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Chemotherapy Plus Cetuximab in Combination With VTX-2337 in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

Sponsor
Celgene (Industry)
Overall Status
Completed
CT.gov ID
NCT01836029
Collaborator
(none)
195
Enrollment
53
Locations
2
Arms
35.2
Actual Duration (Months)
3.7
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to compare the progression-free survival of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) treated with VTX-2337 + cisplatin or carboplatin + 5-FU + cetuximab versus patients treated with cisplatin or carboplatin + 5-FU + cetuximab alone (standard-of-care; SOC). Safety and overall survival will also be evaluated.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

This is a randomized, double-blind, placebo-controlled, parallel group study to evaluate the safety and efficacy of VTX 2337 in combination with cisplatin or carboplatin, 5-FU and cetuximab in prolonging the progression-free survival in subjects with recurrent or metastatic squamous cell carcinoma of the head and neck.

OBJECTIVES:
Primary Objective:

To compare the efficacy of VTX 2337 plus SOC to SOC alone in prolonging the PFS of patients with recurrent or metastatic SCCHN using irRECIST evaluated by independent radiology review.

Secondary Objectives:
To compare the following between the two treatment groups:

  • Safety of VTX 2337 by adverse events, including clinically significant changes in physical examination, peripheral blood hematology, serum chemistry, urinalysis, and ECG.

  • Efficacy of VTX 2337 plus SOC in prolonging the OS of patients with recurrent or metastatic SCCHN.

  • Efficacy of VTX-2337 plus SOC on ORR, DOBR, DCR, and DDC by irRECIST and evaluation by independent radiology review.

  • Efficacy of VTX-2337 plus SOC on ORR, DOBR, DCR, and DDC by RECIST v1.1 and evaluation by independent radiology review.

  • Efficacy of VTX 2337 plus SOC to SOC alone in prolonging the PFS by RECIST v1.1 and evaluation by independent radiology review.

  • Efficacy of VTX 2337 plus SOC to SOC alone in prolonging the PFS by irRECIST and evaluation by investigators.

Exploratory Objectives:

  • To compare genetic polymorphisms that may impact the response of patients to a TLR8 agonist or to cetuximab between the two treatment groups.

  • To compare immune biomarker response to VTX 2337 plus SOC as measured by a multiplexed panel of cytokines, chemokines, and inflammatory markers between the two treatment groups.

  • To compare the effect of immune cell subsets within the tumor on response to VTX-2337 and/or clinical outcome, as measured by immunohistochemistry in primary tumor tissue between the two treatment groups.

  • To assess the PK of VTX-2337.

OUTLINE:

Subjects will be screened for eligibility (within 14 days) and qualified subjects will be randomized 1:1 to 1 of 2 treatment groups: SOC + VTX 2337 or SOC + placebo.

Tumor assessments will be by CT or MRI starting at Week 12 (± 3 days), then at Week 18 (± 3 days) and every 8 weeks (± 7 days) thereafter. Response will be evaluated by immune-related RECIST criteria (irRECIST) and confirmed by an independent radiologist.

Upon independent confirmation of disease progression, active participation in the study is complete and subjects will undergo the End of Treatment evaluations.

Subjects will be followed for survival until ~12 months after the last subject is randomized.

Study Design

Study Type:
Interventional
Actual Enrollment :
195 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Randomized, Double-Blind, Placebo-Controlled Study of Chemotherapy Plus Cetuximab in Combination With VTX 2337 in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck
Actual Study Start Date :
Oct 14, 2013
Actual Primary Completion Date :
Apr 13, 2016
Actual Study Completion Date :
Sep 19, 2016

Arms and Interventions

Arm Intervention/Treatment
Experimental: chemotherapy and cetuximab plus VTX-2337

VTX-2337 (3.0 mg/m2) will be administered on Day 8 and Day 15 of a 21-day cycle for 6 cycles, followed by dosing on Days 8 and 22 of 28-day cycles until disease progression. Cisplatin (100 mg/m2) OR carboplatin (AUC 5 mg/mL/min) will be administered on Day 1 of a 21-day cycle for a maximum of 6 cycles. 5-FU (1000 mg/m2) will be administered on Days 1-4 of a 21-day cycle for a maximum of 6 cycles. Cetuximab (initial dose: 400 mg/m2; remaining doses: 250 mg/m2) will be administered weekly until disease progression.

Drug: VTX-2337
TLR8 Agonist

Drug: Carboplatin
Other Names:
  • paraplatin

    • Drug: Cisplatin
    Other Names:
  • Platin

    • Drug: 5-fluorouracil
    Other Names:
  • 5-FU
  • Efudex
  • Fluorouracil

    		•
    Active Comparator: chemotherapy and cetuximab plus placebo

    Placebo (3.0 mg/m2) will be administered on Day 8 and Day 15 of a 21-day cycle for 6 cycles, followed by dosing on Days 8 and 22 of 28-day cycles until disease progression. Cisplatin (100 mg/m2) OR carboplatin (AUC 5 mg/mL/min) will be administered on Day 1 of a 21-day cycle for a maximum of 6 cycles. 5-FU (1000 mg/m2) will be administered on Days 1-4 of a 21-day cycle for a maximum of 6 cycles. Cetuximab (initial dose: 400 mg/m2; remaining doses: 250 mg/m2) will be administered weekly until disease progression.

