Symptoms and General Pathology

All Conditions

Neoplasms

Mouth and Tooth Diseases

Ear, Nose, and Throat Diseases

Rare Diseases

Recurrence

Carcinoma

Carcinoma, Squamous Cell

Head and Neck Neoplasms

Squamous Cell Carcinoma of Head and Neck

Oropharyngeal Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Disease Attributes

Neoplasms, Squamous Cell

Otorhinolaryngologic Neoplasms

Otorhinolaryngologic Diseases

Pharyngeal Neoplasms

Pharyngeal Diseases

Stomatognathic Diseases

Oral Squamous Cell Carcinoma

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Cetuximab

Immunoglobulins

Antineoplastic Agents, Immunological

Immunoglobulins, Intravenous

Immunologic Factors

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.

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.

Ficlatuzumab

Julie E. Bauman, MD, MPH

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.

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.

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

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

Will be assessed by Foundation for the Accreditation of Cellular Therapy Head and Neck Questionnaire.

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.

To evaluate the relationship between clinical outcomes (Progression-Free Survival and Response Rate) and candidate genomic biomarkers: mutations in PIK3CA, PTEN, and HRAS

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.

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.

Will be estimated for each arm using a Kaplan-Meier curve.

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.

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.

National Cancer Institute (NCI)

University of Arizona

Only AEs meeting one of the below criteria were collected:

* Any AE that is Grade 3 or \>
* Any AE that results in submission of a serious adverse event(SAE)
* Any intolerable Grade 2 AE
* Any Grade AE resulting in a dose reduction of study drugs
* Any Grade 2 laboratory or vital sign values that are deemed clinically significant by the treating investigator
* Any Grade AE in the following categories:

  * Rash
  * Diarrhea
  * Edema, peripheral
  * Edema, head, face and neck
  * Hypoalbuminemia

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

Arm I (Ficlatuzumab)

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

Arm II (Ficlatuzumab, Cetuximab)

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Oral Cavity

Oropharynx

Larynx

Nasopharynx

Paranasal sinus

External auditory canal

Unknown primary

Primary Site

Positive

Negative

HPV status

Median months since last cetuximab treatment

History of platinum

History of anti-PD-1 (checkpoint protein) monoclonal antibody (mAb) treatment

Asymptomatic (0) - Fully active, able to carry on all pre-disease performance without restriction

Symptomatic (1) - restricted in physically strenuous activity but able to carry out light work

Eastern Cooperative Oncology Group Performance Status (ECOG- PS)

Rachel Jarrett

Progression Free Survival (PFS)

hypoalbuminemia

Edema

Acneiform rash

Pneumonitis

Percentage of Participants With Dose Limiting Toxicities or Adverse Events

Overall Survival (OS)

Overall Response Rate (ORR)

Change in Quality of Life

c-Met positivity was compared across groups: HPV+ vs HPV-

Post-hoc comparison of progression free survival (PFS) in cMet positive vs. c-Met negative patients.

Post hoc comparison of PFS in the combination arm by HPV subgroup, adjusted for prognostic factors marginally associated with HPV status (P , .10), was assessed using Cox proportional hazards models. Here we are looking at cMet positivity in HPV- patients in the combination arm.

Post hoc comparison of PFS in the combination arm by HPV subgroup, adjusted for prognostic factors marginally associated with HPV status (P , .10), was assessed using Cox proportional hazards models. Here we are looking at cMet positivity in HPV+ patients in the combination arm.

Post-hoc comparison of progression free survival (PFS) in HGF positive vs. HGF negative patients.

Post hoc comparison of PFS in the combination arm by HPV subgroup, adjusted for prognostic factors marginally associated with HPV status (P , .10), was assessed using Cox proportional hazards models. Here we are looking at HGF expression in HPV- patients in the combination arm.

Post hoc comparison of PFS in the combination arm by HPV subgroup, adjusted for prognostic factors marginally associated with HPV status (P \< .10), was assessed using Cox proportional hazards models. Here we are looking at HGF expression in HPV+ patients in the combination arm.

HPV-negative patients

HPV-positive patients

HGF - HPV-positive

HGF - HPV-negative

C-met positive in HPV-negative patients

C-met positive in HPV-positive patients

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.

