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A Study of the Combination of Cetuximab and Methotrexate in Recurrent or Metastatic Cancer of the Head and Neck (COMMENCE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02054442
Recruitment Status : Active, not recruiting
First Posted : February 4, 2014
Last Update Posted : May 7, 2019
Sponsor:
Collaborators:
Merck Serono International SA
Leiden University Medical Center
Academisch Ziekenhuis Maastricht
Erasmus Medical Center
Medisch Spectrum Twente
Medical Center Haaglanden
Elisabeth-TweeSteden Ziekenhuis
Medical Centre Leeuwarden
Information provided by (Responsible Party):
Radboud University

Brief Summary:
The investigators will perform a randomized phase II study to investigate if the addition of cetuximab to MTX is beneficial for the patient. Because no data on this combination are available the investigators will start with a phase Ib study to investigate the feasibility of the schedule.

Condition or disease Intervention/treatment Phase
Squamous Cell Carcinoma of the Head and Neck Drug: Cetuximab Drug: Methotrexate Phase 1 Phase 2

Detailed Description:

The addition of cetuximab to cisplatin and 5-FU in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) showed an improvement of overall survival (OS), progression free survival (PFS) and response rate (RR). However, cisplatin and 5-FU are toxic cytostatics for the vulnerable recurrent or metastatic SCCHN patient. As one of the primary goals in these patients is palliation, in some patients treatment with cisplatin, 5-FU and cetuximab is not feasible owing to a low performance score (PS of 2) or the patient refusal to receive chemotherapy, i.e. cisplatin and 5-FU, possibly influencing quality of life negatively.

Methotrexate is a cytostatic which has shown to have modest activity in recurrent or metastatic SCCHN. The RR is between 14 and 20%, the median PFS is 3 months, and there is no improvement in OS, which is only 6 months. Toxicity of MTX is very low. Patients with a PS of 2 can be treated with MTX. Patients refusing treatment with cisplatin, 5-FU and cetuximab, frequently choose MTX as palliative treatment.

No data are available on the combination of cetuximab and MTX. The investigators will perform a randomized phase II study to investigate if the addition of cetuximab to MTX is beneficial, i.e. an improvement in the PFS, for the patient. Because no data on this combination are available the investigators will start with a phase Ib study to investigate the feasibility of the schedule.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 52 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib-II Study of the Combination of Cetuximab and Methotrexate in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck. A Study of the Dutch Head and Neck Society
Study Start Date : August 2016
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A: MTX in combination with cetuximab

The dosage of cetuximab will be i.v. 400 mg/m2 over a period of 2h for the first infusion, followed by infusions of 250 mg/m2 over 1 hour once weekly. Cetuximab will be dissolved in 500 ml NaCl 0.9%.

Premedication: H1-receptor antagonist and dexamethasone.

The dosage of MTX (Methotrexate) will be i.v. 40 mg/m2 once weekly, administered within 5-10 minutes. MTX will be dissolved in 50 ml NaCl 0.9%.

Premedication: ondansetron 8 mg.

Treatment will be continued until progressive disease, unacceptable toxicity or refusal by patient.

Drug: Cetuximab
We will perform a randomized phase II study to investigate in first line if the addition of cetuximab to MTX is beneficial, i.e. improvement in the PFS, for the patient.
Other Names:
  • Erbitux
  • L01XC06

Drug: Methotrexate
Other Names:
  • EMTHEXATE
  • L01BA01

Active Comparator: Arm B: MTX

The dosage of MTX (Methotrexate) will be i.v. 40 mg/m2 once weekly, administered within 5-10 minutes. MTX will be dissolved in 50 ml NaCl 0.9%.

Premedication: ondansetron 8 mg.

Treatment will be continued until progressive disease, unacceptable toxicity or refusal by patient.

Drug: Methotrexate
Other Names:
  • EMTHEXATE
  • L01BA01




Primary Outcome Measures :
  1. Incidence of dose limiting toxicity (DLT) [ Time Frame: During the first 4 weeks after start of the combination MTX and cetuximab ]
    In the phase Ib study: toxicity scored with CTC v 4.0*; incidence of dose limiting toxicity (DLT) during the first 4 weeks after start of the combination

  2. Progression free survival [ Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months ]
    In the phase II study: progression free survival (PFS). The analysis of PFS can be performed as soon as the target event (progression or death) has been observed in 98 of the 114 subjects randomized.


Secondary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: Followed up to 12 months after randomization ]
    Overall survival (OS) The analysis of OS can be performed as soon as the target event has been observed in 98 of the 114 subjects randomized.

