Trial of Trientine Plus Pegylated Liposomal Doxorubicin and Carboplatin in Epithelial Ovarian Cancer

Study Overview
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Brief Summary
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Epithelial ovarian cancer (EOC) is the leading cause of gynecological malignancy-related deaths worldwide and is a substantial health threat to women. Many patients eventually develop chemoresistant relapsed disease and die despite surgery and combination chemotherapy. Progress in improving the survival in EOC has been slow, despite significant advances in treatment over the past 25 years. Tubal cancer and peritoneal cancer are thought to be similar in their origin, characteristics and treatment strategies. Based upon basic and animal studies, it is thought that copper chelators overcome platinum resistance. Thus, Trientine combined with carboplatin has been used to treat human cancers. The adverse effects (AEs) are acceptable in previously heavily-treated recurrent ovarian cancer patients, however, the treatment responses are limited. Therefore, here the investigators conduct a phase I trial of Trientine®, pegylated doxorubicin and carboplatin to find the dose-limited toxicities, and maximal toxicity dosage, and to explore whether the combination is applicable in epithelial ovarian, tubal and peritoneal cancers.

Detailed Description
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Epithelial ovarian cancer, tubal, primary peritoneal cancers are lethal gynecologic malignances, with a 5-year survival rate below 25% for patients diagnosed with stage III-IV. Most advanced stage patients respond to cytoreductive surgery and platinum-based chemotherapy; however, >70% of women relapse, and platinum-resistant EOC is uniformly fatal. Physicians often increase the dosage of cytotoxic agents, or use single or combination second-line agents to overcome the drug resistance. Nevertheless, second-line chemotherapy sometimes may not achieve the expected cytotoxic effect and drug resistance may lead to cancer-specific death. Overcoming resistance is an important strategy for improving the therapeutic efficacy in cisplatin-containing cancer chemotherapy. Cu homeostasis in human cells involves the inter-regulatory circuitry composed of Cu, the high-affinity Cu transporter (hCtr1) and transcription factor Sp1. Human copper transporter 1 (htr1) in humans are also involved in the import of antitumor agent cisplatin (Cp). Earlier the investigators also discovered that the magnitude of hCtr1 expression by Cu chelators depends upon the basal levels of hCtr1 expression, and that high levels of hCtr1 expression can be modulated through Cu deprivation in Cp-resistant (CpR) cells, providing a molecular basis for the development of Cu chelators as Cp resistance reversal agents in the clinical settings. D-penicillamine and Cp act synergistically to inhibit tumor growth. The investigators conduct this trial with combination agents, including LipoDox®, carboplatin and Trientine®, to develop the clinical application of copper chelator in conjunction with cytotoxic agents to conquer platinum-resistance. This trial is practical and is of perspective.

Official Title
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Phase I Trial of Copper Chelator in Conjunction With Pegylated Liposomal Doxorubicin and Carboplatin in Patients With Platinum-resistant/-Refractory Epithelial Ovarian Cancer, Tubal Cancer and Primary Peritoneal Cancer

Conditions
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Ovarian Neoplasms Malignant (Excl Germ Cell), Peritoneal Carcinoma, Fallopian Tube Cancer

Intervention / Treatment
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* Drug: trientine dihydrochloride
* Drug: pegylated liposomal doxorubicin
* Drug: carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proved epithelial ovarian cancer, tubal cancer, and primary peritoneal cancer after surgical staging or debulking surgery The first relapse within 1 year after the completion of primary platinum-based chemotherapy (partially platinum-resistant/-sensitive) or disease progression during primary chemotherapy (platinum-refractory). Eastern Cooperative Oncology Group (ECOG) performance status 2 or less Adequate bone marrow function (absolute neutrophil count ≥ 1,500/μl, hemoglobin ≥ 9.0 g/dL and platelet count ≥ 100,000/μl) Serum creatinine ≤ 1.5 mg/dL or a calculated creatinine clearance of at least 50 mL/min, total serum bilirubin ≤ 5.0 mg/dL Alanine transaminase (ALT) or aspartate aminotransferase (AST) ≤ 5 × upper normal limit Patients with reproductive potential had to agree to use an effective method of birth control prior to study entry for the duration of the study participation If there was no available therapy that prolonged survival for at least 3 months Exclusion Criteria: Patients who have metastasis to the central nervous system Patients who have other malignancies within 5 years prior to study entry with the exception of carcinoma in situ of the cervix uteri and non-melanoma skin cancers Patients who are receiving concurrent chemotherapy Patients who have not recovered from surgery within 4 weeks of the study; Patients with a clinically significant medical condition that could be aggravated by treatment or that cannot be controlled Patients with medical and/or psychiatric problems of sufficient severity to limit full compliance with the study or expose patients to undue risk Patients with known anaphylactic response or severe hypersensitivity to study drugs or their analogs Pregnant or lactating women Patients with any evidence of difficulty swallowing, intestinal obstruction or malabsorption disorder interfering with nutrition Patients who were unwilling or unable to provide informed consent

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 75 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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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: trientine with chemotherapy<br>trientine dihydrochloride PO daily (in different dose levels) plus pegylated liposomal doxorubicin IV D1 plus carboplatin IV D1 | Drug: trientine dihydrochloride<br>* trientine dihydrochloride 300MG/CAPSUE PO daily (in different dose levels)<br>* Other names: carboplatin;Drug: pegylated liposomal doxorubicin<br>* pegylated liposomal doxorubicin 40mg/m2 IV D1<br>* Other names: carboplatin;Drug: carboplatin<br>* carboplatin AUC 4 IV D1<br>* Other names: pegylated liposomal doxorubicin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-Limiting Toxicity (DLT) | (1) Grade 4 neutropenia (ANC <500/cumm^3) or thrombocytopenia ≧7 days; (2) Hematologic toxicities ≧ Grade 3, eg. febrile neutropenia <1,000/cumm^3, or platelet count <25,000/cumm^3 with hemorrhage ≧ 7 days; (3) Non-hematologic toxicities ≧ grade 3, eg. ALT or AST, ≧ 7days; other non-hematologic toxicities ≧ grade 3 (except alopecia, non-chemotherapy related nausea/vomiting); (4) Neurologic toxicities ≧ grade 2, eg. dizziness, or lethargy ≧ 3 days | 36 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose, MTD | '3+3' study design. MTD will be defined at the dose level of trientine prior to the level with DLT events ≧ 2/6 participants. | within 36 days after the start of Trientine | 
| Maximum Plasma Concentration [Cmax] of Trientine | Trientine (TETA) prior to and within 24 hrs and 7 days after trientine | 0, 10mins, 30mins, 60mins, 90mins, 120mins, 4h, 6h, 24h, 148h, 150h, 153h, 156h post 1st dose of trientine | 
| Progression-free Survival | Time is calculated from the diagnosis to the last follow-up date if no disease progression , or the date of disease progression after the last treatment cycle of the study drugs | 36 months | 
| Overall Survival | Time is calculated from the diagnosis to the date of the last follow-up date if no death event, or the date of death. | 36 months | 
| Percentage of Participants With Measurable Tumor Treatment Response Assessed by RECIST Criteria 1.1 | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT scan | 176 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Copper chelator, Epithelial ovarian cancer, Tubal cancer, Peritoneal cancer, Trientine, Pegylated liposomal doxorubicin, Carboplatin