Tumor Biomarker Analysis

Genomic Biomarker Analysis

Peripheral Biomarker Analysis

Immune Biomarker Analysis

Randomized

Allocation - Received Intervention

Carcinoma, Verrucous

Salivary Gland Neoplasms

Mouth Neoplasms

Mouth Diseases

Salivary Gland Diseases

Tongue Cancer

Oral Cancer

Anti-Infective Agents

Sirolimus

Temsirolimus

MTOR Inhibitors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Clotrimazole

Miconazole

Antifungal Agents

Immunosuppressive Agents

Protein Kinase Inhibitors

Enzyme Inhibitors

Patients receive temsirolimus IV over 30-60 minutes and cetuximab IV over 1-2 hours once weekly. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Patients receive temsirolimus as in Arm A. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may cross over to Arm A.

Laboratory Biomarker Analysis

Tanguy Seiwert

This phase II trial studies how well giving temsirolimus together with cetuximab works compared to temsirolimus alone in treating patients with recurrent and/or metastatic head and neck cancer who did not respond to previous therapy. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether giving temsirolimus together with cetuximab is more effective than giving temsirolimus alone.

PRIMARY OBJECTIVES:

I. Primary endpoint is progression free survival (PFS) of cetuximab/temsirolimus combination cohort (Arm A) compared to temsirolimus alone (Arm B).

SECONDARY OBJECTIVES:

I. Progression-free survival (PFS) of cetuximab/temsirolimus combination group (Arm A) and temsirolimus control group (Arm B) compared to a historic control cohort.

II. Subgroup analysis of myofibroblast (+) cohort (PFS). III. Overall survival (OS). IV. Toxicities. V. Response (Response Evaluation Criteria in Solid Tumors \[RECIST\])/absolute tumor shrinkage (waterfall plot analysis).

VI. Activity of combination therapy (temsirolimus/cetuximab) after failure (progressive disease \[PD\]) of temsirolimus monotherapy.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive temsirolimus intravenously (IV) over 30-60 minutes and cetuximab IV over 1-2 hours once weekly. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive temsirolimus as in Arm A. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may cross over to Arm A.

After completion of study therapy, patients are followed up for a minimum of 8 weeks and then once a year for 5 years.

Temsirolimus With or Without Cetuximab in Patients With Recurrent and/or Metastatic Head and Neck Cancer Who Did Not Respond to Previous Therapy

A T1 Translational Multicenter Randomized Phase II Study of Temsirolimus Versus Cetuximab Plus Temsirolimus in Patients With Recurrent / Metastatic Head and Neck Cancer, Who Failed Prior EGFR Based Therapy

Progression determined using RECIST criteria: \>=20% increase in the sum of the longest diameters of target lesions from nadir, occurrence of new lesions, or progression of non-target lesions.

Time from randomization until death from any cause

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Statistics reported are for Overall Response (OR) = CR + PR.

PFS at 4 months in Arm A and Arm B will each be compared with a 4-month historical control rate of 21.4%. The historical data appears in two publications, an ASCO abstract: Abidoye, ASCO Annual Meeting 2006: 5568 and de Souza, Davis, et al, Clin Cancer Res 2012; 18(8):2336-2343.

Incidence of hematological toxicities at least possibly related to study drug, graded based on Common Terminology Criteria for Adverse Events version 4

Percentage of responses (if any) after crossover from the control arm to the combination arm will be evaluated qualitatively. This is includes complete and partial responses, and is different from Outcome Measure 8 below, which includes complete and partial responses as well as stable disease.

Assessed according to RECIST. This is includes complete and partial responses as well as stable disease, and is different from Outcome Measure 6 above, which includes only complete and partial responses.

Arm A (Cetuximab and Temsirolimus)

Arm B (Temsirolimus)

Three patients from each treatment arm did not start treatment and are considered non-evaluable.

Dr. Tanguy Seiwert

Progression-free Survival (PFS)

Overall Response Rates (OR)

PFS at 4 months in Arm A was compared with a 4-month historical control rate of 21.4%, using a one-sided test at the 0.05 significant level. The historical data appear in two publications, an ASCO abstract: Abidoye, ASCO Annual Meeting 2006: 5568, and de Souza, Davis, et al, Clin Cancer Res 2012; 18(8):2336-2343 (see Figure 1).

