1. TITLE: Phase II exploratory study to evaluate the efficacy and safety of weekly topotecan in the treatment of persistent or recurring cervical cancer after failure of first line treatment with platinum derivatives.
PROTOCOL CODE: GEICO 2005/01
AIMS:
- To determine the antitumoral activity of weekly topotecan in patients with persistent or recurring cervical cancer (or metastatic cervical cancer) after failure of first line treatment with platinum derivatives.
- To evaluate the global survival and toxicity of weekly administration of topotecan in this cohort of patients.
- To establish if there is correlation between tumoral histology, HPV (Human Papilloma Virus) infection and response to treatment.
INCLUSIÓN CRITERIA:
- Patients with histological diagnosis of persistent or recurring squamous or non-squamous cervical carcinoma and with documented progression of the disease.
- Patients with measurable disease. The patient must present at least one target lesion to be used as evaluation of response according to RECIST criteria. Tumours previously irradiated shall be diagnosed as non-target.
- Patients aged ³ 18 years.
- ECOG functional stage of 0, 1 or 2 (Appendix 1).
- Patients should have received one prior chemotherapy schedule for the first line treatment of carcinoma of cervix with platinum derivatives. Administration of radiotherapy is admitted in first line treatment.
- Prior radiotherapy is admitted providing that < 25% of the bone marrow has been treated and patients have recovered from the acute toxic effects prior to recruitment for the study. Prior radiotherapy of the whole pelvis shall not be authorized. Prior radiotherapy should have been completed at least 4 weeks before starting the study.
- Sufficient organic function for administration of the treatment, which shall include all the following:
- Suitable medullar reserve: neutrophils > 1.5x109/L, platelets > 100x109/L and hemoglobin > 10 g/dL
- Hepatic function: creatinine clearance > 60 mL/min, bilirubin < 1.5 x the upper limit of the normal limits and transaminases < 2,5 x the normal upper limit and alkaline phosphatase < 2,5 x the normal upper limit. For patients with bone metastasis, the inclusion of patients with alkaline phosphatase £ 5 x NUL, providing that ALT and AST < 1,5 x NUL, assuming in these case that the alkaline phosphatase elevation is due solely to osseous metastases.
- Patients of childbearing age should have a negative pregnancy test before starting the treatment and follow an approved method of contraception during the study and up to 3 months after, and they may not be breastfeeding either.
- Life expectancy of at least 12 weeks.
- Therapeutic compliance and geographic proximity that will facilitate proper follow-up
- Signing of the informed consent form.
TOTAL NUMBER OF PATIENTS:
The sample should be calculated by Fleming’s method for phase II clinical trials and based on the study endpoint, namely the rate of objective responses.
Let us suppose that we accept the efficacy of the treatment if we achieve a response rate of 33% and reject the efficacy of the treatment when the response rate is less than 18%. In this case, considering an alpha error of 0.05 and a test power of 80%, 52 evaluable patients should be admitted.
LAYERING:
Body area should be calculated according to the patient’s current height and weight at the start of each cycle.
A cycle is defined as three weeks’ treatment with topotecan, on days 1, 8 and 15. It should be followed by a week’s rest.
The drug should be administered in compliance with the following schedule:
- Topotecan: 3 mg/m2 i.v for 30 minutes on days 1, 8 and 15.
The dose may be increased to 3.5 and 4 mg/m2 in the event of non-toxicity in the previous cycle.
Three cycles will be administered and if there is no evidence of progression after response evaluation, administration should continue until progression of the disease or until unacceptable toxicity appears.
The cycles should be started on the scheduled date at full dosage so long as neutrophils are > 1500/mm3, platelets > 100000/mm3, hemoglobin > 10 g/dl and there is no non-hematological toxicity grade > 1 or same grade as at baseline according to Common Toxicity Criteria (CTC version 2.0), except alopecia, nausea and vomiting. Otherwise, treatment should be deferred for one week, up to a maximum of 4 weeks. If the patient has not recovered from toxicity after 4 weeks, she should be withdrawn from the study.
Any patient who may require a dose reduction should continue receiving the reduced dose for the rest of the study. Any patient with two dose reductions who re-experiences toxicity that would be grounds for a third reduction should be withdrawn from the study medication.
Any discontinuation of the drug dose may be maintained until recuperation, for a maximum of 4 weeks; in the event of it not being possible to resume drug administration, the patient shall withdraw from the study.
2.
Title: Randomized phase II study of the doublet carboplatin-gemcitabine followed by carboplatin-paclitaxel versus carboplatin-paclitaxel in patients with platinum-sensitive relapses of ovarian carcinoma, primary peritoneal carcinomatosis or carcinoma of the fallopian tubes.