    Drug: Carboplatin
    Other Names:
  • paraplatin

    • Drug: Cisplatin
    Other Names:
  • Platin

    • Drug: 5-fluorouracil
    Other Names:
  • 5-FU
  • Efudex
  • Fluorouracil

    • Drug: Placebo

    Outcome Measures

    Primary Outcome Measures

    1. Comparison of Progression Free Survival (PFS) Between Treatment Groups Using irRECIST and Evaluated by Independent Radiology. [PFS is the time from randomization until disease progression or death, whichever comes first.]

      PFS was based on central assessment by a blinded independent radiologist per immune related response evaluation criteria for solid tumors (irRECIST) and was summarized and displayed by treatment arm using Kaplan-Meier methods. Treatments were compared using a stratified log-rank test controlling for randomization stratification factors. The hazard ratio between the 2 treatment arms, as well as the associated one-sided 90% CI and p-value, were presented using a Cox proportional hazards regression model.

    Secondary Outcome Measures

    1. Comparison of Adverse Events (AEs) Between the Two Treatment Groups. [AEs were collected from the first dose of study drug given on Cycle 1 Day 1 until 7 days after the dose of study drug or End of Treatment visit, whichever occurred first. Overall mean duration of exposure was 25.3 weeks.]

      The frequency and severity of adverse events, including any clinically significant changes in physical exam, laboratory values, or other clinical assessment.

    2. Comparison of Overall Survival (OS) Between the 2 Treatment Groups. [OS is the time from randomization until death due to any cause or the date last confirmed to be alive.]

      Estimated using Kaplan-Meier product limit estimates, 1-sided stratified log-rank test, and Cox proportional hazard model; all with 90% 1-sided confidence intervals.

    3. Comparison of the Objective Response Rate Between the Two Treatment Groups p [From the time of randomization until the best response on treatment is documented.]

      Objective response rate is defined as the percentage of subjects who achieve best overall response of irCR or irPR pr irRECIST and evaluated by independent radiology..

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Ability and willingness to provide written informed consent

    • Histologically or cytologically confirmed squamous cell carcinoma of the head and neck

    • Locoregionally recurrent or metastatic disease that has not previously been treated with systemic therapy of recurrent or metastatic disease

    • At least one measurable lesion on screening CT or MRI

    • 18 years of age or older

    • ECOG performance status of 0 or 1

    • Acceptable bone marrow, renal, and hepatic function based upon screening lab tests

    • Willingness to use medically acceptable contraception

    • For females with reproductive potential: a negative serum pregnancy test

    Exclusion Criteria:

    • Disease which is amenable to curative local therapy

    • Nasopharyngeal, salivary gland, lip or sinonasal carcinoma

    • Surgery or irradiation ≤ 4 weeks prior to randomization

    • Prior systemic anti-cancer therapy, unless administered for localized SCCHN and completed at least 6 months prior to disease recurrence

    • Treatment with an investigational agent ≤ 30 days prior to randomization

    • Treatment with corticosteroids within 2 weeks

    • A requirement for chronic systemic immunosuppressive therapy for any reason

    • Prior serious infusion reaction to cetuximab

    • Treatment with an immunotherapy within 30 days

    • Known brain metastases, unless stable for at least 28 days

    • Active autoimmune disease currently requiring therapy

    • Known infection with HIV

    • Significant cardiac disease within 6 months

    • Pregnant or breast-feeding females

    • History of another primary malignancy, with the exception of (i) curatively resected non-melanoma skin cancer, (ii) curatively treated in situ cervical cancer, or (iii) other malignancy curatively treated with no evidence of disease and no anticancer therapy administered for 3 years prior to randomization, with the exception of adjuvant hormonal therapy for breast cancer

    • Other conditions or circumstances that could interfere with the study

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of Arkansas for Medical Sciences Little Rock Arkansas United States 72205
    2 Tower Hematology Oncology Medical Group Beverly Hills California United States 90211
    3 California Cancer Associates for Research and Excellence (CCARE) Escondido California United States 92025
    4 University of California San Diego Moores Cancer Center La Jolla California United States 92093
    5 University of California Norris Comprehensive Cancer Center Los Angeles California United States 90033
    6 University of Colorado Cancer Center Aurora Colorado United States 80045
    7 VA Eastern Colorado Healthcare System Denver Colorado United States 80220
    8 Helen F. Graham Cancer Center Newark Delaware United States 19713
    9 MD Anderson Cancer Center Orlando Florida United States 32806
    10 Northeast Georgia Cancer Care, LLC Athens Georgia United States 30607
    11 Winship Cancer Institute Atlanta Georgia United States 30322
    12 Tripler Army Medical Center Honolulu Hawaii United States 96859
    13 Northwestern University Feinberg School of Medicine Chicago Illinois United States 60611
    14 Carle Cancer Center Urbana Illinois United States 61801
    15 University of Kansas Cancer Center Westwood Kansas United States 66205
    16 Crescent City Research Consortium, LLC Marrero Louisiana United States 70072
    17 Robert W. Veith, MD, LLC Metairie Louisiana United States 70006-2936
    18 Maine Center for Cancer Medicine Scarborough Maine United States 04074
    19 The Sidney Kimmel Comprehensive Cancer Center at John Hopkins Baltimore Maryland United States 21231
    20 Walter Reed National Military Medical Center Bethesda Maryland United States 20889
    21 Dana Farber Cancer Institute Boston Massachusetts United States 02215
    22 Karmanos Cancer Institute Detroit Michigan United States 48201
    23 Henry Ford Health System Detroit Michigan United States 48202
    24 Providence Cancer Institute Southfield Michigan United States 48075
    25 Saint Louis Cancer Care, LLP Bridgeton Missouri United States 63044
    26 Barnes Jewish Hospital Saint Louis Missouri United States 63110
    27 Nevada Cancer Research Foundation Las Vegas Nevada United States 89106
    28 Dartmouth Hitchcock Medical Center Lebanon New Hampshire United States 03756
    29 Oncology and Hematology Specialists, P.A. Denville New Jersey United States 07834
    30 Hackensack University Medical Center Hackensack New Jersey United States 07601
    31 Monter Cancer Center Lake Success New York United States 11042
    32 The Bellevue Hospital New York New York United States 10016
    33 Mount Sinai Medical Center New York New York United States 10029
    34 Stony Brook University Medical Center Stony Brook New York United States 11794
    35 University of North Carolina at Chapel Hill Chapel Hill North Carolina United States 27599
    36 Wake Forest University Baptist Medical Center Winston-Salem North Carolina United States 27103
    37 University of Cincinnati Cincinnati Ohio United States 45267-0502
    38 University Hospitals of Cleveland Cleveland Ohio United States 44106
    39 Cleveland Clinic Cleveland Ohio United States 44195
    40 Saint Charles Medical Center Bend Oregon United States 97701
    41 Providence Cancer Center Portland Oregon United States 97213
    42 Saint Lukes Cancer Centre Easton Pennsylvania United States 18045
    43 Pennsylvania State Hershey Cancer Institute Hershey Pennsylvania United States 17033
    44 University of Pittsburgh Cancer Institute Pittsburgh Pennsylvania United States 15232
    45 Hollings Cancer Center Charleston South Carolina United States 29425
    46 The West Clinic Memphis Tennessee United States 38120
    47 University of Texas Southwestern Medical Center at Dallas Dallas Texas United States 75390-8852
    48 San Antonio Military Medical Center Fort Sam Houston Texas United States 78234
    49 Virginia Cancer Specialists, PD Fairfax Virginia United States 22031
    50 Medical Oncology Associates, PS Spokane Washington United States 99208
    51 Madigan Army Medical Center Tacoma Washington United States 98431
    52 Medical College of Wisconsin Milwaukee Wisconsin United States 53226
    53 Aurora Advanced Healthcare, Inc. Wauwatosa Wisconsin United States 53226

