Vorinostat, Cisplatin, and Radiation Therapy in Treating Patients With Stage III or Stage IV Squamous Cell Cancer of the Oropharynx - Full Text View

Sponsor:	Ohio State University Comprehensive Cancer Center
Collaborator:	National Comprehensive Cancer Network
Information provided by (Responsible Party):	Ohio State University Comprehensive Cancer Center
ClinicalTrials.gov Identifier:	NCT01064921

Purpose

RATIONALE: Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays and other types of radiation to kill tumor cells. Giving vorinostat together with chemotherapy and radiation therapy may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of vorinostat when given together with cisplatin and radiation therapy in treating patients with stage III or stage IVa squamous cell cancer of the oropharynx which is either unresectable or borderline resectable.

Condition	Intervention	Phase
Stage III Squamous Cell Carcinoma of the Oropharynx Stage IV Squamous Cell Carcinoma of the Oropharynx	Drug: vorinostat Drug: cisplatin Radiation: radiation therapy Other: laboratory biomarker analysis Genetic: protein expression analysis Procedure: biopsy Genetic: polymerase chain reaction Genetic: DNA methylation analysis Other: immunohistochemistry staining method Other: immunoenzyme technique Other: fluorescence activated cell sorting Other: flow cytometry	Phase 1

Study Type:	Interventional
Study Design:	Endpoint Classification: Safety Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Phase I Trial of Vorinostat in the Treatment of Advanced Oropharyngeal Carcinoma of the Head and Neck

Resource links provided by NLM:

MedlinePlus related topics: Cancer

Drug Information available for: Cisplatin Vorinostat

U.S. FDA Resources

Further study details as provided by Ohio State University Comprehensive Cancer Center:

Primary Outcome Measures:

Maximum tolerated dose of vorinostat in combination with concurrent chemoradiation therapy [ Time Frame: Weekly during treatment; Every 2 weeks for the first month after treatment completion; Then every 4 weeks until day 153 ] [ Designated as safety issue: Yes ]
The toxic effects of the combination of vorinostat and cisplatin using NCI CTCAE v. 4.0 [ Time Frame: Weekly during treatment; Every 2 weeks for the first month after treatment completion; Then every 4 weeks until day 153 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Tumor responses to vorinostat or vorinostat combined with chemoradiation. [ Time Frame: Days 35, 56 then after Day 153 every 12 weeks for 24 months ] [ Designated as safety issue: No ]
Complete response rate [ Time Frame: Days 35, 56 then after Day 153 every 12 weeks for 24 months ] [ Designated as safety issue: No ]
Overall survival [ Time Frame: Days 35, 56 then after Day 153 every 12 weeks for 24 months ] [ Designated as safety issue: No ]
Progression free survival [ Time Frame: Days 35, 56 then after Day 153 every 12 weeks for 24 months ] [ Designated as safety issue: No ]
Relationship between Vorinostat therapy and tumor suppressor genes product assessed by Fas and FasL protein expression level in tumor and the normal mucosa [ Time Frame: Before, post SAHA treatment, and post the concurrent chemoradiation /SAHA therapy ] [ Designated as safety issue: No ]
HPV-specific T-cell in patients with HPV+ tumors [ Time Frame: After the run in period of vorinostat but before the start of RT; Day 35; 2 weeks after the completion of RT; Day 153 ] [ Designated as safety issue: No ]

Estimated Enrollment:	38
Study Start Date:	February 2010
Estimated Primary Completion Date:	January 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Arm I Patients receive oral vorinostat on days 0-2 and cisplatin IV on days 7, 21 and 35. Patients undergo radiotherapy 5 days a week beginning on day 7. Patients also receive concurrent oral vorinostat along with the radiotherapy to be given 3 days per week (Monday, Tuesday, and Wednesday).	Drug: vorinostat The first vorinostat dose level is 100mg, and the second dose will be 200mg, third dose will be 300mg. If the first vorinostat dose level is found to be excessively toxic, the patient will be reduced to -1 dosing level then if still too toxic reduced again to dose level -2. Dose escalation of vorinostat will continue in increments of 100 mg (i.e., 200 mg on dosing days, 300 mg on dosing days). Vorinostat will be given 3 consecutive days per week (e.g. Monday, Tuesday, Wednesday). Other Names: L-001079038 SAHA suberoylanilide hydroxamic acid Zolinza Drug: cisplatin Given IV Other Names: CACP CDDP CPDD DDP Neoplatin PDD Radiation: radiation therapy Standard chemoradiation therapy X 7 weeks (Days 7-56), concurrent with oral Vorinostat given three days per week (Mon, Tues, Wed) Other Names: irradiation radiotherapy therapy, radiation Other: laboratory biomarker analysis Correlative study Genetic: protein expression analysis Correlative study Procedure: biopsy Correlative study Other Name: biopsies Genetic: polymerase chain reaction Correlative study Other Name: PCR Genetic: DNA methylation analysis Correlative study Other: immunohistochemistry staining method Correlative study Other Name: immunohistochemistry Other: immunoenzyme technique Correlative study Other Name: immunoenzyme techniques Other: fluorescence activated cell sorting Correlative study Other Names: FACS Fractionation, Fluorescence Activated Cell Sorting Other: flow cytometry Correlative study

