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Patients with primary and secondary liver cancer may participate in this study. The purpose is to perform an analysis of the effects of doxorubicin and its metabolite doxorubicinol on the body (doxorubicin pharmacokinetics ) after conventional transarterial chemoembolization (cTACE). cTACE is a procedure in which chemotherapy drugs are injected, followed by an injection of small beads to block the tumor-feeding arteries. Doxorubicin is a chemotherapeutic agent used in the cTACE procedure. This study will examine doxorubicin pharmacokinetics in patients who: 1) receive whole liver cTACE; and 2) receive super-selective CTACE (i.e., delivered in close proximity to the tumor).
Patients with primary and secondary liver cancer may participate in this study. The purpose is to perform an analysis of the effects of doxorubicin and its metabolite doxorubicinol on the body (doxorubicin pharmacokinetics ) after conventional transarterial chemoembolization (cTACE). A pharmacokinetics profile (PK profile) will be constructed and will include peak of plasma concentration (Cmax), time of maximum concentration (TMax), and area under the concentration curve (AUC). This composite measure will be used to compare patients in cTACE lobar administration and cTACE superselective administration. In addition, the PK profile will be correlated with toxicity, tumor burden, body surface area, and gender. Feasibility and safety will also be assessed.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| whole liver lobe cTACE doxorubicin | Active Comparator | Participants in this arm are administered 10 cc of chemotherapy, with 50mg doxorubicin and 10 mg of mitomycin-C via cTACE delivered in a lobar (whole liver) manner. |
|
| superselective cTACE doxorubicin | Active Comparator | Participants in this arm are administered 10 cc of chemotherapy, with 50mg doxorubicin and 10 mg of mitomycin-C via cTACE delivered in a super-selective (close to the tumor) manner. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| whole liver lobe cTACE doxorubicin | Drug | Doxorubicin CTACE administered in a whole liver lobe manner. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Pharmacokinetics Profile-- Peak of Plasma Concentration (Dose-normalized) | Peak of plasma concentration (Cmax) of both doxorubicin and doxorubicinol reported for 10 lobar subjects, 10 superselective subjects with Lipiodol distribution to 1 segment, and 10 superselective subjects with Lipiodol distribution to multiple segments after dose normalization. | 0, 5, 10, 20, 40 minutes, 1, 2, 4, 24 hours, and 3-4 weeks post dose |
| Pharmacokinetics Profile-- Peak of Plasma Concentration | Peak of plasma concentration (Cmax) of doxorubicin and doxorubicinol reported for 10 lobar subjects, 10 superselective subjects with Lipiodol distribution to 1 segment, and 10 superselective subjects with Lipiodol distribution to multiple segments. | 0, 5, 10, 20, 40 minutes, 1, 2, 4, 24 hours, and 3-4 weeks post dose |
| Pharmacokinetics Profile-- Area Under the Concentration Time Curve (Dose Normalized) | Area under the concentration time curve (AUC) reported for doxorubicin and doxorubicinol reported for 10 lobar subjects, 10 superselective subjects with Lipiodol distribution to 1 segment, and 10 superselective subjects with Lipiodol distribution to multiple segments after dose normalization. | 0, 5, 10, 20, 40 minutes, 1, 2, 4, 24 hours, and 3-4 weeks post dose |
| Pharmacokinetics Profile-- Area Under the Concentration Time Curve | Area under the concentration time curve (AUC) reported for doxorubicin and doxorubicinol reported for 10 lobar subjects, 10 superselective subjects with Lipiodol distribution to 1 segment, and 10 superselective subjects with Lipiodol distribution to multiple segments. | 0, 5, 10, 20, 40 minutes, 1, 2, 4, 24 hours, and 3-4 weeks post dose |
| Pharmacokinetics Profile-- Time of Maximum Concentration | Median time of maximum concentration (Tmax) reported for doxorubicin and doxorubicinol reported for 10 lobar subjects, 10 superselective subjects with Lipiodol distribution to 1 segment, and 10 superselective subjects with Lipiodol distribution to multiple segments. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Technical Success of cTACE Procedure. | Feasibility/technical success (yes/no) is measured by ability to administer a therapeutic dose, which is determined clinically. | assessed at baseline (at the time of the cTACE procedure) |