    Sponsors and Collaborators

    • Celgene

    Investigators

    • Study Chair: Ezra Cohen, MD, University of Chicago
    • Study Chair: Robert Ferris, MD, PhD, University of Pittsburgh
    • Study Director: Amar Patel, MD, Celgene

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Celgene
    ClinicalTrials.gov Identifier:
    NCT01836029
    Other Study ID Numbers:
    • VRXP-A202
    First Posted:
    Apr 19, 2013
    Last Update Posted:
    Oct 29, 2019
    Last Verified:
    Oct 1, 2019
    Keywords provided by Celgene
    SCCHN
    HNSCC
    Additional relevant MeSH terms:
    Carcinoma
    Carcinoma, Squamous Cell
    Squamous Cell Carcinoma of Head and Neck
    Carboplatin
    Fluorouracil

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Chemotherapy and Cetuximab Plus VTX-2337 Chemotherapy and Cetuximab Plus Placebo
    Arm/Group Description VTX-2337 (3.0 mg/m2) will be administered on Day 8 and Day 15 of a 21-day cycle for 6 cycles, followed by dosing on Days 8 and 22 of 28-day cycles until disease progression. Cisplatin (100 mg/m2) OR carboplatin (AUC 5 mg/mL/min) will be administered on Day 1 of a 21-day cycle for a maximum of 6 cycles. 5-FU (1000 mg/m2) will be administered on Days 1-4 of a 21-day cycle for a maximum of 6 cycles. Cetuximab (initial dose: 400 mg/m2; remaining doses: 250 mg/m2) will be administered weekly until disease progression. VTX-2337: TLR8 Agonist Carboplatin Cisplatin 5-fluorouracil Placebo (3.0 mg/m2) will be administered on Day 8 and Day 15 of a 21-day cycle for 6 cycles, followed by dosing on Days 8 and 22 of 28-day cycles until disease progression. Cisplatin (100 mg/m2) OR carboplatin (AUC 5 mg/mL/min) will be administered on Day 1 of a 21-day cycle for a maximum of 6 cycles. 5-FU (1000 mg/m2) will be administered on Days 1-4 of a 21-day cycle for a maximum of 6 cycles. Cetuximab (initial dose: 400 mg/m2; remaining doses: 250 mg/m2) will be administered weekly until disease progression. Carboplatin Cisplatin 5-fluorouracil Placebo
    Period Title: Overall Study
    STARTED 100 95
    COMPLETED 100 95
    NOT COMPLETED 0 0

