Head and Neck Basaloid Carcinoma, Recurrent Head and Neck Squamous Cell Carcinoma, Recurrent Oropharyngeal Squamous Cell Carcinoma, Squamous Cell Carcinoma of Unknown Primary Origin, Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity, Stage IV Nasopharyngeal Keratinizing Squamous Cell Carcinoma, Stage IV Oropharyngeal Squamous Cell Carcinoma, Stage IVA Lip and Oral Cavity Squamous Cell Carcinoma, Stage IVA Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma, Stage IVA Nasopharyngeal Keratinizing Squamous Cell Carcinoma, Stage IVA Oropharyngeal Squamous Cell Carcinoma, Stage IVB Lip and Oral Cavity Squamous Cell Carcinoma, Stage IVB Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma, Stage IVB Nasopharyngeal Keratinizing Squamous Cell Carcinoma, Stage IVB Oropharyngeal Squamous Cell Carcinoma, Stage IVC Lip and Oral Cavity Squamous Cell Carcinoma, Stage IVC Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma, Stage IVC Nasopharyngeal Keratinizing Squamous Cell Carcinoma, Stage IVC Oropharyngeal Squamous Cell Carcinoma, Head and Neck Cancer, Oropharyngeal Cancer, HNSCC, Stage IV Lip and Oral Cavity Squamous Cell Carcinoma
Conditions
Keywords
Head and Neck Cancer, Oropharyngeal Cancer, Squamous Cell Carcinoma, lip carcinoma, oral cavity carcinoma, HNSCC, Head and Neck Squamous Cell Carcinoma, AVEO
Brief summary
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.
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.
Interventions
Given IV
Given IV
Sponsors
Study design
Eligibility
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | 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. |
| Overall Response Rate (ORR) | 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. |
| Percentage of Participants With Dose Limiting Toxicities or Adverse Events | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Tumor Biomarker Analysis | 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. |
| Genomic Biomarker Analysis | 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 |
| Peripheral Biomarker Analysis | 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. |
| Immune Biomarker Analysis | 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. |
| Change in Quality of Life | 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. |
Countries
United States
Participant flow
Recruitment details
This multicenter study was conducted at the University of Arizona, Emory University, Fox Chase Cancer Center, Medical University of South Carolina, Yale Cancer Center, and Moffitt Cancer Center. The study opened to accrual on 12/05/2017 and closed to accrual on 12/05/2020. Potential patients were identified in the cancer center clinic by study investigators or referred. Weekly tumor board meetings are held at each institution where patients are discussed and referred to clinical trials.
Pre-assignment details
Of the 78 patients who signed consent, only 60 were randomized. 18 patients were excluded, 15 were determined to be ineligible after the screening period and 3 declined to participate after signing consent.
Participants by arm
| Arm | Count |
|---|---|
| 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.
Ficlatuzumab: Given IV | 27 |
| 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.
Cetuximab: Given IV
Ficlatuzumab: Given IV | 33 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Allocation - Received Intervention | Adverse Event | 1 | 0 |
| Allocation - Received Intervention | Death | 1 | 3 |
| Allocation - Received Intervention | Disease progression | 19 | 25 |
| Allocation - Received Intervention | Lost to Follow-up | 1 | 0 |
| Allocation - Received Intervention | Physician Decision | 1 | 1 |
| Allocation - Received Intervention | Withdrawal by Subject | 3 | 2 |
| Randomized | Physician Decision | 1 | 1 |
Baseline characteristics
| Characteristic | Arm II (Ficlatuzumab, Cetuximab) | Arm I (Ficlatuzumab) | Total |
|---|---|---|---|
| Age, Continuous | 63 years | 65 years | 63.5 years |
| Eastern Cooperative Oncology Group Performance Status (ECOG- PS) Asymptomatic (0) - Fully active, able to carry on all pre-disease performance without restriction | 6 participants | 9 participants | 15 participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG- PS) Symptomatic (1) - restricted in physically strenuous activity but able to carry out light work | 27 participants | 18 participants | 45 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants | 23 Participants | 52 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| History of anti-PD-1 (checkpoint protein) monoclonal antibody (mAb) treatment | 31 participants | 25 participants | 56 participants |
| History of platinum | 32 participants | 27 participants | 59 participants |
| HPV status Negative | 16 participants | 16 participants | 32 participants |
| HPV status Positive | 17 participants | 11 participants | 28 participants |
| Median months since last cetuximab treatment | 3.6 Months | 2.7 Months | 3.5 Months |
| Primary Site External auditory canal | 1 participants | 0 participants | 1 participants |
| Primary Site Larynx | 4 participants | 3 participants | 7 participants |
| Primary Site Nasopharynx | 1 participants | 2 participants | 3 participants |
| Primary Site Oral Cavity | 6 participants | 8 participants | 14 participants |
| Primary Site Oropharynx | 20 participants | 11 participants | 31 participants |
| Primary Site Paranasal sinus | 0 participants | 2 participants | 2 participants |
| Primary Site Unknown primary | 1 participants | 1 participants | 2 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 30 Participants | 24 Participants | 54 Participants |
| Region of Enrollment United States | 33 participants | 27 participants | 60 participants |
| Sex: Female, Male Female | 3 Participants | 6 Participants | 9 Participants |
| Sex: Female, Male Male | 30 Participants | 21 Participants | 51 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 26 | 3 / 32 |
| other Total, other adverse events | 24 / 26 | 31 / 32 |
| serious Total, serious adverse events | 7 / 26 | 18 / 32 |
Outcome results
Progression Free Survival (PFS)
Will be estimated for each arm using a Kaplan-Meier curve.
Time frame: From the date of randomization until the date of progression or death, assessed up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Ficlatuzumab) | Progression Free Survival (PFS) | 1.8 months |
| Arm II (Ficlatuzumab, Cetuximab) | Progression Free Survival (PFS) | 3.7 months |
Overall Response Rate (ORR)
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.
Time frame: Up to 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Ficlatuzumab) | Overall Response Rate (ORR) | 1 Participants |
| Arm II (Ficlatuzumab, Cetuximab) | Overall Response Rate (ORR) | 6 Participants |
Overall Survival (OS)
Will be estimated for each arm using a Kaplan-Meier curve.
Time frame: From the date of randomization until the date of death, assessed up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Ficlatuzumab) | Overall Survival (OS) | 6.4 months |
| Arm II (Ficlatuzumab, Cetuximab) | Overall Survival (OS) | 7.4 months |
Percentage of Participants With Dose Limiting Toxicities or Adverse Events
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.
Time frame: Up to 2 years
Population: The most common AEs are notated below.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Ficlatuzumab) | Percentage of Participants With Dose Limiting Toxicities or Adverse Events | hypoalbuminemia | 66 percentage of participants |
| Arm I (Ficlatuzumab) | Percentage of Participants With Dose Limiting Toxicities or Adverse Events | Edema | 25 percentage of participants |
| Arm I (Ficlatuzumab) | Percentage of Participants With Dose Limiting Toxicities or Adverse Events | Acneiform rash | 12 percentage of participants |
| Arm I (Ficlatuzumab) | Percentage of Participants With Dose Limiting Toxicities or Adverse Events | Pneumonitis | 8 percentage of participants |
| Arm II (Ficlatuzumab, Cetuximab) | Percentage of Participants With Dose Limiting Toxicities or Adverse Events | Pneumonitis | 3 percentage of participants |
| Arm II (Ficlatuzumab, Cetuximab) | Percentage of Participants With Dose Limiting Toxicities or Adverse Events | hypoalbuminemia | 76 percentage of participants |
| Arm II (Ficlatuzumab, Cetuximab) | Percentage of Participants With Dose Limiting Toxicities or Adverse Events | Acneiform rash | 82 percentage of participants |
| Arm II (Ficlatuzumab, Cetuximab) | Percentage of Participants With Dose Limiting Toxicities or Adverse Events | Edema | 44 percentage of participants |
Change in Quality of Life
Will be assessed by Foundation for the Accreditation of Cellular Therapy Head and Neck Questionnaire.
Time frame: Pre-study (within 4 weeks of study registration) and Week 4, Cycle 2 of Intervention
Genomic Biomarker Analysis
To evaluate the relationship between clinical outcomes (Progression-Free Survival and Response Rate) and candidate genomic biomarkers: mutations in PIK3CA, PTEN, and HRAS
Time frame: Up to 2 years
Immune Biomarker Analysis
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.
Time frame: Up to 2 years
Peripheral Biomarker Analysis
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.
Time frame: Up to 2 years
Tumor Biomarker Analysis
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.
Time frame: Up to 2 years
Population: Exploratory biomarker analysis was only conducted for the combination arm. The monotherapy arm closed for futility. It would be costly and would not add value to study biomarkers in the setting of an inactive agent to perform analyses for the monotherapy arm thus the limited funds available for correlatives were allocated to the combination arm.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm II (Ficlatuzumab, Cetuximab) | Tumor Biomarker Analysis | HPV-negative patients | 13 Participants |
| Arm II (Ficlatuzumab, Cetuximab) | Tumor Biomarker Analysis | HPV-positive patients | 13 Participants |
| Arm II (Ficlatuzumab, Cetuximab) | Tumor Biomarker Analysis | HGF - HPV-positive | 13 Participants |
| Arm II (Ficlatuzumab, Cetuximab) | Tumor Biomarker Analysis | HGF - HPV-negative | 13 Participants |
| Arm II (Ficlatuzumab, Cetuximab) | Tumor Biomarker Analysis | C-met positive in HPV-negative patients | 9 Participants |
| Arm II (Ficlatuzumab, Cetuximab) | Tumor Biomarker Analysis | C-met positive in HPV-positive patients | 2 Participants |