PROTOCOL CODE: GEICO-0104
OBJECTIVES:
a) Determine the clinical response rate of the standard combination carboplatin-paclitaxel as opposed to sequential treatment with the combinations gemcitabine-carboplatin and paclitaxel-carboplatin in the relapse of platinum-sensitive ovarian cancer, primary peritoneal carcinomatosis or carcinoma of fallopian tubes among patients that have received previous treatment with a taxane and a derivative of platinum.
b) Determine the progression free survival and duration of response.
c) Determine the toxicity of both regimens.
d) Analysis of quality of life.
e) Overall survival.
INCLUSION CRITERIA:
Patients that fulfil all the following criteria will be included in the study:
• Obtain their informed consent in writing.
• Recurrent ovarian epithelial cancer, primary peritoneal carcinomatosis or carcinoma of the tubes histologically tested and previously treated.
• Maximum of 2 lines of previous treatment.
• The last line of treatment received by the patient should include a derivative of platinum (cisplatin or carboplatin) and fulfil platinum-sensitivity criteria according to the definition by Thigpen (they are considered platinum-sensitive those patients that respond initially to a treatment with platinum and present an interval free of platinum longer than 6 months. The interval free of platinum is considered to be the time lapsed from the last cycle with platinum and the date of the relapse or progression).
• Patients should have received a taxane (docetaxel or paclitaxel) in some of the lines of previous treatment.
• Presence of disease measurable one-dimensionally and/or evaluable by means of Rustin criteria for the marker CA-125 (see 8.b.1.1. assessment of clinical response).
• Over 18 years of age.
• Functional state ECOG < 2.
• Life expectancy longer than 12 weeks.
• Adequate renal, liver and haematological function defined according to the following criteria.
-
Creatinine clearance> 40 ml/min
- Bilirubin < 1,5 x upper limit of normal
- Transaminases < 2,5 x upper limit of normal
(in the event of hepatic metastases < 5 x upper limit of normal).
- Time of protombin> 50%
- Hemoglobin > 10 mg/dL
- Platelets > 100.000 / mm3
- Neutrophils > 2000 / mm3
• Geographical vicinity that allows the protocol to be carried out adequately.
• In the case of women of fertile age appropriate birth-control measures should be adopted.
TOTAL NUMBER OF PATIENTS:
110 evaluable patients will be recruited in this study based on the following criteria:
For the experimental arm we assume the hypothesis zero (H0) that the response rate is 65% (the one expected with the standard paclitaxel-carboplatin regimen), compared to the alternative (H1) that the response rate is of at least 80%. To study these hypotheses with a level of significance of 0,05% and a power of 80%, a total of 55 assessable patients would be needed in each arm.
STRATIFICATION:
• ARM A: Paclitaxel + carboplatin: A cycle is defined as three weeks of treatment in which paclitaxel and carboplatin will be administered on day 1 followed by a three-week rest. Both drugs will be administered in the following scheme:
3-hour infusion of Paclitaxel. The paclitaxel infusion will be administered in the following way:
-
Dexamethasone 20 mg IV 30 minutes before paclitaxel.
- Diphenhydramine 50 mg (o Dexclorfeniramine 5
mg) IV 30 minutes before paclitaxel.
- Cimetidine 300 mg (o Ranitidine 50 mg) IV 30
minutes before paclitaxel.
Next, carboplatin is administered in 30-60-minute infusions with a calculated dose using the Calvert formula.
8 cycles will be administered to all the patients unless progression of the disease is observed or the treatment is suspended by decision of the patient or of the investigator.
•
ARM B: Gemcitabine + carboplatin followed by Paclitaxel + carboplatin:
First sequence: A cycle is defined as three weeks of treatment in which carboplatin will be administered together with gemcitabine on day 1, repeating gemcitabine on day 8 followed by a two-week rest. Both drugs will be administered in the following scheme:
Gemcitabine: in 30-60-minute infusions on days 1 and 8.
Only on day 1 and after gemcitabine, carboplatin is administered in infusion of 30-60 minutes with a dose calculated using the Calvert formula.
4 cycles will be administered to all the patients unless progression of the disease is observed or the treatment is suspended by decision of the patient or of the investigator (in which case treatment will proceed to the second sequence of the treatment).
Second sequence: the treatment will be administered in the same way as in arm A. 4 cycles will be administered to all the patients unless progression of the disease is observed or the treatment is suspended by the decision of the patient or of the investigator.