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

Primary Purpose

Squamous Cell Carcinoma of the Head and Neck

Status
Unknown status
Phase
Phase 1
Locations
Netherlands
Study Type
Interventional
Intervention
Cetuximab
Methotrexate
Sponsored by
Radboud University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Squamous Cell Carcinoma of the Head and Neck focused on measuring cetuximab, methotrexate, squamous cell carcinoma head neck, palliative chemotherapy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Medical Centre Haaglanden
  • Medisch Spectrum Twente
  • Medical Centre Leeuwarden
  • Leiden University Medical Center
  • Academisch Ziekenhuis Maastricht
  • Radboud university medical center
  • Erasmus Medical Center
  • St. Elisabeth Ziekenhuis

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Arm A: MTX in combination with cetuximab

Arm B: MTX

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Incidence of dose limiting toxicity (DLT)
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
Progression free survival
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

Overall survival (OS)
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.
Response rate (RR)
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.

Full Information

First Posted
January 31, 2014
Last Updated
March 11, 2021
Sponsor
Radboud University Medical Center
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
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1. Study Identification

Unique Protocol Identification Number
NCT02054442
Brief Title
A Study of the Combination of Cetuximab and Methotrexate in Recurrent or Metastatic Cancer of the Head and Neck
Acronym
COMMENCE
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 Type
Interventional

2. Study Status

Record Verification Date
March 2021
Overall Recruitment Status
Unknown status
Study Start Date
August 2016 (undefined)
Primary Completion Date
December 2021 (Anticipated)
Study Completion Date
December 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Radboud University Medical Center
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

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Squamous Cell Carcinoma of the Head and Neck
Keywords
cetuximab, methotrexate, squamous cell carcinoma head neck, palliative chemotherapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
52 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm A: MTX in combination with cetuximab
Arm Type
Experimental
Arm Description
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.
Arm Title
Arm B: MTX
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Cetuximab
Other Intervention Name(s)
Erbitux, L01XC06
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Methotrexate
Other Intervention Name(s)
EMTHEXATE, L01BA01
Primary Outcome Measure Information:
Title
Incidence of dose limiting toxicity (DLT)
Description
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
Time Frame
During the first 4 weeks after start of the combination MTX and cetuximab
Title
Progression free survival
Description
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.
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
Secondary Outcome Measure Information:
Title
Overall survival (OS)
Description
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.
Time Frame
Followed up to 12 months after randomization
Title
Response rate (RR)
Description
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.
Time Frame
Till end of treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Carla M van Herpen, MD, PhD
Organizational Affiliation
Radboud University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Medical Centre Haaglanden
City
Den Haag
Country
Netherlands
Facility Name
Medisch Spectrum Twente
City
Enschede
Country
Netherlands
Facility Name
Medical Centre Leeuwarden
City
Leeuwarden
Country
Netherlands
Facility Name
Leiden University Medical Center
City
Leiden
Country
Netherlands
Facility Name
Academisch Ziekenhuis Maastricht
City
Maastricht
Country
Netherlands
Facility Name
Radboud university medical center
City
Nijmegen
Country
Netherlands
Facility Name
Erasmus Medical Center
City
Rotterdam
Country
Netherlands
Facility Name
St. Elisabeth Ziekenhuis
City
Tilburg
Country
Netherlands

12. IPD Sharing Statement

Learn more about this trial

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

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