Ficlatuzumab, Cisplatin and IMRT in Locally Advanced Head and Neck Squamous Cell Carcinoma

NCT02277184 | Terminated Phase 1 DMC

• 1 other identifier: 13-060
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 3

Brief Summary

Head and neck squamous cell carcinoma (HNSCC) is the most common cancer arising in the upper aerodigestive tract, and is the sixth leading incident cancer worldwide. Despite advances in multimodality therapy, 5-year overall survival (OS) is 40-60%, and has increased only incrementally in the past two decades. The current standard of care for primary nonsurgical management of locally advanced HNSCC is concurrent cisplatin-radiotheray, which significantly improved OS, progression-free survival, and locoregional control compared with radiotherapy alone in the landmark Intergroup trial 0126. The MET proto-oncogene encodes c-Met, a heterodimeric growth factor receptor bound exclusively by its ligand, hepatocyte growth factor (HGF). In the laboratory, activation of the HGF/c-Met pathway is associated with resistance to cisplatin and radiotherapy in HNSCC. We hypothesize that the addition of an HGF/c-Met pathway inhibitor to cisplatin-radiotherapy may improve outcomes in HNSCC. Ficlatuzumab (AV-299) is a humanized HGF-inhibitory IgG1 monoclonal antibody. The primary objective of this study is to establish the recommended phase II dose (RP2D) of the combination of ficlatuzumab, cisplatin and intensity-modulated radiotherapy (IMRT), in patients with locally advanced HNSCC. The dose-finding study design will follow a Narayana k-in-a-row design with k set to 3 to target a 33% DLT rate. In the dose-finding phase, a total of either 10 or 14 patients will be treated. If no DLTs are observed among 10 patients, the highest dose tier will be declared the RP2D. Otherwise the RP2D will be estimated from DLTs across all dose levels by isotonic regression. The secondary objective is to estimate biomarker association with preliminary clinical response. We will evaluate biomarkers of HGF/cMet pathway activation in tumor tissue, plasma, and immune cells.

Conditions

Carcinoma, Squamous Cell of Head and Neck

Keywords

Intermediate Risk HNSCC; High Risk HNSCC; Previously Untreated, Locally Advanced HNSCC; Undifferentiated carcinoma; Poorly differentiated carcinoma of the oral cavity; Poorly differentiated carcinoma of the oropharynx; Poorly differentiated carcinoma of the larynx; Poorly differentiated carcinoma of the hypopharynx

Outcome Measures

Primary Outcomes (1)

• Establish the recommended-for-phase II dose (RP2D) of the combination of ficlatuzumab, cisplatin and intensity-modulated radiotherapy (IMRT)

  A dose escalation/de-escalation plan will be conducted according to an adaptive Narayana k-in-a-row design.We will select the dose of ficlatuzumab that is close to but does not exceed a 33% dose limiting toxicity (DLT) rate when administered with a fixed standard dose of cisplatin and IMRT. The observation period for identifying a DLT will be 10 weeks, or 2 weeks following completion of IMRT, whichever comes later. Note: to be considered a DLT, the toxicity must be at least possibly related to ficlatuzumab.In the dose-finding phase, a total of 10 patients will be treated if no DLTs are observed or 14 patients if at least one DLT occurs. If no DLTs are observed among the first 10 patients the recommended for phase 2 dose (RP2D) will be set to dose tier 3. If a DLT is observed and 14 patients are treated and observed, the RP2D will be estimated from DLTs across all dose levels by isotonic regression.

  1 year

Secondary Outcomes (7)

• Evaluate the preliminary efficacy of the combination of ficlatuzumab, cisplatin and intensity-modulated radiotherapy as curative-intent treatment for patients with locally advanced HNSCC

  5 years

• Evaluate biomarkers of HGF/c-Met pathway activation in baseline tumor biopsies, to correlate with preliminary efficacy data

  5 years

• Evaluate change in biomarkers of HGF/c-Met pathway activation after a single dose of ficlatuzumab, prior to initiation of cisplatin-IMRT, to correlate with preliminary efficacy data

  5 years

• Evaluate pharmacodynamic plasma biomarkers of HGF/c-Met pathway activation to correlate with preliminary efficacy data.