| Assessment and Frequency of Toxicities (Laboratory and Clinical Adverse Events) According to NCI Common Toxicity Criteria for AE (CTCAE) 5.0. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Todd Schlachter, M.D. | Yale University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Yale University, Department of Diagnostic Radiology | New Haven | Connecticut | 06520 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33063185 | Derived | Savic LJ, Chapiro J, Funai E, Bousabarah K, Schobert IT, Isufi E, Geschwind JH, Stark S, He P, Rudek MA, Perez Lozada JC, Ayyagari R, Pollak J, Schlachter T. Prospective study of Lipiodol distribution as an imaging marker for doxorubicin pharmacokinetics during conventional transarterial chemoembolization of liver malignancies. Eur Radiol. 2021 May;31(5):3002-3014. doi: 10.1007/s00330-020-07380-w. Epub 2020 Oct 15. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Superselective cTACE Doxorubicin (One Segment) | Participants in this arm are administered 10 cc of chemotherapy, with 50mg doxorubicin and 10 mg of mitomycin-C via Lipiodol cTACE delivered in a super-selective (close to the tumor) manner. superselective cTACE doxorubicin: Doxorubicin CTACE administered in a super-selective (close to the tumor) manner. Lipiodol delivered to single segment. |
| FG001 | Superselective cTACE (2+ Segments) | Participants in this arm are administered 10 cc of chemotherapy, with 50mg doxorubicin and 10 mg of mitomycin-C via Lipiodol cTACE delivered in a super-selective (close to the tumor) manner. superselective cTACE doxorubicin: Doxorubicin CTACE administered in a super-selective (close to the tumor) manner. Lipiodol distributed to multiple segments. |
| FG002 | Whole Liver Lobe cTACE Doxorubicin | Participants in this arm are administered 10 cc of chemotherapy, with 50mg doxorubicin and 10 mg of mitomycin-C via Lipiodol cTACE delivered in a lobar (whole liver) manner. whole liver lobe cTACE doxorubicin: Doxorubicin CTACE administered in a whole liver lobe manner. Lipiodol distributed to entire liver lobe. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Superselective cTACE Doxorubicin (One Segment) | Participants in this arm are administered 10 cc of chemotherapy, with 50mg doxorubicin and 10 mg of mitomycin-C via Lipiodol cTACE delivered in a super-selective (close to the tumor) manner. superselective cTACE doxorubicin: Doxorubicin CTACE administered in a super-selective (close to the tumor) manner. Lipiodol delivered to single segment. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Pharmacokinetics Profile-- Peak of Plasma Concentration (Dose-normalized) | Peak of plasma concentration (Cmax) of both doxorubicin and doxorubicinol reported for 10 lobar subjects, 10 superselective subjects with Lipiodol distribution to 1 segment, and 10 superselective subjects with Lipiodol distribution to multiple segments after dose normalization. | 6 of 10 lobar, 7 of 10 single segment selective, and 9 of 10 multisegment patients received max 50mg dose of doxorubicin. Dose-normalized concentrations reported for all. Same distributions apply to doxorubicinol results. In addition, for 1 lobar patient and 8 selective patients, doxorubicinol concentrations were below limit of quantification. | Posted | Mean | Standard Deviation | ng/mL/mg | 0, 5, 10, 20, 40 minutes, 1, 2, 4, 24 hours, and 3-4 weeks post dose |
|
Up to 4 weeks post cTACE
Adverse events determined by regular laboratory tests and clinical visits, reviewed by investigators.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Superselective cTACE Doxorubicin (One Segment) | Participants in this arm are administered 10 cc of chemotherapy, with 50mg doxorubicin and 10 mg of mitomycin-C via Lipiodol cTACE delivered in a super-selective (close to the tumor) manner. superselective cTACE doxorubicin: Doxorubicin CTACE administered in a super-selective (close to the tumor) manner. Lipiodol delivered to single segment. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cardiac arrest | Cardiac disorders | CTCAE (5.0) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Alkaline phosphatase increased | Investigations | CTCAE (5.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Todd Schlachter, MD | Yale University | (203) 785-5885 | todd.schlachter@yale.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 20, 2017 | Dec 5, 2019 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Apr 20, 2017 | Jun 16, 2020 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D008113 | Liver Neoplasms |
| ID | Term |
|---|---|
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D004066 | Digestive System Diseases |
