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Report for Clinical Trial NCT01164891

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

A Phase I, Open-label, Excretion Balance, Pharmacokinetic and Metabolism Study After Single Oral Dose of 14C-labeled RO5185426 in Previously Treated and Untreated Patients With Metastatic Melanoma

This open-label, non-randomized study will assess the mass balance, metabolism, routes and rates of elimination as well as efficacy and safety of RO5185426 (RG7204; PLEXXIKON; PLX4032) in previously treated or untreated patients with metastatic melanoma. Patients will receive continuous twice daily oral treatment with RO5185426. On Day 15, a 14C-labeled dose will be administered. Anticipated time on study treatment is until disease progression occurs.

NCT01164891 Malignant Melanoma
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

1 Interventions

Name: RO5185426

Description: Continuous oral dosing b.i.d. , on Day 15 a C isotope labeled dose will be administered

Type: Drug

Single Arm


Primary Outcomes

Measure: Plasma RO5185426 Trough Concentrations on Days 15,16, and 17

Time: Pre-dose on Days 15, 16 and 17

Description: Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). 14C-labeled RO5185426 given was equivalent to ≤1 millisieverts (mSv).

Measure: Maximum Plasma Concentration of 14C-labeled RO5185426 (Cmax) in Both Blood and Plasma

Time: 0 hour (prior to evening dose) on Day 14; 0 hour (pre dose), 1, 2, 4, 6, 12, 24, 36, 48, 72, 96, 168, 216, 312 hours post dose on Day 15, and then every 96 hour until recovery criteria met (maximum: 432 hours)

Description: Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments).

Measure: Time to Reach Cmax in Both Blood and Plasma

Time: 0 hour (prior to evening dose) on Day 14; 0 hour (pre dose), 1, 2, 4, 6, 12, 24, 36, 48, 72, 96, 168, 216, 312 hours post dose on Day 15, and then every 96 hour until recovery criteria met (maximum: 432 hours)

Description: Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). 14C-labeled RO5185426 given was equivalent to ≤1mSv.

Measure: Area Under the Plasma Concentration Time Curve From Time Zero to the Last Quantifiable Sample (AUClast) of 14C-RO5185426 in Both Blood and Plasma

Time: 0 hour (prior to evening dose) on Day 14; 0 hour (pre dose), 1, 2, 4, 6, 12, 24, 36, 48, 72, 96, 168, 216, 312 hours post dose on Day 15, and then every 96 hour until recovery criteria met (maximum: 432 hours)

Description: Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments).

Measure: Half-life of 14C-labeled RO5185426 in Both Blood and Plasma

Time: 0 hour (prior to evening dose) on Day 14; 0 hour (pre dose), 1, 2, 4, 6, 12, 24, 36, 48, 72, 96, 168, 216, 312 hours post dose on Day 15, and then every 96 hour until recovery criteria met (maximum: 432 hours)

Description: Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments).

Measure: AUC Ratio of Blood:Plasma 14C-labeled RO5185426

Time: 0 hour (prior to evening dose) on Day 14; 0 hour (pre dose), 1, 2, 4, 6, 12, 24, 36, 48, 72, 96, 168, 216, 312 hours post dose on Day 15, and then every 96 hour until recovery criteria met (maximum: 432 hours)

Description: Urinary and fecal samples were analyze for the percentage dose recovered as total radioactivity. The radioactivity was determined on a Packard liquid scintillation counter. Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments).

Measure: 14C-labeled RO5185426 Recovery: Percentage of Dose Excreted in Feces and Urine

Time: Urine:0 hour (pre dose),in quantitative fraction(0-6,6-12,12-24 hours) post dose on Day 15,during 24 hour interval thereafter;Feces:From Day 14 upto pre dose on Day 15,during 24 hour interval post dose until recovery criterion;(maximum:432 hours for both)

Description: Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). Plasma samples were pooled over three time intervals for this analysis based on available radioactive counts (4 + 6 hours, 12 + 24 hours, and 36 + 48 hours). Radioactivity was measured in terms of region of interest by high performance liquid chromatography. The radiolabelled components in each chromatogram were evaluated to determine retention times and peak area values. Data for 14C-labeled RO5185426 and 14C-labeled metabolite (mono-hydroxy) are reported.

Measure: Percentage of Total Integrated Radioactivity in Plasma of 14C-labeled RO5185426 and 14C-labeled Metabolite

Time: 4+6 hours, 12 +24 hours, 36+48 hours post dose on Day 15

Description: Collection of samples for radioactivity continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48 hour interval assessments). Plasma samples were pooled over three time intervals for this analysis based on available radioactive counts (4 + 6 hours, 12 + 24 hours, and 36 + 48 hours). The concentrations were measured in nanogram equivalent per gram which was calculated based on ratio of dosed radioactivity and the last dose of RO5185426. The concentration values represented the drug portion of the last dose. Data for 14C-labeled RO5185426 and 14C-labeled metabolite (mono-hydroxy) are reported.

