Ficlatuzumab and Cetuximab in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (HNSCC)

NCT02277197 | Completed Phase 1 DMC

• 1 other identifier: 13-059
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 3

Brief Summary

The epidermal growth factor receptor (EGFR) is both oncogene and prognostic biomarker in head and neck squamous cell carcinoma (HNSCC). EGFR's functional importance in HNSCC resulted in development of the first molecularly targeted strategy, the anti-EGFR monoclonal antibody cetuximab. Given the lack of therapeutic options for patients with recurrent/metastatic HNSCC after failure of cetuximab, there is strong scientific interest in understanding resistance in order to identify new therapies for this population. A possible resistance mechanism to anti-EGFR therapy in HNSCC is primary or compensatory activation of alternate growth factor receptors including c-Met. The MET oncogene encodes c-Met, an RTK bound exclusively by the ligand, hepatocyte growth factor (HGF). The HGF/c-Met signaling pathway converges with the EGFR network at both the PI3K/Akt and MAPK nodes. Laboratory data suggest the ability for reciprocal compensation between EGFR and c-Met. We hypothesize that HGF/c-Met pathway inhibition may overcome resistance to cetuximab in patients with HNSCC, such as those with clinical cetuximab resistance. Ficlatuzumab (AV-299) is a humanized HGF-inhibitory immunoglobulin G1 (IgG1) monoclonal antibody. The primary objective of this phase 1b study is to find the recommended phase II dose (RP2D) of the combination of ficlatuzumab and cetuximab in patients with recurrent/metastaticHNSCC. The dose-finding study design will follow a Narayana k-in-a-row design with k set to 2 to target a 33% rate of dose-limiting toxicity (DLT). In the dose-finding phase, a total of 8 patients will be treated if no DLTs are observed or 14 patients if at least one DLT occurs. An expansion cohort will then proceed at RP2D until 12 patients have been treated at that dose level with the combination of ficlatuzumab and cetuximab. We will evaluate biomarkers of HGF/cMet pathway activation in baseline tissue, plasma and immune cells for a preliminary relationship with clinical activity.

Conditions

Carcinoma, Squamous Cell of Head and Neck; Squamous Cell Carcinoma of the Head and Neck; Squamous Cell Carcinoma, Head And Neck

Outcome Measures

Primary Outcomes (1)

• Establish the recommended-for-phase II dose (RP2D) of the combination of ficlatuzumab and cetuximab.

  A dose escalation/de-escalation plan will be conducted according to an adaptive Narayana k-in-a-row design.45 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 q2week dose of cetuximab. The observation period for identifying a DLT will be the first cycle, which consists of two doses of ficlatuzumab, or 4 weeks.In the dose-finding phase, a total of 8 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 8 patients, the recommended for phase 2 dose (RP2D) will be set to dose tier 2. 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. More than one patient can be enrolled at the same time.

  1 year

Secondary Outcomes (7)

• Preliminary clinical efficacy of the combination of cetuximab and ficlatuzumab in patients with R/M HNSCC, including PFS, RR, and OS.

  5 year

• Evaluate the relationship between tumor HGF and c-Met expression in baseline research biopsies and preliminary efficacy data

  5 years

• Describe biomarkers of HGF/c-Met and EGFR pathway activation in archived and baseline tumor biopsies

  5 years

• Evaluate peripheral (blood) pharmacodynamic biomarkers of HGF/c-Met and EGFR pathway activation to correlate with preliminary efficacy data

  5 years

• Describe dendritic and T cell phenotypes in archived and baseline tumor biopsies

  5 years

Study Arms (1)

Ficlatuzumab and Cetuximab

EXPERIMENTAL

Ficlatuzumab will be administered as an IV infusion over 30-60 minutes, once every 2 weeks. Ficlatuzumab will be administered 30-60 minutes after the completion of the cetuximab infusion. Cetuximab will be administered as an IV infusion once every 2 weeks. The first dose will be administered over 120 minutes (± 15 minutes). Subsequent doses may be infused over 60 minutes (± 15 minutes). The starting dose of cetuximab (dose tier 1) will be 500 mg/m2. Cetuximab will be administered prior to ficlatuzumab.