  5 years

• Describe the prevalence of PIK3CA, PTEN, and HRAS mutations in patients' tumors

  5 years

Study Arms (1)

Ficlatuzumab, Cisplatin and IMRT

EXPERIMENTAL

Ficlatuzumab will be administered as an IV infusion over 30-60 minutes, once every two weeks beginning the week prior to cisplatin-IMRT (week -1), for a total of 4 doses. Cisplatin will be administered as an IV infusion over 60 minutes on Monday, Tuesday, or Wednesday of each treatment week beginning concurrent with IMRT during week 1 of study treatment (and one week following the first dose of ficlatuzumab) for a total of 7 doses. IMRT: Treatment will be delivered once daily, 5 fractions per week, 35 - 37 fractions, no weekends or holidays over 7 - 8 weeks. All targets will be treated sequentially.

Drug: Ficlatuzumab; Drug: Cisplatin; Radiation: Intensity Modulated Radiotherapy (IMRT)

Interventions

Ficlatuzumab DRUG

Ficlatuzumab Concentrate for Injection, 20 mg/mL, is formulated in 10 mM histidine buffer pH 5.8. The formulation also includes 142 mM arginine (for isotonicity) and 0.01% polysorbate 80. The product is sterile filtered and aseptically filled into washed and depyrogenated 5 mL glass vials.The product is a clear to slightly opalescent, colorless to slightly yellow, solution. Ficlatuzumab Concentrate for Injection is to be administered by IV infusion as an admixture with normal saline solution. The admixture solution in an IV bag is connected to an infusion set containing a 0.22 µm low protein-binding in line filter. The filtered admixture solution is clear to slightly opalescent. Ficlatuzumab is to be stored under refrigerated conditions (2C - 8C)

Also known as: AV-299, SCH900 105

Ficlatuzumab, Cisplatin and IMRT

Cisplatin DRUG

Each vial contains 10 mg of DDP, 19 mg of sodium chloride, 100 mg of mannitol, and hydrochloric acid for pH adjustment. One vial is reconstituted with 10 ml of sterile water. The pH range will be 3.5 to 4.5. Cisplatin will be given as a bolus, infused over 1-2 hours along with appropriate hydration and anti-emetics. Reconstituted solution of cisplatin is stable for 20 hours when stored at 27°C and should be protected from light if not used within 6 hours. The vials and injection should not be refrigerated. Cisplatin has been shown to react with aluminum needles, producing a black precipitate within 30 minutes.

Also known as: PLATINOL

Ficlatuzumab, Cisplatin and IMRT

Intensity Modulated Radiotherapy (IMRT) RADIATION

Immobilization should be performed to ensure daily reproducibility of setup.Treatment planning CT scans will be required to define tumor, clinical and planning target volumes.The treatment planning CT scan should be performed with IV contrast. All tissues to be irradiated must be included in the CT scan. Targets are defined as primary (requiring a higher dose) and secondary (targets at lower risk requiring a lower dose). The primary target is the PTV3 of the primary tumor and lymph nodes containing clinical or radiographic evidence of metastases. The secondary target is the PTVs consist of an area at intermediate risk (PTV2) and that containing the lowest risk of lymph node involvement (PTV2). The treatment plan will be based on an analysis of the volumetric dose, including dose volume histogram (DVH) analyses of the PTV and critical normal structures. Inverse planning will be utilized to deliver optimal dose to the PTVs while excluding noninvolved normal tissue.

