Trabectedin/Caelyx vs Cisplatin Hypersensitivity in Relapsed Ovarian Cancer Patients Allergic to Platinum

Study Overview
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Brief Summary
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Observational, clinical study. Intention to include 40 patients (20 patients treated with trabectedin and 20 with cisplatin hypersensitivity) The investigators investigate the role of trabectedin in combination with PLD and cisplatin in treating platinum sensitive ROC being allergic to carboplatin. The investigators focus on adverse events and evaluate if these are tolerable for the patients and further evaluate the measurable treatment effect on the tumor burden.

Detailed Description
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INTRODUCTION Trabectedin (Yondelis®) is a tetrahydroisoquinoline alkaloid that is produced synthetically. It acts by interfering with DNA transcription factors, DNA binding proteins, and DNA repair pathways. This results in cell cycle arrest and apoptosis. Trabectedin (T) probably causes DNA double-strand breaks. Trabectedin decreases the level of proangiogenic VEGF, CCL2, and interleucin-6 (IL-6) which indicate that trabectedin is cytotoxic with immune regulatory effects (1). Since 2007 trabectedin mainly has been used in the treatment of soft tissue sarcomas (1). In meningioma trabectedin has been used in a murine model of ovarian cancer (2). A combined treatment of trabectedin and anti-PD1 antibody produces a synergic antitumor effect (3). In a phase III international multicentre study the addition of trabectedin to pegylated liposomal doxyrubicin (PLD) (Caelyx) has shown to improve progression free survival and overall response rate compared to PLD alone in second-line treatment of recurrent ovarian cancer (ROC) (4). Trabectedin can replace platinum in clinical settings where there has been serious allergic reaction adverse effect from platinum (Carboplatin) (4). In many of these patients Carboplatin has been replaced by Cisplatin hypersensitivity regimen (CH). In patients with serious side effects to Cisplatin or other factors that impair the treatment of Cisplatin, trabectedin is a good alternative (4). Trabectedin may also have a therapeutic role in patients with recurrent BRCA mutated ovarian cancer patients (5,6). When combined with PLD, trabectedin improves progression free survival (PFS) and objective response rate (ORR) in the second line-treatment of ROC. The combination led to manageable and non-cumulative overall toxicity with a fewer PLD-associated adverse events (7,8,9). The majority of patients treated with trabectedin are given the combination with PDL and patients treated with cisplatin have the combination with paclitaxel. In the present study the investigators will examine the role of trabectedin in combination with PLD and cisplatin in treating platinum sensitive ROC being allergic to carboplatin. The investigators will focus on adverse events and evaluate if these are tolerable for the patients and further evaluate the measurable treatment effect on the tumor burden. Primary aims: To investigate if trabectedin in combination with pegylated liposomal doxyrubicin (PLD) is applicable to replace desensitising cisplatin ROC treatment. Secondary aims: Effect on tumor burden (CT by RISK criteria, vaginal ultrasound, CA125). Level of adverse effects. To calculate the PFS of the two cohorts (trabectedin and cisplatin). To calculate cancer specific survival (CSS) of the two cohorts (trabectedin and cisplatin) MATERIAL AND METHODS A description of the indication of treatment and follow-up after treatment with trabectedin in combination with PLD or cisplatin at the Oslo University Hospital (OUS), Department of gynecologic cancer. This study is retrospective and prospective in design. Totally 20 patients treated with trabectedin in combination with PLD and 20 patients with cisplatin will be included in the study. Platinum sensitive tumors are defined as tumors recurring 6 months or more after previouis platinum treatment. In the study the investigators will mainly include patients having allergic reactions to carboplatin.

Official Title
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Trabectedin (T) in Combination With Pegylated Liposomal Doxyrubicin (PLD) Compared to Cisplatin Hypersensitivity (CH) Treatment in Recurrent Ovarian Cancer Patients Allergic to Carboplatin

Conditions
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Ovarian Neoplasm, Chemotherapeutic Toxicity, Chemotherapy Effect, Chemotherapy-induced Neutropenia, Chemotherapy-induced Nausea and Vomiting

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women with recurrent ovarian cancer and allergic reaction to carboplatin or other serious side effects to carboplatin Exclusion Criteria: - Patients not treated with carboplatin previously

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS | Progression Free Survival | From date of end of recurrent treatment (date of last cycle) with trabectedin/PLD or cisplatin hypersensitivity/paclitaxel until the date of first documented progression or date of death from any cause whichever came first, assessed up to 130 months. | 
| Side effects | Side effects of recurrent treatment from trabectedin/PLD and cisplatin hypersensitivity/paclitaxel. | The side effects are assessed until 28 days after each cycle, up to 8 weeks after last cycle with trabectedin or cisplatin hypersensitivity. Each cycle is 28 days until 6 cycles.. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cancer Specific survival (CSS) | Cancer Specific survival | From date of primary diagnosis until date of last observation or death of ovarian cancer, whichever came first, assessed up to 36 years. | 
| Drug Interactions | Interactions between trabectedin/PLD or cisplatin hypersensitivity/paclitaxel and other drugs the patients use during recurrent treatment (Examples: antihypertensive drugs, drugs inhibition of CYP450 2C8/3A4). The drugs are defined as mild increase-moderate increase -severe increase, mild decrease, modereate decrease, and severe decrease (6 categories) of trabectedin, PLD, cisplatin hypersensitivity or paclitaxel effect. The categories are obtained from the Drug Interactions Checker at www.drugs.com. | From date of start recurrent treatment with trabectedin/PLD or cisplatin hypersensitivity/paclitaxel until date of last cycle with trabectedin/PLD or cisplatin hypersens/paclitaxel. The data are assessed at each cycle, 2 weeks after each cycle until 6. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ovarian cancer, Pegylated Liposomal Doxorubicin, Trabectedin, Cisplatin hypersensitivity, Paclitaxel