Ovarian Neoplasms Malignant (Excl Germ Cell)Phase 1/2TrientineNCT03480750

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

A Phase 1/2 study testing trientine dihydrochloride, pegylated liposomal doxorubicin and carboplatin in people with Ovarian Neoplasms Malignant (Excl Germ Cell) and Peritoneal Carcinoma, run by National Cheng-Kung University Hospital.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 20 to 75 years, women only
Conditions the study is for: Ovarian Neoplasms Malignant (Excl Germ Cell), Peritoneal Carcinoma, Fallopian Tube Cancer
What is being tested?: trientine dihydrochloride, pegylated liposomal doxorubicin and carboplatin
Type of treatment: Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 18 participants
Where: No sites listed yet
Study dates: Sep 2012to Dec 2019
Phase: Phase 1/2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 20 to 75 years
Women only
No healthy volunteers
Adult, Older adult

Who may be able to join

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

Who cannot join

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

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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

About this study

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

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.

Read the 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.

Conditions: Ovarian Neoplasms Malignant (Excl Germ Cell), Peritoneal Carcinoma, Fallopian Tube Cancer
Being tested: trientine dihydrochloride, pegylated liposomal doxorubicin, carboplatin
Keywords: Copper chelator, Epithelial ovarian cancer, Tubal cancer, Peritoneal cancer, Trientine, Pegylated liposomal doxorubicin, Carboplatin
Medical subject headings: Fallopian Tube Neoplasms, Carcinoma, Ovarian Epithelial

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

trientine dihydrochlorideDrug
Also called pegylated liposomal doxorubicin, carboplatin
trientine dihydrochloride 300MG/CAPSUE PO daily (in different dose levels)
pegylated liposomal doxorubicinDrug
Also called trientine dihydrochloride, carboplatin
pegylated liposomal doxorubicin 40mg/m2 IV D1
carboplatinDrug
Also called trientine dihydrochloride, pegylated liposomal doxorubicin
carboplatin AUC 4 IV D1

Study groups in NCT03480750
Study group	Role	What they receive
trientine with chemotherapy	Experimental	trientine dihydrochloride PO daily (in different dose levels) plus pegylated liposomal doxorubicin IV D1 plus carboplatin IV D1 Receives: Drug: trientine dihydrochloride; Drug: pegylated liposomal doxorubicin; Drug: carboplatin

What is being measured

The primary outcome is the main question the study is designed to answer.

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
Measured: 36 days

Secondary outcomes (5)

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.
Measured: 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
Measured: 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
Measured: 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.
Measured: 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
Measured: 176 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Sep 2012Dec 2019

First posted29 Mar 2018
Study startSep 2012
Primary completionOct 2015
Study completionDec 2019

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Ovarian Neoplasms Malignant (Excl Germ Cell)Studies of the same condition, open and under way.
More trials run by National Cheng-Kung University HospitalThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1/2
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrolment: 18 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03480750
Sponsor's protocol ID: BR-100-074
Acronym: Trientine
Status last verified: Oct 2020
First submitted: 2 Mar 2018
Last updated: 10 Nov 2020
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
FDA-regulated drug: No
Individual data sharing: No

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.
PubMed 31179244

Study at a glance

From the registry record, last updated by the sponsor on 10 Nov 2020. Recruitment status is as the sponsor reported it: confirm with the study team.

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
ClinicalTrials.gov ID: NCT03480750
Acronym / sponsor ID: Trientine / BR-100-074
Conditions: 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
Phase: Phase 1/2
Study type: Interventional
Recruitment status: Completed
Enrolment: 18 participants (actual)
Lead sponsor: National Cheng-Kung University HospitalUniversity, hospital or other
Study start: Sep 2012 (actual)
Primary completion: Oct 2015 (actual)
Study completion: Dec 2019 (actual)
First posted: 29 Mar 2018 (actual)
Results: Posted 10 Nov 2020

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Number of arms: 1

Arm	Type	Receives
trientine with chemotherapy	Experimental	Drug: trientine dihydrochloride, Drug: pegylated liposomal doxorubicin, Drug: carboplatintrientine dihydrochloride PO daily (in different dose levels) plus pegylated liposomal doxorubicin IV D1 plus carboplatin IV D1

