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

Brief Title

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

Official Title

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

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.

Study Phase

Phase 1/Phase 2

Study Type

Interventional

Primary Outcome

Number of Participants With Dose-Limiting Toxicity (DLT)

Secondary Outcome

 Maximum Tolerated Dose, MTD

Condition

Ovarian Neoplasms Malignant (Excl Germ Cell)

Intervention

trientine dihydrochloride

Study Arms / Comparison Groups

 trientine with chemotherapy

Description:  trientine dihydrochloride PO daily (in different dose levels) plus pegylated liposomal doxorubicin IV D1 plus carboplatin IV D1

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status

Drug

Estimated Enrollment

Start Date

September 2012

Completion Date

December 2019

Primary Completion Date

October 2015

Eligibility Criteria

        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

Gender

Female

Ages

20 Years - 75 Years

Accepts Healthy Volunteers

No

Contacts

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Administrative Informations

NCT ID

NCT03480750

Organization ID

BR-100-074

Responsible Party

Principal Investigator

Study Sponsor

National Cheng-Kung University Hospital

Study Sponsor

, ,

Verification Date

October 2020