    Baseline Characteristics

    Arm/Group Title Chemotherapy and Cetuximab Plus VTX-2337 Chemotherapy and Cetuximab Plus Placebo Total
    Arm/Group Description VTX-2337 (3.0 mg/m2) will be administered on Day 8 and Day 15 of a 21-day cycle for 6 cycles, followed by dosing on Days 8 and 22 of 28-day cycles until disease progression. Cisplatin (100 mg/m2) OR carboplatin (AUC 5 mg/mL/min) will be administered on Day 1 of a 21-day cycle for a maximum of 6 cycles. 5-FU (1000 mg/m2) will be administered on Days 1-4 of a 21-day cycle for a maximum of 6 cycles. Cetuximab (initial dose: 400 mg/m2; remaining doses: 250 mg/m2) will be administered weekly until disease progression. VTX-2337: TLR8 Agonist Carboplatin Cisplatin 5-fluorouracil Placebo (3.0 mg/m2) will be administered on Day 8 and Day 15 of a 21-day cycle for 6 cycles, followed by dosing on Days 8 and 22 of 28-day cycles until disease progression. Cisplatin (100 mg/m2) OR carboplatin (AUC 5 mg/mL/min) will be administered on Day 1 of a 21-day cycle for a maximum of 6 cycles. 5-FU (1000 mg/m2) will be administered on Days 1-4 of a 21-day cycle for a maximum of 6 cycles. Cetuximab (initial dose: 400 mg/m2; remaining doses: 250 mg/m2) will be administered weekly until disease progression. Carboplatin Cisplatin 5-fluorouracil Placebo Total of all reporting groups
    Overall Participants 100 95 195
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    57.1
    (10.07)
    59.9
    (9.08)
    58.5
    (9.68)
    Age, Customized (Count of Participants)
    <40 years
    6
    6%
    1
    1.1%
    7
    3.6%
    40-49 years
    9
    9%
    9
    9.5%
    18
    9.2%
    50-59 years
    47
    47%
    35
    36.8%
    82
    42.1%
    60-69 years
    29
    29%
    37
    38.9%
    66
    33.8%
    70-79 years
    8
    8%
    13
    13.7%
    21
    10.8%
    >=80 years
    1
    1%
    0
    0%
    1
    0.5%
    Sex: Female, Male (Count of Participants)
    Female
    15
    15%
    14
    14.7%
    29
    14.9%
    Male
    85
    85%
    81
    85.3%
    166
    85.1%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    1
    1%
    2
    2.1%
    3
    1.5%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    15
    15%
    12
    12.6%
    27
    13.8%
    White
    81
    81%
    78
    82.1%
    159
    81.5%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    3
    3%
    3
    3.2%
    6
    3.1%
    Region of Enrollment (Count of Participants)
    United States
    100
    100%
    95
    100%
    195
    100%

    Outcome Measures

    1. Primary Outcome
    Title Comparison of Progression Free Survival (PFS) Between Treatment Groups Using irRECIST and Evaluated by Independent Radiology.
    Description PFS was based on central assessment by a blinded independent radiologist per immune related response evaluation criteria for solid tumors (irRECIST) and was summarized and displayed by treatment arm using Kaplan-Meier methods. Treatments were compared using a stratified log-rank test controlling for randomization stratification factors. The hazard ratio between the 2 treatment arms, as well as the associated one-sided 90% CI and p-value, were presented using a Cox proportional hazards regression model.
    Time Frame PFS is the time from randomization until disease progression or death, whichever comes first.

    Outcome Measure Data

    Analysis Population Description
    ITT population
    Arm/Group Title Chemotherapy and Cetuximab Plus VTX-2337 Chemotherapy and Cetuximab Plus Placebo
    Arm/Group Description VTX-2337 (3.0 mg/m2) will be administered on Day 8 and Day 15 of a 21-day cycle for 6 cycles, followed by dosing on Days 8 and 22 of 28-day cycles until disease progression. Cisplatin (100 mg/m2) OR carboplatin (AUC 5 mg/mL/min) will be administered on Day 1 of a 21-day cycle for a maximum of 6 cycles. 5-FU (1000 mg/m2) will be administered on Days 1-4 of a 21-day cycle for a maximum of 6 cycles. Cetuximab (initial dose: 400 mg/m2; remaining doses: 250 mg/m2) will be administered weekly until disease progression. VTX-2337: TLR8 Agonist Carboplatin Cisplatin 5-fluorouracil Placebo (3.0 mg/m2) will be administered on Day 8 and Day 15 of a 21-day cycle for 6 cycles, followed by dosing on Days 8 and 22 of 28-day cycles until disease progression. Cisplatin (100 mg/m2) OR carboplatin (AUC 5 mg/mL/min) will be administered on Day 1 of a 21-day cycle for a maximum of 6 cycles. 5-FU (1000 mg/m2) will be administered on Days 1-4 of a 21-day cycle for a maximum of 6 cycles. Cetuximab (initial dose: 400 mg/m2; remaining doses: 250 mg/m2) will be administered weekly until disease progression. Carboplatin Cisplatin 5-fluorouracil Placebo
    Measure Participants 100 95
    Median (90% Confidence Interval) [days]
    185
    181
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Chemotherapy and Cetuximab Plus VTX-2337, Chemotherapy and Cetuximab Plus Placebo
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.266
    Comments The 1-sided p-value based on a log-rank test stratified by randomization stratification factors.
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.99
    Confidence Interval (1-Sided) 90%
    to 1.22
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Comparison of Adverse Events (AEs) Between the Two Treatment Groups.
    Description The frequency and severity of adverse events, including any clinically significant changes in physical exam, laboratory values, or other clinical assessment.
    Time Frame AEs were collected from the first dose of study drug given on Cycle 1 Day 1 until 7 days after the dose of study drug or End of Treatment visit, whichever occurred first. Overall mean duration of exposure was 25.3 weeks.

