatic Adenocarcinoma
  • Stage IA Pancreatic Cancer
  • Stage IB Pancreatic Cancer
  • Stage IIA Pancreatic Cancer
  • Stage IIB Pancreatic Cancer
  • Stage III Pancreatic Cancer
  • Recurrent Pancreatic Carcinoma

Interventions

DrugSynonymsArms
GemcitabinedFdC, dFdCydTreatment (chemotherapy, chemoradiation)
SorafenibBAY 54-9085, Nexavar, SFNTreatment (chemotherapy, chemoradiation)
VorinostatL-001079038, SAHA, Suberanilohydroxamic Acid, Suberoylanilide Hydroxamic AcidTreatment (chemotherapy, chemoradiation)

Purpose

This is a phase 1 study of concurrent chemoradiation using a regimen of sorafenib and vorinostat with gemcitabine and radiation following chemotherapy in patients with pancreatic cancer to find the RP2D of the concurrent chemoradiation combination. A traditional 3+3 dose-escalation design will be conducted for the sorafenib and vorinostat dose escalation. Adenocarcinoma of the pancreas without distant metastasis that has been treated with ≥ 1 prior therapy (not including radiation) encompassing at least 2 months. Adequate hematologic, hepatic, and renal function. Ability to take oral medication. To determine the doses and schedule appropriate for phase 2 study of sorafenib and vorinostat with concurrent gemcitabine and radiation therapy (RT) as neoadjuvant treatment of pancreatic cancer following chemotherapy.

Detailed Description

      To determine the doses and schedule appropriate for phase 2 study of sorafenib and vorinostat
      with concurrent gemcitabine and radiation therapy (RT) as neoadjuvant treatment of pancreatic
      cancer following chemotherapy. RP2Ds and schedule of sorafenib and vorinostat defined as the
      doses and schedule that are the same as or less than the MTDs and schedule.

      This is a dose-escalation trial employing a standard "3+3" schema of sorafenib and
      vorinostat.

      The sample size with a total of 5 proposed dose levels and starting at dose level 1B for dose
      escalation, the number of patients evaluable for DLT ranges from 4-30. To account for about
      20% patients anticipated to subsequently be found to be not evaluable for toxicity,
      authorization for enrollment of 36 patients will be sought from regulatory authorities.
      Likely scenarios probably involve 12-24 evaluable patients and therefore 15-30 patients will
      be enrolled in the study.

      After completion of study treatment, patients are followed up for 30 days and then every 2-3
      months up to 2 years or until death.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (chemotherapy, chemoradiation)ExperimentalPatients must receive neoadjuvant chemotherapy (multiple regimens are acceptable) prior to enrollment onto this clinical trial. Chemoradiation study treatment should start within 6 weeks of completing chemotherapy. Patients receive gemcitabine IV infusion over 30 minutes (200 mg/m2 weekly) x 6, concurrent administration of oral sorafenib and oral vorinostat (both per dose-escalation schema), and concurrent RT( 3-Dimensional Conformal Radiation Therapy or Intensity-Modulated Radiation Therapy) administered at 1.8-Gy fractions to a total dose of 50.4 Gy over 5 ½ weeks (28 daily fractions). Correlative studies will be performed by collecting peripheral blood samples at several time-points for circulating tumor cells (CTC) enumeration and to evaluate CD95 density. Samples will be analyzed by negative-selection techniques (RosetteSep) or with ApoStream dielectrophoretic field-flow fractionation (DEPfff) enrichment device.
  • Gemcitabine
  • Sorafenib
  • Vorinostat

Eligibility Criteria

        Inclusion Criteria:

          -  Adenocarcinoma of the pancreas

          -  Prior therapy with ≥ 1 prior systemic therapy over a period of at least 2 months (eg,
             at least two 4-week cycles of a regimen such as gemcitabine and nab-paclitaxel; or at
             least four 2-week cycles of a regimen such as FOLFOX, FOLFIRINOX, or FOLFIRI)
             -Candidate for additional therapy consisting of radiation with gemcitabine-
             radiosensitization.

