ITOV04: Trial of High Dose Topotecan With Carboplatin in Patients With Relapsed Ovarian Carcinoma

Sponsor

Assistance Publique - Hôpitaux de Paris (Other)

Overall Status

Terminated

CT.gov ID

NCT01177501

Collaborator

(none)

Enrollment

Location

Arm

Duration (Months)

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The early relapse of ovarian cancer occurring within 6 months of chemotherapy including platinum regimen are called relapses 'platinum resistant' consecutively patients die quickly of their disease. For relapses occurring between 6 and 12 months, no recommendation occur and few studies are conducted. Therefore it seems interesting to develop a research on intensive chemotherapy using a combination of carboplatin (a drug widely used in most ovarian cancer) with Topotecan , use in a high dose protocol. Topotecan has demonstrated its efficacy in relapse ovarian cancer and its possible use in high doses, a recent study (ITOV01) have demonstrated the feasibility of dose escalation of topotecan monotherapy (MTD set at 9 mg / m² / dx 5 days). This project is a feasibility research of the combination of topotecan and carboplatin in a high dose escalation protocol for early ovarian cancer relapse occurring 6 to 12 months after conventional chemotherapy-based platinum salts.

Condition or Disease	Intervention/Treatment	Phase
Ovarian Cancer Relapses	Drug: Topotecan	Phase 1

Detailed Description

The combination Topotecan plus carboplatin at high doses has been published by Miles Prince et al in 2001. In a triple combination, the authors were able to define the Maximum Tolerated Dose (MTD) of 3.5 mg / m² / day x 5 days for topotecan, 250 mg / m² for paclitaxel and AUC at 12 for carboplatin (46). The MTD of topotecan combined with carboplatin (AUC 16) and VP 16 could not be determined by Carroll et al (47). However, in the study ITOV01bis (ASCO abstract 2007 No. 1661), the MTD of topotecan was determined in combination with cyclophosphamide at 120 mg / kg and was fixed at 9 mg/m2/jx 5 days, the same as the DMT used in monotherapy ITOV 01).

Studies related above, the combination of high dose of topotecan and carboplatin seems possible with a limited dose of carboplatin at AUC 20, an allocation of 5 days for both drugs [with a fixed daily AUC 4 for carboplatin , same as the program TAXIF I in germ cell tumors, published by our team (Annual Oncology 2004) as well as TAXIF II developed by Tenon's hospital] with an administration time of 30 minutes daily for topotecan and 2 hours for carboplatin.

these data justify the pattern of our study:

established treatment of 5 consecutive days provides the best therapeutic index,
infusion of 30 minutes, seems to give less non-haematological toxicity compare to continuous infusion, which prevailed in the trial ITOV 01,
Rescue by blood stem cells (collected by chemotherapy mobilization-type high-dose cyclophosphamide followed by hematopoietic growth factors (G-CSF, Filgrastim) reinjection is scheduled to H96 after the treatment end ,
six sequential doses established in the absence of limiting toxicity, as follows: 7.5 - 8.0 - 8.5 - 9.0 - 9.5 - 10.0 mg/m2. Steps 9.5 mg / m² and 10 mg / m will be discussed after approval by an independent committee in charge of the studyContinuation of Topotecan at conventional dose can be done thanks to clinical data based on efficacy and tolerance

Study Design

Study Type:

Interventional

Actual Enrollment :

3 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I Trial of High-dose Topotecan in Association With Carboplatin, With Peripheral Blood Stem Cell Support in Patients With First Relapsed Ovarian Carcinoma Without Platinum-treatment Since 6-12 Months

Study Start Date :

Apr 1, 2009

Actual Primary Completion Date :

Mar 1, 2012

Actual Study Completion Date :

Mar 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Topotecan	Drug: Topotecan Six sequential doses established in the absence of limiting toxicity, as follows : 7.5 - 8.0 - 8.5 - 9.0 - 10.0 mg/m²

Arm

Intervention/Treatment

Experimental: Topotecan

Drug: Topotecan

Six sequential doses established in the absence of limiting toxicity, as follows : 7.5 - 8.0 - 8.5 - 9.0 - 10.0 mg/m²

Outcome Measures

Primary Outcome Measures

Identification of the maximum tolerated dose (MTD) of topotecan at 6 weeks [at 6 weeks after the first administration of topotecan]
Evaluation of limiting toxicities (toxic death, grade IV non-hematopoietic or haematopoietic toxicity)of topotecan

Secondary Outcome Measures

Pharmacokinetic of topotecan [At 1 and 5 days after the first administration of topotecan]
Pharmacokinetic of carboplatin [At 1 and 5 days after the first administration of topotecan]
The response to therapy [From the first day of the administration of topotecan to 2 years]
The duration of response and the overall survival [From the first day of the administration of topotecan to 2 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Primary ovarian or tubal adenocarcinoma, or peritoneal carcinoma histologically proved
Age between 18 and 65
ECOG criteria £ 2
Patients with first relapsed ovarian carcinoma without platinum-treatment since 6-12 months and after first-line therapy with platinum salt and taxanes together or successively
Negative viral serology (HbS, HbC and HIV)
Informed consent
Patients with social security

Exclusion Criteria:

Refractory (relapse < 6 months) or sensitive (relapse > 12 months) relapsed ovarian carcinoma
Life expectancy < 3 months
Previous treatment with pelvic radiography
Previous treatment with Topotecan or other topoisomer I inhibitor
Non resolutive intestinal obstruction under symptomatic treatment
Creatinine > or equal at 1.25N and/or creatinine clearance < or equal at 60 ml/mn
Bilirubin > 1.25N ; transaminase and alkaline phosphatase > 2N (3N if hepatic metastases were present)
Abnormal heart (ultrasound only) (FR < 30%; FEVG < 50%)
White blood cells < or equal at 4.0 x 109/L, Neutrophils < or equal at 1.5 x 109/L, platelets < or equal at 100 x 109/L
Neuropathy: grade > or equal at 2
Epilepsy
Symptomatic cerebral metastases
Serious psychiatric pathology
Uncontrolled serious infection
Patient that already received peripheral blood stem cell support
Haematopoeitic growth factors allergy
More than one line chemotherapy
Impossibility to use an central veinous access
Hypersensibility to carboplatin or other platinum containing products
Participation to an other clinical trial
Absence of effective contraception