    Outcome Measure Data

    Analysis Population Description
    Safety population: subjects who received at least 1 dose of VTX-2337 or placebo.
    Arm/Group Title Chemotherapy and Cetuximab Plus VTX-2337 Chemotherapy and Cetuximab Plus Placebo
    Arm/Group Description VTX-2337 (3.0 mg/m2) will be administered on Day 8 and Day 15 of a 21-day cycle for 6 cycles, followed by dosing on Days 8 and 22 of 28-day cycles until disease progression. Cisplatin (100 mg/m2) OR carboplatin (AUC 5 mg/mL/min) will be administered on Day 1 of a 21-day cycle for a maximum of 6 cycles. 5-FU (1000 mg/m2) will be administered on Days 1-4 of a 21-day cycle for a maximum of 6 cycles. Cetuximab (initial dose: 400 mg/m2; remaining doses: 250 mg/m2) will be administered weekly until disease progression. VTX-2337: TLR8 Agonist Carboplatin Cisplatin 5-fluorouracil Placebo (3.0 mg/m2) will be administered on Day 8 and Day 15 of a 21-day cycle for 6 cycles, followed by dosing on Days 8 and 22 of 28-day cycles until disease progression. Cisplatin (100 mg/m2) OR carboplatin (AUC 5 mg/mL/min) will be administered on Day 1 of a 21-day cycle for a maximum of 6 cycles. 5-FU (1000 mg/m2) will be administered on Days 1-4 of a 21-day cycle for a maximum of 6 cycles. Cetuximab (initial dose: 400 mg/m2; remaining doses: 250 mg/m2) will be administered weekly until disease progression. Carboplatin Cisplatin 5-fluorouracil Placebo
    Measure Participants 89 86
    Subjects with TEAE
    100
    100%
    100
    105.3%
    Subjects with Grade 3 and above TEAE
    84.3
    84.3%
    83.7
    88.1%
    Subjects with serious TEAE
    39.3
    39.3%
    39.5
    41.6%
    Subjects with TEAE with outcome of death
    4.5
    4.5%
    8.1
    8.5%
    Subjects discontinued treatment due to TEAE
    19.1
    19.1%
    18.6
    19.6%
    3. Secondary Outcome
    Title Comparison of Overall Survival (OS) Between the 2 Treatment Groups.
    Description Estimated using Kaplan-Meier product limit estimates, 1-sided stratified log-rank test, and Cox proportional hazard model; all with 90% 1-sided confidence intervals.
    Time Frame OS is the time from randomization until death due to any cause or the date last confirmed to be alive.

    Outcome Measure Data

    Analysis Population Description
    ITT population
    Arm/Group Title Chemotherapy and Cetuximab Plus VTX-2337 Chemotherapy and Cetuximab Plus Placebo
    Arm/Group Description VTX-2337 (3.0 mg/m2) will be administered on Day 8 and Day 15 of a 21-day cycle for 6 cycles, followed by dosing on Days 8 and 22 of 28-day cycles until disease progression. Cisplatin (100 mg/m2) OR carboplatin (AUC 5 mg/mL/min) will be administered on Day 1 of a 21-day cycle for a maximum of 6 cycles. 5-FU (1000 mg/m2) will be administered on Days 1-4 of a 21-day cycle for a maximum of 6 cycles. Cetuximab (initial dose: 400 mg/m2; remaining doses: 250 mg/m2) will be administered weekly until disease progression. VTX-2337: TLR8 Agonist Carboplatin Cisplatin 5-fluorouracil Placebo (3.0 mg/m2) will be administered on Day 8 and Day 15 of a 21-day cycle for 6 cycles, followed by dosing on Days 8 and 22 of 28-day cycles until disease progression. Cisplatin (100 mg/m2) OR carboplatin (AUC 5 mg/mL/min) will be administered on Day 1 of a 21-day cycle for a maximum of 6 cycles. 5-FU (1000 mg/m2) will be administered on Days 1-4 of a 21-day cycle for a maximum of 6 cycles. Cetuximab (initial dose: 400 mg/m2; remaining doses: 250 mg/m2) will be administered weekly until disease progression. Carboplatin Cisplatin 5-fluorouracil Placebo
    Measure Participants 100 95
    Median (90% Confidence Interval) [days]
    412
    343
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Chemotherapy and Cetuximab Plus VTX-2337, Chemotherapy and Cetuximab Plus Placebo
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.399
    Comments The 1-sided p-value based on a log-rank test stratified by randomization stratification factors.
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.95
    Confidence Interval (1-Sided) 90%
    to 1.22
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    Title Comparison of the Objective Response Rate Between the Two Treatment Groups p
    Description Objective response rate is defined as the percentage of subjects who achieve best overall response of irCR or irPR pr irRECIST and evaluated by independent radiology..
    Time Frame From the time of randomization until the best response on treatment is documented.

    Outcome Measure Data

    Analysis Population Description
    ITT population
    Arm/Group Title Chemotherapy and Cetuximab Plus VTX-2337 Chemotherapy and Cetuximab Plus Placebo
    Arm/Group Description VTX-2337 (3.0 mg/m2) will be administered on Day 8 and Day 15 of a 21-day cycle for 6 cycles, followed by dosing on Days 8 and 22 of 28-day cycles until disease progression. Cisplatin (100 mg/m2) OR carboplatin (AUC 5 mg/mL/min) will be administered on Day 1 of a 21-day cycle for a maximum of 6 cycles. 5-FU (1000 mg/m2) will be administered on Days 1-4 of a 21-day cycle for a maximum of 6 cycles. Cetuximab (initial dose: 400 mg/m2; remaining doses: 250 mg/m2) will be administered weekly until disease progression. VTX-2337: TLR8 Agonist Carboplatin Cisplatin 5-fluorouracil Placebo (3.0 mg/m2) will be administered on Day 8 and Day 15 of a 21-day cycle for 6 cycles, followed by dosing on Days 8 and 22 of 28-day cycles until disease progression. Cisplatin (100 mg/m2) OR carboplatin (AUC 5 mg/mL/min) will be administered on Day 1 of a 21-day cycle for a maximum of 6 cycles. 5-FU (1000 mg/m2) will be administered on Days 1-4 of a 21-day cycle for a maximum of 6 cycles. Cetuximab (initial dose: 400 mg/m2; remaining doses: 250 mg/m2) will be administered weekly until disease progression. Carboplatin Cisplatin 5-fluorouracil Placebo
    Measure Participants 100 95
    Number [percentage of participants]
    38.0
    38%
    33.7
    35.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Chemotherapy and Cetuximab Plus VTX-2337, Chemotherapy and Cetuximab Plus Placebo
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.536
    Comments p-values are from Cochran-Mantel-Haenszel tests controlling for randomization stratification factors and comparing tumor response rates between the treatment groups.
    Method Cochran-Mantel-Haenszel
    Comments

