Approval Probability 71%
TA Base Rate26%
Adjusted LOA41%
ML RiskLOW_RISK
| NCT ID | Title | Phase | Status | Enrollment | Velocity | Design | Start | Completion | Last Updated | Sites | Countries |
|---|---|---|---|---|---|---|---|---|---|---|---|
| NCT01227889 | A Study Comparing GSK2118436 to Dacarbazine (DTIC) in Previously Untreated Subjects With BRAF Mutation Positive Advanced (Stage III) or Metastatic (Stage IV) Melanoma | PHASE3 | COMPLETED | 251 | — | — | Dec 23, 2010 | Sep 16, 2016 | Oct 4, 2017 | 94 | United States, Australia +10 |
| NCT01738451 | A Study to Evaluate the Effect of Repeat Oral Dosing of GSK2118436 on Cardiac Repolarization in Subjects With V600 BRAF Mutation-Positive Tumors | PHASE1 | COMPLETED | 50 | — | — | Jan 22, 2013 | Nov 28, 2014 | Nov 13, 2017 | 8 | United States, Australia +1 |
| NCT01582997 | A Phase I Study to Investigate the Safety, Tolerability and Pharmacokinetic Profile of of GSK2118436 in Japanese Subjects With BRAF Mutation Positive Solid Tumors | PHASE1 | COMPLETED | 12 | — | — | May 11, 2012 | Apr 16, 2015 | Nov 13, 2017 | 2 | Japan |
| NCT01340833 | Determination of the Absolute Bioavailability of GSK2118436 Following a Single Oral Dose Co-Administered With an Intravenous Radiolabelled Microtracer of GSK2118436 in Subjects With BRAF Mutant Solid Tumors | PHASE1 | COMPLETED | 6 | — | — | Jun 8, 2011 | Sep 12, 2011 | Nov 13, 2017 | 1 | United States |
| NCT01262963 | An Absorption, Distribution, Metabolism and Excretion (ADME) Study of Single Oral Dose [14C] GSK2118436 in Subjects With BRAF Mutant Solid Tumors | PHASE1 | COMPLETED | 4 | — | — | Jan 26, 2011 | Apr 8, 2011 | Nov 13, 2017 | 1 | United States |
| NCT00880321 | A Phase I Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of GSK2118436 in Subjects With Solid Tumors | PHASE1 | COMPLETED | 170 | — | — | Jun 4, 2009 | Mar 20, 2012 | Nov 13, 2017 | 8 | United States, Australia |
PFS is defined as the interval of time between the date of randomization and the earlier of the date of disease progression or the date of death due to any cause. Disease progression was based on radiographic or photographic evidence, and assessments were made by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm). For participants who did not progress or die, PFS was censored at the date of last contact. Data are presented as median and 96% confidence interval.
PFS is defined as the interval of time between the date of randomization and the earlier of the date of disease progression or the date of death due to any cause. Disease progression was based on radiographic or photographic evidence, and assessments were made by an independent radiologist according to RECIST version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. For participants who did not progress or die, PFS was censored at the date of last contact.
Safety and tolerability parameter will include a complete (head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen \[liver and spleen\], lymph nodes, extremities, height and weight) and brief (skin, lungs, cardiovascular system, abdomen \[liver and spleen\] and weight) physical examination at Baseline and at the end of Part 1 of the study.
Safety and tolerability parameter will include measurement of vital signs (recording of systolic and diastolic blood pressure, temperature, and pulse rate) at Baseline and at the end of Part 1 of the study.
Safety and tolerability parameter will include ECGs readings (heart rate and measurement of RR, PR, QRS, QT, and QTc intervals) at Baseline and at the end of Part 1 of the study.
Safety and tolerability parameter will include laboratory values (hematology, clinical chemistry, coagulation, liver function tests, cardiac enzyme and beta-hCG/serum or urine pregnancy test for female subjects of childbearing potential only) at Baseline and at end of Part 1 of the study.
Change from Baseline in QTcF interval at each time point for GSK2118436 will be calculated as average of 3 Holter ECG replicates per time point minus the value at Baseline.