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| superselective cTACE doxorubicin | Drug | Doxorubicin CTACE administered in a super-selective (close to the tumor) manner. |
|
| 0, 5, 10, 20, 40 minutes, 1, 2, 4, 24 hours, and 3-4 weeks post dose |
Adverse events assessed by CTCAE 5.0 and stratified by Lipiodol distribution. 30 patients were reviewed for toxicities. |
| up to 4 weeks post cTACE |
| BG001 | Superselective cTACE (2+ Segments) | Participants in this arm are administered 10 cc of chemotherapy, with 50mg doxorubicin and 10 mg of mitomycin-C via Lipiodol cTACE delivered in a super-selective (close to the tumor) manner. superselective cTACE doxorubicin: Doxorubicin CTACE administered in a super-selective (close to the tumor) manner. Lipiodol distributed to multiple segments. |
| BG002 | Whole Liver Lobe cTACE Doxorubicin | Participants in this arm are administered 10 cc of chemotherapy, with 50mg doxorubicin and 10 mg of mitomycin-C via Lipiodol cTACE delivered in a lobar (whole liver) manner. whole liver lobe cTACE doxorubicin: Doxorubicin CTACE administered in a whole liver lobe manner. Lipiodol distributed to entire liver lobe. |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Full Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Superselective cTACE (2+ Segments) | Participants in this arm are administered 10 cc of chemotherapy, with 50mg doxorubicin and 10 mg of mitomycin-C via Lipiodol cTACE delivered in a super-selective (close to the tumor) manner. superselective cTACE doxorubicin: Doxorubicin CTACE administered in a super-selective (close to the tumor) manner. Lipiodol distributed to multiple segments. |
| OG002 | Whole Liver Lobe cTACE Doxorubicin | Participants in this arm are administered 10 cc of chemotherapy, with 50mg doxorubicin and 10 mg of mitomycin-C via Lipiodol cTACE delivered in a lobar (whole liver) manner. whole liver lobe cTACE doxorubicin: Doxorubicin CTACE administered in a whole liver lobe manner. Lipiodol distributed to entire liver lobe. |
|
|
|
| Primary | Pharmacokinetics Profile-- Peak of Plasma Concentration | Peak of plasma concentration (Cmax) of doxorubicin and doxorubicinol reported for 10 lobar subjects, 10 superselective subjects with Lipiodol distribution to 1 segment, and 10 superselective subjects with Lipiodol distribution to multiple segments. | 6 of 10 lobar, 7 of 10 single segment selective, and 9 of 10 multisegment patients received max 50mg dose of doxorubicin. Dose-normalized concentrations reported for all. Same distributions apply to doxorubicinol results. In addition, for 1 lobar patient and 8 selective patients, doxorubicinol concentrations were below limit of quantification. | Posted | Mean | Standard Deviation | ng/mL | 0, 5, 10, 20, 40 minutes, 1, 2, 4, 24 hours, and 3-4 weeks post dose |
|
|
|
| Primary | Pharmacokinetics Profile-- Area Under the Concentration Time Curve (Dose Normalized) | Area under the concentration time curve (AUC) reported for doxorubicin and doxorubicinol reported for 10 lobar subjects, 10 superselective subjects with Lipiodol distribution to 1 segment, and 10 superselective subjects with Lipiodol distribution to multiple segments after dose normalization. | Posted | Mean | Standard Deviation | ng*h/mL/mg | 0, 5, 10, 20, 40 minutes, 1, 2, 4, 24 hours, and 3-4 weeks post dose |
|
|
|
|
| Primary | Pharmacokinetics Profile-- Area Under the Concentration Time Curve | Area under the concentration time curve (AUC) reported for doxorubicin and doxorubicinol reported for 10 lobar subjects, 10 superselective subjects with Lipiodol distribution to 1 segment, and 10 superselective subjects with Lipiodol distribution to multiple segments. | Posted | Mean | Standard Deviation | ng*h/mL | 0, 5, 10, 20, 40 minutes, 1, 2, 4, 24 hours, and 3-4 weeks post dose |
|
|
|
| Primary | Pharmacokinetics Profile-- Time of Maximum Concentration | Median time of maximum concentration (Tmax) reported for doxorubicin and doxorubicinol reported for 10 lobar subjects, 10 superselective subjects with Lipiodol distribution to 1 segment, and 10 superselective subjects with Lipiodol distribution to multiple segments. | Posted | Median | Full Range | hours | 0, 5, 10, 20, 40 minutes, 1, 2, 4, 24 hours, and 3-4 weeks post dose |
|
|
|
| Secondary | Number of Participants With Technical Success of cTACE Procedure. | Feasibility/technical success (yes/no) is measured by ability to administer a therapeutic dose, which is determined clinically. | Posted | Count of Participants | Participants | assessed at baseline (at the time of the cTACE procedure) |
|
|
|
