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

• Sponsor: National Cheng-Kung University Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT03480750
• Collaborator: (none)
• Enrollment: 18
• Arm: 1
• Actual Duration (Months): 87

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Ovarian Neoplasms Malignant (Excl Germ Cell); Peritoneal Carcinoma; Fallopian Tube Cancer	Drug: trientine dihydrochloride; Drug: pegylated liposomal doxorubicin; Drug: carboplatin	Phase 1/Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Sep 1, 2012
• Actual Primary Completion Date: Oct 1, 2015
• Actual Study Completion Date: Dec 1, 2019

Arms and Interventions

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: pegylated liposomal doxorubicin carboplatin ; Drug: pegylated liposomal doxorubicin; pegylated liposomal doxorubicin 40mg/m2 IV D1; Other Names: trientine dihydrochloride carboplatin ; Drug: carboplatin; carboplatin AUC 4 IV D1; Other Names: trientine dihydrochloride pegylated liposomal doxorubicin

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. 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

3. 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

4. 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.

5. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 75 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• National Cheng-Kung University Hospital

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Cheng- Yang Chou, professor, National Cheng-Kung University Hospital
• ClinicalTrials.gov Identifier: NCT03480750
• Other Study ID Numbers: BR-100-074
• First Posted: Mar 29, 2018
• Last Update Posted: Nov 10, 2020
• Last Verified: Oct 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Cheng- Yang Chou, professor, National Cheng-Kung University Hospital: Copper chelator; Epithelial ovarian cancer; Tubal cancer; Peritoneal cancer; Trientine; Pegylated liposomal doxorubicin; Carboplatin
• Additional relevant MeSH terms: Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Fallopian Tube Neoplasms; Neoplasms; Carboplatin; Doxorubicin; Liposomal doxorubicin; Trientine

Study Results

Participant Flow

Recruitment Details	Between September 1, 2012 and October 30, 2015, eligible patients were enrolled in a medical center, National Cheng Kung University Hospital.

Arm/Group Title	Trientine With Chemotherapy Dose Level 1 (300mg)	Trientine With Chemotherapy Dose Level 2 (600mg)	Trientine With Chemotherapy Dose Level 3 (900mg)	Trientine With Chemotherapy Dose Level 4 (1200mg)	Trientine With Chemotherapy Dose Level 5 (1500mg)	Trientine With Chemotherapy Dose Level 6 (1800mg)
Arm/Group Description	trientine dihydrochloride: trientine dihydrochloride 300MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1	trientine dihydrochloride: trientine dihydrochloride 600MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1	trientine dihydrochloride: trientine dihydrochloride 900MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1	trientine dihydrochloride: trientine dihydrochloride 1200MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1	trientine dihydrochloride: trientine dihydrochloride 1500MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1	trientine dihydrochloride: trientine dihydrochloride 1800MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1
Period Title: Overall Study
STARTED	3	4	3	3	3	2
COMPLETED	3	3	3	3	3	1
NOT COMPLETED	0	1	0	0	0	1