    Adverse Events

    Time Frame AE data was collected from the first patient's Cycle 1 Day 1, 14 Oct 2013, through primary analysis data cut date, 13 Apr 2016. AEs were collected from the first dose of study drug given on Cycle 1 Day 1 until 7 days after the dose of study drug or End of Treatment visit, whichever occurred first. The whole period equals to 2.5 years.
    Adverse Event Reporting Description AEs were collected through reporting voluntarily by the subject, discovery via questioning by the investigator or clinical personnel, or identification through physical examination, laboratory test or other means. Overall mean duration of exposure was 25.3 weeks for study drug.
    Arm/Group Title Chemotherapy and Cetuximab Plus VTX-2337 Chemotherapy and Cetuximab Plus Placebo
    Arm/Group Description VTX-2337 (3.0 mg/m2) will be administered on Day 8 and Day 15 of a 21-day cycle for 6 cycles, followed by dosing on Days 8 and 22 of 28-day cycles until disease progression. Cisplatin (100 mg/m2) OR carboplatin (AUC 5 mg/mL/min) will be administered on Day 1 of a 21-day cycle for a maximum of 6 cycles. 5-FU (1000 mg/m2) will be administered on Days 1-4 of a 21-day cycle for a maximum of 6 cycles. Cetuximab (initial dose: 400 mg/m2; remaining doses: 250 mg/m2) will be administered weekly until disease progression. VTX-2337: TLR8 Agonist Carboplatin Cisplatin 5-fluorouracil Placebo (3.0 mg/m2) will be administered on Day 8 and Day 15 of a 21-day cycle for 6 cycles, followed by dosing on Days 8 and 22 of 28-day cycles until disease progression. Cisplatin (100 mg/m2) OR carboplatin (AUC 5 mg/mL/min) will be administered on Day 1 of a 21-day cycle for a maximum of 6 cycles. 5-FU (1000 mg/m2) will be administered on Days 1-4 of a 21-day cycle for a maximum of 6 cycles. Cetuximab (initial dose: 400 mg/m2; remaining doses: 250 mg/m2) will be administered weekly until disease progression. Carboplatin Cisplatin 5-fluorouracil Placebo
    All Cause Mortality
    Chemotherapy and Cetuximab Plus VTX-2337 Chemotherapy and Cetuximab Plus Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    Chemotherapy and Cetuximab Plus VTX-2337 Chemotherapy and Cetuximab Plus Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 35/89 (39.3%) 34/86 (39.5%)
    Blood and lymphatic system disorders
    Neutropenia 7/89 (7.9%) 2/86 (2.3%)
    Anaemia 3/89 (3.4%) 0/86 (0%)
    Pancytopenia 1/89 (1.1%) 2/86 (2.3%)
    Thrombocytopenia 2/89 (2.2%) 1/86 (1.2%)
    Leukopenia 1/89 (1.1%) 0/86 (0%)
    Febrile neutropenia 3/89 (3.4%) 4/86 (4.7%)
    Cardiac disorders
    Cardiac arrest 0/89 (0%) 2/86 (2.3%)
    Acute coronary syndrome 1/89 (1.1%) 0/86 (0%)
    Acute myocardial infarction 1/89 (1.1%) 0/86 (0%)
    Atrioventricular block second degree 0/89 (0%) 1/86 (1.2%)
    Cardiac failure congestive 1/89 (1.1%) 0/86 (0%)
    Palpitations 1/89 (1.1%) 0/86 (0%)
    Pericarditis 0/89 (0%) 1/86 (1.2%)
    Sinus tachycardia 0/89 (0%) 1/86 (1.2%)
    Gastrointestinal disorders
    vomitting 5/89 (5.6%) 3/86 (3.5%)
    Nausea 4/89 (4.5%) 2/86 (2.3%)
    Abdominal pain 1/89 (1.1%) 0/86 (0%)
    Colitis 0/89 (0%) 1/86 (1.2%)
    Diarrhoea 1/89 (1.1%) 1/86 (1.2%)
    Dysphagia 1/89 (1.1%) 1/86 (1.2%)
    Enterocolitis 0/89 (0%) 1/86 (1.2%)
    Haematemesis 1/89 (1.1%) 0/86 (0%)
    Ileus 0/89 (0%) 1/86 (1.2%)
    Melaena 1/89 (1.1%) 0/86 (0%)
    Mouth haemorrhage 1/89 (1.1%) 0/86 (0%)
    Oesophageal perforation 0/89 (0%) 1/86 (1.2%)
    Pneumatosis intestinalis 0/89 (0%) 1/86 (1.2%)
    Pneumoperitoneum 1/89 (1.1%) 0/86 (0%)
    Small intestinal obstruction 1/89 (1.1%) 0/86 (0%)
    Stomatitis 0/89 (0%) 2/86 (2.3%)
    General disorders
    Fatigue 2/89 (2.2%) 1/86 (1.2%)
    Asthenia 0/89 (0%) 1/86 (1.2%)
    Death 0/89 (0%) 2/86 (2.3%)
