Evaluation of TRANSKRIP ® Plus Chemotherapy in Recurrent-Persistent Cervical Cancer

The purpose of this study is to determine the efficacy and safety the combination of TRANSKRIP ® vs placebo plus Carboplatin/Paclitaxel as first line treatment in patients with recurrent-persistent cervical cancer.

HYPOTHESIS: It is estimated that adding TRANSKRIP ® to the chemotherapy an increase will occur in the survival of at least 3.6 months superior compared to the patients receiving only QT (17.9 months for TRANSKRIP plus QT and 14.3 months for QT, i.e. a 20% of difference).

Sample size: Data from GOG (Gynecologic Oncology Group) 240 study was used to define it where at 36 months the survival rate was 39.5% for the control group. Losses of 20%, 95% α, 80% β, among groups of 1 ratio and a better 20% survival in the experimental group were considered. From the above, 230 are included which will be in blocks of 10.

Study overview: In patients who meet the inclusion criteria an informed consent oral and written will be granted, once accepted screening test will be made to determine exclusion criteria (CAT, laboratories). If they meet all criteria, patients will be assigned to the following treatment groups:

Group A (115 patients): TRANSKRIP® (Hydralazine: 1 oral tablet every 24 hours, 182 mg for rapid acetylators, and 83 mg for low acetylators and Magnesium valproate: orally 30 mg/K weight every 8 hours) starting 1 week prior the first day of the QT Carboplatin based (5 area under curve (AUC) 1hour/day 1) plus Paclitaxel (175 175mg/m2/body surface (BS) 3hour/day 1) for every 21 days for 6 cycles.

Group B (115 patients): Placebo (orally) starting 1 week before the first day of the QT Carboplatin based (5 AUC 1hour/day 1) plus Paclitaxel (175 175mg/m2/BS 3hour/day 1) for every 21 days for 6 cycles.

Patients included in the study will be conducted to determine their acetylator genotype by polymerase chain reaction (PCR) sequencing N-acetyltransferase 2 (NAT2) gene, and blood samples will be sent to the central laboratory CIDAT S.A de C.V. Those with slow acetylation result will receive 83 mg/day of Hydralazine plus 30 mg/Kg/day of magnesium Valproate, patients with fast acetylation result will receive 182 mg/day of Hydralazine plus 30 mg/Kg/day of magnesium Valproate.

Assigning patients: Randomization will be automatically generated in a computer and with the randomization program; the list will be generated by the Contract Research Organization (CRO) hired for this study. The flasks will be labeled by the Alpharma Manufacturing Department, from the random list that identifies the treatment that every patient receives.

Dose adjustments: All patients should have, previous to the chemotherapy administration, an absolute neutrophil count \>1500/µL and platelets greater than 100,000/µL. If they have smaller numbers, treatment will be delayed during 1-2 weeks, until achieving these levels. There won't be dose adjustment of the chemotherapy. The chemotherapy dosage should not exceed the initial dose calculation, unless the patient has a weight change greater than 10% requiring the new dose calculation. A patient which cannot take the drug during 6 weeks since the last treatment should be discontinued from the study. In case of renal toxicity grade 3-4, the dosage of carboplatin will be decreased to 50%.

Dose reduction of magnesium Valproate: If a patient shows somnolence grade 3 and/or ataxia grade 3 magnesium valproate will be suspended for 3 days or until the toxicity is at least grade 2 and will restart to 20 mg/Kg. If after 7 days somnolence grade 3 is not presented it will be increased to 30 mg/Kg and will continue with this dose until the end of the study. If toxicity grade 3 is resubmitted the patient will continue with 20 mg/Kg until the end of the study.

Dose reduction of hydralazine: If a patient shows hypotension grade 3, hydralazine will be suspended for 3 days or until the toxicity is at least grade 2 and will restart to 50% of the dose. If after 7 days hypotension grade 3 is not presented it will increase to 100% of the dose and will continue with this dose until the end of the study.

Procedures No more than 14 days before the initiation of study drug, the state of the disease form every patient will be evaluated with the following procedures: Medical history and physical examination,Evaluation of the performance status (ECOG scale), complete blood count (CBC), Blood chemistry, Liver Function test (LFT), Electrolytes, antinuclear antibodies, Measurement of palpable or visible lesions, as well as those determined by imaging studies by computed tomography of the abdomen, thorax and pelvis, Quality of life questionnaires will be applied to know their basal state.

