Ficlatuzumab w/wo Cetuximab in Patients w/Cetuximab-Resistant, Recurrent or Metastatic Head/Neck Squamous Cell Carcinoma

July 17, 2023 updated by: University of Arizona

A Randomized, Phase II Study of Ficlatuzumab With or Without Cetuximab in Patients With Cetuximab-Resistant, Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

This randomized phase II trial studies how well ficlatuzumab with or without cetuximab works in treating patients with head and neck squamous cell carcinoma that has come back or spread to other places in the body and resistant to cetuximab treatment. Monoclonal antibodies, such as ficlatuzumab and cetuximab, may block growth signals that lets a tumor cell survive and reproduce, and helps the immune system recognize and fight head and neck squamous cell carcinoma.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

PRIMARY OBJECTIVES:

I. To assess the efficacy of ficlatuzumab, with or without concurrent cetuximab, in patients with cetuximab-resistant, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) as measured by progression-free survival (PFS).

SECONDARY OBJECTIVES:

I. To describe toxicity. II. To evaluate response rate and overall survival in both treatment arms.

EXPLORATORY OBJECTIVES I. To describe patient reported quality of life

II. To evaluate the relationship between clinical outcomes (Progression-Free Survival and Response Rate) and candidate tumoral, genomic, peripheral, and immune biomarkers, potentially including but not limited to:

  • Tumor Hepatocyte Growth Factor (HGF) and tyrosine-protein kinase Met (cMet) expression
  • mutations in PIK3CA, phosphatase and tensin homolog (PTEN), and HumanRAS proto-oncogene (HRAS);
  • peripheral serum biomarkers including HGF, soluble HGF, and interleukin 6 (IL6);
  • peripheral lymphocyte populations;
  • archived and baseline immune infiltrate;
  • tumor Human Papilloma Virus (HPV) status.

OUTLINE: Patients are randomized into 1 of 2 arms.

Arm I: Patients receive ficlatuzumab intravenously (IV) over 30-60 minutes every 2 weeks in the absence of disease progression or unaccepted toxicity. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Arm II: Patients receive cetuximab IV over 60 -120 minutes and ficlatuzumab IV over 30-60 minutes every 2 weeks in the absence of disease progression or unaccepted toxicity. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Study Type

Interventional

Enrollment (Actual)

78

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Arizona
      • Tucson, Arizona, United States, 85719
        • The University of Arizona Cancer Center
    • Connecticut
      • New Haven, Connecticut, United States, 06520
        • Yale Cancer Center
    • Florida
      • Tampa, Florida, United States, 33612
        • Moffitt Cancer Center
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Winship Cancer Institute of Emory University
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19111
        • Fox Chase Cancer Center
    • South Carolina
      • Charleston, South Carolina, United States, 29425
        • Medical University of South Carolina

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

- Patients must have histologically confirmed HNSCC from any primary site, except nasopharyngeal if World Health Organization (WHO) Type III (non-keratinizing and Epstein-Barr virus (EBV)-positive)).

Eligible histologies include:

  • Basaloid, poorly differentiated, and undifferentiated carcinoma histologies.
  • Nasopharyngeal carcinoma, WHO Type I and II (keratinizing, non-EBV positive).
  • Paranasal sinus, lip and external auditory canal sites.
  • Squamous cell carcinoma of unknown primary, clearly related to the head and neck.

Note: Documentation of primary site diagnosis must be submitted with the registration request.

  • Patients must have recurrent and/or 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. Note: Patients who decline radical surgery are eligible.
  • For patients with oropharyngeal primary site or unknown primary site only: Patients must have known tumoral HPV status (p16). (Acceptable standards include p16 immunohistochemistry (where a tumor is classified as p16-positive when showing diffuse nuclear and cytoplasmic staining in at least 70% of tumor cells) and/or assessment of HPV DNA.) Note: For these subjects, documentation of p16 status must be submitted with the registration packet.
  • Patients must be cetuximab-resistant by fulfilling at least one of the two criteria defined below:
  • Disease persistence or recurrence within 6 months of completing definitive radiotherapy with concurrent cetuximab for locally advanced disease. Induction chemotherapy, if given, may or may not have included cetuximab.
  • Disease progression during, or within 6 months, of cetuximab treatment in the recurrent and/or metastatic setting.