| Secondary | Assessment and Frequency of Toxicities (Laboratory and Clinical Adverse Events) According to NCI Common Toxicity Criteria for AE (CTCAE) 5.0. | Adverse events assessed by CTCAE 5.0 and stratified by Lipiodol distribution. 30 patients were reviewed for toxicities. | 1 participant in the superselective cTACE (2+ segment) population did not experience any adverse events. | Posted | Number | participants | up to 4 weeks post cTACE |
|
|
|
| 1 |
| 10 |
| 1 |
| 10 |
| 10 |
| 10 |
| EG001 | Superselective cTACE (2+ Segments) | Participants in this arm are administered 10 cc of chemotherapy, with 50mg doxorubicin and 10 mg of mitomycin-C via Lipiodol cTACE delivered in a super-selective (close to the tumor) manner. superselective cTACE doxorubicin: Doxorubicin CTACE administered in a super-selective (close to the tumor) manner. Lipiodol distributed to multiple segments. | 0 | 10 | 1 | 10 | 9 | 10 |
| EG002 | Whole Liver Lobe cTACE Doxorubicin | Participants in this arm are administered 10 cc of chemotherapy, with 50mg doxorubicin and 10 mg of mitomycin-C via Lipiodol cTACE delivered in a lobar (whole liver) manner. whole liver lobe cTACE doxorubicin: Doxorubicin CTACE administered in a whole liver lobe manner. Lipiodol distributed to entire liver lobe. | 0 | 10 | 0 | 10 | 10 | 10 |
| Hyponatremia | Metabolism and nutrition disorders | CTCAE (5.0) | Systematic Assessment |
|
| Aspartate aminotransferase | Investigations | CTCAE (5.0) | Systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | CTCAE (5.0) | Systematic Assessment |
|
| INR increased | Investigations | CTCAE (5.0) | Systematic Assessment |
|
| Blood bilirubin increased | Investigations | CTCAE (5.0) | Systematic Assessment |
|
| Hypoalbuminemia | Metabolism and nutrition disorders | CTCAE (5.0) | Systematic Assessment |
|
| Hyperglycemia | Metabolism and nutrition disorders | CTCAE (5.0) | Systematic Assessment |
|
| Hyperkalemia | Metabolism and nutrition disorders | CTCAE (5.0) | Systematic Assessment |
|
| Hyponatremia | Metabolism and nutrition disorders | CTCAE (5.0) | Systematic Assessment |
|
| Anemia | Blood and lymphatic system disorders | CTCAE (5.0) | Systematic Assessment |
|
| Platelet count decreased | Investigations | CTCAE (5.0) | Systematic Assessment |
|
| White blood cell decreased | Investigations | CTCAE (5.0) | Systematic Assessment |
|
| Lymphocyte count decreased | Investigations | CTCAE (5.0) | Systematic Assessment |
|
| Neutrophil count decreased | Investigations | CTCAE (5.0) | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | CTCAE (5.0) | Systematic Assessment |
|
| Fatigue | General disorders | CTCAE (5.0) | Systematic Assessment |
|
| Fever | General disorders | CTCAE (5.0) | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | CTCAE (5.0) | Systematic Assessment |
|
| Alopecia | Skin and subcutaneous tissue disorders | CTCAE (5.0) | Systematic Assessment |
|
| Anorexia | Metabolism and nutrition disorders | CTCAE (5.0) | Systematic Assessment |
|
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| D008107 |
| Liver Diseases |
|
|
To achieve high probability (80% power) to detect 50% change with 5% significance level, calculated total sample size was 30 participants for time-concentration-curves for doxorubicinol. |
| Kruskal-Wallis |
| 0.041 |
Two-sided p-values <0.05 considered statistically significant. |
| Other |
|
|
|
| Alanine aminotransferase increased (Grade 2) |
|
| INR increased (Grade 1) |
|
| INR increased (Grade 2) |
|
| Blood bilirubin increased (Grade 1) |
|
| Blood bilirubin increased (Grade 2) |
|
| Hypoalbuminemia (Grade 1) |
|
| Hyperglycemia (Grade 1) |
|
| Hyperglycemia (Grade 3) |
|
| Hyperkalemia (Grade 1) |
|
| Hyponatremia (Grade 1) |
|
| Hyponatremia (Grade 4) |
|
| Anemia (Grade 1) |
|
| Anemia (Grade 2) |
|
| Platelet count decreased (Grade 1) |
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| Platelet count decreased (Grade 2) |
|
| White blood cell decreased (Grade 1) |
|
| Lymphocyte count decreased (Grade 1) |
|
| Lymphocyte count decreased (Grade 2) |
|
| Neutrophil count decreased (Grade 1) |
|
| Neutrophil count decreased (Grade 3) |
|
| Abdominal pain (Grade 1) |
|
| Abdominal pain (Grade 2) |
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| Fatigue (Grade 1) |
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| Fatigue (Grade 2) |
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| Fever (Grade 1) |
|
| Nausea (Grade 1) |
|
| Nausea (Grade 2) |
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| Alopecia (Grade 1) |
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| Anorexia (Grade 1) |
|