Adverse Events will be graded by the investigator according to the NCI-CTCAE (version 4.0)
| Arm | Type | Description |
|---|---|---|
| GSK2118436 | EXPERIMENTAL | Subjects in this arm will receive GSK2118436 150 mg twice daily. |
| Dacarbazine (DTIC) | ACTIVE_COMPARATOR | Subjects will receive intravenous dacarbazine (DTIC) 1000 mg/m2 every 3 weeks |
| Crossover | EXPERIMENTAL | Subjects who initially receive DTIC will be allowed to receive GSK2118436 after initial progression. |
| Part 1(Cohort 1): GSK2118436 225 mg | EXPERIMENTAL | GSK2118436 (3 capsules of 75 mg) will be administered orally at the dose of 225 mg BID from Day 1 to 7 (and single dose on Day 8) under fasted conditions, either 1 hour before or 2 hours after a meal. |
| Part 1(Cohort 2): GSK2118436 300 mg | EXPERIMENTAL | GSK2118436 (4 capsules of 75 mg) will be administered orally at the dose of 300 mg BID from Day 1 to 7 (and single dose on Day 8) under fasted conditions, either 1 hour before or 2 hours after a meal. If 225 mg BID is not tolerated in Part 1 /Cohort 1, then Part 1/Cohort 2 will not be initiated and 150 mg BID will be used in Part 2. |
| Part 2: GSK2118436 300 mg (or highest tolerated dose) | EXPERIMENTAL | Subjects will receive a single dose of GSK2118436/placebo (4 capsules of 75 mg/highest tolerated dose) orally on the first 2 days of the study followed by 2 doses daily for 6 days and a single dose on the 9th day. There will be 1 day when a placebo will be given. All doses will be administered under fasted conditions, either 1 hour before or 2 hours after a meal. |
| Dose Escalation Part | EXPERIMENTAL | Dose escalation will be conducted to assess safety, tolerability, single and repeat dose PK profile and preliminary efficacy of GSK2118436 . The dose may be escalated to the overseas recommended phase III dose. |
| Study Medication | EXPERIMENTAL | GSK2118436 |
| Part 1 | EXPERIMENTAL | Part 1 will identify the recommended Part 2 dose using a dose-escalation procedure. Escalation may proceed until either a maximum tolerated dose is established, or the toxicokinetic safety limit is reached. Subjects may dose up to three times a day. |
| Part 2 | EXPERIMENTAL | Part 2 will explore further the safety, tolerability, and clinical activity of GSK2118436 in subjects with BRAF mutation-positive tumors using the recommended part 2 dose identified during Part 1. Biologically active doses will be identified by measurement of pharmacodynamic markers in tumor tissue and blood across a range of doses and these doses may be explored in Part 2. |
| Name | Type | Description |
|---|---|---|
| GSK2118436 | DRUG | 150 mg twice daily |
| Dacarbazine (DTIC) | DRUG | Intravenous (IV), 1000 mg/m2 every 3 weeks until initial progression |
| GSK2118436 75 mg | DRUG | Each capsule contains 75 mg of GSK2118436A as the mesylate salt, micronized particles as active equivalents. |
| Placebo | DRUG | Matching placebo capsules will be administered in Part 2 of the study. |
| Midazolam | DRUG | Midazolam will be administered alone and with GSK2118436 in a sub-set of subjects in Part 2 to study the effect of GSK2118436 on CYP3A using midazolam as a probe. |
Inclusion Criteria: * Adults at least 18 years of age * Has advanced (unresectable Stage III) or metastatic (Stage IV) melanoma that is BRAF mutation positive (V600E) * Is treatment naive for advanced (unresectable) or metastatic melanoma, with the exception of Interleukin 2 (IL-2) which is allowed...
| Company | Ticker | Trials | Lead Phase | Drugs |
|---|---|---|---|---|
| GE Healthcare Technologies Inc. | GEHC | 1 | PHASE1 | GEH200520 / GEH200521 - Part A |
| Zimmer Biomet Holdings, Inc. | ZBH | 1 | — | Undisclosed |
| Ascentage Pharma Group International Unsponsored ADR | AAPG | 1 | PHASE1 | Olverembatinib |