    Medical device complication 1/89 (1.1%) 0/86 (0%)
    Non-cardiac chest pain 0/89 (0%) 1/86 (1.2%)
    Pain 1/89 (1.1%) 2/86 (2.3%)
    Pyrexia 3/89 (3.4%) 0/86 (0%)
    Immune system disorders
    Anaphylactic reaction 1/89 (1.1%) 1/86 (1.2%)
    Cytokine release syndrome 1/89 (1.1%) 0/86 (0%)
    Hypersensitivity 0/89 (0%) 1/86 (1.2%)
    Infections and infestations
    Pneumonia 5/89 (5.6%) 5/86 (5.8%)
    Sepsis 2/89 (2.2%) 4/86 (4.7%)
    Lung infection 3/89 (3.4%) 1/86 (1.2%)
    Acinetobacter bacteraemia 0/89 (0%) 1/86 (1.2%)
    Bacteraemia 1/89 (1.1%) 1/86 (1.2%)
    Clostridium difficile infection 0/89 (0%) 1/86 (1.2%)
    Device related infection 0/89 (0%) 1/86 (1.2%)
    Infection 1/89 (1.1%) 0/86 (0%)
    Neutropenic sepsis 0/89 (0%) 2/86 (2.3%)
    Pneumonia bacterial 0/89 (0%) 1/86 (1.2%)
    Soft tissue infection 1/89 (1.1%) 0/86 (0%)
    Staphylococcal infection 1/89 (1.1%) 0/86 (0%)
    Staphylococcal sepsis 1/89 (1.1%) 0/86 (0%)
    Tracheitis 0/89 (0%) 1/86 (1.2%)
    Urinary tract infection 1/89 (1.1%) 0/86 (0%)
    Injury, poisoning and procedural complications
    Fall 0/89 (0%) 1/86 (1.2%)
    Feeding tube complication 0/89 (0%) 1/86 (1.2%)
    Forearm fracture 0/89 (0%) 1/86 (1.2%)
    Hip fracture 1/89 (1.1%) 1/86 (1.2%)
    Radiation mucositis 0/89 (0%) 1/86 (1.2%)
    Subdural haematoma 0/89 (0%) 1/86 (1.2%)
    Investigations
    Occult blood positive 1/89 (1.1%) 0/86 (0%)
    Metabolism and nutrition disorders
    Dehydration 5/89 (5.6%) 4/86 (4.7%)
    Acidosis 0/89 (0%) 1/86 (1.2%)
    Failure to thrive 0/89 (0%) 2/86 (2.3%)
    Hypercalcaemia 1/89 (1.1%) 0/86 (0%)
    Metabolic syndrome 1/89 (1.1%) 0/86 (0%)
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain 1/89 (1.1%) 0/86 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain 0/89 (0%) 1/86 (1.2%)
    Tumour haemorrhage 0/89 (0%) 1/86 (1.2%)
    Nervous system disorders
    Cerebrovascular accident 0/89 (0%) 2/86 (2.3%)
    Convulsion 0/89 (0%) 1/86 (1.2%)
    Haemorrhage intracranial 1/89 (1.1%) 0/86 (0%)
    Headache 1/89 (1.1%) 1/86 (1.2%)
    Ischaemic stroke 1/89 (1.1%) 0/86 (0%)
    Syncope 0/89 (0%) 2/86 (2.3%)
    Psychiatric disorders
    Mental status changes 1/89 (1.1%) 0/86 (0%)
    Renal and urinary disorders
    Renal failure acute 0/89 (0%) 2/86 (2.3%)
    Respiratory, thoracic and mediastinal disorders
    Pulmonary emolism 3/89 (3.4%) 2/86 (2.3%)
    Pneumonia aspiration 2/89 (2.2%) 2/86 (2.3%)
    Pleural effusion 1/89 (1.1%) 2/86 (2.3%)
    Respiratory failure 2/89 (2.2%) 1/86 (1.2%)
    Acute respiratory failure 0/89 (0%) 1/86 (1.2%)
    Aspiration 2/89 (2.2%) 0/86 (0%)
    Dyspnoea 0/89 (0%) 2/86 (2.3%)
    Hypoxia 1/89 (1.1%) 1/86 (1.2%)
    Pneumothorax 1/89 (1.1%) 1/86 (1.2%)
    Respiratory disorder 1/89 (1.1%) 0/86 (0%)
    Upper airway obstruction 1/89 (1.1%) 0/86 (0%)
    Skin and subcutaneous tissue disorders
    Swelling face 1/89 (1.1%) 0/86 (0%)
    Surgical and medical procedures
    Wound treatment 0/89 (0%) 1/86 (1.2%)
    Vascular disorders
    Hypotension 1/89 (1.1%) 4/86 (4.7%)
    Embolism 1/89 (1.1%) 1/86 (1.2%)
    Shock haemorrhagic 0/89 (0%) 1/86 (1.2%)
    Vena cava thrombosis 1/89 (1.1%) 0/86 (0%)
    Other (Not Including Serious) Adverse Events
    Chemotherapy and Cetuximab Plus VTX-2337 Chemotherapy and Cetuximab Plus Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 89/89 (100%) 86/86 (100%)
    Blood and lymphatic system disorders
    Anaemia 53/89 (59.6%) 39/86 (45.3%)
    Leukopenia 38/89 (42.7%) 29/86 (33.7%)
    Lymphopenia 10/89 (11.2%) 9/86 (10.5%)
    Neutropenia 50/89 (56.2%) 45/86 (52.3%)
    Thrombocytopenia 50/89 (56.2%) 43/86 (50%)
    Cardiac disorders
    Tachycardia 8/89 (9%) 4/86 (4.7%)
    Gastrointestinal disorders
