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

Phase 1

Completed

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

Interventions: Drug: trientine dihydrochloride
Drug: pegylated liposomal doxorubicin
Drug: carboplatin

Registration Number: NCT03480750

Lead Sponsor: National Cheng-Kung University Hospital

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 18

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
trientine with chemotherapy	trientine dihydrochloride	trientine dihydrochloride PO daily (in different dose levels) plus pegylated liposomal doxorubicin IV D1 plus carboplatin IV D1
trientine with chemotherapy	pegylated liposomal doxorubicin	trientine dihydrochloride PO daily (in different dose levels) plus pegylated liposomal doxorubicin IV D1 plus carboplatin IV D1
trientine with chemotherapy	carboplatin	trientine dihydrochloride PO daily (in different dose levels) plus pegylated liposomal doxorubicin IV D1 plus carboplatin IV D1

Primary Outcome Measures

Name	Time	Method
Number of Participants With Dose-Limiting Toxicity (DLT)	36 days	(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

Secondary Outcome Measures

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