Measure: Plasma 14C-labeled RO5185426 and 14C-labeled Metabolite Levels

Time: 4+6 hours, 12 +24 hours, 36+48 hours post dose on Day 15

Description: Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). Fecal samples were pooled over two time intervals for this analysis (0-24 + 24-48 hours, 48-72 + 72-96 hours). Radioactivity was measured in terms of region of interest by high performance liquid chromatography. The radiolabelled components in each chromatogram were evaluated to determine retention times and peak area values. Data for 14C-labeled RO5185426 and 14C-labeled metabolites (glucosylation, mono-hydroxy, and glucuronide) are reported.

Measure: Percentage of Total Integrated Radioactivity in Feces of 14C-labeled RO5185426 and 14C-labeled Metabolite

Time: 0-24 + 24-48 hours, 48-72 + 72-96 hours post dose on Day 15

Description: Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). Fecal samples were pooled over 2 time intervals (0-24 + 24-48 hours, 48-72 + 72-96 hours) for measurement of 14C-labeled RO5185426 and 14C-labeled metabolites (glucosylation, mono-hydroxy, glucuronide) levels.

Measure: Percentage of Total Dose in 14C-labeled RO5185426 and 14C-labeled Metabolite in Pooled Fecal Samples

Time: 0-24 + 24-48 hours, 48-72 + 72-96 hours post dose on Day 15

Description: Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). Urine samples were pooled over period of 96 hours (pool of 0-6 + 6-12 + 12-24 + 24-48 + 48-72 + 72-96 hour samples), Radioactivity was measured in terms of region of interest by high performance liquid chromatography. The radiolabelled components in each chromatogram were evaluated to determine retention times and peak area values. Data for 14C-labeled RO5185426 and 14C-labeled metabolites (2 unknown metabolites, glucosylation, mono-hydroxy) are reported.

Measure: Percentage of Total Integrated Radioactivity in Urine of 14C-labeled RO5185426 and 14C-labeled Metabolite

Time: 0 up to 96 hours post dose on Day 15

Description: Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). Urine samples were pooled over period of 96 hours (pool of 0-6 + 6-12 + 12-24 + 24-48 + 48-72 + 72-96 hour samples). Data for parent drug (RO5185426) and metabolites (2 unknown metabolites, glucosylation, mono-hydroxy) are reported.

Measure: Percentage of Total Dose in 14C-labeled RO5185426 and 14C-labeled Metabolite in Pooled Urine Samples

Time: 0 up to 96 hours post dose on Day 15

Secondary Outcomes

Description: Best overall response (according to Response Evaluation Criteria In Solid Tumors 1.1 criteria) was defined as best response recorded from start of treatment until disease progression which included complete response (CR) or partial response (PR) that had been confirmed by second tumor assessment no less than (<) 4 weeks after criteria for response were first met. Confirmed CR: disappearance of all target and non-target lesions; no new lesions, and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 millimeters (mm). Confirmed PR: at least 30% decrease in sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. Disease progression: at least 20% increase in sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesions.

Measure: Number of Participants With a Response by Confirmed Best Overall Response

Time: From Baseline then Day 1 of Cycle 3 thereafter, Day 1 of every other cycle (every 2 months) until disease progression, withdrawal from study or death (maximum 841 days)

Description: Overall survival was defined as the time from the date of first treatment to the date of death, regardless of the cause of death.

Measure: Overall Survival

Time: From Baseline then Day 1 of Cycle 3 thereafter, Day 1 of every other cycle (every 2 months) until death (maximum 841 days)

Purpose: Treatment

Single Group Assignment


There is one SNP

SNPs


1 V600E

Overall survival was defined as the time from the date of first treatment to the date of death, regardless of the cause of death.. Inclusion Criteria: - Adult patients, >/= 18 years of age - Histologically confirmed metastatic melanoma, surgically incurable and unresectable Stage IIIc or IV (AJCC) - Prior treatment for metastatic melanoma allowed; >/= 28 days must be elapsed since previous systemic treatment prior to first administration of study drug - Positive BRAF V600E mutation result (by Roche CoDx test) - ECOG performance status 0-1 - Adequate hematologic, renal and liver function - Body Mass Index (BMI) 18 to 32 kg/m2 inclusive Exclusion Criteria: - Active CNS lesions - History of or known spinal cord compression, or carcinomatous meningitis - Anticipated or ongoing administration of any anticancer therapies other than those administered in this study - Refractory nausea or vomiting, or other medical conditions that are capable of altering the absorption, metabolism or elimination of the study drug - Known clinically significant active infection - Known HIV positivity or AIDS-related illness, active HBV, or active HCV - Previous malignancy within the past 5 years, except for basal or squamous cell carcinoma of the skin, melanoma in situ, and carcinoma in situ of the cervix - Clinically significant cardiovascular disease or incident within the 6 months prior to study drug administration - Patients who have had at least one dose of study drug (RO5185426 or comparator) in a clinical trial that includes RO5185426 Inclusion Criteria: - Adult patients, >/= 18 years of age - Histologically confirmed metastatic melanoma, surgically incurable and unresectable Stage IIIc or IV (AJCC) - Prior treatment for metastatic melanoma allowed; >/= 28 days must be elapsed since previous systemic treatment prior to first administration of study drug - Positive BRAF V600E mutation result (by Roche CoDx test) - ECOG performance status 0-1 - Adequate hematologic, renal and liver function - Body Mass Index (BMI) 18 to 32 kg/m2 inclusive Exclusion Criteria: - Active CNS lesions - History of or known spinal cord compression, or carcinomatous meningitis - Anticipated or ongoing administration of any anticancer therapies other than those administered in this study - Refractory nausea or vomiting, or other medical conditions that are capable of altering the absorption, metabolism or elimination of the study drug - Known clinically significant active infection - Known HIV positivity or AIDS-related illness, active HBV, or active HCV - Previous malignancy within the past 5 years, except for basal or squamous cell carcinoma of the skin, melanoma in situ, and carcinoma in situ of the cervix - Clinically significant cardiovascular disease or incident within the 6 months prior to study drug administration - Patients who have had at least one dose of study drug (RO5185426 or comparator) in a clinical trial that includes RO5185426 Malignant Melanoma Melanoma null --- V600E ---