Note: Prior cetuximab exposure may have occurred in any line of therapy (first line, second line, etc.) and is not required to be the most recent therapy received.

  • Patients must be platinum-resistant or platinum-ineligible by fulfilling at least one of the three criteria defined below:
  • Disease persistence or recurrence within 6 months of completing definitive radiotherapy for locally advanced disease, where platinum chemotherapy was administered as a component of induction and/or concurrent systemic treatment.
  • Disease progression during, or within 6 months, of treatment with platinum chemotherapy (e.g., carboplatin or cisplatin) in the recurrent and/or metastatic setting.
  • The patient is not an acceptable candidate for platinum chemotherapy due to medical comorbidities, in the judgment of the local investigator.

Note: Prior platinum exposure may have occurred in any line of therapy (first line, second line, etc.) and is not required to be the most recent therapy received.

- Patients must have prior exposure to an anti-PD1 (programmed cell death protein 1) or anti-PDL1 (programmed cell death ligand 1) monoclonal antibody (mAb), if eligible for immunotherapy in the judgment of the local investigator.

Note: Prior exposure to investigational immunotherapies, including anti-CTLA4 (cytotoxic T-lymphocyte-associated antigen 4), anti-OX40, anti-CD40 (cluster of differentiation 40), anti-CD27, anti-TNFR (tumor necrosis factor receptor) antibodies or other investigational immunotherapies, is acceptable.

  • Patients must have Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 at time of informed consent (see Appendix B).
  • Patients must be age ≥ 18 years.
  • Patients must consent to a research biopsy of tumor tissue at baseline, for conduct of correlative studies. In cases where a fresh biopsy is not feasible (i.e., if an accessible tumor site cannot be biopsied with acceptable clinical risk), archival tissue may be submitted instead, after discussion with and approval by the Sponsor-Investigator.
  • Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1 (see section 6) per scan within 28 days prior to registration.
  • Patients must have adequate electrolytes, liver, renal, and hematology function as defined below within 28 days of registration:
  • Absolute neutrophil count (ANC) ≥ 1500/mm3
  • Platelet count (PLT) ≥ 75,000/mm3
  • Creatinine clearance ≥ 30 mL/min per estimated by the Cockraft-Gault formula:

  • Calculated Creatinine Clearance = [(140-age) X (actual body weight in kg) X (0.85 if female)]/(72 X serum creatinine)

    * Total bilirubin ≤ 1.5 times upper-limit of normal (ULN)

  • AST (aspartate aminotransferase) ≤ 3 times ULN
  • ALT (alanine aminotransferase) ≤ 3 times ULN
  • Magnesium ≥ 1.2 mg/dL or 0.5 mmol/L
  • Corrected Calcium ≥ 8.0 mg/dL or 2.0 mmol/L
  • Potassium ≥ 3.0 mmol/L (Note: Patients may be supplemented to achieve acceptable electrolyte values.)
  • Serum albumin ≥ 25 g/L (≥ 2.5 g/dL)
  • Patients must sign written informed consent prior to beginning study screening procedures. Patients must have the ability to understand and the willingness to sign a written informed consent document.
  • Women of child-bearing potential (WOCBP) must agree to have a pregnancy test within 14 days prior to registration and a repeated test within 3 days of the first dose of ficlatuzumab.
  • Patients must agree to use highly effective contraceptive measures while on study and for 60 days after the last dose of study drug. This includes: Men of reproductive potential AND women of childbearing potential.
  • Effective birth control includes (a) intrauterine device (IUD) plus one barrier method; or (b) 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm).

Exclusion Criteria

  • Nasopharyngeal primary site if WHO Type III (non-keratinizing and EBV-positive as established at the local site).
  • 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 tivantinib (ARQ197).
  • Uncontrolled central nervous system (CNS) metastases, including leptomeningeal metastases, are not allowed.

