Fallopian Tube Cancer, Ovarian Neoplasms Malignant (Excl Germ Cell), Peritoneal Carcinoma
Conditions
Keywords
Copper chelator, Epithelial ovarian cancer, Tubal cancer, Peritoneal cancer, Trientine, Pegylated liposomal doxorubicin, Carboplatin
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.
Interventions
trientine dihydrochloride 300MG/CAPSUE PO daily (in different dose levels)
DRUGpegylated liposomal doxorubicin
pegylated liposomal doxorubicin 40mg/m2 IV D1
DRUGcarboplatin
carboplatin AUC 4 IV D1
Sponsors
National Cheng-Kung University Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
20 Years to 75 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 |
| 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 |
| 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. |
| 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 |
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.
Participants by arm
| Arm | Count |
|---|---|
| Trientine With Chemotherapy Dose Level 1 (300mg) trientine dihydrochloride: trientine dihydrochloride 300MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1 | 3 |
| Trientine With Chemotherapy Dose Level 2 (600mg) trientine dihydrochloride: trientine dihydrochloride 600MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1 | 4 |
| Trientine With Chemotherapy Dose Level 3 (900mg) trientine dihydrochloride: trientine dihydrochloride 900MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1 | 3 |
| Trientine With Chemotherapy Dose Level 4 (1200mg) trientine dihydrochloride: trientine dihydrochloride 1200MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1 | 3 |
| Trientine With Chemotherapy Dose Level 5 (1500mg) trientine dihydrochloride: trientine dihydrochloride 1500MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1 | 3 |
| Trientine With Chemotherapy Dose Level 6 (1800mg) trientine dihydrochloride: trientine dihydrochloride 1800MG/CAPSUE PO daily pegylated liposomal doxorubicin: pegylated liposomal doxorubicin 40mg/m2 IV D1 carboplatin: carboplatin AUC 4 IV D1 | 2 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | The interruption in Trientine shippment | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | 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 1 (300mg) | Trientine With Chemotherapy Dose Level 5 (1500mg) | Trientine With Chemotherapy Dose Level 6 (1800mg) | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 1 Participants | 3 Participants | 2 Participants | 3 Participants | 2 Participants | 15 Participants |
| Age, Continuous | 56.3 years | 63.7 years | 50.7 years | 60.3 years | 47 years | 56 years | 55.7 years |
| Histology Clear cell carcinoma | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 4 Participants |
| Histology Mixed endometrioid and clear cell carcinoma | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Histology Mixed serous and clear cell carcinoma | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Histology Mucinous adenocarcinoma | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Histology Serous adenocarcinoma | 3 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 2 Participants | 10 Participants |
| Interval from the end of primary chemotherapy 6-12 months | 4 Participants | 2 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 11 Participants |
| Interval from the end of primary chemotherapy < 6 months | 0 Participants | 1 Participants | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 2 Participants | 18 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Taiwan | 4 participants | 3 participants | 3 participants | 3 participants | 3 participants | 2 participants | 18 participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 2 Participants | 18 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 1 / 2 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 2 / 2 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 1 / 3 | 0 / 3 | 0 / 3 | 0 / 2 |
Outcome results
Primary
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
Time frame: 36 days
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Trientine With Chemotherapy at Dose Level 1 (300mg/d) | Number of Participants With Dose-Limiting Toxicity (DLT) | 0 Participants |
| Trientine With Chemotherapy at Dose Level 2 (600mg/d) | Number of Participants With Dose-Limiting Toxicity (DLT) | 0 Participants |
| Trientine With Chemotherapy at Dose Level 3 (900mg/d) | Number of Participants With Dose-Limiting Toxicity (DLT) | 0 Participants |
| Trientine With Chemotherapy at Dose Level 4 (1200mg/d) | Number of Participants With Dose-Limiting Toxicity (DLT) | 0 Participants |
| Trientine With Chemotherapy Dose Level 5 (1500mg/d) | Number of Participants With Dose-Limiting Toxicity (DLT) | 0 Participants |
| Trientine With Chemotherapy Dose Level 6 (1800mg/d) | Number of Participants With Dose-Limiting Toxicity (DLT) | 0 Participants |
Secondary
Maximum Plasma Concentration [Cmax] of Trientine
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trientine With Chemotherapy at Dose Level 1 (300mg/d) | Maximum Plasma Concentration [Cmax] of Trientine | 1.87 mg/L |
| Trientine With Chemotherapy at Dose Level 2 (600mg/d) | Maximum Plasma Concentration [Cmax] of Trientine | 5.07 mg/L |
| Trientine With Chemotherapy at Dose Level 3 (900mg/d) | Maximum Plasma Concentration [Cmax] of Trientine | 11.54 mg/L |
| Trientine With Chemotherapy at Dose Level 4 (1200mg/d) | Maximum Plasma Concentration [Cmax] of Trientine | 14.98 mg/L |
| Trientine With Chemotherapy Dose Level 5 (1500mg/d) | Maximum Plasma Concentration [Cmax] of Trientine | 13.08 mg/L |
| Trientine With Chemotherapy Dose Level 6 (1800mg/d) | Maximum Plasma Concentration [Cmax] of Trientine | 29.35 mg/L |
Secondary
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.
Time frame: within 36 days after the start of Trientine
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Trientine With Chemotherapy at Dose Level 1 (300mg/d) | Maximum Tolerated Dose, MTD | NA mg |
Secondary
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.
Time frame: 36 months
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Trientine With Chemotherapy at Dose Level 1 (300mg/d) | Overall Survival | 14.4 months |
Secondary
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
Time frame: 176 days
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trientine With Chemotherapy at Dose Level 1 (300mg/d) | Percentage of Participants With Measurable Tumor Treatment Response Assessed by RECIST Criteria 1.1 | Clinical benefit rates | 43.8 percentage of participants |
| Trientine With Chemotherapy at Dose Level 1 (300mg/d) | Percentage of Participants With Measurable Tumor Treatment Response Assessed by RECIST Criteria 1.1 | Response rates | 25.0 percentage of participants |
Secondary
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
Time frame: 36 months
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Trientine With Chemotherapy at Dose Level 1 (300mg/d) | Progression-free Survival | 4.6 months |