Arms

Assigned Interventions

Experimental: Arm I

Patients receive oral vorinostat on days 0-2 and cisplatin IV on days 7, 21 and 35. Patients undergo radiotherapy 5 days a week beginning on day 7. Patients also receive concurrent oral vorinostat along with the radiotherapy to be given 3 days per week (Monday, Tuesday, and Wednesday).

Drug: vorinostat

The first vorinostat dose level is 100mg, and the second dose will be 200mg, third dose will be 300mg. If the first vorinostat dose level is found to be excessively toxic, the patient will be reduced to -1 dosing level then if still too toxic reduced again to dose level -2. Dose escalation of vorinostat will continue in increments of 100 mg (i.e., 200 mg on dosing days, 300 mg on dosing days). Vorinostat will be given 3 consecutive days per week (e.g. Monday, Tuesday, Wednesday).

Other Names:

L-001079038
SAHA
suberoylanilide hydroxamic acid
Zolinza

Drug: cisplatin

Given IV

Other Names:

CACP
CDDP
CPDD
DDP
Neoplatin
PDD

Radiation: radiation therapy

Standard chemoradiation therapy X 7 weeks (Days 7-56), concurrent with oral Vorinostat given three days per week (Mon, Tues, Wed)

Other Names:

irradiation
radiotherapy
therapy, radiation

Other: laboratory biomarker analysis

Correlative study

Genetic: protein expression analysis

Correlative study

Procedure: biopsy

Correlative study

Other Name: biopsies

Genetic: polymerase chain reaction

Correlative study

Other Name: PCR

Genetic: DNA methylation analysis

Correlative study

Other: immunohistochemistry staining method

Correlative study

Other Name: immunohistochemistry

Other: immunoenzyme technique

Correlative study

Other Name: immunoenzyme techniques

Other: fluorescence activated cell sorting

Correlative study

Other Names:

FACS
Fractionation, Fluorescence Activated Cell Sorting

Other: flow cytometry

Correlative study

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximally tolerated dose of Vorinostat in combination with concurrent chemoradiotherapy for the treatment of advance stage OPSCC.

SECONDARY OBJECTIVES:

l. To determine the complete response rate, overall survival and progression free survival using the maximally tolerated dose of Vorinostat.

TERTIARY OBJECTIVES:

I. To assess treatment related acute and late toxicities when combining Vorinostat with chemoradiation and correlate these toxicities to molecular markers of apoptosis in tumor and normal oral mucosa.