          -  Able to initiate study treatment no later than 6 weeks from last dose of any
             antineoplastic component of prior therapy regimen.

          -  Recovery from ≥ grade 2 toxicities of prior therapy regimen to grade 1 or baseline,
             with the exception of anemia and lymphopenia and chronic residual toxicities that in
             the opinion of the investigator are not clinically relevant given the known
             safety/toxicity profiles of gemicitabine, sorafenib, and vorinostat (eg, alopecia,
             changes in pigmentation, stable endocrinopathies). Patients with ≤ grade 2 peripheral
             sensory or motor neuropathy are eligible..

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x upper limit
             of normal (ULN) for the laboratory

          -  Total bilirubin =< 1.5 x ULN for the laboratory at the time of enrollment, all forms
             of biliary stents allowed

          -  Creatinine clearance >= 45 mL/min as calculated by the standard Cockcroft-Gault
             equation using age, actual weight, creatinine and gender

          -  International normalized ratio (INR) =< 1.5

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

          -  Platelets >= 100,000/mm^3 (may not be transfused to meet this level for enrollment)

          -  Measurable or evaluable disease by Response Evaluation Criteria in Solid Tumors
             (RECIST) (version [v]1.1

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Women of childbearing potential must have a negative serum pregnancy test performed
             within 7 days prior to the start of treatment

          -  Women of childbearing potential and men must agree to use a medically accepted form of
             birth control during the treatment and for 2 months following completion of study
             treatment

        Exclusion Criteria:

          -  Prior radiotherapy for pancreatic cancer

          -  Prior surgical resection of pancreatic cancer

          -  Evidence of metastatic disease

          -  Any investigational agent within 4 weeks of study treatment initiation

          -  Diagnosis or treatment for another malignancy within 3 years of enrollment, with the
             exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
             the skin, any in situ malignancy, or low-risk prostate cancer after curative therapy

          -  Intolerance of protocol agents as follows:

               -  Known or presumed intolerance of gemcitabine, vorinostat or sorafenib

               -  Experienced any of the following toxicities with prior gemcitabine adminstration
                  (if given): capillary leak syndrome, posterior reversible encephalopathy,
                  hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, unexplained
                  dyspnea or other evidence of severe pulmonary toxicity, or severe hepatic
                  toxicity

          -  Unable to swallow medication

          -  Suspected malabsorption or obstruction; note: use of pancreatic enzyme supplements is
             allowed to control malabsorption

          -  Contraindication to antiangiogenic agents, including:

               -  Bronchopulmonary hemorrhage/bleeding event >= grade 2 (Common Terminology
                  Criteria for Adverse Events [CTCAE] v4.0) within 12 weeks prior to of treatment

               -  Any other hemorrhage/bleeding event >= grade 3 (CTCAE v4.0) within 12 weeks prior
                  to initiation of treatment

               -  Serious non-healing wound, ulcer, or bone fracture

          -  Arterial thrombotic or embolic events such as a myocardial infarction or
             cerebrovascular accident (including transient ischemic attacks) within the 6 months
             prior to initiation of treatment. Incidental clinically insignificant embolic
             phenomena that do not require anti-coagulants are not excluded. Also,tumor-associated
             thrombus of locally-involved vessels does not count as an exclusion criterion.

          -  Clinically significant cardiac disease, including major cardiac dysfunction, such as
             uncontrolled angina, clinical congestive heart failure with New York Heart Association
             (NYHA) class III or IV, ventricular arrhythmias requiring anti-arrhythmic therapy,
             recent (within 6 months) myocardial infarction or unstable coronary artery disease

          -  Concomitant use of other histone deacetylase (HDAC) inhibitors

          -  Planned ongoing administration of STRONG cytochrome P450, family 3, subfamily A,
             polypeptide 4 (CYP3A4) inducers. Examples of clinical inducers and classifications of
             strong, moderate, and weak interactions are available through the FDA website (Table
             3-3 of website):
             http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteracti
             onsLabeling/ucm093664.htm

          -  Persistent heart rate (HR) < 50 or > 120 beats per minute (bpm).