Baseline Characteristics

Arm/Group Title	Trientine With Chemotherapy Dose Level 1 (300mg)	Trientine With Chemotherapy Dose Level 2 (600mg)	Trientine With Chemotherapy Dose Level 3 (900mg)	Trientine With Chemotherapy Dose Level 4 (1200mg)	Trientine With Chemotherapy Dose Level 5 (1500mg)	Trientine With Chemotherapy Dose Level 6 (1800mg)	Total
Arm/Group Description	trientine dihydrochloride: trientine dihydrochloride 300MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1	trientine dihydrochloride: trientine dihydrochloride 600MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1	trientine dihydrochloride: trientine dihydrochloride 900MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1	trientine dihydrochloride: trientine dihydrochloride 1200MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1	trientine dihydrochloride: trientine dihydrochloride 1500MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1	trientine dihydrochloride: trientine dihydrochloride 1800MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1	Total of all reporting groups
Overall Participants	3	4	3	3	3	2	18
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	2 66.7%	4 100%	1 33.3%	3 100%	3 100%	2 100%	15 83.3%
>=65 years	1 33.3%	0 0%	2 66.7%	0 0%	0 0%	0 0%	3 16.7%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60.3	56.3	63.7	50.7	47	56	55.7
Sex: Female, Male (Count of Participants)
Female	3 100%	4 100%	3 100%	3 100%	3 100%	2 100%	18 100%
Male	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	3 100%	4 100%	3 100%	3 100%	3 100%	2 100%	18 100%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Taiwan	3 100%	4 100%	3 100%	3 100%	3 100%	2 100%	18 100%
Interval from the end of primary chemotherapy (Count of Participants)
< 6 months	2 66.7%	0 0%	1 33.3%	2 66.7%	1 33.3%	1 50%	7 38.9%
6-12 months	1 33.3%	4 100%	2 66.7%	1 33.3%	2 66.7%	1 50%	11 61.1%
Histology (Count of Participants)
Serous adenocarcinoma	1 33.3%	3 75%	1 33.3%	1 33.3%	2 66.7%	2 100%	10 55.6%
Clear cell carcinoma	0 0%	0 0%	1 33.3%	2 66.7%	1 33.3%	0 0%	4 22.2%
Mucinous adenocarcinoma	1 33.3%	0 0%	1 33.3%	0 0%	0 0%	0 0%	2 11.1%
Mixed serous and clear cell carcinoma	1 33.3%	0 0%	0 0%	0 0%	0 0%	0 0%	1 5.6%
Mixed endometrioid and clear cell carcinoma	0 0%	1 25%	0 0%	0 0%	0 0%	0 0%	1 5.6%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Trientine With Chemotherapy at Dose Level 1 (300mg/d)	Trientine With Chemotherapy at Dose Level 2 (600mg/d)	Trientine With Chemotherapy at Dose Level 3 (900mg/d)	Trientine With Chemotherapy at Dose Level 4 (1200mg/d)	Trientine With Chemotherapy Dose Level 5 (1500mg/d)	Trientine With Chemotherapy Dose Level 6 (1800mg/d)
Arm/Group Description	trientine dihydrochloride PO daily plus pegylated liposomal doxorubicin IV D1 plus carboplatin IV D1 trientine dihydrochloride: trientine dihydrochloride 300MG/CAPSUE PO daily (at 1st dose level: 300mg) pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1	rientine dihydrochloride PO daily plus pegylated liposomal doxorubicin IV D1 plus carboplatin IV D1 trientine dihydrochloride: trientine dihydrochloride 300MG/CAPSUE PO daily (at 2nd dose level: 600mg) pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1	trientine dihydrochloride PO daily plus pegylated liposomal doxorubicin IV D1 plus carboplatin IV D1 trientine dihydrochloride: trientine dihydrochloride 300MG/CAPSUE PO daily (at 3rd dose level: 900mg) pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1	trientine dihydrochloride PO daily plus pegylated liposomal doxorubicin IV D1 plus carboplatin IV D1 trientine dihydrochloride: trientine dihydrochloride 300MG/CAPSUE PO daily (at 4th dose level: 1200mg) pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1	trientine dihydrochloride PO daily plus pegylated liposomal doxorubicin IV D1 plus carboplatin IV D1 trientine dihydrochloride: trientine dihydrochloride 300MG/CAPSUE PO daily (at 5th dose level: 1500mg) pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1	trientine dihydrochloride PO daily plus pegylated liposomal doxorubicin IV D1 plus carboplatin IV D1 trientine dihydrochloride: trientine dihydrochloride 300MG/CAPSUE PO daily (at 6th dose level: 1800mg) pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1
Measure Participants	3	3	3	3	3	2
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Trientine With Chemotherapy Dose Level 1 - 6 (300 -1800mg)
Arm/Group Description	trientine dihydrochloride: trientine dihydrochloride 300 - 1800MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1
Measure Participants	17
Number [mg]	NA

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Trientine With Chemotherapy Dose Level 1 (300mg)	Trientine With Chemotherapy Dose Level 2 (600mg)	Trientine With Chemotherapy Dose Level 3 (900mg)	Trientine With Chemotherapy Dose Level 4 (1200mg)	Trientine With Chemotherapy Dose Level 5 (1500mg)	Trientine With Chemotherapy Dose Level 6 (1800mg)
Arm/Group Description	trientine dihydrochloride: trientine dihydrochloride 300MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1	trientine dihydrochloride: trientine dihydrochloride 600MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1	trientine dihydrochloride: trientine dihydrochloride 900MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1	trientine dihydrochloride: trientine dihydrochloride 1200MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1	trientine dihydrochloride: trientine dihydrochloride 1500MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1	trientine dihydrochloride: trientine dihydrochloride 1800MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1
Measure Participants	3	3	3	3	3	2
Median (Inter-Quartile Range) [mg/L]	1.87	5.07	11.54	14.98	13.08	29.35

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

According the protocol for this secondary outcome, data collected from participants receiving different dose levels were intended to be combined and analyzed as a single group.

