Clinical trial NCT02054442: A Study of the Combination of Cetuximab and Methotrexate in Recurrent or Metastatic Cancer of the Head and Neck
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
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Squamous Cell Carcinoma of the Head and Neck
Keywords: cetuximab
methotrexate
squamous cell carcinoma head neck
palliative chemotherapy
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: Merck Serono International SA
name: Leiden University Medical Center
name: Academisch Ziekenhuis Maastricht
name: Erasmus Medical Center
name: Medisch Spectrum Twente
name: Medical Center Haaglanden
name: Elisabeth-TweeSteden Ziekenhuis
name: Frisius Medisch Centrum
First posted: 2014-02-04
Enrollment: 52
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Incidence of dose limiting toxicity (DLT)
timeFrame: During the first 4 weeks after start of the combination MTX and cetuximab
measure: Progression free survival
timeFrame: 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 outcomes:
measure: Overall survival (OS)
timeFrame: Followed up to 12 months after randomization
measure: Response rate (RR)
timeFrame: Till end of treatment
Other outcomes:
Locations:
city: Den Haag
country: Netherlands
facility: Medical Centre Haaglanden
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
city: Leeuwarden
country: Netherlands
facility: Medical Centre Leeuwarden
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Maastricht
country: Netherlands
facility: Academisch Ziekenhuis Maastricht
city: Nijmegen
country: Netherlands
facility: Radboud university medical center
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
city: Tilburg
country: Netherlands
facility: St. Elisabeth Ziekenhuis
Study officials:
affiliation: Radboud University Medical Center
name: Carla M van Herpen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: