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

Primary Purpose

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

Status
Completed
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
trientine dihydrochloride
pegylated liposomal doxorubicin
carboplatin
Sponsored by
National Cheng-Kung University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Ovarian Neoplasms Malignant (Excl Germ Cell) focused on measuring Copper chelator, Epithelial ovarian cancer, Tubal cancer, Peritoneal cancer, Trientine, Pegylated liposomal doxorubicin, Carboplatin

Eligibility Criteria

20 Years - 75 Years (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    trientine with chemotherapy

    Arm Description

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

    Outcomes

    Primary Outcome Measures

    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

    Secondary Outcome Measures

    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.
    Maximum Plasma Concentration [Cmax] of Trientine
    Trientine (TETA) prior to and within 24 hrs and 7 days after 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
    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.
    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

    Full Information

    First Posted
    March 2, 2018
    Last Updated
    October 18, 2020
    Sponsor
    National Cheng-Kung University Hospital
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    1. Study Identification

    Unique Protocol Identification Number
    NCT03480750
    Brief Title
    Trial of Trientine Plus Pegylated Liposomal Doxorubicin and Carboplatin in Epithelial Ovarian Cancer
    Acronym
    Trientine
    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
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    October 2020
    Overall Recruitment Status
    Completed
    Study Start Date
    September 2012 (Actual)
    Primary Completion Date
    October 2015 (Actual)
    Study Completion Date
    December 2019 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    National Cheng-Kung University Hospital

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Product Manufactured in and Exported from the U.S.
    No
    Data Monitoring Committee
    No

    5. Study Description

    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Ovarian Neoplasms Malignant (Excl Germ Cell), Peritoneal Carcinoma, Fallopian Tube Cancer
    Keywords
    Copper chelator, Epithelial ovarian cancer, Tubal cancer, Peritoneal cancer, Trientine, Pegylated liposomal doxorubicin, Carboplatin

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 1, Phase 2
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    18 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    trientine with chemotherapy
    Arm Type
    Experimental
    Arm Description
    trientine dihydrochloride PO daily (in different dose levels) plus pegylated liposomal doxorubicin IV D1 plus carboplatin IV D1
    Intervention Type
    Drug
    Intervention Name(s)
    trientine dihydrochloride
    Other Intervention Name(s)
    pegylated liposomal doxorubicin, carboplatin
    Intervention Description
    trientine dihydrochloride 300MG/CAPSUE PO daily (in different dose levels)
    Intervention Type
    Drug
    Intervention Name(s)
    pegylated liposomal doxorubicin
    Other Intervention Name(s)
    trientine dihydrochloride, carboplatin
    Intervention Description
    pegylated liposomal doxorubicin 40mg/m2 IV D1
    Intervention Type
    Drug
    Intervention Name(s)
    carboplatin
    Other Intervention Name(s)
    trientine dihydrochloride, pegylated liposomal doxorubicin
    Intervention Description
    carboplatin AUC 4 IV D1
    Primary Outcome Measure Information:
    Title
    Number of Participants With Dose-Limiting Toxicity (DLT)
    Description
    (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
    Time Frame
    36 days
    Secondary Outcome Measure Information:
    Title
    Maximum Tolerated Dose, MTD
    Description
    '3+3' study design. MTD will be defined at the dose level of trientine prior to the level with DLT events ≧ 2/6 participants.
    Time Frame
    within 36 days after the start of Trientine
    Title
    Maximum Plasma Concentration [Cmax] of Trientine
    Description
    Trientine (TETA) prior to and within 24 hrs and 7 days after trientine
    Time Frame
    0, 10mins, 30mins, 60mins, 90mins, 120mins, 4h, 6h, 24h, 148h, 150h, 153h, 156h post 1st dose of trientine
    Title
    Progression-free Survival
    Description
    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
    Time Frame
    36 months
    Title
    Overall Survival
    Description
    Time is calculated from the diagnosis to the date of the last follow-up date if no death event, or the date of death.
    Time Frame
    36 months
    Title
    Percentage of Participants With Measurable Tumor Treatment Response Assessed by RECIST Criteria 1.1
    Description
    Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT scan
    Time Frame
    176 days

    10. Eligibility

    Sex
    Female
    Gender Based
    Yes
    Gender Eligibility Description
    female gender for gynecologic cancer (epithelial ovarian cancer, tubal cancer, and primary peritoneal cancer)
    Minimum Age & Unit of Time
    20 Years
    Maximum Age & Unit of Time
    75 Years
    Accepts Healthy Volunteers
    No
    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

    12. IPD Sharing Statement

    Plan to Share IPD
    No
    Citations:
    PubMed Identifier
    31179244
    Citation
    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.
    Results Reference
    derived

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

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