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Report for Clinical Trial NCT00405587

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

A Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of PLX4032 in Patients With Solid Tumors

The primary objective of this FIH study is to assess the safety and pharmacokinetics of PLX4032 in patients with solid tumors. The secondary objective is to assess the pharmacodynamic activity in paired biopsy specimens obtained from patients with malignant melanoma who have the V600E BRAF oncogenic mutation.

NCT00405587 Malignant Melanoma Colorectal Carcinoma
MeSH: Melanoma Colorectal Neoplasms
HPO: Cutaneous melanoma Melanoma Neoplasm of the large intestine

1 Interventions

Name: PLX4032

Description: Oral capsules administered BID

Type: Drug

PLX4032


Primary Outcomes

Description: AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

Measure: Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 1 - Dose Escalation: Original Formulation

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Description: AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

Measure: Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 15 - Dose Escalation: Original Formulation

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Measure: Peak Concentration (Cmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8

Measure: Peak Concentration (Cmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose on Day 15, pre-morning dose on Day 16

Measure: Time to Peak Concentration (Tmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8

Measure: Time to Peak Concentration (Tmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, pre-morning dose on Day 16

Description: AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

Measure: AUC of RO5185426 on Day 1 - Dose Escalation: MBP Formulation

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Description: AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

Measure: AUC of RO5185426 on Day 15 - Dose Escalation: MBP Formulation

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Description: Accumulation ratio is the ratio of AUC (0-8 hour) on Day 15 / AUC (0-8 hour) on Day 1.

Measure: Mean RO5185426 Accumulation Ratios - Dose Escalation: MBP Formulation

Time: Day 1 and Day 15: pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose

Description: Accumulation ratio is the ratio of AUC (0-8 hour) on Day 15 / AUC (0-8 hour) on Day 1.

Measure: Mean RO5185426 Accumulation Ratios - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC

Time: Day 1 and Day 15: pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose

Measure: Cmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8

Measure: Cmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16

Measure: Tmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8

Measure: Tmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16

Description: AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

Measure: AUC of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Description: AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

Measure: AUC of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Measure: Cmax of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8

Measure: Cmax of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15 and pre-morning dose on Day 16

Measure: Tmax of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- CRC

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8

Measure: Tmax of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- CRC

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16

Description: BOR of confirmed /unconfirmed (total) response was defined as CR or PR recorded from baseline until disease progression/recurrence according to Response Evaluation Criteria In Solid Tumors (RECIST) v 1.0 criteria. For target lesions (TLs), CR was defined as the disappearance of all TLs, and PR was defined as at least a 30 percent (%) decrease in the sum of longest diameters of the TLs, taking as a reference the baseline (BL) sum of longest diameters. For non-target lesions (NTLs), CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Confirmed responses were those which were confirmed by repeat assessments performed no less than four weeks after the criteria for response are first met. Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.

Measure: Percentage of Participants With a Confirmed and an Unconfirmed Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) According to RECIST Version (v) 1.0 - Extension: BRAFV600E- Positive Melanoma

Time: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)

Description: BOR of CR or PR was recorded from baseline until disease progression/recurrence according to RECIST v 1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of longest diameters of the TLs, taking as a reference the BL sum of longest diameters. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Confirmed responses were those which were confirmed by repeat assessments performed no less than four weeks after the criteria for response are first met Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.

Measure: Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Extension: BRAFV600E- Positive CRC

Time: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)

Description: BOR of CR or PR was recorded from baseline until disease progression/recurrence according to RECIST v 1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of longest diameters of the TLs, taking as a reference the BL sum of longest diameters. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.

Measure: Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: Original Formulation

Time: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)

Description: BOR of CR or PR was recorded from baseline until disease progression/recurrence according to RECIST v 1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of longest diameters of the TLs, taking as a reference the BL sum of longest diameters. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.

Measure: Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: MBP Formulation

Time: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)

Secondary Outcomes

Description: Duration of response for participants with confirmed CR or PR was the period of time measured between the date that the criteria for objective CR or PR (whichever status was recorded first) was met, and the first date that recurrent or PD was objectively documented (or death if before progression). PD was at least a 20% increase in the sum of longest diameters of TLs taking as reference the smallest sum of longest diameters recorded since the baseline measurements, or the appearance of one or more new lesion(s). In the event of no disease progression or documented death prior to study termination, analysis cutoff, or initiation of confounding anticancer therapy, duration of response was censored at the date of the last evaluable tumor assessment.

Measure: Duration of CR or PR Using RECIST v 1.0 - Extension BRAFV600E- Positive Melanoma

Time: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)

Description: PFS was the period of time measured from the date of initiation of therapy to the date of the appearance of new metastatic lesions, objective tumor progression, or death if before progression. PD was defined according to the RECIST criteria (v 1.0) as increase by at least 20% in the sum of the longest diameters of each TL, taking as a reference the smallest sum of the longest diameters, reported since the start of treatment, or appearance of one or more new lesions. For Non-TLs, PD was defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs.

Measure: Percentage of Participants With Progression-Free Survival (PFS) Using RECIST v 1.0 - Melanoma Extension Cohort

Time: Month 1, 3, 4, 6, 9, and Last event (350) days

Description: PFS was the period of time measured from the date of initiation of therapy to the date of the appearance of new metastatic lesions, objective tumor progression, or death if before progression. PD was at least a 20% increase in the sum of longest diameters of TLs taking as reference the smallest sum of longest diameters recorded since the baseline measurements, or the appearance of one or more new lesion(s). For Non-TLs, disease progression was defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. In the event of no disease progression or documented death prior to study termination, analysis cutoff, or start of confounding anticancer therapy, PFS was censored at the date of the last evaluable tumor assessment.

Measure: PFS Using RECIST v1.0 - Extension BRAFV600E Positive Melanoma

Time: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 421 days)

Measure: Percentage of Participants Who Died - Extension: BRAFV600E- Positive Melanoma

Time: Screening, BL, until PD, or end of efficacy follow-up, up to 444 days

Description: OS was the period of time measured from the date of initiation of therapy to the date of the death. In the event of no death prior to study termination or analysis data cutoff, OS was censored at the last known date that the patient was alive as documented on the follow-up case report form. If this date was not available, then the last known alive date from the database was used.

Measure: Overall Survival (OS) - Extension: BRAFV600E- Positive Melanoma

Time: Screening, BL, until PD, or end of efficacy follow-up, up to 444 days

Description: Time to CR or PR was defined as the interval between the date of the first treatment to the date of the first documentation of confirmed CR or PR whichever occurred first, and not the date of confirmation at the subsequent tumor assessment. Time to response = Date of first response - initial dose date + 1.

Measure: Time to CR or PR Using RECIST v1.0 - Extension: BRAFV600E- Positive Melanoma

Time: Screening, BL, and up to 168 days

Description: AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

Measure: Mean Dose-Normalized Steady-State AUC of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Measure: Mean Dose-Normalized Steady-State Cmax of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1 and 15, pre-morning dose on Day 2 and Day 8, and Day 16

Description: Tumor uptake of FDG was assessed by means of positron-emission tomography (PET)

Measure: Decrease in Tumor Uptake of 18F-fluorodeoxyglucose (FDG)

Time: BL and Day 15

Measure: Cmax of RO5185426 - Food Effect

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1 and 15, pre-morning dose on Day 2, Day 8, and Day 16

Description: The immunohisto-chemical analyses of the expression of phosphorylated ERK, cyclin D1, and Ki-67 in tumor-biopsy specimens was performed using hematoxylin and eosin staining.

Measure: Tumor Levels of Phosphorylated Extracellular Signal-Regulated Kinapse (ERK), Cyclin D1, and Ki-67

Time: BL and Day 15

Purpose: Treatment

Single Group Assignment


There is one SNP

SNPs


1 V600E

The secondary objective is to assess the pharmacodynamic activity in paired biopsy specimens obtained from patients with malignant melanoma who have the V600E BRAF oncogenic mutation. --- V600E ---

Two extension cohorts of patients with confirmed V600E mutations will be recruited, consisting of advanced melanoma and metastatic colorectal carcinoma. --- 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
Neoplasm of the large intestine
Genes 120
FLCN SDHC MLH1 PMS2 APC EPCAM SDHC PALLD SRC BUB1 APC GREM1 NTHL1 PMS1 PTEN SDHB MSH6 APC KIT SDHD KRAS BMPR1A FAN1 CTNNB1 MSH3 POLD1 KRAS RNF43 KEAP1 DICER1 DLC1 BMPR1A MSH2 MSH6 PIK3CA CDKN2A FGFR3 BMPR1A MUTYH PIK3CA BMPR1A EP300 FOXE1 ENG SMAD7 AXIN2 CHEK2 MLH1 RPS20 BRCA1 RPS19 PRKAR1A APC GPR35 MLH1 AKT1 POLE SMAD4 KIT TP53 TRIP13 COL14A1 MDM2 SMAD4 POLE BRCA2 AKT1 MSH6 HABP2 NRAS MUTYH BUB1B DOCK8 TGFBR2 STK11 AXIN2 EPCAM BUB3 DCC AXIN2 TCF4 KLLN MSH2 APC TP53 SEC23B PTEN TGFBR2 SEMA4A POLD1 PIK3CA PDGFRA MINPP1 APC SH3KBP1 BMPR1A TP53 BUB1 AAGAB SMAD4 BMPR1A MST1 MLH3 MSH2 PALB2 FLCN SDHA PMS2 SDHB BUB1B MSH2 MLH1 CEP57 MLH3 TP53 PTPRJ PMS1 APC CDKN2A APC