    Constipation 30/89 (33.7%) 23/86 (26.7%)
    Diarrhoea 28/89 (31.5%) 26/86 (30.2%)
    Dry mouth 2/89 (2.2%) 9/86 (10.5%)
    Dyspepsia 7/89 (7.9%) 5/86 (5.8%)
    Dysphagia 11/89 (12.4%) 15/86 (17.4%)
    Gastrooesophageal reflux disease 2/89 (2.2%) 7/86 (8.1%)
    Nausea 36/89 (40.4%) 29/86 (33.7%)
    Oral pain 5/89 (5.6%) 5/86 (5.8%)
    Stomatitis 34/89 (38.2%) 42/86 (48.8%)
    Vomiting 32/89 (36%) 24/86 (27.9%)
    General disorders
    Asthenia 4/89 (4.5%) 6/86 (7%)
    Chills 33/89 (37.1%) 5/86 (5.8%)
    Fatigue 38/89 (42.7%) 39/86 (45.3%)
    Influenza like illness 13/89 (14.6%) 3/86 (3.5%)
    Injection site reactions 35/89 (39.3%) 0/86 (0%)
    Pain 4/89 (4.5%) 6/86 (7%)
    Pyrexia 38/89 (42.7%) 10/86 (11.6%)
    Immune system disorders
    Cytokine release syndrome 7/89 (7.9%) 3/86 (3.5%)
    Infections and infestations
    Paronychia 8/89 (9%) 10/86 (11.6%)
    Pneumonia 8/89 (9%) 7/86 (8.1%)
    Investigations
    Alanine aminotransferase increased 3/89 (3.4%) 8/86 (9.3%)
    Blood alkaline phosphatase increased 8/89 (9%) 9/86 (10.5%)
    Weight decreased 24/89 (27%) 26/86 (30.2%)
    Metabolism and nutrition disorders
    Decreased appetite 22/89 (24.7%) 15/86 (17.4%)
    Dehydration 15/89 (16.9%) 19/86 (22.1%)
    Hyperglycaemia 11/89 (12.4%) 8/86 (9.3%)
    Hypoalbuminaemia 14/89 (15.7%) 9/86 (10.5%)
    Hypocalcaemia 9/89 (10.1%) 10/86 (11.6%)
    Hypokalaemia 29/89 (32.6%) 24/86 (27.9%)
    Hypomagnesaemia 26/89 (29.2%) 31/86 (36%)
    Hyponatraemia 14/89 (15.7%) 13/86 (15.1%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 12/89 (13.5%) 6/86 (7%)
    Back pain 10/89 (11.2%) 6/86 (7%)
    Musculoskeletal pain 4/89 (4.5%) 5/86 (5.8%)
    Neck pain 7/89 (7.9%) 6/86 (7%)
    Pain in extremity 3/89 (3.4%) 8/86 (9.3%)
    Nervous system disorders
    Dizziness 13/89 (14.6%) 20/86 (23.3%)
    Dysgeusia 11/89 (12.4%) 8/86 (9.3%)
    Headache 10/89 (11.2%) 13/86 (15.1%)
    Neuropathy peripheral 9/89 (10.1%) 10/86 (11.6%)
    Psychiatric disorders
    Anxiety 6/89 (6.7%) 7/86 (8.1%)
    Depression 8/89 (9%) 6/86 (7%)
    Insomnia 5/89 (5.6%) 8/86 (9.3%)
    Respiratory, thoracic and mediastinal disorders
    Cough 15/89 (16.9%) 16/86 (18.6%)
    Dysphonia 3/89 (3.4%) 7/86 (8.1%)
    Dyspnoea 8/89 (9%) 14/86 (16.3%)
    Epistaxis 8/89 (9%) 4/86 (4.7%)
    Haemoptysis 5/89 (5.6%) 5/86 (5.8%)
    Oropharyngeal pain 7/89 (7.9%) 8/86 (9.3%)
    Skin and subcutaneous tissue disorders
    Alopecia 4/89 (4.5%) 6/86 (7%)
    Dermatitis acneiform 43/89 (48.3%) 31/86 (36%)
    Dry skin 10/89 (11.2%) 20/86 (23.3%)
    Pruritus 5/89 (5.6%) 9/86 (10.5%)
    Rash 17/89 (19.1%) 23/86 (26.7%)
    Rash maculo-papular 9/89 (10.1%) 5/86 (5.8%)
    Skin fissures 12/89 (13.5%) 20/86 (23.3%)
    Vascular disorders
    Hypertension 4/89 (4.5%) 5/86 (5.8%)
    Hypotension 4/89 (4.5%) 15/86 (17.4%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    PI should not publish the site's results prior to the sponsor's 1st multi-site publication. PI can publish if no multi-site publication within 18 months after the study has been completed or terminated, provided that the site's results are statistically significant and consistent with the multi-site publication. Prior to submitting or presenting, PI should provide sponsor to review and comment. If requested by sponsor, PI should delay publication/presentation for up to 120 days.

    Results Point of Contact

    Name/Title Kristi Manjarrez
    Organization VentiRx
    Phone 206 689 2256
    Email kmanjarrez@ventirx.com
    Responsible Party:
    Celgene
    ClinicalTrials.gov Identifier:
    NCT01836029
    Other Study ID Numbers:
    • VRXP-A202
    First Posted:
    Apr 19, 2013
    Last Update Posted:
    Oct 29, 2019
    Last Verified:
    Oct 1, 2019