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Report for Clinical Trial NCT01107418

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

A Phase I, Randomized, Open-label, Multi-center, Multiple Dose Study to Investigate the Pharmacokinetics and Pharmacodynamics of RO5185426 Administered as 240 mg Tablets to Previously Treated BRAF V600E Positive Metastatic Melanoma Patients

This open-label study will assess the pharmacokinetics, efficacy and safety of RO5185426 administered as 240mg tablets in previously treated patients with metastatic melanoma. Patients will be randomized to receive one of four dose-levels of RO5185426 [RG7204; PLEXXIKON; PLX4032] orally twice daily on days 1 to 15 (morning dose). Starting on day 22, treatment with RO5185426 may be resumed at a dose of 960 mg twice daily and continued until disease progression. Target sample size is <100 patients.

NCT01107418 Malignant Melanoma
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

5 Interventions

Name: RO5185426

Description: dosage b) orally twice daily, days 1-15 (morning dose)

Type: Drug

2

Name: RO5185426

Description: dosage c) orally twice daily, days 1-15 (morning dose)

Type: Drug

3

Name: RO5185426

Description: dosage d) orally twice daily, days 1-15 (morning dose)

Type: Drug

4

Name: RO5185426

Description: 960 mg orally twice daily, from day 22 onward

Type: Drug

1 2 3 4

Name: RO5185426

Description: dosage a) orally twice daily, days 1-15 (morning dose)

Type: Drug

1


Primary Outcomes

Measure: Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 1

Time: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1

Measure: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24h]) of Vemurafenib on Day 1

Time: Pre-dose, 1, 2, 4, 5, 8, 24 hours post-dose on Day 1

Measure: Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 1

Time: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1

Measure: Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 1

Time: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1

Measure: Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 9

Time: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9

Measure: Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 9

Time: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9

Measure: Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 9

Time: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9

Measure: Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 15

Time: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 15

Measure: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24h]) of Vemurafenib on Day 15

Time: Pre-dose, 1, 2, 4, 5, 8, 24 hours post-dose on Day 15

Measure: Area Under the Plasma Concentration-Time Curve From Time Zero to 168 Hours (AUC[0-168h]) of Vemurafenib on Day 15

Time: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15

Measure: Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 15

Time: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15

Measure: Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 15

Time: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15

Description: Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.

Measure: Apparent Clearance (CL/F) of Vemurafenib on Day 15

Time: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15

Description: Time measured for vemurafenib plasma concentrations to decrease by one-half (t1/2) was calculated as 0.693 divided by apparent first-order terminal elimination rate constant (0.693/kel).

Measure: Terminal Elimination Half-Life (t1/2) of Vemurafenib on Day 15

Time: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15

Description: Accumulation ratio was calculated as, AUC(0-8) on Day 15 divided by AUC(0-8) on Day 1.

Measure: Accumulation Ratio of Vemurafenib on Day 15

Time: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1 and 15

Secondary Outcomes

Description: Confirmed best overall response was defined as having best objective response as CR or PR, as assessed by investigator and confirmed at least 28 days after initial response. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1). CR was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) were required to demonstrate a reduction to normal (short axis less than [<] 10 millimeters [mm]). PR was defined as a 30 percent (%) decrease in the sum of the diameters of the target lesions taking as a reference the baseline sum diameter. Percentage of participants with best overall response of confirmed CR or PR are reported.

Measure: Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR)

Time: Up to approximately 3 years (assessed at Cycle 1 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, thereafter every 2 cycles and then every 4 cycles after Cycle 13)

Description: OS was defined as the time, in months, from the date of the first study drug administration to the date of death, regardless of the cause of death.

Measure: Overall Survival (OS)

Time: Up to approximately 3 years (assessed at Cycle 1 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, thereafter every 2 cycles and then every 4 cycles after Cycle 13)

Purpose: Treatment

Allocation: Non-Randomized

Parallel Assignment


There is one SNP

SNPs


1 V600E

A Phase I, Randomized, Open-label, Multi-center, Multiple Dose Study to Investigate the Pharmacokinetics and Pharmacodynamics of RO5185426 Administered as 240 mg Tablets to Previously Treated BRAF V600E Positive Metastatic Melanoma Patients. --- V600E ---

OS was defined as the time, in months, from the date of the first study drug administration to the date of death, regardless of the cause of death.. Inclusion Criteria: - adult patients, >/=18 years of age - histologically confirmed metastatic melanoma, stage IIIc or IV (AJCC) - failure of at least one prior standard of care regimen - positive for BRAF V600E mutation (by Roche CoDx BRAF mutation assay) - ECOG performance status 0 or 1 - adequate hematologic, renal and liver function Exclusion Criteria: - active CNS lesions on CT/MRI within 28 days prior to enrollment - history of spinal cord compression o carcinomatous meningitis - anticipated or ongoing anti-cancer therapies other than those administered in this study - previous treatment with BRAF inhibitor (sorafenib allowed) or MEK inhibitor - severe cardiovascular disease within 6 months prior to study - 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 Inclusion Criteria: - adult patients, >/=18 years of age - histologically confirmed metastatic melanoma, stage IIIc or IV (AJCC) - failure of at least one prior standard of care regimen - positive for BRAF V600E mutation (by Roche CoDx BRAF mutation assay) - ECOG performance status 0 or 1 - adequate hematologic, renal and liver function Exclusion Criteria: - active CNS lesions on CT/MRI within 28 days prior to enrollment - history of spinal cord compression o carcinomatous meningitis - anticipated or ongoing anti-cancer therapies other than those administered in this study - previous treatment with BRAF inhibitor (sorafenib allowed) or MEK inhibitor - severe cardiovascular disease within 6 months prior to study - 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 Malignant Melanoma Melanoma null --- V600E ---

OS was defined as the time, in months, from the date of the first study drug administration to the date of death, regardless of the cause of death.. Inclusion Criteria: - adult patients, >/=18 years of age - histologically confirmed metastatic melanoma, stage IIIc or IV (AJCC) - failure of at least one prior standard of care regimen - positive for BRAF V600E mutation (by Roche CoDx BRAF mutation assay) - ECOG performance status 0 or 1 - adequate hematologic, renal and liver function Exclusion Criteria: - active CNS lesions on CT/MRI within 28 days prior to enrollment - history of spinal cord compression o carcinomatous meningitis - anticipated or ongoing anti-cancer therapies other than those administered in this study - previous treatment with BRAF inhibitor (sorafenib allowed) or MEK inhibitor - severe cardiovascular disease within 6 months prior to study - 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 Inclusion Criteria: - adult patients, >/=18 years of age - histologically confirmed metastatic melanoma, stage IIIc or IV (AJCC) - failure of at least one prior standard of care regimen - positive for BRAF V600E mutation (by Roche CoDx BRAF mutation assay) - ECOG performance status 0 or 1 - adequate hematologic, renal and liver function Exclusion Criteria: - active CNS lesions on CT/MRI within 28 days prior to enrollment - history of spinal cord compression o carcinomatous meningitis - anticipated or ongoing anti-cancer therapies other than those administered in this study - previous treatment with BRAF inhibitor (sorafenib allowed) or MEK inhibitor - severe cardiovascular disease within 6 months prior to study - 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 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