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

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

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.

Study Overview

• Status: Completed
• Conditions: Fallopian Tube Cancer; Peritoneal Carcinoma; Ovarian Neoplasms Malignant (Excl Germ Cell)
• Intervention / Treatment: Drug: trientine dihydrochloride; Drug: pegylated liposomal doxorubicin; Drug: carboplatin

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.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2; Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: trientine with chemotherapy; trientine dihydrochloride PO daily (in different dose levels) plus pegylated liposomal doxorubicin IV D1 plus carboplatin IV D1

Drug: trientine dihydrochloride; trientine dihydrochloride 300MG/CAPSUE PO daily (in different dose levels); Other Names: carboplatin; pegylated liposomal doxorubicin; Drug: pegylated liposomal doxorubicin; pegylated liposomal doxorubicin 40mg/m2 IV D1; Other Names: carboplatin; trientine dihydrochloride; Drug: carboplatin; carboplatin AUC 4 IV D1; Other Names: pegylated liposomal doxorubicin; trientine dihydrochloride

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Cheng-Kung University Hospital

Publications and helpful links

General Publications

• Huang YF, Kuo MT, Liu YS, Cheng YM, Wu PY, Chou CY. A Dose Escalation Study of Trientine Plus Carboplatin and Pegylated Liposomal Doxorubicin in Women With a First Relapse of Epithelial Ovarian, Tubal, and Peritoneal Cancer Within 12 Months After Platinum-Based Chemotherapy. Front Oncol. 2019 May 24;9:437. doi: 10.3389/fonc.2019.00437. eCollection 2019.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2012
• Primary Completion (Actual): October 1, 2015
• Study Completion (Actual): December 1, 2019

Study Registration Dates

• First Submitted: March 2, 2018
• First Submitted That Met QC Criteria: March 21, 2018
• First Posted (Actual): March 29, 2018

Study Record Updates

• Last Update Posted (Actual): November 10, 2020
• Last Update Submitted That Met QC Criteria: October 18, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Carboplatin; Pegylated liposomal doxorubicin; Peritoneal cancer; Epithelial ovarian cancer; Trientine; Copper chelator; Tubal cancer
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Fallopian Tube Diseases; Neoplasms; Ovarian Neoplasms; Fallopian Tube Neoplasms; Carcinoma, Ovarian Epithelial; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Chelating Agents; Sequestering Agents; Carboplatin; Doxorubicin; Liposomal doxorubicin; Trientine
• Other Study ID Numbers: BR-100-074

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• product manufactured in and exported from the U.S.: No