Note: Subjects with previously treated brain metastases will be allowed if the brain metastases have been stable without steroid treatment for at least 2 weeks (radiotherapy or surgery).

  • Failure to recover to Grade 1 or baseline from all toxic effects of previous chemotherapy, radiation therapy, biologic therapy, immunotherapy, 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 in the exclusion criteria below),
  • Hypokalemia (acceptable values detailed in the exclusion criteria below), and
  • The acceptable ANC and PLT inclusion criteria values above.
  • Treatment with cetuximab 2 weeks prior to the first dose of study drug. A washout period of 2 weeks from prior cetuximab is required if applicable.
  • Treatment with cytotoxic chemotherapy, targeted therapy, immunotherapy or investigational drug 3 weeks prior to the first dose of study drug. A washout period of 3 weeks from any prior cytotoxic chemotherapy, targeted therapy, immunotherapy or investigational drug is required, if applicable.
  • Significant underlying pulmonary disease, including pulmonary hypertension or interstitial pneumonitis.
  • Peripheral edema ≥ Grade 2 per NCI-CTCAE version 4.0.
  • Significant cardiovascular disease, including:
  • Cardiac failure New York Heart Association (NYHA) class III or IV.
  • Myocardial infarction within 6 months prior to registration.
  • Severe or unstable angina within 6 months prior to registration.
  • History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation).
  • Cardiac arrhythmia requiring anti-arrhythmic medication(s). (Beta-blockers, calcium channel blockers, and digoxin administered for the purpose of rate control of supraventricular tachycardia, including atrial fibrillation and atrial flutter, are not classified as anti-arrhythmic medications for purposes of trial eligibility.)
  • Significant thrombotic or embolic events within 28 days prior to registration. (Significant thrombotic or embolic events include but are not limited to stroke or transient ischemic attack (TIA). Catheter-related thrombosis is not a cause for exclusion. Diagnosis of deep vein thrombosis or pulmonary embolism is allowed if it occurred > 28 days prior to registration and the patient is asymptomatic and stable on anti-coagulation therapy.)
  • Any other medical condition (e.g., alcohol abuse) or psychiatric condition that, in the opinion of the local Investigator, might interfere with the subject's participation in the trial or interfere with the interpretation of trial results.
  • History of second malignancy within 2 years prior to registration except:
  • Excised and cured non-melanoma skin cancer,
  • Carcinoma in situ of breast or cervix,
  • Superficial bladder cancer,
  • Stage I differentiated thyroid cancer that is resected or observed,

  • pT1a /pT1b prostate cancer comprising < 5% of resected tissue with normal prostate specific antigen (PSA) since resection, or

    * cT1a/cT1b prostate cancer treated with brachytherapy or external beam radiation therapy with normal PSA since radiation.

  • Not completely recovered from any previous surgery. Note: Complete recovery is in the opinion of the treating investigator. Consult the Sponsor-Investigator, if needed.
  • Active systemic infection requiring systemic antibiotics or antifungals within 7 days prior to first dose of study drug, except tetracycline family antibiotics (tetracycline, doxycycline, minocycline) administered for the management of cetuximab-related rash may be continued per the Investigator's judgment.

Note: Active topical infections (for example oral thrush) do not exclude a subject even if treated with systemic antibiotics or systemic antifungals.

  • History of severe infusion reaction to cetuximab or a monoclonal antibody.
  • Known to be Human immunodeficiency virus (HIV) positive. Note: HIV testing is not required for entry into this protocol.
  • Women who are pregnant or breastfeeding. (A negative urine pregnancy test must be confirmed within 14 days of registration and repeated within 3 days of the first dose of study drug.)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Arm I (ficlatuzumab)
Patients receive ficlatuzumab IV over 30-60 minutes every 2 weeks in the absence of disease progression or unaccepted toxicity. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Drug: Ficlatuzumab
Given IV
Other Names:
  • AV-299
  • SCH 900105
  • Anti-HGF Monoclonal Antibody SCH900105
Experimental: Arm II (ficlatuzumab, cetuximab)
Patients receive cetuximab IV over 60 -120 minutes and ficlatuzumab IV over 30-60 minutes every 2 weeks in the absence of disease progression or unaccepted toxicity. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Biological: Cetuximab
Given IV
Other Names:
  • Erbitux
  • IMC-C225
  • Chimeric Anti-EGFR Monoclonal Antibody
  • Chimeric MoAb C225
  • Chimeric Monoclonal Antibody C225
Drug: Ficlatuzumab
Given IV
Other Names:
  • AV-299
  • SCH 900105
  • Anti-HGF Monoclonal Antibody SCH900105