II. To evaluate the effect of Vorinostat on tumor immune surveillance, particularly in HPV positive patients.

III. To illustrate that Vorinostat alters the methylation status of commonly methylated genes in OPSCC.

OUTLINE: This is a dose-escalation study of vorinostat. Patients receive oral vorinostat on days 0-2 and cisplatin IV on days 7, 21, and 35. Patients undergo radiotherapy 5 days a week beginning on day 7. Patients also receive concurrent oral vorinostat along with the radiotherapy to be given 3 days per week (Monday, Tuesday, and Wednesday). Treatment continues for 7 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Patients with histologically confirmed unresectable or borderline resectable squamous cell carcinoma of the oropharynx will be eligible for enrollment to the clinical trial
Oropharyngeal sites of tumor include tonsil, soft palate, base of tongue, lateral and posterior pharyngeal wall
Patient must be AJCC Stage III (T3N0, T1-2N1) or Stage IVa (T1-4N2-3M0, T4N0-1 M0) and be either unresectable or borderline resectable
No prior therapy for the tumor, including extensive surgery, radiation therapy, chemotherapy, immunotherapy, targeted therapy or any other investigational agents; surgical biopsy prior to beginning the study is allowable
Prior malignancies at sites other than the head and neck are allowable if there has been greater than or equal to a 3 year disease free interval; basal cell carcinoma of the skin and in-situ cervix dysplasias are allowable within this 3 year interval if completely resected
There must be documentation of evaluable tumor within four weeks of beginning therapy
ECOG Performance Status 0-2, (Karnofsky > 60%)
Ability to understand and the willingness to sign a written informed consent
Patient must have normal liver and bone marrow function
Absolute neutrophil count (ANC) >= 1,500/mcL
Platelets >= 100,000/mcL
Hemoglobin >= 9 g/dL
Prothrombin Time or INR =< 1.5x upper limit of normal (ULN) unless receiving therapeutic anticoagulation
Partial thromboplastin time (PTT) =< 1.2 times the ULN unless the patient is receiving therapeutic anticoagulation
K levels preferred normal limits with no clinical abnormalities
Mg levels preferred normal limits with no clinical abnormalities
Creatinine =< ULN OR Calculated creatinine clearance >= 50 mL/min
Serum total bilirubin =< 1.5 X ULN
AST (SGOT) and ALT (SGPT) =< 2.5 X ULN
Alkaline Phosphatase =< 2.5 X ULN
No known malabsorption syndrome
Female patients of childbearing potential must be willing to use birth control; the 2 birth control methods can be either 2 barrier methods or a barrier method plus a hormonal method to prevent pregnancy, used throughout the study starting with visit 1
The following are considered adequate barrier methods of contraception: diaphragm, condom (by the partner) or sponge; other methods of contraception such as copper intrauterine device or spermicide may be used
Appropriate hormonal contraceptives will include any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents); female patient of childbearing potential has a negative serum pregnancy test β-hCG within 7 days prior to receiving the first dose of vorinostat
Male patients agree to use an adequate method of contraception for the duration of the study
The patient must have a life expectancy of at least 12 weeks
Patients on coumadin therapy are eligible for study

Exclusion Criteria:

Major surgery or trauma occurring within 28 days of starting the trial
History of allergic reactions attributed to compounds similar in chemical or biological composition to Vorinostat or other agents used in this study
Gastrointestinal tract disease or previous surgical procedures resulting in an inability to take oral or enteral medication or a requirement for IV alimentation
Pregnant women; breast feeding should be discontinued during treatment
Active peptic ulcer disease
Uncontrolled comorbid illness including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina, untreated or new cardiac arrhythmia, psychiatric or social condition which would limit the patient's understanding of and compliance with the study
Prisoners and other vulnerable populations
Patients who have had prior treatment with an HDAC inhibitor (e.g., romidepsin (Depsipeptide), NSC-630176, MS 275, LAQ-824, belinostat (PXD-101), LBH589, MGCD0103, CRA024781, etc)
Patients who have received compounds with HDAC inhibitor-like activity, such as valproic acid, as anti-tumor therapy should not enroll in this study; patients who have received such compounds for other indications, e.g. valproic acid for epilepsy, may enroll after a 30-day washout period
Patient is currently participating or has participated in a study with an investigational compound or device within 30 days of initial dosing with study drug(s)
Patients with known active viral hepatitis or known HIV infection

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01064921

Locations

United States, Ohio
Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center	Recruiting
Columbus, Ohio, United States, 43210
Contact: Theodoros N. Teknos 614-293-8074 Ted.Teknos@osumc.edu
Principal Investigator: Theodoros N. Teknos

Sponsors and Collaborators

Ohio State University Comprehensive Cancer Center

National Comprehensive Cancer Network

Investigators

Principal Investigator:

Theodoros Teknos

Arthur G. James Cancer Hospital & Richard J. Solove Research Institute

More Information

Additional Information:

Jamesline 1-800-293-5066 This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Ohio State University Comprehensive Cancer Center
ClinicalTrials.gov Identifier:	NCT01064921 History of Changes
Other Study ID Numbers:	OSU-09120, NCI-2009-01606
Study First Received:	February 5, 2010
Last Updated:	November 17, 2011
Health Authority:	United States: Institutional Review Board

Keywords provided by Ohio State University Comprehensive Cancer Center:

oropharyngeal cancer
recurrent squamous cell carcinoma of the oropharynx

Additional relevant MeSH terms:

Carcinoma
Carcinoma, Squamous Cell
Neoplasms, Squamous Cell
Oropharyngeal Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Pharyngeal Neoplasms
Otorhinolaryngologic Neoplasms
Head and Neck Neoplasms
Neoplasms by Site
Pharyngeal Diseases

Stomatognathic Diseases
Otorhinolaryngologic Diseases
Vorinostat
Cisplatin
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Radiation-Sensitizing Agents
Physiological Effects of Drugs
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on May 24, 2012