PFS at 4 months in Arm B was compared with a 4-month historical control rate of 21.4%, using a one-sided test at the 0.05 significant level. The historical data appear in two publications, an ASCO abstract: Abidoye, ASCO Annual Meeting 2006: 5568, and de Souza, Davis, et al, Clin Cancer Res 2012; 18(8):2336-2343 (see Figure 1).

Note: Each arm is separately compared to an historical rate of 21.4%, based on a one-sided test at the 0.05 significant level. Since the 90% CIs each exclude 21.4%, the 4-month PFS rate in both arms exceeds the fixed historical control rate.

PFS vs. Historical Control Cohort

Grade 3 or Higher Hematological Toxicity

Percentage of Responses After Crossover From Control Arm to the Combination Arm, Assessed According to RECIST

Myofibroblast status was not determined. Concerns about the validity/technical feasibility as well as availability of the assay led us to decide to not perform the assay. We do not intend to perform this assay anymore.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Ficlatuzumab w/wo Cetuximab in Patients w/Cetuximab-Resistant, Recurrent or Metastatic Head/Neck Squamous Cell Carcinoma	NCT03422536	Head and Neck B... Recurrent Head ... Recurrent Oroph... Squamous Cell C... Stage IV Squamo... Stage IV Squamo... Stage IV Nasoph... Stage IV Oropha... Stage IVA Lip a... Stage IVA Nasal... Stage IVA Nasop... Stage IVA Oroph... Stage IVB Lip a... Stage IVB Nasal... Stage IVB Nasop... Stage IVB Oroph... Stage IVC Lip a... Stage IVC Nasal... Stage IVC Nasop... Stage IVC Oroph... Head and Neck C... Oropharyngeal C... HNSCC Stage IV Lip an...	Cetuximab Ficlatuzumab	18 Years -	University of Arizona
Temsirolimus With or Without Cetuximab in Patients With Recurrent and/or Metastatic Head and Neck Cancer Who Did Not Respond to Previous Therapy	NCT01256385	Recurrent Hypop... Recurrent Laryn... Recurrent Laryn... Recurrent Lip a... Recurrent Metas... Recurrent Nasal... Recurrent Nasop... Recurrent Oral ... Recurrent Oroph... Recurrent Saliv... Salivary Gland ... Squamous Cell C... Stage IV Hypoph... Stage IV Nasoph... Stage IVA Laryn... Stage IVA Laryn... Stage IVA Lip a... Stage IVA Major... Stage IVA Nasal... Stage IVA Oral ... Stage IVA Oroph... Stage IVB Laryn... Stage IVB Laryn... Stage IVB Lip a... Stage IVB Major... Stage IVB Nasal... Stage IVB Oral ... Stage IVB Oroph... Stage IVC Laryn... Stage IVC Laryn... Stage IVC Lip a... Stage IVC Major... Stage IVC Nasal... Stage IVC Oral ... Stage IVC Oroph... Tongue Carcinom...	Cetuximab Laboratory Biom... Temsirolimus	18 Years -	National Cancer Institute (NCI)
Ficlatuzumab w/wo Cetuximab in Patients w/Cetuximab-Resistant, Recurrent or Metastatic Head/Neck Squamous Cell Carcinoma	NCT03422536	Head and Neck B... Recurrent Head ... Recurrent Oroph... Squamous Cell C... Stage IV Squamo... Stage IV Squamo... Stage IV Nasoph... Stage IV Oropha... Stage IVA Lip a... Stage IVA Nasal... Stage IVA Nasop... Stage IVA Oroph... Stage IVB Lip a... Stage IVB Nasal... Stage IVB Nasop... Stage IVB Oroph... Stage IVC Lip a... Stage IVC Nasal... Stage IVC Nasop... Stage IVC Oroph... Head and Neck C... Oropharyngeal C... HNSCC Stage IV Lip an...	Cetuximab Ficlatuzumab	18 Years -	University of Arizona

Spots Global Cancer Trial Database for stage ivb lip and oral cavity squamous cell carcinoma