Who may qualify

Ages: 20 to 75 years
Sex: Female only
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (8 listed)

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

Key exclusion criteria (10 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
trientine dihydrochlorideAlso: pegylated liposomal doxorubicin, carboplatintrientine dihydrochloride 300MG/CAPSUE PO daily (in different dose levels)	Drug	trientine with chemotherapy
pegylated liposomal doxorubicinAlso: trientine dihydrochloride, carboplatinpegylated liposomal doxorubicin 40mg/m2 IV D1	Drug	trientine with chemotherapy
carboplatinAlso: trientine dihydrochloride, pegylated liposomal doxorubicincarboplatin AUC 4 IV D1	Drug	trientine with chemotherapy

Primary outcome

Number of Participants With Dose-Limiting Toxicity (DLT)
Time frame: 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

5 secondary outcomes

Maximum Tolerated Dose, MTD
Time frame: within 36 days after the start of Trientine
Maximum Plasma Concentration [Cmax] of Trientine
Time frame: 0, 10mins, 30mins, 60mins, 90mins, 120mins, 4h, 6h, 24h, 148h, 150h, 153h, 156h post 1st dose of trientine
Progression-free Survival
Time frame: 36 months
Overall Survival
Time frame: 36 months
Percentage of Participants With Measurable Tumor Treatment Response Assessed by RECIST Criteria 1.1
Time frame: 176 days

Results and safety

Results posted to the registry on 10 Nov 2020, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Trientine With Chemotherapy Dose Level 1 (300mg)	3	3
Trientine With Chemotherapy Dose Level 2 (600mg)	4	3
Trientine With Chemotherapy Dose Level 3 (900mg)	3	3
Trientine With Chemotherapy Dose Level 4 (1200mg)	3	3
Trientine With Chemotherapy Dose Level 5 (1500mg)	3	3
Trientine With Chemotherapy Dose Level 6 (1800mg)	2	1

Primary outcome: Number of Participants With Dose-Limiting Toxicity (DLT)

Time frame: 36 days. Count of participants. Unit: Participants

Measure	Trientine With Chemotherapy at Dose Level 1 (300mg/d) n = 3	Trientine With Chemotherapy at Dose Level 2 (600mg/d) n = 3	Trientine With Chemotherapy at Dose Level 3 (900mg/d) n = 3	Trientine With Chemotherapy at Dose Level 4 (1200mg/d) n = 3	Trientine With Chemotherapy Dose Level 5 (1500mg/d) n = 3	Trientine With Chemotherapy Dose Level 6 (1800mg/d) n = 2
Value	0	0	0	0	0	0

Population analysed: One participant receiving 600 mg/day declined the trial drugs and did not proceed with treatment.Therefore, an additional participant was included at the same dose level.

5 secondary outcomes are reported in the full results.

Adverse events

Time frame: All-Cause Mortality was assessed up to 36 months and Serious and Other (non-serious) Adverse Events were assessed within the planned 6-month treatment duration. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Trientine With Chemotherapy Dose Level 1 (300mg)	0 of 3 (0%)	3 of 3 (100%)	2 of 3
Trientine With Chemotherapy Dose Level 2 (600mg)	0 of 3 (0%)	3 of 3 (100%)	3 of 3
Trientine With Chemotherapy Dose Level 3 (900mg)	1 of 3 (33.3%)	3 of 3 (100%)	3 of 3
Trientine With Chemotherapy Dose Level 4 (1200mg)	0 of 3 (0%)	3 of 3 (100%)	3 of 3
Trientine With Chemotherapy Dose Level 5 (1500mg)	0 of 3 (0%)	3 of 3 (100%)	3 of 3
Trientine With Chemotherapy Dose Level 6 (1800mg)	0 of 2 (0%)	2 of 2 (100%)	1 of 2

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 10 Nov 2020.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 31179244Huang 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.
Individual participant dataSharing planned: No

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

The record lists no contact. Use the official record to reach the sponsor.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 Nov 2020. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 10 Nov 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With Dose-Limiting Toxicity (DLT) (time frame: 36 days). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03480750, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Nov 2020.