Ficlatuzumab, Cisplatin and IMRT

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically confirmed squamous cell carcinoma, undifferentiated carcinoma, or poorly differentiated carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx with no evidence of distant metastasis. Biopsy sampling of primary tumor with pathology report documentation of confirmed diagnostic tissue type is required. Patients should be evaluated by a Radiation Oncologist, Medical Oncologist and Otolaryngologist prior to enrolling on study.
• Patients must have high risk or intermediate risk disease, defined below. Staging evaluation should be determined by imaging studies and complete head and neck exam in accordance with the American Joint committee on Cancer Staging Manual, 7th edition
• o High risk patients must meet one of the following criteria:
• Unresectable oral cavity
• Larynx: T4 any N; T2-3 and ≥N2a
• Hypopharynx and p16(-) oropharynx: Stage III-IVb except T1N1
• p16(-) Oropharnyx: Stage III-IVb except T1N1
• o Intermediate risk, p16(+) oropharynx patients must meet one of the following criteria:
• T3 or ≥ N2a AND ≥10 pack-years tobacco exposure (See Tobacco Assessment Form, Appendix A)
• T4 disease, irrespective of smoking status
• N3 disease, irrespective of smoking status
• Note: for oropharyngeal patients, p16 status must be known, and can be performed at the local site. p16-positive disease is defined as ≥70% of tumor cells demonstrating diffuse nuclear and cytoplasmic staining by p16 immunohistochemistry (IHC). A positive test for HPV-16 by in-situ hybridization (ISH), if this is the local site preference for assessing HPV status, may substitute for p16 IHC testing. p16 staining is not required for non-oropharyngeal sites.
• Patients must be untreated with curative-intent surgery for current diagnosis of Stage III, IVa, or IVb disease. Diagnostic biopsy of primary tumor and/or nodal sites is permitted.
• Diagnostic simple tonsillectomy is permitted, provided patient has RECIST-measurable nodal disease.
• Patients with a second HNSCC primary tumor are eligible for this study, provided more than 2 years have elapsed since the first diagnosis of HNSCC, the original tumor was managed with surgery only (no adjuvant chemotherapy or radiotherapy), and has not recurred.

You may not qualify if:

• History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational agent.
• Distant metastatic disease including CNS or leptomeningeal metastases is not allowed.
• Left ventricular ejection fraction (LVEF) ≤ 50%.
• Significant pulmonary disease, including pulmonary hypertension or interstitial pneumonitis.
• Decreased serum albumin \< 30 g/L (\< 3 g/dL).
• Peripheral edema ≥ Grade 2 per NCI-CTCAE version 4.0.
• Significant electrolyte imbalance prior to enrollment:
• Hypomagnesemia \< 1.2 mg/dL or 0.5 mmol/L.
• Hypocalcemia \< 8.0 mg/dL or 2.0 mmol/L.
• Hypokalemia \< 3.0 mmol/L.
• Significant dermatological disease including but not limited to, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg. blepharitis, cheilitis, cellulitis, cyst).
• Peripheral neuropathy ≥ Grade 2
• Significant cardiovascular disease, including:
• Cardiac failure New York Heart Association (NYHA) class III or IV.
• Myocardial infarction, severe or unstable angina within 6 months prior to Study Day 1.

Sponsors & Collaborators

• Julie E. Bauman, MD, MPH: lead
• AVEO Pharmaceuticals, Inc.: collaborator

Study Sites (3)

UPMC Presbyterian

Pittsburgh, Pennsylvania, 15213, United States

Location

Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

Location

UPMC Shadyside

Pittsburgh, Pennsylvania, 15232, United States

Location

MeSH Terms

Conditions

Squamous Cell Carcinoma of Head and Neck; Carcinoma

Interventions

ficlatuzumab; Cisplatin; Radiotherapy, Intensity-Modulated

Condition Hierarchy (Ancestors)

Carcinoma, Squamous Cell; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Head and Neck Neoplasms; Neoplasms by Site

Intervention Hierarchy (Ancestors)

Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Radiotherapy, Conformal; Radiotherapy, Computer-Assisted; Radiotherapy; Therapeutics

Study Officials

• Julie E Bauman, MD, MPH

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Director of the Head and Neck Cancer Section and Thyroid Cancer Section in the Division of Hematology-Oncology at the University of Pittsburgh School of Medicine

Study Record Dates

• First Submitted: October 25, 2014
• First Posted: October 28, 2014
• Study Start: September 1, 2015
• Primary Completion: September 1, 2016
• Study Completion: September 1, 2016
• Last Updated: November 13, 2017

Record last verified: 2017-11

Locations

US (3)