Palliative Treatment Clinical Trial
Official title:
Phase III Clinical Trial: "Evaluation of the Combination of Nimotuzumab and Cisplatin-Vinorelbine in First Line Chemotherapy in the Survival of Patients With Recurring-Persistent Cervical Carcinoma"
This study evauates the global survival of patients following administration of mAb
Nimotuzumab hR3 + chemotherapy in the treatment of cervical cancer in first line therapy,
after relapsing from chemo-radiotherapy.
It is a Phase III, multi-centric, randomized, double blind study; 168 patients will be
assigned to Nimotuzumab + Cisplatin/Vinorelbine or placebo + Cisplatin/Vinorelbine. After
progression, a second line chemotherapy based on carboplatino/taxol will be administered in
both groups. Concomitant administration of Nimotuzumab will be continued every 14 days until
limiting toxicity or ECOCG >3.
Tumor markers such as Kras, p53, KI67, and EGFR will be identified. Cardiac toxicity will be
evaluated using MRI.
Specific Objectives
1. To determine the global survival of patients treated with mAb Nimotuzumab hR3 in
patients with cervical tumors of epithelial origin relapsing from first line treatment.
2. To determine disease free survival in patients treated with mAb Nimotuzumab hR3 for
cervical tumors of epithelial origin when relapsing from first line treatment.
3. To determine the anti-tumoral response of mAb Nimotuzumab hR3 in patients with cervical
tumors of epithelial origin relapsing from first line treatment.
4. To determine progression time of patients with cervical tumors of epithelial origin
relapsing from first line treatment who were treated with mAb Nimotuzumab hR3 in
combination with chemotherapy.
5. To evaluate the safety of mAb Nimotuzumab hR3 when treating patients with cervical
tumors of epithelial origin relapsing from first line treatment in combination with
Cisplatin/Vinorelbine chemotherapy.
6. To evaluate the appearing of HAMA response in patients treated with mAb Nimotuzumab
hR3.
7. To evaluate the diminishing of associated symptoms in patients with cervical tumors of
epithelial origin in relapse treated with mAb Nimotuzumab hR3.
8. To evaluate the quality of life of both groups using questionnaires QLQ C-30 and QLQ CX
24 for patients with cervical cancer (See appendixes).
9. To evaluate the toxicity using V3 Toxicity criteria.
10. To evaluate cardiac toxicity through MUGA or cardiac USG in both groups.
11. For feasibility purposes it will be conducted a MUGA and Rs MG only in Mexican patients
to evaluate their cardiac function in order to compare both studies before and after
clinical evaluation
Whenever possible, researcher shall perform a pre-treatment biopsy to assess the EGF-R
expression and its characteristics using immunohistochemical techniques. EGFR expression
will not constitute an inclusion criterion in this trial but will be correlated
retrospectively with the antitumor clinical response of those patients on whom a
pre-treatment biopsy was performed.
A QLQ-c30v3 test will be applied for it has the characteristic of evaluating the impact of
the disease and its treatment on the patient's functioning in the physical, psychological
and social areas. The QLQ Cx24 Questionnaire is a specific instrument for measuring the
quality of life in patients with cervical cancer through different clinical phases.