Arm/Group Title	Trientine With Chemotherapy
Arm/Group Description	trientine dihydrochloride PO daily [through dose level 1 (300mg/day) to level 6 (1800mg/day)] plus pegylated liposomal doxorubicin IV D1 plus carboplatin IV D1 trientine dihydrochloride: trientine dihydrochloride 300MG/CAPSUE PO daily [through dose level 1 (300mg/day) to level 6 (1800mg/day)] pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1
Measure Participants	16
Median (95% Confidence Interval) [months]	4.6

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

According the protocol for this secondary outcome, data collected from participants receiving different dose levels were intended to be combined and analyzed as a single group

Arm/Group Title	Trientine With Chemotherapy
Arm/Group Description	trientine dihydrochloride PO daily (in different dose levels) plus pegylated liposomal doxorubicin IV D1 plus carboplatin IV D1 trientine dihydrochloride: trientine dihydrochloride 300MG/CAPSUE PO daily (in different dose levels) pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1
Measure Participants	16
Median (95% Confidence Interval) [months]	14.4

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Two participants who declined any of the study agents after enrollment or declined the initial chemotherapy drug after a 7-day course of trientine were deemed ineligible for this analysis. According the protocol for this secondary outcome, all participants were not described separately.

Arm/Group Title	Trientine With Chemotherapy
Arm/Group Description	trientine dihydrochloride PO daily (in different dose levels) plus pegylated liposomal doxorubicin IV D1 plus carboplatin IV D1 trientine dihydrochloride: trientine dihydrochloride 300MG/CAPSUE PO daily (in different dose levels) pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1
Measure Participants	16
Clinical benefit rates	43.8 1460%
Response rates	25.0 833.3%

