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CompletedNCT01696955Updated Dec 19, 2018Results posted

Cetuximab With or Without Tivantinib in Treating Patients With Head and Neck Cancer That Is Recurrent, Metastatic, or Cannot Be Removed by Surgery

A Phase 2 interventional study of Cetuximab and Laboratory Biomarker Analysis in Head and Neck Squamous Cell Carcinoma and Recurrent Head and Neck Carcinoma, sponsored by National Cancer Institute (NCI). Completed at 24 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2018-12-19.

Sponsored by National Cancer Institute (NCI) · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
81
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study summary

This randomized phase II trial studies how well cetuximab with or without tivantinib works in treating patients with head and neck cancer that has come back (recurrent), has spread to other places in the body (metastatic), or cannot be removed by surgery. Monoclonal antibodies, such as cetuximab, may interfere with the ability of tumor cells to grow and spread. Tivantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether cetuximab is more effective with or without tivantinib in treating patients with head and neck cancer.

Read the detailed description

PRIMARY OBJECTIVES:

I. Response rate (comparing the cetuximab/ARQ 197 [tivantinib] combination with cetuximab single agent activity).

SECONDARY OBJECTIVES:

I. Continuous tumor shrinkage. II. Progression-free survival (PFS). III. Overall survival (OS). IV. Objectives I, II, and III above, as well as response rates, will be assessed and compared between treatment arms in the subgroup of patients with high mesenchymal epithelial transition factor (c-MET) expression, and/or high c-MET copy number.

V. Single agent activity for ARQ 197 (tivantinib) in patients who have failed cetuximab.

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

ARM I: Patients receive cetuximab intravenously (IV) over 60-120 minutes on days 1 and 15 and tivantinib orally (PO) twice daily (BID) on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive cetuximab IV over 60-120 minutes on days 1 and 15. Patients who fail cetuximab as a single agent may receive single agent tivantinib PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 5 years.

02

Conditions studied

  • Head and Neck Squamous Cell Carcinoma
  • Recurrent Head and Neck Carcinoma
03

In context

Carcinoma

6,741 studies on the registry are indexed under Carcinoma; 1,161 are open to participants now.

This study's enrollment of 81 is above the median of 45 across 5,170 interventional studies indexed under Carcinoma.

Browse Carcinoma studies →

Lead sponsor

National Cancer Institute (NCI) is the lead sponsor of 3,506 studies on the registry; 334 are open to participants now.

Of its 402 completed or terminated interventional studies of FDA-regulated products, 365 (91%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  • Histologically/cytologically confirmed diagnosis of squamous cell carcinoma of head and neck origin not amenable to curative intent therapy; both human papillomavirus (HPV) positive (+) and HPV negative (-) are eligible, but status has to be known prior to randomization (although not required for consenting); any type of tissue based HPV assessment is acceptable (e.g. p16 immunohistochemistry [IHC] or HPV in situ hybridization [ISH]); if local HPV testing is not available slides can be sent to the University of Chicago for HPV testing; please note that p16 IHC is generally only considered to be accurate for oropharyngeal tumors
  • Presence of measurable lesions (as per Response Evaluation Criteria in Solid Tumors [RECIST] 1.1); generally a >= 10 mm tumor lesion (in the longest diameter by computed tomography [CT] scan) or a lymph node >= 15 mm (short axis) is considered measurable disease when evaluated by CT scan (with a slice thickness no greater than 5 mm)
  • Availability of tissue (10 tumor containing formalin-fixed, paraffin-embedded [FFPE] slides/sections)
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1
  • Patients who have received cetuximab or another inhibitor of epidermal growth factor receptor (EGFR) in the curative intent treatment setting (e.g. with radiation or during induction chemotherapy [prior to definitive, curative intent therapy]) are eligible for the study
  • Life expectancy of greater than 8 weeks
  • Hemoglobin >= 9.0 g/dL
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin =\< 1.5 x institutional upper limit of normal
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =\< 2.5 x institutional upper limit of normal
  • Serum creatinine =\< 1.5 x institutional upper limit of normal OR creatinine clearance >= 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal
  • Patients must be able to swallow ARQ 197 (tivantinib) by mouth, unless adequate data about administration by gastrostomy (G)-tube becomes available; tablets may be crushed, but must be taken orally
  • Human immunodeficiency virus (HIV)-positive patients with normal immune function (cluster of differentiation [CD]4 count > 200) are eligible if there are no drug interactions with ARQ 197 (tivantinib) or cetuximab
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of ARQ 197 (tivantinib) administration
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion criteria

Exclusion Criteria:

  • Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier
  • Nasopharyngeal tumors that show lymphoepithelioma histology
  • Patients who have received more than 2 prior cytotoxic treatments in the palliative treatment setting are ineligible
  • Patients who have received treatment with an EGFR or MET inhibitor in the palliative treatment setting are ineligible
  • Patients with known, active brain metastases should be excluded from this clinical trial; patients with treated brain metastases stable for >= 12 weeks are eligible; use of corticosteroid (for patients with brain metastasis and other indications for corticosteroid use) is acceptable on a low maintenance or tapering dose schedule
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to ARQ 197 (tivantinib) or cetuximab
  • Concurrent life-threatening diseases: patients with diseases which with reasonable certainty do not limit life expectancy to 12 months or less are eligible; assessment of such concurrent illnesses should be by the principal investigator
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with ARQ 197 (tivantinib)
  • Concurrent use of warfarin (therapeutic use) is allowed, but requires close monitoring of prothrombin time (PT)/international normalized ratio (INR)
  • History of congestive heart failure defined as class II to IV per New York Heart Association (NYHA) classification; active coronary artery disease (CAD), clinically significant bradycardia or other uncontrolled, cardiac arrhythmia defined as >= grade 3 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, or uncontrolled hypertension; myocardial infarction occurring within 6 months prior to study entry (myocardial infarction occurring > 6 months prior to study entry is permitted)
  • Patients may not be receiving any other investigational agents
05

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
81 participants (actual)

Study arms

  • Experimental
    Arm I (cetuximab and tivantinib)

    Patients receive cetuximab IV over 60-120 minutes on days 1 and 15 and tivantinib PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

    Biological: Cetuximab · Other: Laboratory Biomarker Analysis · Drug: Tivantinib

  • Experimental
    Arm II (cetuximab)

    Patients receive cetuximab IV over 60-120 minutes on days 1 and 15. Patients who fail cetuximab as a single agent may receive single agent tivantinib PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

    Biological: Cetuximab · Other: Laboratory Biomarker Analysis

Interventions

  • BiologicalCetuximab

    Given IV

  • OtherLaboratory Biomarker Analysis

    Correlative studies

  • DrugTivantinib

    Given PO

06

What researchers measure

Primary outcomes

  1. Overall Response Rate

    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; Overall Response (OR) = CR + PR

    Time frame: Up to 1 year

Secondary outcomes

  1. c-MET Copy Number

    Change in copy number from baseline to 8 weeks

    Time frame: Baseline to 8 weeks

  2. c-MET Expression

    Change in c-MET expression from baseline to 8 weeks

    Time frame: Baseline to 8 weeks

  3. Change in Tumor Burden

    Early change in tumor burden measured using the sum of longest diameters of target lesions, expressed as percent change from baseline.

    Time frame: Baseline to 8 weeks

  4. Overall Survival

    Time from randomization until death or date last known alive

    Time frame: Up to 5 years

  5. Progression-free Survival

    Time from randomization until disease progression/death from any cause or date last know progression-free

    Time frame: Up to 3 years

  6. Overall Response Rate of Single-agent Tivantinib After Failure of Cetuximab

    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; Overall Response (OR) = CR + PR

    Time frame: Up to 1 year

Other outcomes

  1. Number of Participants With Adverse Events While on Single-agent Tivantinib After Failure of Cetuximab

    Non-serious adverse events, CTCAE (4.0)

    Time frame: Up to 3 years

  2. Number of Patients With Serious Adverse Events While on Single-agent Tivantinib After Failure of Cetuximab

    CTCAE (4.0)

    Time frame: 3 years

07

Results

Posted Dec 19, 2018

Participant flow

Main Study
Participant flow — Main Study
MilestoneArm I (Cetuximab and Tivantinib)Arm II (Cetuximab)
Started4239
Completed4038
Not completed21
Withdrew: Protocol violation10
Withdrew: Withdrawal by subject11
Failure on Cetuximab-Received Tivantinib
Participant flow — Failure on Cetuximab-Received Tivantinib
MilestoneArm I (Cetuximab and Tivantinib)Arm II (Cetuximab)
Started015
Completed015
Not completed00

Outcome measures

PrimaryOverall Response Rate

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; Overall Response (OR) = CR + PR

Time frame:
Up to 1 year
Reported as:
Count of participants · Participants
Overall Response Rate
ParticipantsArm I (Cetuximab and Tivantinib)Arm II (Cetuximab)
Complete response10
Partial response23
Statistical analysis
  • Arm I (Cetuximab and Tivantinib) vs Arm II (Cetuximab) · Fisher Exact · p = 0.99
Secondaryc-MET Copy Number

Change in copy number from baseline to 8 weeks

Time frame:
Baseline to 8 weeks

No measurements were reported for this outcome.