Drug: Ficlatuzumab; Drug: Cetuximab

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 (2o C- 8oC)

Also known as: AV-299, SCH 900 105

Ficlatuzumab and Cetuximab

Cetuximab DRUG

Cetuximab is supplied as a 50-mL, single-use vial containing 100 mg of cetuximab at a concentration of 2 mg/mL in phosphate buffered saline. The solution should be clear and colorless and may contain a small amount of easily visible white amorphous cetuximab particulates. Cetuximab can be administered via infusion pump or syringe pump, it must not be administered as an IV push or bolus. Cetuximab must be administered with the use of a low protein binding 0.22-micrometer in-line filter. Maximum infusion rate should not exceed 5 mL/min. Store vials under refrigeration at 2C to 8C (36F to 46F). DO NOT FREEZE. Following the cetuximab infusion, a one-hour observation period is recommended.

Also known as: Erbitux, IMC-C225, C225, CAS number: 205923-56-4, Lilly compound number: LY2939777, Chemical name: Chimeric anti-EGFR antibody

Ficlatuzumab and Cetuximab

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 HNSCC, from any primary site. Nasopharyngeal carcinoma, WHO Type I (keratinizing), will be included. Squamous cell carcinoma of unknown primary, clearly related to the head and neck, will be included.
• Recurrent/metastatic disease, fulfilling at least one of the criteria defined below:
• Incurable disease as assessed by surgical or radiation oncology
• Metastatic (M1) disease
• Persistent or progressive disease following curative-intent radiation, and not a candidate for surgical salvage due to incurability or morbidity. Patients who decline radical surgery are eligible.
• In the dose-finding phase, patients may be cetuximab-exposed or cetuximab-naïve. If the most recent line of therapy included cetuximab, a two-week washout period without cetuximab dosing is required.
• Patients must have previously received, not tolerated, or been judged clinically unsuitable for platinum-containing therapy.
• In the dose-expansion phase, patients must be cetuximab-resistant by fulfilling at least one of the criteria defined below:
• Disease recurrence within 6 months of completing definitive radiotherapy for locally advanced disease. Radiation must have included concurrent cetuximab. Induction chemotherapy, if given, may or may not have included cetuximab.
• Disease progression during, or within 6 months, of cetuximab treatment in the recurrent/metastatic setting. Prior cetuximab exposure may have occurred in first, second and/or third line.
• If the most recent line of therapy included cetuximab, a two-week washout period without cetuximab dosing is required.
• Eastern Cooperative Oncology Group Performance Status 0-1 at time of informed consent (see Appendix B)
• Age ≥ 18 years
• Patients must consent to a research biopsy of tumor tissue at baseline, for conduct of correlative studies. Archived biopsy material may not be substituted.
• Measurable disease per RECIST criteria, version 1.1 (see section 6)

You may not qualify if:

• Nasopharyngeal primary site, if WHO Type II or III (non-keratinizing)
• History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational agent.
• Prior treatment with an HGF/cMet inhibitor such as rilotumumab, crizotinib, MetMAb, or ARQ197
• Uncontrolled central nervous system (CNS) metastases, including leptomeningeal metastases, are not allowed. Subjects with previously treated brain metastases will be allowed if the brain metastases have been stable without steroid treatment for at least 4 weeks following prior treatment (radiotherapy or surgery).
• Failure to recover to Grade 1 or baseline from all toxic effects of previous chemotherapy, radiation therapy, biologic therapy, and/or experimental therapy, with the exception of: alopecia, Grade ≤ 2 peripheral neuropathy, Grade ≤ 2 cetuximab-related rash or other skin changes, hypomagnesemia (acceptable values detailed below), hypokalemia (acceptable values detailed below), and the acceptable hematologic values summarized above. A washout period of 2 weeks from prior cetuximab is required; a washout period of 3 weeks from any prior cytotoxic chemotherapy or investigational drug is required.
• 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 (note that patients may be supplemented to achieve acceptable electrolyte values):
• 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). Exception: patients with Grade ≤ 2 cetuximab-related rash, xerosis, fissures or paronychial inflammation are eligible.
• Significant cardiovascular disease, including:
• Cardiac failure New York Heart Association (NYHA) class III or IV.

Sponsors & Collaborators

• James J Lee: 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

Interventions

ficlatuzumab; Cetuximab

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• James Ohr, DO

  Attending Physician, UPMC Hillman Cancer Center

  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: Assistant Professor of Medicine

Study Record Dates

• First Submitted: October 25, 2014
• First Posted: October 28, 2014
• Study Start: August 1, 2015
• Primary Completion: June 1, 2016
• Study Completion: February 1, 2018
• Last Updated: April 18, 2019

Record last verified: 2019-04

Locations

US (3)