Primary objective:• Phase Ib: to assess the feasibility and safety of the addition of cetuximab to methotrexate for recurrent or metastatic SCCHN • Phase II: to assess the efficacy of the addition of cetuximab to methotrexate for recurrent or…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoints:
• Phase Ib: Toxicity scored with CTC v 4.0*; dose limiting toxicity (DLT)
during the first 4 weeks after start of the combination
• Phase II: PFS
*Toxicity scored according CTC v 4.0 will be done during the complete study
period both in the phase Ib and phase II study
Secondary outcome
Secondary endpoints:
• OS
• RR according to RECIST 1.1
• Quality of life (QoL)
Background summary
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. We 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 we will start with a phase Ib study to
investigate the feasibility of the schedule.
Study objective
Primary objective:
• Phase Ib: to assess the feasibility and safety of the addition of cetuximab
to methotrexate for recurrent or metastatic SCCHN
• Phase II: to assess the efficacy of the addition of cetuximab to methotrexate
for recurrent or metastatic SCCHN
Secondary objectives:
In both the phase Ib and phase II
• To assess overall survival (OS)
• To assess response rate (RR)
• To assess toxicity
• To assess quality of life (QoL)
• To assess HPV positivity in relation to PFS/OS/response
Study design
Phase Ib (non-dose-escalating) - randomized phase II study
A phase I b study will started with fixed dosages of cetuximab and
methotrexate. We will investigate if the combination of cetuximab and
methotrexate is safe. Thereafter a comparative randomized phase II study will
be started in which patients are treated in combination with methotrexate with
or without cetuximab.
Patients will be randomized to the two treatment arms using an adaptive
minimization procedure and the following stratification factors:
- Participating institution
- PS (0 and 1 versus 2)
- Local or locoregional recurrence (yes versus no)
Intervention
Addition of cetuximab to MTX : comparative randomized phase II study in which
patients are treated with methotrexate with or without cetuximab.
Study burden and risks
For patients with recurrent or metastatic squamous cell carcinoma of the head
and neck treatment is not yet optimal and physicians are looking for a
treatment displaying less side effects and better quality of life. In this
study we investigate whether the addition of cetuximab to methotrexate shows a
better effect on disease with an improved progression free survival (PFS) for
the patient.
The aim of this study is to find a more effective treatment, however,
displaying less toxicity and less burdensome compared to the treatment which
showed to be life-prolonging (Cetuximab, cisplatin and 5-FU).
A standard treatment patients may choose (not participating in the study) is a
combination of 3 medicines, Cetuximab, cisplatin and 5-FU. Patients need to
receive a long line, 1 time per 3 weeks admitted into the hospital during 2
days, an infuser at home and 2 visits to the hospital specially for this
infuser and weekly visits to the policlinic. Besides that this treatment is
very intensive for this group of patients, the treatment is also more toxic, in
particular caused by cisplatin en 5-FU.
In case patients find treatment with Cetuximab, cisplatin en 5-FU to much
burdensome, often treatment with Methotrexate only will be offered, which means
that patients weekly visit the policlinic and day care facility, during 45
minutes, including infusion.
If the patients participate in the study, about half of the patients will
receive Methotrexate only and the other half of the patients will receive
Cetuximab combined with Methotrexate. This implies about 1 hour extra time for
infusion per week. Patients participating in this study and randomized for a
treatment with the combination of Cetuximab and methotrexate, possibly will
display more side effects due to Cetuximab. However, addition of Cetuximab may
possibly lead to an improved progression free survival (PFS) for the patient.
In summary, if we try to describe the extra burden for the patient
participating in this study, this burden is much less compared to the treatment
with the combination of 3 medicines, Cetuximab, cisplatin and 5-FU. If patients
are randomized for Methotrexate in combination with Cetuximab, patients need to
stay in the hospital 1 hour per week extra compared to treatment with
Methotrexate only, however this is still less burdensome. More information on
the issue of burden can be found in attachment 2 of the patientinformationsheet
"Onderzoeken bij deelname of geen deelname aan de studie".
In addition, we estimate the risk on extra side effects as a consequence of
participation in the study, to be low. Please, find additional explanation in
question E9 of this form.
Geert Grooteplein Zuid 8
Nijmegen 6525 GA
NL
Geert Grooteplein Zuid 8
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
• Cytologically/histologically-proven SCCHN
• Recurrent or metastatic SCCHN
• At least one measurable 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: oral cavity, oropharynx, hypopharynx or larynx
• 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:
o Absolute neutrophil count (ANC) >= 1.5 x 109 /L
o Hemoglobin (Hb) >= 9 g/dl=5.6 mmol/l (which may be achieved by transfusion)
o Platelets (PLT) >= 100 x 109/L
o AST and ALT <= 2.5 x ULN (upper limit of normal)
o Serum bilirubin <= 1.5 x ULN
o 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-002886-20-NL |
| CCMO | NL45128.091.13 |
| Other | nog niet beschikbaar |