Secondaryc-MET Expression

Change in c-MET expression from baseline to 8 weeks

Time frame:
Baseline to 8 weeks

No measurements were reported for this outcome.

SecondaryChange in Tumor Burden

Early change in tumor burden measured using the sum of longest diameters of target lesions, expressed as percent change from baseline.

Time frame:
Baseline to 8 weeks
Reported as:
Mean · percent change
Change in Tumor Burden
percent changeArm I (Cetuximab and Tivantinib)Arm II (Cetuximab)
Change in Tumor Burden15.0 ± 6.19.0 ± 5.5
Statistical analysis
  • Arm I (Cetuximab and Tivantinib) vs Arm II (Cetuximab) · t-test, 2 sided · p = 0.47
SecondaryOverall Survival

Time from randomization until death or date last known alive

Time frame:
Up to 5 years
Reported as:
Median · months
Overall Survival
monthsArm I (Cetuximab and Tivantinib)Arm II (Cetuximab)
Overall Survival7.4 (4.7 to 10.3)8.6 (5.7 to 11.5)
Statistical analysis
  • Arm I (Cetuximab and Tivantinib) vs Arm II (Cetuximab) · Log Rank · p = 0.99
SecondaryProgression-free Survival

Time from randomization until disease progression/death from any cause or date last know progression-free

Time frame:
Up to 3 years
Reported as:
Median · months
Progression-free Survival
monthsArm I (Cetuximab and Tivantinib)Arm II (Cetuximab)
Progression-free Survival3.5 (1.8 to 3.9)3.5 (2.0 to 3.9)
Statistical analysis
  • Arm I (Cetuximab and Tivantinib) vs Arm II (Cetuximab) · Log Rank · p = 0.58
SecondaryOverall Response Rate of Single-agent Tivantinib After Failure of Cetuximab

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; Overall Response (OR) = CR + PR

Time frame:
Up to 1 year
Reported as:
Count of participants · Participants
Overall Response Rate of Single-agent Tivantinib After Failure of Cetuximab
ParticipantsArm I (Cetuximab and Tivantinib)Tivantinib After Cetuximab Failure
Overall Response Rate of Single-agent Tivantinib After Failure of Cetuximab—0
Other pre-specifiedNumber of Participants With Adverse Events While on Single-agent Tivantinib After Failure of Cetuximab

Non-serious adverse events, CTCAE (4.0)

Time frame:
Up to 3 years
Reported as:
Count of participants · Participants
Number of Participants With Adverse Events While on Single-agent Tivantinib After Failure of Cetuximab
ParticipantsArm I (Cetuximab and Tivantinib)Tivantinib After Cetuximab Failure
Number of Participants With Adverse Events While on Single-agent Tivantinib After Failure of Cetuximab—9
Other pre-specifiedNumber of Patients With Serious Adverse Events While on Single-agent Tivantinib After Failure of Cetuximab

CTCAE (4.0)

Time frame:
3 years
Reported as:
Count of participants · Participants
Number of Patients With Serious Adverse Events While on Single-agent Tivantinib After Failure of Cetuximab
ParticipantsArm I (Cetuximab and Tivantinib)Tivantinib After Cetuximab Failure
Number of Patients With Serious Adverse Events While on Single-agent Tivantinib After Failure of Cetuximab—4

Adverse events

Collected over 3 years. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Arm I (Cetuximab and Tivantinib)36/40 (90%)19/40 (47.5%)38/40 (95%)
Arm II (Cetuximab)35/38 (92.1%)18/38 (47.4%)35/38 (92.1%)
Single-agent Tivantinib After Failure of Cetuximab2/15 (13.3%)4/15 (26.7%)9/15 (60%)
Most frequent serious events
Showing 10 of 46
Most frequent serious events
EventArm I (Cetuximab and Tivantinib)Arm II (Cetuximab)Single-agent Tivantinib After Failure of Cetuximab
Lung infectionInfections and infestations1/401/382/15
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specifyNeoplasms benign, malignant and unspecified (incl cysts and polyps)5/402/381/15
Neutrophil count decreasedInvestigations4/400/380/15
DehydrationMetabolism and nutrition disorders2/403/380/15
Febrile neutropeniaBlood and lymphatic system disorders3/400/381/15
White blood cell decreasedInvestigations3/400/380/15
Atrial fibrillationCardiac disorders0/401/381/15
PainGeneral disorders0/401/381/15
DyspneaRespiratory, thoracic and mediastinal disorders1/400/381/15
VomitingGastrointestinal disorders1/400/381/15
Most frequent other events
Showing 10 of 69
Most frequent other events
EventArm I (Cetuximab and Tivantinib)Arm II (Cetuximab)Single-agent Tivantinib After Failure of Cetuximab
FatigueGeneral disorders21/4017/383/15
Rash acneiformSkin and subcutaneous tissue disorders20/4019/381/15
AnemiaBlood and lymphatic system disorders16/409/383/15
AnorexiaMetabolism and nutrition disorders12/4010/380/15
NauseaGastrointestinal disorders12/4010/381/15
HyponatremiaMetabolism and nutrition disorders11/403/382/15
ConstipationGastrointestinal disorders7/4010/381/15
HypomagnesemiaMetabolism and nutrition disorders9/4010/383/15
Rash maculo-papularSkin and subcutaneous tissue disorders10/4010/382/15
Lymphocyte count decreasedInvestigations10/404/383/15