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression Free Survival (PFS)
Time Frame: From the date of randomization until the date of progression or death, assessed up to 2 years
Will be estimated for each arm using a Kaplan-Meier curve.
From the date of randomization until the date of progression or death, assessed up to 2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of Participants With Dose Limiting Toxicities or Adverse Events
Time Frame: Up to 2 years
The percentage of participants with dose limiting toxicities in each dosing cohort will be reported, as will the percentage of participants with adverse events in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events version 4 grading criteria. Will be tabulated and reported with 95% exact confidence intervals.
Up to 2 years
Overall Survival (OS)
Time Frame: From the date of randomization until the date of death, assessed up to 2 years
Will be estimated for each arm using a Kaplan-Meier curve.
From the date of randomization until the date of death, assessed up to 2 years
Overall Response Rate (ORR)
Time Frame: Up to 2 years
Will be assessed by Response Evaluation Criteria in Solid Tumors version 1.1 (RESIST v1.1) for target lesions and assessed by CT/MRI w/ contrast: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), the regression of all Target lesions (the sum) by 30% with no progression of Non-targets or presence of new lesion; Overall Response (OR) = CR + PR. Will be tabulated and reported with 95% exact confidence intervals.
Up to 2 years

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Quality of Life
Time Frame: Pre-study (within 4 weeks of study registration) and Week 4, Cycle 2 of Intervention
Will be assessed by Foundation for the Accreditation of Cellular Therapy Head and Neck Questionnaire.
Pre-study (within 4 weeks of study registration) and Week 4, Cycle 2 of Intervention
Tumor Biomarker Analysis
Time Frame: Up to 2 years
Will evaluate the relationship between clinical outcomes (progression free survival, response rate) and candidate tumoral biomarkers: Tumor HGF and cMET expression. The relationship with clinical response will be assessed.
Up to 2 years
Genomic Biomarker Analysis
Time Frame: Up to 2 years
To evaluate the relationship between clinical outcomes (Progression-Free Survival and Response Rate) and candidate genomic biomarkers: mutations in PIK3CA, PTEN, and HRAS
Up to 2 years
Peripheral Biomarker Analysis
Time Frame: Up to 2 years
Will evaluate the relationship between clinical outcomes (progression free survival, response rate) and candidate peripheral biomarkers: peripheral serum biomarkers including HGF, soluble HGF, and IL6; peripheral lymphocyte populations. The relationship with clinical response will be assessed.
Up to 2 years
Immune Biomarker Analysis
Time Frame: Up to 2 years
Will evaluate the relationship between clinical outcomes (progression free survival, response rate) and candidate immune biomarkers: archived and baseline immune filtrate; tumor HPV status. The relationship with clinical response will be assessed.
Up to 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Arizona

Collaborators

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Julie E. Bauman, MD, MPH, The University of Arizona

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 5, 2017

Primary Completion (Actual)

March 29, 2022

Study Completion (Actual)

April 5, 2022

Study Registration Dates

First Submitted

January 19, 2018

First Submitted That Met QC Criteria

February 2, 2018

First Posted (Actual)

February 5, 2018

Study Record Updates

Last Update Posted (Actual)

July 19, 2023

Last Update Submitted That Met QC Criteria

July 17, 2023

Last Verified

July 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1710965268 (Other Identifier: The University of Arizona Medical Center-University Campus)
  • P30CA023074 (U.S. NIH Grant/Contract)
  • NCI-2017-02209 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
  • AV-299-17-117i (Other Identifier: Aveo Oncology and Biodesix)

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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