          -  QT(c) ≥ 481 ms (>= grade 2) on electrocardiogram (ECG) prior to initiation of
             treatment

               -  If baseline QTc on screening ECG meets exclusion criteria:

                    -  Check potassium and magnesium serum levels

                    -  Correct any identified hypokalemia and/or hypomagnesemia and repeat ECG to
                       confirm exclusion of patient due to QTc

               -  For patients with HR 60-100 beats per minute (bpm), no manual read of QTc is
                  required

               -  For patients with baseline HR < 60 or > 100 bpm, manual read of QT by
                  cardiologist is required, with Fridericia correction applied to determine QTc

          -  Planned ongoing treatment with other drugs thought to potentially adversely interact
             with study drugs; if such medications have been used, patients must be off of these
             agents for >= 2 weeks prior to initiation of treatment:

               -  Anticoagulants at therapeutic doses

               -  Immunosuppressants such as tacrolimus, leflunomide or tofacitinib, roflumilast,
                  pimecrolimus

          -  Serious uncontrolled infection > grade 2 (CTCAE v4.0)

          -  Medical, psychological, or social conditions that, in the opinion of the investigator,
             may increase the patient's risk or interfere with the patient's participation in the
             study or hinder evaluation of the study results
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase 2 dose and schedule
Time Frame:18-36 months
Safety Issue:
Description:To determine the doses and schedule appropriate for phase 2 study of sorafenib and vorinostat with concurrent gemcitabine and radiation therapy (RT) as neoadjuvant treatment of pancreatic cancer following chemotherapy.

Secondary Outcome Measures

Measure:Incidence of adverse events using National Cancer Institute CTCAE v4.0
Time Frame:Up to 30 days following last administration of the chemoradiation treatment
Safety Issue:
Description:Adverse events using NCI Common Terminology Criteria for Adverse Events, Version 4.0. Adverse events will be listed and summary descriptive statistics will be calculated.
Measure:Surgical mortality for patients who received chemoradiation
Time Frame:90 day post-surgical mortality
Safety Issue:
Description:
Measure:Tumor response (complete response or partial response) measured using RECIST version 1.1
Time Frame:Up to 2 years
Safety Issue:
Description:Will be summarized using descriptive statistics for each cohort, along with their corresponding 95% confidence intervals. Logistic regression may be used to model the rates by adjusting potential clinical characteristics (such as age, gender, and tumor grade). Tumor response measured using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. At the completion of concurrent chemoradiation.
Measure:Percentage of patients able to undergo resection after neoadjuvant therapy (chemotherapy followed by concurrent chemoradiation)
Time Frame:Up to 2 years
Safety Issue:
Description:Will be summarized using descriptive statistics for each cohort, along with their corresponding 95% confidence intervals. Logistic regression may be used to model the rates by adjusting potential clinical characteristics (such as age, gender, and tumor grade).
Measure:R0 resection rate defined as the percentage of patients able to undergo margin-negative resection following neoadjuvant therapy
Time Frame:Up to 2 years
Safety Issue:
Description:Will be summarized using descriptive statistics for each cohort, along with their corresponding 95% confidence intervals. Logistic regression may be used to model the rates by adjusting potential clinical characteristics (such as age, gender, and tumor grade).
Measure:Progression-free survival PFS evaluated using RECIST v1.1
Time Frame:Time from the first day a patient receives study treatment until objective tumor progression or death, whichever occurs first, assessed up to 2 years
Safety Issue:
Description:The Kaplan-Meier method will be used to describe PFS time; median PFS time will be estimated, along with 95% confidence interval. A Cox regression model may be used to model PFS time, adjusting for any effects of potential clinical characteristics.
Measure:Overall Survival
Time Frame:Time from the first day a patient receives study treatment until death by any cause, assessed up to 2 years
Safety Issue:
Description:The Kaplan-Meier method will be used to describe OS time; median OS time will be estimated, along with 95% confidence interval. A Cox regression model may be used to model OS time, adjusting for any effects of potential clinical characteristics.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Virginia Commonwealth University

Last Updated