Baseline characteristics

Age, Continuous
Age, Continuous(years)Arm I (Cetuximab and Tivantinib)Arm II (Cetuximab)Total
Mean60.5 (37 to 90)63.6 (35 to 87)62.0 (35 to 90)
Sex: Female, Male
Sex: Female, Male(Participants)Arm I (Cetuximab and Tivantinib)Arm II (Cetuximab)Total
Female6612
Male343266
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Arm I (Cetuximab and Tivantinib)Arm II (Cetuximab)Total
American Indian or Alaska Native000
Asian325
Native Hawaiian or Other Pacific Islander000
Black or African American437
White323365
More than one race000
Unknown or Not Reported101
Region of Enrollment
Region of Enrollment(Participants)Arm I (Cetuximab and Tivantinib)Arm II (Cetuximab)Total
United States403878
08

Study locations

24 sites
  • Mayo Clinic in Arizona
    Scottsdale, Arizona 85259, United States
  • City of Hope Comprehensive Cancer Center
    Duarte, California 91010, United States
  • USC / Norris Comprehensive Cancer Center
    Los Angeles, California 90033, United States
  • University of California Davis Comprehensive Cancer Center
    Sacramento, California 95817, United States
  • City of Hope South Pasadena
    South Pasadena, California 91030, United States
  • Northwestern University
    Chicago, Illinois 60611, United States
  • University of Chicago Comprehensive Cancer Center
    Chicago, Illinois 60637, United States
  • Decatur Memorial Hospital
    Decatur, Illinois 62526, United States
  • NorthShore University HealthSystem-Evanston Hospital
    Evanston, Illinois 60201, United States
  • Ingalls Memorial Hospital
    Harvey, Illinois 60426, United States
  • Illinois CancerCare-Peoria
    Peoria, Illinois 61615, United States
  • Southern Illinois University School of Medicine
    Springfield, Illinois 62702, United States
  • Fort Wayne Medical Oncology and Hematology Inc-Parkview
    Fort Wayne, Indiana 46845, United States
  • Indiana University/Melvin and Bren Simon Cancer Center
    Indianapolis, Indiana 46202, United States
  • University of Iowa/Holden Comprehensive Cancer Center
    Iowa City, Iowa 52242, United States
  • University of Maryland/Greenebaum Cancer Center
    Baltimore, Maryland 21201, United States
  • University of Michigan Comprehensive Cancer Center
    Ann Arbor, Michigan 48109, United States
  • Wayne State University/Karmanos Cancer Institute
    Detroit, Michigan 48201, United States
  • Mayo Clinic
    Rochester, Minnesota 55905, United States
  • Metro Minnesota Community Oncology Research Consortium
    Saint Louis Park, Minnesota 55416, United States
  • Washington University School of Medicine
    Saint Louis, Missouri 63110, United States
  • Mercy Hospital Saint Louis
    Saint Louis, Missouri 63141, United States
  • Penn State Milton S Hershey Medical Center
    Hershey, Pennsylvania 17033-0850, United States
  • University of Pittsburgh Cancer Institute (UPCI)
    Pittsburgh, Pennsylvania 15232, United States
09

References and documents

Study documents

  • Protocol and statistical analysis plan · Apr 19, 2016

Documents are hosted by the registry — open the source record to download them.

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Dec 19, 2018, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT01696955
Lead sponsor
National Cancer Institute (NCI)
Responsible party
Sponsor
First posted
Oct 2, 2012
Start date
Aug 20, 2012
Primary completion
May 5, 2017
Completion
May 5, 2017
Results posted
Dec 19, 2018
Last update
Dec 19, 2018

Study contacts

Tanguy Seiwert
principal investigator · University of Chicago Comprehensive Cancer Center

Oversight

Data monitoring committee
No
View the source record on ClinicalTrials.gov ↗

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