Overall survival was defined as the time from the date of first treatment to the date of death, regardless of the cause of death.. Inclusion Criteria: - Adult patients, >/= 18 years of age - Histologically confirmed metastatic melanoma, surgically incurable and unresectable Stage IIIc or IV (AJCC) - Prior treatment for metastatic melanoma allowed; >/= 28 days must be elapsed since previous systemic treatment prior to first administration of study drug - Positive BRAF V600E mutation result (by Roche CoDx test) - ECOG performance status 0-1 - Adequate hematologic, renal and liver function - Body Mass Index (BMI) 18 to 32 kg/m2 inclusive Exclusion Criteria: - Active CNS lesions - History of or known spinal cord compression, or carcinomatous meningitis - Anticipated or ongoing administration of any anticancer therapies other than those administered in this study - Refractory nausea or vomiting, or other medical conditions that are capable of altering the absorption, metabolism or elimination of the study drug - Known clinically significant active infection - Known HIV positivity or AIDS-related illness, active HBV, or active HCV - Previous malignancy within the past 5 years, except for basal or squamous cell carcinoma of the skin, melanoma in situ, and carcinoma in situ of the cervix - Clinically significant cardiovascular disease or incident within the 6 months prior to study drug administration - Patients who have had at least one dose of study drug (RO5185426 or comparator) in a clinical trial that includes RO5185426 Inclusion Criteria: - Adult patients, >/= 18 years of age - Histologically confirmed metastatic melanoma, surgically incurable and unresectable Stage IIIc or IV (AJCC) - Prior treatment for metastatic melanoma allowed; >/= 28 days must be elapsed since previous systemic treatment prior to first administration of study drug - Positive BRAF V600E mutation result (by Roche CoDx test) - ECOG performance status 0-1 - Adequate hematologic, renal and liver function - Body Mass Index (BMI) 18 to 32 kg/m2 inclusive Exclusion Criteria: - Active CNS lesions - History of or known spinal cord compression, or carcinomatous meningitis - Anticipated or ongoing administration of any anticancer therapies other than those administered in this study - Refractory nausea or vomiting, or other medical conditions that are capable of altering the absorption, metabolism or elimination of the study drug - Known clinically significant active infection - Known HIV positivity or AIDS-related illness, active HBV, or active HCV - Previous malignancy within the past 5 years, except for basal or squamous cell carcinoma of the skin, melanoma in situ, and carcinoma in situ of the cervix - Clinically significant cardiovascular disease or incident within the 6 months prior to study drug administration - Patients who have had at least one dose of study drug (RO5185426 or comparator) in a clinical trial that includes RO5185426 Malignant Melanoma Melanoma null --- V600E --- --- V600E ---



HPO Nodes


HPO:
Cutaneous melanoma
Genes 15
HRAS MITF CDKN2A BRAF NRAS NRAS WRN CDKN2A CXCR4 BAP1 POLH CDK4 ERCC3 XPC MC1R
Melanoma
Genes 98
MGMT NRAS POT1 NRAS XPA CTSC BRCA1 SDHC ERCC4 CXCR4 RAD51C CDKN2B ERCC3 XPC PALLD ERCC2 ERCC2 CHEK2 CDKN2A RAD51D GNAQ SDHD KRAS MBTPS2 BAP1 BAP1 CYSLTR2 RNF43 BAP1 CDKN2A PTPN11 CDK4 BRCA2 ERCC3 MITF TERF2IP ERCC4 CHEK2 BRCA1 TRPV3 POT1 OCA2 TERT CDKN2A AKT1 CDKN2A SF3B1 ERCC6 ERCC5 ERCC5 MDM2 BRCA2 BAP1 GNA11 ACD BRIP1 HRAS MRE11 BRAF TYR TP53 KLLN SEC23B PTEN PIK3CA XPA PERP MITF RAF1 BRAF POLH TP53 BARD1 NRAS SMAD4 RAD50 DDB2 ERCC2 NBN TERT MC1R SLC45A2 WRN PALB2 DDB2 PALB2 CDKN2A SDHB MC1R RAD51 TP53 XPC ERCC3 PTEN CDKN2A POLH CDK4 MC1R