TREATMENT
INDUCTION PHASE:
200 mg mAb Nimotuzumab will be administered once a week (12 weeks) in combination with a
Platin based chemotherapy (Cisplatin/Vinorelbine) in cycles administered every 21 days (up
to 6). Both therapies will be administered endovenously. Response will be assessed after the
3rd chemotherapy + mAb vs placebo cycle through physical examination, CAR, or MRI. IF THERE
IS A PARTIAL RESPONSE OR STABLE DISEASE in line with RECIST, patient shall continue planned
treatment until 6th CT + mAb vs placebo cycle is completed. In case of PROGRESSION, another
treatment scheme should be considered according to researcher criteria. Following 6th
Chemotherapy + mAb vs placebo cycle patient should be assessed again after 28 days through
physical examination, MRI and CAT to measure lesions and through RECIST criteria. 6th cycle
evaluation will be based on basal target lesions measured at the beginning of study. IF
STABLE DISEASE OR ANTITUMORAL RESPONSE IS ESTABLISHED patient will continue to the next
planned study phase. In the event of PROGRESSION, a second line chemotherapy should be
considered. During second line chemotherapy evaluation, Nimotuzumab administration every 14
days will be maintained
FOLLOW-UP THERAPY:
In case of STABLE DISEASE or ANTITUMORAL RESPONSE (complete or partial), an mAb hR3 vs
Placebo dose will be maintained every 14 days without chemotherapy after this concomitancy
phase until patient shows progression. mAb Nimotuzumab hR3 will be administered endovenously
in a 250 mL saline solution in 30 min. infusion ambulatory. Following drug administration,
patient should remain in the health care institution for at least 4 hours in order to
guarantee immediate adverse reactions detection and its appropriate treatment.
EVALUATION OF RESPONSE
Survival of patient will be determined from the moment of inclusion until death, for two
years.
Therapeutic success will be considered to have occurred when the patient survives more than
10.5 months in the branch treated with mAb Nimotuzumab, or when the difference between both
groups is not less than 4 months and that of the mAb group is not greater than 10.5 months.
Therapeutic failure will be considered to have occurred when the patient does not survive
the 6.5 months that are habitually reported in the literature, which is the median survival
of patients treated only with Platinum
IMAGE RESPONSE CRITERIA:
An evaluation of target lesions will be made (complete response, partial response,
progressive disease, stable disease)
HAMA RESPONSE WITH ELISA
EGF-R EXPRESSION The EGF-R expression will be evaluated in the samples of tumors from the
patients using Immunohistochemical techniques. The pre-inclusion EGFR expression will not
constitute an inclusion criterion, but it will be correlated retrospectively with the
antitumoral clinical response.
DETERMINATION OF KRAS, KI 65, P53. Evaluation of the QLQ- 30 and Cx24 questionnaires will be
done in cycles 3 and 6 of the first line of chemotherapy, and in the 3rd and 6th cycles of
the second line of chemotherapy.
ADVERSE EVENTS All adverse events during the trial will be documented in patient's file and
in the report forms of each case. Every adverse event will be reported including the strat
date, termination date, severity, and possible relation with the drug studied (occurrence of
and AE, description of AE, intensisity of AE, casualty relation, attitude following AE)
Severity of adverse events will be evaluated according to the following taxonomy:
Serious adverse event (Grade 3): Event that threatens the life of patient. Hospitalization
of patient is required with the possible interruption of the drug studied.
Moderate adverse event (Grade 2): Patient requires a symptomatic treatment to continue with
her customary daily actvities. A more frequent evaluation is required until adverse event
disappears.
Mild adverse event (Grade 1): Patient may continue with her daily activities and does not
requiere complementary pharmacological treatment.
Characterization of Adverse Events Main researcher will evaluate each adverse event and will
determine their relation with the drug being studied according to the following possible
cases. He/she will record his/her evaluation in the Adverse Event Report.
0.- Unrelated The adverse event cannot be related to the use of the drug studied or there is
no temporal or causal relation of the identified effect (other than the use of the drug
studied)
1. - Possibly related There is a temporal association or the cause of the effect may be
related with other ethiologies (probable causes). The relation with the drug studied
cannot be excluded.
2. - Probably related There is a temporal association although there are other possible
but not probable causes
Reporting of Adverse Events will be made as follows:
1. Report to the monitor no later than 24 hours when a patient is still being studied.
2. Reporting of adverse event within 30 days when the patient has finished the study.
3. A summary of the clinical history will be prepared including a detailed description of
adverse events (regardless the adverse event might be associated or not to the drug or
procedures of the study).
4. All serious adverse events shall be reported to the Institutional Ethic Committee and
to the Research Host Hospital
5. A Report on Adverse Events will be made using the Health Secretariat format
A report will be delivered to the monitor to perform the pertaining actions.
