Induction Chemotherapy With Afatinib, Ribavirin, and Weekly Carboplatin/Paclitaxel for Stage IVA/IVB HPV Associated Oropharynx Squamous Cell Cancer (OPSCC)

Sponsor

Memorial Sloan Kettering Cancer Center (Other)

Overall Status

Completed

CT.gov ID

NCT01721525

Collaborator

National Comprehensive Cancer Network (Other), Boehringer Ingelheim (Industry)

Enrollment

Locations

Arm

59.5

Actual Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study seeks to develop a new induction chemotherapy regimen which is a combination of two pill drugs taken by mouth and two drugs given by vein. This is a phase I study, which means that the primary goal is to establish the recommended dose of an investigational drug when added to chemotherapy. The researchers wish to evaluate the effects, good and bad, of the investigational drug.

Condition or Disease	Intervention/Treatment	Phase
Head and Neck Cancer Squamous Cell Cancer	Drug: Afatinib, Ribavirin, and weekly carboplatin/paclitaxel	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

10 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I Study of Induction Chemotherapy With Afatinib, Ribavirin, and Weekly Carboplatin/Paclitaxel for Stage IVA/IVB HPV Associated Oropharynx Squamous Cell Cancer (OPSCC)

Actual Study Start Date :

Nov 1, 2012

Actual Primary Completion Date :

Oct 16, 2017

Actual Study Completion Date :

Oct 16, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: afatinib, ribavirin, and weekly carboplatin/paclitaxel This will be a single institution phase I study with an expansion cohort. Up to 2 dose levels of daily afatinib will be studied: 30 mg/day and 40 mg/day. The doses of ribavirin, carboplatin, and paclitaxel are fixed. A standard 3 + 3 phase I dose escalation design will be used.	Drug: Afatinib, Ribavirin, and weekly carboplatin/paclitaxel Patients will receive oral daily afatinib (days 1 - 21, per dose escalation scheme) plus daily oral ribavirin (days 1- 21) and paclitaxel (80 mg/m2 intravenously, days 1 and 8) + carboplatin (AUC 1.5 intravenously, days 1 and 8) of a 21-day cycle. Ribavirin will be administered according to standard weight-based dosing for this drug (1). Subjects ≤75 kg receive Ribavirin 400 mg PO qAM and 600 mg PO qPM (= 1000 mg/day). Subjects > 75 kg receive Ribavirin 600 mg PO BID (=1200 mg/day). During the Dose Escalation portion of the study (Part 1), research bloodwork for pharmacokinetics is performed on days 1 and 8 of Cycle 1 only. Other Names: During the Expansion Cohort (Part 2), there is a two week run in of afatinib + ribavirin. The Expansion Cohort begins with a Run-In period of approximately 14 days, in which patients receive only afatinib + ribavirin. On Day -14 (Start of the of the Run-In), patients begin afatinib once daily (at 40 mg/daily the dose established in Part 1) and ribavirin twice daily according to standard weight-based dosing. Both afatinib and ribavirin are self-administered each day during the Run-In period.

Arm

Intervention/Treatment

Experimental: afatinib, ribavirin, and weekly carboplatin/paclitaxel

This will be a single institution phase I study with an expansion cohort. Up to 2 dose levels of daily afatinib will be studied: 30 mg/day and 40 mg/day. The doses of ribavirin, carboplatin, and paclitaxel are fixed. A standard 3 + 3 phase I dose escalation design will be used.

Drug: Afatinib, Ribavirin, and weekly carboplatin/paclitaxel

Patients will receive oral daily afatinib (days 1 - 21, per dose escalation scheme) plus daily oral ribavirin (days 1- 21) and paclitaxel (80 mg/m2 intravenously, days 1 and 8) + carboplatin (AUC 1.5 intravenously, days 1 and 8) of a 21-day cycle. Ribavirin will be administered according to standard weight-based dosing for this drug (1). Subjects ≤75 kg receive Ribavirin 400 mg PO qAM and 600 mg PO qPM (= 1000 mg/day). Subjects > 75 kg receive Ribavirin 600 mg PO BID (=1200 mg/day). During the Dose Escalation portion of the study (Part 1), research bloodwork for pharmacokinetics is performed on days 1 and 8 of Cycle 1 only.

Other Names:

During the Expansion Cohort (Part 2), there is a two week run in of afatinib +

ribavirin. The Expansion Cohort begins with a Run-In period of approximately

14 days, in which patients receive only afatinib + ribavirin. On Day -14

(Start of the of the Run-In), patients begin afatinib once daily (at 40 mg/daily the dose

established in Part 1) and ribavirin twice daily according to standard

weight-based dosing. Both afatinib and ribavirin are self-administered each

day during the Run-In period.

Outcome Measures

Primary Outcome Measures

maximum tolerated dose (For Dose Escalation Portion of the study) [1 year]
of daily oral afatinib administered with standard daily weight based ribavirin and intravenous carboplatin and paclitaxel, Up to 2 dose levels of daily afatinib will be studied: 30 mg/day and 40 mg/day. The doses of ribavirin, carboplatin, and paclitaxel are fixed. A standard 3 + 3 phase I dose escalation design will be used.
expression of PTPN13 (For Expansion Cohort only) [1 year]
To determine if a two week run-in with afatinib and ribavirin results in increased expression of PTPN13, as determined by IHC in pre and post treatment biopsies.

Secondary Outcome Measures

safety and tolerability (toxicity) [1 year]
Adverse events (AEs) will be assessed according to NCI common toxicity criteria (CTC) version 4.0. Dose Limiting Toxicity (DLT) include all toxicities of grade 3 or higher felt to be possibly, probably, or definitely related to study drug.
objective response rate [1 year]
Response and progression will be evaluated in this study using modified international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) (51). Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.
pharmacokinetics [1 year]
PK measurements will be collected from patients in the dose excalation cohort during the first cycle of therapy. The area under the curve (AUC0→∞), half-life (t½), and maximum concentration (Cmax) for afatinib will be determined by noncompartmental analysis.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Department of Pathology at MSKCC confirmation of diagnosis of oropharynx squamous cell cancer, stage IVA/IVB, that is HPV associated.

Evidence of HPV can be p16 immunohistochemistry and/or HPV in situ hybridization positive test result on tumor tissue, either at MSKCC or other CLIA-approved lab.

Age ≥ 18 years of age
Karnofsky Performance Status ≥ 80
Adequate organ function, as follows:

Adequate bone marrow reserve: absolute neutrophil count (ANC) ≥ 1.5 X 109/L, platelets ≥ 160 X 109/L, hemoglobin ≥ 12 g/dL Hepatic: total bilirubin within normal limits (≤ 1.0 mg/dL); alkaline phosphatase (AP), aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 1.5 X ULN (upper limit of normal) Renal: Serum creatinine ≤ 1.3 mg/dL. Patients with serum creatinine > 1.3 mg/dL may be eligible if creatinine clearance (CrCl) ≥ 55 mL/min based on the standard Cockroft and Gault formula.

Patients of childbearing potential must have a negative serum pregnancy test within 14 days of treatment. Patients must agree to use a reliable method of birth control during and for 6 months following the last dose of study drug.
Ability to swallow oral medication.
Expansion Cohort only: At least one unstained slide from pre-treatment diagnostic biopsy or fine needle aspirate must be available for correlative immunohistochemistry study.

Exclusion Criteria:

Prior chemotherapy or radiation for tonsillar or base of tongue squamous cell cancer
History of hemolytic anemia or thalassemia
Active infection or serious underlying medical condition that would impair the patient's ability to receive protocol treatment.
Current therapeutic anticoagulation with Coumadin (warfarin)
Current or prior treatment with ribavirin
Known active Hepatitis B or C
Any prior documented history of transient ischemic attack (TIA) or cerebrovascular accident (CVA)
New York Heart Association (NYHA) Grade II or greater congestive heart failure
Clinically significant peripheral vascular disease
Inability to discontinue any of the following potent P-gp inhibitors (cyclosporine, erythromycin, ketoconazole, itraconazole, quinidine, phenobarbital salt with quinidine, ritonavir, valspodar, verapamil) or inducers (St John's wort, rifampicin).
Known pre-existing interstitial lung disease.
Presence of poorly controlled gastrointestinal disorders that could affect the absorption of the trial drug (e.g. Crohn's disease, ulcerative colitis, malabsorption, or CTC grade ≥2 diarrhea of any etiology) based on treating physician assessment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Memorial Sloan Kettering Cancer Center at Basking Ridge	Basking Ridge	New Jersey	United States	07939
2	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065