Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02349867
Recruitment Status : Active, not recruiting
First Posted : January 29, 2015
Last Update Posted : October 22, 2021
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Virginia Commonwealth University

Brief Summary:
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. Recommended phase II dose RP2Ds and schedule of sorafenib and vorinostat defined as the doses and schedule that are the same as or less than the maximum tolerated dose (MTD) and schedule.

Condition or disease Intervention/treatment Phase
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 Drug: Gemcitabine Drug: Sorafenib Drug: Vorinostat Radiation: 3-Dimensional Conformal Radiation Therapy Radiation: Intensity-Modulated Radiation Therapy Other: RosetteSep Other: DEPfff Phase 1

Detailed 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 recommended phase II dose (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.This is a dose-escalation trial employing a standard "3+3" schema of sorafenib and vorinostat.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 23 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Study of Neoadjuvant Chemotherapy, Followed by Concurrent Chemoradiation With Gemcitabine, Sorafenib, and Vorinostat in Pancreatic Cancer
Actual Study Start Date : January 29, 2015
Actual Primary Completion Date : May 13, 2020
Estimated Study Completion Date : September 30, 2024


Arm Intervention/treatment
Experimental: Treatment (chemotherapy, chemoradiation)
Participants 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).
Drug: Gemcitabine
Given IV
Other Names:
  • dFdC
  • dFdCyd

Drug: Sorafenib
Given PO
Other Names:
  • BAY 54-9085
  • Nexavar
  • SFN

Drug: Vorinostat
Given PO
Other Names:
  • L-001079038
  • SAHA
  • Suberanilohydroxamic Acid
  • Suberoylanilide Hydroxamic Acid

Radiation: 3-Dimensional Conformal Radiation Therapy
Undergo 3D CRT
Other Names:
  • 3D-CRT
  • Conformal Therapy
  • Radiation Conformal Therapy

Radiation: Intensity-Modulated Radiation Therapy
Undergo IMRT
Other Names:
  • IMRT
  • Intensity Modulated RT
  • Intensity-Modulated Radiotherapy

Other: RosetteSep
Circulating tumor cells (CTCs) will be captured and analyzed, when detected. Pancreatic cancer has been a difficult tumor in which to detect CTCs (41). Utilization of techniques that do not require cell surface marker expression will be explored. Samples will either be analyzed by negative-selection techniques (RosetteSep). Peripheral blood samples will be collected at several time-points for CTC enumeration and to evaluate CD95 density.
Other Name: negative-selection techniques

Other: DEPfff
Circulating tumor cells (CTCs) will be captured and analyzed, when detected. Pancreatic cancer has been a difficult tumor in which to detect CTCs (41). Utilization of techniques that do not require cell surface marker expression will be explored. Samples will either be analyzed by with the ApoStream dielectrophoretic field-flow fractionation (DEPfff) enrichment device. Peripheral blood samples will be collected at several time-points for CTC enumeration and to evaluate CD95 density.
Other Name: ApoStream dielectrophoretic field-flow fractionation




Primary Outcome Measures :
  1. Recommended phase 2 dose and schedule [ Time Frame: 18-36 months ]
    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 :
  1. Number of participants with adverse events using National Cancer Institute CTCAE v4.0 [ Time Frame: Up to 30 days following last administration of the chemoradiation treatment ]
    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.

  2. Tumor response (complete response or partial response) measured using RECIST version 1.1 [ Time Frame: Up to 2 years ]
    Evaluate number of participants with tumor response measured using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. At the completion of concurrent chemoradiation. Tumor response will be measured as complete response, partial response, stable disease, or tumor progression.

  3. Surgery [ Time Frame: Up to 2 years ]
    Number of participants able to undergo resection after neoadjuvant therapy (chemotherapy followed by concurrent chemoradiation)

  4. R0 Resection rate [ Time Frame: Up to 2 years ]
    Determine the number of patients able to undergo margin-negative resection following neoadjuvant therapy.

  5. Progression-free survival (PFS) [ Time Frame: Up to 2 Years ]
    Number of participants with progression free survival (PFS) defined as the percentage of patients able to undergo margin-negative resection following neoadjuvant therapy

  6. Overall Survival [ Time Frame: Up to 2 Years ]
    The number of participants with overall survival (OS) defined as the time from the date of diagnosis until death by any cause



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 9 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/DrugInteractionsLabeling/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 of >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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02349867


Locations
Layout table for location information
United States, Virginia
Virginia Commonwealth University/Massey Cancer Center
Richmond, Virginia, United States, 23298
Sponsors and Collaborators
Virginia Commonwealth University
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: Andrew Poklepovic, MD Massey Cancer Center
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Virginia Commonwealth University
ClinicalTrials.gov Identifier: NCT02349867    
Other Study ID Numbers: MCC-12-07328
NCI-2015-00017 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
MCC-12-07328 ( Other Identifier: Virginia Commonwealth University/Massey Cancer Center )
P30CA016059 ( U.S. NIH Grant/Contract )
First Posted: January 29, 2015    Key Record Dates
Last Update Posted: October 22, 2021
Last Verified: October 2021

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Pancreatic Neoplasms
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Gemcitabine
Sorafenib
Vorinostat
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Protein Kinase Inhibitors
Histone Deacetylase Inhibitors