Why Study Cardiac Function In different toxicities, cardiac toxicity was mentioned
previously as one of the side effects of treatment with chemotherapy. In other studies, in
which a molecular target directed against the VEG + chemotherapy has been studied, it has
demonstrated cardiac toxicity, which makes it necessary to consider it.
Currently, the evaluation of cardiac function takes place through Nuclear Medicine and has
been established as a safe, effective, and low-cost method. Basal, MUGA and ECG measurements
will be made prior chemotherapy in cycle 6 of first line CT. In case of second line
chemotherapies, measurements will be made in cycles 3 and 6.
The importance of quality of life means: good state of mental, physical, and social health
in patients that survive the cancer (Brunner et al.1995). Patients treated with radiotherapy
vs. surgery or both, in local advanced cervical cancer, demonstrate that they do not achieve
the same quality of life two years after the treatment compared to the control group (Klee
et al. 2000, Cull et al. 1993). The EORTC developed and validated a program in order to
evaluate the quality of life of patients that suffer from cancer (above all, cervical and
breast cancer) before and during the treatment. The QLQ-c30v 3 (Holzner et al. 2001, Fayer
et al. 2002, Aaronson 1993), has the characteristic of evaluating the impact of the disease
and its treatment on the patient's functioning in the following areas: physical,
psychological, and social.
Recently, the QLQ Cx 24 questionnaire (Greimel et al. 2006) is a specific instrument for
measuring the quality of life in patients with cervical cancer, validated by the EORTC. It
has the capacity to assess quality of life in different clinical stages; it evaluates
aspects of the female reproductive system, sex life, and the discomforts caused by the local
treatment; it has a Cronbach Alfa coefficient of 72%-82%; the disadvantage is that this
questionnaire must be self-evaluative, and the majority of our patients have to be helped
due to the fact that 80% of our population has an incomplete primary school education.
Basal measurements will be made prior chemotherapy in cycle 3, then in cycle 6 of first line
chemotherapy. In the case of second line chemotherapies, measurements will be made at the
beginning of second line chemotherapy and in cycles 3 and 6 of such chemotherapy.
During follow-up, Questionnaires QLQ 30 and CX 24 will be preformed every 6 months during
the first two years and afterwards, annually until completion of 5 years.
FOLLOW-UP Post-study follow-up visits will be made every 3 months during the first 2 years;
every 4 months during third year; every 6 months in the following year, and later on,
annually or until progression.
The information collected during that period will be as follows:
Limited clinical history and physical examination; performance status assessment including
weight and tumor lesion measurements for lesions than can be measured through a physical
examination or image studies: BH, QS, PFH; relapsing, progression or recurrence date.
Cardiac function will be assessed with MUGA every 6 months during the first year and later
on, annually.
Evaluation of Questionnaires QLQ- 30 and Cx24 will be performed every 6 months during the
follow-up and for the first twol years, and then, annually up to 5 years.
Blinding procedure and methods for code treatment opening and access. Main clinical
researcher is the ultimate person responsible for the appropriate patient attention and
he/she will determine if patient shall continue or not the treatment being researched in the
event an adverse event appears bearing a risk to the life of patient.
In each clinical site, the researcher or pharmaceutical person responsible for the
institution will be provided with sealed envelopes stating the treatment each patient is
receiving. If a patient needs clinical management due to the presence of severe or
unexpected adverse events related to the product being studied and for which it is required
to know the treatment patient is receiving, randomization envelopes will be opened.
Opening the randomization envelope will only be justified when a severe or unexpected averse
event is present. In that case, the procedure followed and explanations for that procedure
shall be recorded on patient's clinical history.
Sealed envelopes containing the treatment assigned for each patient will be prepared by the
designated person at the CIM Regulatory Affairs Department and he/she will also label the
vials based on the randomized list stating the treatment each patient is receiving.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
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