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
Adverse Event Reporting Description	Adverse event severity was graded according to the Common Terminology Criteria for Adverse Events, version 4.03. All participants who received at least one dose of any of the study agents were considered evaluable for safety.
Arm/Group Title	Trientine With Chemotherapy Dose Level 1 (300mg)		Trientine With Chemotherapy Dose Level 2 (600mg)		Trientine With Chemotherapy Dose Level 3 (900mg)		Trientine With Chemotherapy Dose Level 4 (1200mg)		Trientine With Chemotherapy Dose Level 5 (1500mg)		Trientine With Chemotherapy Dose Level 6 (1800mg)
Arm/Group Description	trientine dihydrochloride: trientine dihydrochloride 300MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1		trientine dihydrochloride: trientine dihydrochloride 600MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1		trientine dihydrochloride: trientine dihydrochloride 900MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1		trientine dihydrochloride: trientine dihydrochloride 1200MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1		trientine dihydrochloride: trientine dihydrochloride 1500MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1		trientine dihydrochloride: trientine dihydrochloride 1800MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1
All Cause Mortality
	Trientine With Chemotherapy Dose Level 1 (300mg)		Trientine With Chemotherapy Dose Level 2 (600mg)		Trientine With Chemotherapy Dose Level 3 (900mg)		Trientine With Chemotherapy Dose Level 4 (1200mg)		Trientine With Chemotherapy Dose Level 5 (1500mg)		Trientine With Chemotherapy Dose Level 6 (1800mg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)		3/3 (100%)		3/3 (100%)		3/3 (100%)		3/3 (100%)		1/2 (50%)
Serious Adverse Events
	Trientine With Chemotherapy Dose Level 1 (300mg)		Trientine With Chemotherapy Dose Level 2 (600mg)		Trientine With Chemotherapy Dose Level 3 (900mg)		Trientine With Chemotherapy Dose Level 4 (1200mg)		Trientine With Chemotherapy Dose Level 5 (1500mg)		Trientine With Chemotherapy Dose Level 6 (1800mg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/2 (0%)
Blood and lymphatic system disorders
Thrombocytopenia	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0
Other (Not Including Serious) Adverse Events
	Trientine With Chemotherapy Dose Level 1 (300mg)		Trientine With Chemotherapy Dose Level 2 (600mg)		Trientine With Chemotherapy Dose Level 3 (900mg)		Trientine With Chemotherapy Dose Level 4 (1200mg)		Trientine With Chemotherapy Dose Level 5 (1500mg)		Trientine With Chemotherapy Dose Level 6 (1800mg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		3/3 (100%)		3/3 (100%)		3/3 (100%)		3/3 (100%)		2/2 (100%)
Blood and lymphatic system disorders
Anemia	3/3 (100%)	5	2/3 (66.7%)	2	3/3 (100%)	6	3/3 (100%)	5	3/3 (100%)	5	2/2 (100%)	2
Gastrointestinal disorders
Nausea	3/3 (100%)	4	2/3 (66.7%)	2	3/3 (100%)	3	3/3 (100%)	4	3/3 (100%)	3	1/2 (50%)	1
Vomiting	3/3 (100%)	3	2/3 (66.7%)	2	3/3 (100%)	3	3/3 (100%)	4	3/3 (100%)	3	1/2 (50%)	1
Constipation	1/3 (33.3%)	1	2/3 (66.7%)	2	2/3 (66.7%)	2	2/3 (66.7%)	2	1/3 (33.3%)	1	0/2 (0%)	0
Diarrhea	1/3 (33.3%)	1	2/3 (66.7%)	2	3/3 (100%)	3	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0
Mucositis	0/3 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	2/3 (66.7%)	2	3/3 (100%)	4	1/2 (50%)	1
General disorders
Fatigue	2/3 (66.7%)	2	0/3 (0%)	0	1/3 (33.3%)	1	3/3 (100%)	3	2/3 (66.7%)	2	0/2 (0%)	0
Fever	0/3 (0%)	0	0/3 (0%)	0	2/3 (66.7%)	2	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0
Investigations
Leukopenia	1/3 (33.3%)	1	1/3 (33.3%)	1	2/3 (66.7%)	2	2/3 (66.7%)	2	3/3 (100%)	4	0/2 (0%)	0
Neutrophil count decreased	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	0/2 (0%)	0
Thrombocytopenia	1/3 (33.3%)	1	1/3 (33.3%)	1	3/3 (100%)	3	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0
Aspartate aminotransferase increased	3/3 (100%)	3	2/3 (66.7%)	2	2/3 (66.7%)	2	1/3 (33.3%)	1	1/3 (33.3%)	1	1/2 (50%)	1
Alanine aminotransferase increased	3/3 (100%)	3	1/3 (33.3%)	1	1/3 (33.3%)	1	1/3 (33.3%)	1	1/3 (33.3%)	1	0/2 (0%)	0
Alkaline phosphatase increased	3/3 (100%)	3	1/3 (33.3%)	1	1/3 (33.3%)	1	1/3 (33.3%)	1	1/3 (33.3%)	1	0/2 (0%)	0
Metabolism and nutrition disorders
Anorexia	2/3 (66.7%)	2	0/3 (0%)	0	3/3 (100%)	5	3/3 (100%)	5	3/3 (100%)	4	2/2 (100%)	2
Hyponatremia	1/3 (33.3%)	1	0/3 (0%)	0	3/3 (100%)	3	1/3 (33.3%)	1	0/3 (0%)	0	0/2 (0%)	0
Hyperkalemia	0/3 (0%)	0	0/3 (0%)	0	2/3 (66.7%)	2	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0
Nervous system disorders
Paresthesia	1/3 (33.3%)	1	3/3 (100%)	3	1/3 (33.3%)	1	1/3 (33.3%)	1	2/3 (66.7%)	2	1/2 (50%)	1
Dizziness	0/3 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	1/3 (33.3%)	1	2/3 (66.7%)	2	1/2 (50%)	1
Skin and subcutaneous tissue disorders
Hand-foot syndrome	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	2/3 (66.7%)	2	1/2 (50%)	1
Skin rash	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	3/3 (100%)	4	0/2 (0%)	0
Alopecia	1/3 (33.3%)	1	0/3 (0%)	0	1/3 (33.3%)	1	2/3 (66.7%)	2	2/3 (66.7%)	2	2/2 (100%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.