Combination of Nimotuzumab Cisplatin-Vinorelbine in First Line Chemotherapy in Recurring-Persistent Cervical Carcinoma
Condition: Cervical Cancer Recurrent or Persistent; Palliative Treatment; Monoclonal Antibody in Cervical Cancer Treatment
MeSH terms: Uterine Cervical Neoplasms
Study type: Interventional
Phase: Phase 3

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): mAb Nimotuzumab; Placebo
Intervention type(s): Drug; Device
Intervention description(s): This group will receive a dose of 200 mg mAb hR3 (weekly over 18 weeks) plus chemotherapy (6 cycles every 21 days of Cisplatin (CDDP) 50 mg/m2 on day 1/, Vinorelbine 30 mg/m2 on day 1 and day 8); This group will receive a placebo in addition to chemotherapy in a similar regimen. Once the chemotherapy is completed a maintenance dose will be administered with 200 mg/dose of mAb hR3 every 14 days until progression.
Intervention MeSH terms: Nimotuzumab
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Cervical cancer; Recurrent or persistent tumor; Monoclonal antibody