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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01177501
Recruitment Status : Terminated (choice of the principal investigator)
First Posted : August 9, 2010
Last Update Posted : November 19, 2012
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

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

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Study Type : Interventional  (Clinical Trial)
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 : April 2009
Actual Primary Completion Date : March 2012
Actual Study Completion Date : March 2012

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

Primary Outcome Measures :
  1. Identification of the maximum tolerated dose (MTD) of topotecan at 6 weeks [ Time Frame: 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 :
  1. Pharmacokinetic of topotecan [ Time Frame: At 1 and 5 days after the first administration of topotecan ]
  2. Pharmacokinetic of carboplatin [ Time Frame: At 1 and 5 days after the first administration of topotecan ]
  3. The response to therapy [ Time Frame: From the first day of the administration of topotecan to 2 years ]
  4. The duration of response and the overall survival [ Time Frame: From the first day of the administration of topotecan to 2 years ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01177501

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Frédéric Selle
Paris, France, 75020
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
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Principal Investigator: Frédéric Selle, MD Assistance Publique - Hôpitaux de Paris

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Responsible Party: Assistance Publique - Hôpitaux de Paris Identifier: NCT01177501    
Other Study ID Numbers: P 050603
First Posted: August 9, 2010    Key Record Dates
Last Update Posted: November 19, 2012
Last Verified: November 2012
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Ovarian cancer
Higt dose chemotherapy
Additional relevant MeSH terms:
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Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Endocrine Gland Neoplasms
Neoplasms by Site
Ovarian Diseases
Adnexal Diseases
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents