Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Gastrointestinal Agents

Dabrafenib

Vemurafenib

Lactitol

Protein Kinase Inhibitors

Enzyme Inhibitors

150 mg oral dabrafenib twice a day until disease progression, death, or unacceptable adverse events.

Phase I is 3+3 dose escalation study to identify the recommended phase 2 dose (RP2D)

Dose Level -1: BKM120 60 mg daily, Vemurafenib 480 mg bid

Dose Level 1: BKM120 60 mg daily, Vemurafenib 720 mg bid

Dose Level 2: BKM120 80 mg daiy, Vemurafenib 720 mg bid

Dose Level 3: BKM120 100 mg daiy, Vemurafenib 720 mg bid

Dose Level 4: BKM120 100 mg daiy, Vemurafenib 960 mg bid

Phase II is a single-stage, single arm prospective trial: patients will receive BKM120 and vemurafenib at the RP2D

BKM120 Combined with Vemurafenib (PLX4032)

This is a phase 1/2 clinical trial with the goal of determining whether the addition of the investigational agent BKM120 to vemurafenib will lead to improved 6-month progression-free survival in patients with BRAFV600E/K mutant melanoma.

The phase 1 portion of this trial is a dose escalation study; the phase 2 portion is a single-stage, single arm prospective clinical trial. All patients will receive continuous doses of vemurafenib twice a day and BKM120 once a day.

In the phase 1 portion of the study, there will be a 7 day lead-in period to allow for single dose pharmacokinetic analysis of BKM120 alone. Cycle 1 (28 days) is the dose-limiting toxicity (DLT) period. During phase 1, vemurafenib and BKM120 doses will be escalated using a standard 3+3 dose escalation scheme with the goal of identifying the recommended phase 2 dose.

In the phase 2 portion of the study, patients will receive continuous doses of vemurafenib and BKM120 starting on day 1 of the first cycle. In the phase 2 portion of the study, patients will receive vemurafenib and BKM120 at the recommended phase 2 dose.

BKM120 Combined With Vemurafenib (PLX4032) in BRAFV600E/K Mutant Advanced Melanoma

A Phase 1/2 Trial of BKM120 Combined With Vemurafenib (PLX4032) in BRAFV600E/K Mutant Advanced Melanoma (Novartis Study Number CBKM120ZUS21T)

RP2D determined by maximum tolerated dose (MTD), post-dose-limiting toxicity (DLT) period toxicity, and pharmacokinetic data

6 month progression-free survival rate (PFS6) determined by tumor assessments, clinical tests and laboratory tests

Objective response rate determined by tumor assessments, clinical tests and laboratory tests.

Determined by clinical and laboratory tests, and adverse events (AE) assessments

PTEN expression associated with better PFS determined by laboratory tests.

Greater reduction in PI3K-pathway signaling associated with better PFS determined by laboratory tests and tumor assessments.

Responding tumors lack gene expression signatures of PI3K pathway activation, and progressing tumors demonstrate gene expression signatures of PI3K pathway activation - determined by laboratory tests and tumor assessments.

Responding tumors lack gene expression signatures of MAPK pathway activation, and progressing tumors demonstrate gene expression signatures of MAPK pathway activation - determined by laboratory tests and tumor assessments.

Novartis

University of California, San Francisco

Assistant Clinical Professor - Melanoma Oncology

150 mg oral dabrafenib twice a day (bid) until disease progression, death, or unacceptable adverse events.

Dose Level -1:

BKM120 60 mg daily Vemurafenib 480 mg bid

Phase I, Dose Level 1:

BKM120 60 mg daily Vemurafenib 720 mg bid

Phase I, Dose Level 2:

BKM120 80 mg daily Vemurafenib 720 mg bid

Phase I, Dose Level 3:

BKM120 100 mg daily Vemurafenib 720 mg bid Phase I, Dose Level 4 BKM120 100 mg daily Vemurafenib 960 mg bid Phase II 150 mg oral dabrafenib twice a day (bid) until disease progression, death, or unacceptable adverse events.

BKM120 Combined with Vemurafenib (PLX4032): Phase I is 3+3 dose escalation study to identify the recommended phase 2 dose (RP2D)

Vemurafenib-Naïve

Vemurafenib-Resistant

Total

Age, Continuous

Sex: Female, Male

Study was terminated early due to dose limiting toxicities.

Alain Algazi

Vemurafenib-Naïve and Vemurafenib-Resistant populations received:

150 mg oral dabrafenib twice a day (bid) until disease progression, death, or unacceptable adverse events.

Dose Level -1:

BKM120 60 mg daily Vemurafenib 480 mg bid

Phase I, Dose Level 1:

BKM120 60 mg daily Vemurafenib 720 mg bid

Determination of MTD

Phase 1 - Safety & Recommended Phase 2 Dose (RP2D)

150 mg oral dabrafenib twice a day (bid) until disease progression, death, or unacceptable adverse events.

Dose Level -1:

BKM120 60 mg daily Vemurafenib 480 mg bid

Phase I, Dose Level 1:

BKM120 60 mg daily Vemurafenib 720 mg bid

Phase I, Dose Level 2:

BKM120 80 mg daily Vemurafenib 720 mg bid

Phase I, Dose Level 3:

BKM120 100 mg daily Vemurafenib 720 mg bid

Phase I, Dose Level 4 BKM120 100 mg daily Vemurafenib 960 mg bid

Phase II 150 mg oral dabrafenib twice a day (bid) until disease progression, death, or unacceptable adverse events.

BKM120 Combined with Vemurafenib (PLX4032): Phase I is 3+3 dose escalation study to identify the recommended phase 2 dose (RP2D)

Data were not collected, study never advanced to Phase II.

Phase 2 - Progression-free Survival Rate

Secondary Outcome 1 Phase 2 - Objective Response Rate

Secondary Outcome 2 Phase 2 - Safety and Tolerability

Secondary Outcome 3 Phase 2 - Phosphatase and TENsin (PTEN) Expression

Data not collected: study was terminated early due to dose limiting toxicities.

Secondary Outcome 4 Phase 2 - Phosphatidylinositol 3-kinase (PI3K)-Pathway Signaling Reduction Levels

Secondary Outcome 5 Phase 2 - PI3K Pathway Gene Expression Levels

Secondary Outcome 6 Phase 2 - MAPK Pathway Gene Expression Levels

Dose Level -1

Phase I, Dose 1

Phase I, Dose 2

Phase I, Dose 3

Phase I, Dose 4

Phase II

Paclitaxel

Albumin-Bound Paclitaxel

Trametinib

Investigator Choice of DTIC or paclitaxel

MEK inhibitor after documented progression on Chemotherapy Arm

GSK1120212

Chemotherapy

GSK Clinical Trials

This is a two-arm, open-label, randomized Phase III study comparing single agent GSK1120212 to chemotherapy (either dacarbazine or paclitaxel) in subjects with Stage IIIc or Stage IV malignant cutaneous melanoma. All subjects must have a BRAF mutation-positive tumour sample. Subjects who have received up to one prior regimen of chemotherapy in the advanced or metastatic melanoma setting will be enrolled into the study. Subjects with any prior BRAF or MEK inhibitor use will be excluded. Approximately 297 subjects will be enrolled with 2:1 randomization (198 subjects into the GSK1120212 arm and 99 subjects into the chemotherapy arm). The primary endpoint for the statistical analysis will be a comparison of progression free survival for subjects receiving GSK1120212 compared to chemotherapy. Subjects who have progression on chemotherapy will be offered the option to receive GSK1120212.

GSK1120212 vs Chemotherapy in Advanced or Metastatic BRAF V600E/K Mutation-positive Melanoma

A Phase III Randomized, Open-label Study Comparing GSK1120212 to Chemotherapy in Subjects With Advanced or Metastatic BRAF V600E/K Mutation-positive Melanoma

Progression-free survival (PFS) is defined as the time from randomization to the first documented occurrence of disease progression (PD) or death. PFS for investigator-assessed and blinded, independent, central review committee (BRIC)-assessed responses was summarized per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, which is a set of published rules defining when cancer participants improve (respond), stay the same (stabilize), or worsen (progress) during treatment. Disease progression is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 millimeters (mm) or the appearance of at least 1 new lesion, or the worsening of non-target lesions significant enough to require study treatment discontinuation. Primary Efficacy Population included all participants with BRAF V600E mutation-positive melanoma without a history of brain metastases.

PFS is defined as the time from the date of randomization to the first documented occurrence of PD or death. Investigator-assessed and BRIC-assessed PFS were summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. Intend-To-Treat (ITT) Population included all randomized participants regardless of whether or not treatment was administered.

PFS is defined as the time from the date of randomization to the first documented occurrence of PD or death. Investigator-assessed PFS was summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation.

Overall survival was defined as the time from the date of randomization to the date of death due to any cause.

Overall survival was defined as the time from the date of randomization to the date of death due to any cause. NA indicates data was not available.

OR is defined as the number of participants with evidence of complete response (CR; disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator and an independent review per RECIST, Version 1.1.

OR is defined as the number of participants with evidence of complete response (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator and an independent review per RECIST, Version 1.1.

OR is defined as the number of participants with evidence of complete response (disappearance of all extranodal lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator per RECIST, Version 1.1.

OR is defined as the number of participants with evidence of complete response (CR; disappearance of all extranodal lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator per RECIST, Version 1.1.

OR is defined as the number of participants with evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 millimeters in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator in participants following cross-over to Trametinib. The evaluation was carried out by the Investigator per RECIST, Version 1.1. Cross-over Population included the subset of participants who were randomized to CT and who elected to cross-over to Trametinib following disease progression on CT. Only participants who received at least one dose of Trametinib were included in this population.

DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD (at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation) or death due to any cause. DoR for the investigator-assessed (INVA) response data were summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available.

DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD (at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation) or death due to any cause. DoR for the independently-assessed (INDA) response data were summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available.

DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. DoR for the INVA response data was summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available.

DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. DoR for the INDA response data was summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available.

DoR is defined as the time from the first documented evidence of CR (disappearance of all extra nodal lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. DoR data were summarized per RECIST, Version 1.1Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available.

PFS is defined as the time from the first dose of cross-over therapy to the first documented occurrence of PD or death. PFS was summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation.

GlaxoSmithKline

Serious adverse events (SAEs) and non-serious AEs were collected in the Safety Population, comprised of all randomized participants included in the study who received at least one dose of study medication.

Participants with histologically confirmed cutaneous advanced or metastatic melanoma (Stage IIIC or Stage IV), with a BRAF (a human gene encoding for protein called B-Raf, which is involved in a signaling pathway and is important for cell growth) V600 E/K mutation-positive tumor sample as determined via the central BRAF mutation assay, received a Trametinib 2 milligram (mg) tablet once daily until disease progression, death, or withdrawal.

Participants with histologically confirmed cutaneous advanced or metastatic melanoma (Stage IIIC or Stage IV), with a BRAF V600 E/K mutation-positive tumor sample as determined via the central BRAF mutation assay, received an intravenous (IV) dose of Dacarbazine 1000 mg per square meter every 3 weeks or Paclitaxel 175 mg per square meter every 3 weeks at the discretion of the investigator, provided the participant had not received that type of chemotherapy before randomization, until disease progression, death, or withdrawal.

Participants randomized to chemotherapy and who did not receive subsequent anti-cancer therapy after discontinuing chemotherapy were allowed to cross-over to Trametinib and received 2 mg tablet once daily until disease progression, death or withdrawal.

Cross-over From Chemotherapy to Trametinib

Race/Ethnicity, Customized

GSK Response Center

Investigator-Assessed

Independent Review

Progression-free Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases as Assessed by the Investigator and Independent Review

Independent radiologist assessed-Assessed

Progression-free Survival in All Participants

PFS in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases and Without Prior Chemotherapy as Assessed by the Investigator

PFS in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases and With Prior Chemotherapy as Assessed by the Investigator

Overall Survival in All Participants

Overall Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases

Investigator-Assessed: CR

Investigator-Assessed: PR

Independent Review: CR

Independent Review: PR

Number of BRAF V600E Mutation-positive Participants Without a History of Brain Metastases With Overall Response (OR) as Assessed by the Investigator and Independent Review

Number of Participants With OR as Assessed by the Investigator and Independent Review

V600E Mutation, CR

V600E Mutation, PR

Number of BRAF V600E Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator

V600K Mutation, CR

V600K Mutation, PR

Number of BRAF V600K Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator

Number of Participants With OR Following Cross-over to Trametinib

Duration of Response (DoR) for All BRAF V600E Mutation-positive Participants Without a Prior History of Brain Metastases Classified as Confirmed Responders (CR or PR) as Assessed by the Investigator Review

DoR for All BRAF V600E Mutation-positive Participants Without a Prior History of Brain Metastases Classified as Confirmed Responders (CR or PR) as Assessed by the Independent Review

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
BKM120 Combined With Vemurafenib (PLX4032) in BRAFV600E/K Mutant Advanced Melanoma	NCT01512251	BRAF Mutant Met...	BKM120 Combined...	18 Years -	University of California, San Francisco
GSK1120212 vs Chemotherapy in Advanced or Metastatic BRAF V600E/K Mutation-positive Melanoma	NCT01245062	Melanoma	GSK1120212 Chemotherapy	18 Years -	GlaxoSmithKline

Spots Global Cancer Trial Database for braf mutant metastatic melanoma