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Trial record 48 of 200 for:    Oral Cancer | Recruiting Studies | NIH

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

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ClinicalTrials.gov Identifier: NCT02349867
Recruitment Status : Recruiting
First Posted : January 29, 2015
Last Update Posted : December 2, 2017
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Virginia Commonwealth University

Brief Summary:
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.

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:

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
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
Estimated Primary Completion Date : May 1, 2019
Estimated Study Completion Date : May 1, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment (chemotherapy, chemoradiation)
Patients 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.
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 ]
    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 :
  1. Incidence of 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. Surgical mortality for patients who received chemoradiation [ Time Frame: 90 day post-surgical mortality ]
  3. Tumor response (complete response or partial response) measured using RECIST version 1.1 [ Time Frame: Up to 2 years ]
    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.

  4. Percentage of patients able to undergo resection after neoadjuvant therapy (chemotherapy followed by concurrent chemoradiation) [ Time Frame: Up to 2 years ]
    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).

  5. R0 resection rate defined as the percentage of patients able to undergo margin-negative resection following neoadjuvant therapy [ Time Frame: Up to 2 years ]
    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).

  6. 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 ]
    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.

  7. Overall Survival [ Time Frame: Time from the first day a patient receives study treatment until death by any cause, assessed up to 2 years ]
    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.



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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 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/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 60-100 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


Contacts
Contact: Andrew Poklepovic, MD 804-628-2321 andrew.poklepovic@vcuhealth.org
Contact: Karly Rogers, RN 804-827-1025 masseysiit@vcu.edu

Locations
United States, Virginia
Virginia Commonwealth University/Massey Cancer Center Recruiting
Richmond, Virginia, United States, 23298
Contact: Andrew Poklepovic, MD    804-628-2321    andrew.poklepovic@vcuhealth.org   
Contact: Karly Rogers, RN    804-827-1025    masseysiit@vcu.edu   
Principal Investigator: Andrew Poklepovic, MD         
Sponsors and Collaborators
Virginia Commonwealth University
National Cancer Institute (NCI)
Investigators
Principal Investigator: Andrew Poklepovic, MD Massey Cancer Center

Responsible Party: Virginia Commonwealth University
ClinicalTrials.gov Identifier: NCT02349867     History of Changes
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: December 2, 2017
Last Verified: November 2017

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:
Pancreatic Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Adenocarcinoma
Carcinoma
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Gemcitabine
Sorafenib
Vorinostat
Niacinamide
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
Vitamin B Complex
Vitamins
Micronutrients