At the beginning of each cycle: Medical history and physical examination, Evaluation of the performance status (ECOG scale), CBC, Blood chemistry, LFT, Electrolytes, antinuclear antibodies, Hydralazine levels and valproic acid in blood (every 2 cycles), Toxicity evaluation with the established criteria by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE V.3.0).

At the end of 3 and 6 cycles: Medical history and physical examination, Evaluation of the performance status (ECOG scale), CBC, Blood chemistry, LFT, Electrolytes, antinuclear antibodies, Measurement of palpable or visible lesions, as well as those determined by imaging studies by computed tomography, Quality of life questionnaires (QLQ) Cx-30 and C-24 will be applied.

Follow up visits post-treatment will be every 3 months the first 2 years, every 4 months the third year, every 6 months the fourth year and later annually or until progression. During this period Clinical History and physical examination, assessment of performance status, weight and tumor lesion measurements by physical examination or by imaging studies will be obtained. CBC, Blood chemistry, LFT, electrolytes and antinuclear antibodies. Relapse, progression or recurrence date. Quality of life will be evaluated every 6 months during follow to complete 2 years of starting the patient in the study.

Patients will participate in this study during the period prior to treatment and during the QT (Carboplatin plus paclitaxel) administration, or until the experimental treatment with TRANSKRIP® vs Placebo is suspended. Patients may withdraw from the study by progression of the disease, intolerable toxicity, withdrawal of consent by the patient or investigator decision to suspend the participation of the patient in the study. In case of suspending the treatment, patient will continue monitoring or under non-protocol treatment by the treatment service.

Efficacy criteria. The measuring tumor (s) is defined as: Dimensionally measurable: The minimum size of the lesion to be considerable measurable s 10 mm if the cuts from the scanner are of at most 5mm and 20mm with higher cuts of 5mm. A maximum of 5 blank lesions by organ and/or 10 total lesions will be identified. The sum of the maximum diameters from each of the lesions will be considered as the basal measure from the sum of the maximum diameters and this number will be used to categorize the answer. Unidimensionally measurable disease, lesions in previously irradiated fields, ascites, pleural effusions, bone, blastic or mixed metastases or abdominal masses that can be palpated but not measured shall not be considered measurable. To determine the disease status during the study will be evaluated by RECIST criteria.

Clinical Adverse Events: Initially, the staff study site will interrogate each patient and will write the occurrence and nature of the condition (s) of presentation and any preexistent condition (s). During the study, the staff will interrogate the patient and will write any change in the preexistent condition (s) and/or the occurrence and nature of any adverse event. All the adverse events should be reported to the regulatory agency and to the appropriated pharmaceutical companies according to the local regulations.

The staff study site should report to the local regulatory body (COFEPRIS and to the respective committees of the National Cancer Institute), any severe adverse event possibly related to the study drugs including: death, initial or prolonged hospitalization, laying in life threatening, severe or permanent disability or congenital anomaly.

Patient substitution: It is considered replaceable, any patient that has been randomized, but for some reason it has not receive any doses of Transkrip vs placebo, to not affect the trust and power of the sample.

Statistical analysis: All patients who receive the first cycle of chemotherapy study will be evaluated for safety.

All patients who meet histological diagnosis of cancer, presence of dimensionally measurable disease and evaluation with computed axial tomography (CAT) and/or Magnetic Resonance Imaging (MRI) after the third cycle will be evaluated for efficacy.

All confidence intervals will be built with a level of significance of α = 0.05 (Confidence level of 95%). One interim analysis is expected and one final analysis, the first one after included the first 115 patients and upon completion the QT, final analysis is expected at 19 months that the last patient has been included. Intention analysis to treatment to all patients included and by protocol to those who meet the criteria for analysis will be carried out.

Processing and analysis of the data base will be made with the Statistical Package for the Social Sciences (IBM SPSS) version 19.0 ® for Microsoft. The demographic, clinical, of treatment and disease characteristics, will be analyzed, through descriptive statistics: measures of central and dispersion tendency: range, measure, median, mode, standard deviation, proportions and ratios.

Global Survival. It is considered as an initial event the subject inclusion in the study and final event of death. Survival times will be estimated by the no parametric estimator of Kaplan-Meier. Variances and confidence intervals for those will be estimated. Survival curves will be compared by logrank test, considering a bilateral test, and the significance level of 95%. Format Cox regression will be applied to evaluate the influence of control variables in the survival time. Also survival times will be calculated considering as an initial event the disease diagnose and progression.

Objective Response: for parameters for nominal and ordinal scale Chi square test or Fisher exact will be used. For quantitative variables or intervals T Student test will be used if homogeneity.