  2. Response rate (RR) [ Time Frame: Till end of treatment ]
    The difference in RR rates between both treatment arms will be analyzed using a stratified Cochran Mantel Haenszel test at a one-sided alpha-level of 0.05. In addition to the response rates in both arms, the odds ratio will be reported together with 90% confidence intervals. The impact of various demographic and disease characteristics (e.g. HPV positivity), on RR will be investigated using an exploratory logistic regression model.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Cytologically/histologically-proven SCCHN
  • Recurrent or metastatic SCCHN
  • At least one measurable lesion as determined by RECIST v1.1 is required. Lesions in previously irradiated areas should not be considered measurable unless there is clear evidence of progression in such lesions since the radiotherapy.
  • No prior systemic treatment for recurrent or metastatic disease
  • Primary site: (1) oral cavity, (2) oropharynx, (3) hypopharynx, (4) larynx, or (5) unknown primary squamous cell carcinoma in the head and neck region presenting originally with lymph node metastases (N1-N3).
  • Time between prior treatment and inclusion in the study (> 3 months). Palliative RT in case of painful bone metastases is allowed in phase II and after 4 weeks in phase Ib
  • Ineligible (due to medical co-morbidities) or intolerant to platinum-based therapy per medical history or refusing cisplatin-based chemotherapy by the patient
  • WHO performance status 0-2.
  • Age >18 years
  • Adequate organ function and laboratory parameters as defined by:

    • Absolute neutrophil count (ANC) ≥ 1.5 x 109 /L
    • Hemoglobin (Hb) ≥ 9 g/dl 5.6 mmol/l (which may be achieved by transfusion)
    • Platelets (PLT) ≥ 100 x 109/L
    • AST and ALT ≤ 2.5 x ULN (upper limit of normal)
    • Serum bilirubin ≤ 1.5 x ULN
    • Calculated creatinine clearance or MDRD > 60ml/min
  • Recovered from all adverse events (AEs) of previous anti-cancer therapies. AEs related to prior radiotherapy are allowed.
  • Written informed consent

Exclusion Criteria:

  • Serious active infections
  • Patients (M/F) with reproductive potential not implementing adequate contraceptives measures
  • Prior treatment with EGFR inhibitors or MTX
  • Concomitant (or within 4 weeks before randomization) administration of any other experimental drug under investigation
  • Concurrent treatment with any other anti-cancer therapy.
  • Central nervous system involvement
  • Lung fibrosis
  • Pleural effusion or ascites or other third space effusions
  • History of another malignancy within 2 years prior to starting study treatment, except cured basal cell carcinoma of the skin, excised carcinoma in situ of the cervix, or other head and neck cancer.
  • Pregnancy or lactation
  • Any other condition that would, in the Investigator's judgment, preclude patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g. infection/inflammation, intestinal obstruction, social/psychological complications.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02054442


Locations
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Netherlands
Medical Centre Haaglanden
Den Haag, Netherlands
Medisch Spectrum Twente
Enschede, Netherlands
Medical Centre Leeuwarden
Leeuwarden, Netherlands
Leiden University Medical Center
Leiden, Netherlands
Academisch Ziekenhuis Maastricht
Maastricht, Netherlands
Radboud university medical center
Nijmegen, Netherlands
Erasmus Medical Center
Rotterdam, Netherlands
St. Elisabeth Ziekenhuis
Tilburg, Netherlands
Sponsors and Collaborators
Radboud University
Merck Serono International SA
Leiden University Medical Center
Academisch Ziekenhuis Maastricht
Erasmus Medical Center
Medisch Spectrum Twente
Medical Center Haaglanden
Elisabeth-TweeSteden Ziekenhuis
Medical Centre Leeuwarden
Investigators
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Principal Investigator: Carla M van Herpen, MD, PhD Radboud University

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Responsible Party: Radboud University
ClinicalTrials.gov Identifier: NCT02054442    
Other Study ID Numbers: MOHN01
2013-002886-20 ( EudraCT Number )
DHNS 2013-01 ( Other Identifier: Dutch Head and Neck Society )
First Posted: February 4, 2014    Key Record Dates
Last Update Posted: May 7, 2019
Last Verified: May 2019
Keywords provided by Radboud University:
cetuximab
methotrexate
squamous cell carcinoma head neck
palliative chemotherapy
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Squamous Cell
Squamous Cell Carcinoma of Head and Neck
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Head and Neck Neoplasms
Neoplasms by Site
Methotrexate
Cetuximab
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Antineoplastic Agents, Immunological