Toxicity: incidence of adverse effects will be estimated, as well as their frequency by severity, the laboratory values during treatment. Frequency of abnormal laboratory values will be estimated.

Quality of life: The linear transformation of the data was performed to obtain values on a scale of 0-100. In the case of missing data, the calculation of gross score in both the numerator and denominator, will be made taking into account only the items with response. Thus avoiding the values are affected by extremes. Baseline analysis between groups by obtaining mean and standard deviation or median and interquartile ranges, after analysis of data normality by Kolmogorov-Smirnov took place. The bivariate analysis was evaluated by student test for independent samples when the data is parametric or Mann Whitney test for nonparametric data. With an alpha of 0.05 two-tailed. Besides an intragroup longitudinal analysis will be performed to monitor changes in the quality of life through% change between the first and second assessment and bivariate analysis using paired t or Wilcoxon. With an alpha of 0.05 two-tailed.

Progression free survival: It is considered as an initial event the subject inclusion in the study and final event the progression of disease. Survival times will be estimated by the no parametric estimator of Kaplan-Meier. Variances and confidence intervals for those will be estimated. Survival curves will be compared by logrank test, considering a bilateral test, and the significance level of 95%. Format Cox regression will be applied to evaluate the influence of control variables in the survival time.

Eligibility Criteria:
Inclusion Criteria:

* Operating status ECOG: 0-2
* Negative pregnancy test or reproduction potential is zero, determined either by surgery, radiation or menopause, or mitigated with the use of some approved contraceptive method (IUD or hormonal contraceptive during the study and at least 3 months after the study).
* Patients with histological diagnosis of persistent/recurrent cervical cancer, local and/or systemic, with disease measurable by physical examination and TAC. REQUIRED confirmation by biopsy of the recurrence or, persistence only if: lesion is single, less than 2 cm and/or has no sharp edges.
* Chemo-radiotherapy to pelvis or pelvis plus extended fields (may have received concomitant chemotherapy as a radiosensitizer) provided it is within 90 days from the last application and the secondary radiation acute effects have disappeared.
* Hemoglobin equal or greater than 9 g/L. (allowed transfusion prior to treatment to reach this hemoglobin level).
* Leukocytes greater or equal to 4000/mm3.
* Platelets equal or greater to 100 000 mm3.
* Hepatic: Total bilirubin up to 1.5 times normal value, albumin equal or greater to 2: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) lower or equal to 2.5 times the regular superior limit.
* Renal: Normal creatinine. If high, the extent debugging must be greater than 60 mL/min.
* With the exception of alopecia, patients should have resolution of all acute toxic effects of any prior surgery, radiotherapy or chemotherapy, such effects qualified according to the Common Toxicity Criteria (CTC version 3.0) from the National Cancer Institute (NCI), or within the limits shown in laboratory parameters mentioned above.
* Be willing and able to comply with the programmed visits, the treatment plan and laboratory tests.
* The ability to understand the nature of the study and give a report written consent.

Exclusion Criteria:

* Small cell and/or neuroendocrine cervical cancer.
* History of allergy to hydralazine, magnesium valproate or sulfa.
* Any disease of collagen present (Systemic Lupus Erythematosus (SLE), Rheumatoid arthritis (RA), etc), or history of the same.
* Recent or past condition of symptomatic postural hypotension diagnosed by a clinician.
* Secondary heart failure to aortic stenosis or any other condition where a vasodilator is contraindicated.
* Recent or past condition of active disease of the central nervous system, including seizures.
* Previous or current use of magnesium valproate and/or any other anticonvulsive.
* Pregnant patients or nursing.
* Prior cancer within the last 5 years or in presence of a second primary tumor (except carcinoma of the cervix in situ or basal cell carcinoma of the skin adequately treated).
* Use of any of the research agents in the month prior to enrollment in this study.
* Serious concomitant systemic disorders incompatible with the study at the discretion of the investigator.
* Recently receiving another onco-specific treatment research.
* The recently or previously diagnosed hypertension and controlled with any antihypertensive or a combination of them (provided that they do not include hydralazine) WON'T be an exclusion criteria.

Criteria Treatment Interruption

* A patient will be discontinued from the study under the following circumstances.
* If there is evidence of disease progression.
* Unacceptable toxicity.
* If the clinician considers that a change of therapy will be for the best interest of the patient.
* If the patient requests the discontinuation.
* If a patient gets pregnant or does not use an adequate birth control (for patients able to conceive).