A Phase 1b Open Label, Dose Escalation Study of PLX3397 in Combination With Vemurafenib in V600-mutated BRAF Melanoma

• Sponsor: Daiichi Sankyo, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01826448
• Collaborator: Plexxikon (Industry)
• Enrollment: 13
• Locations: 6
• Arms: 4
• Actual Duration (Months): 10.5
• Patients Per Site: 2.2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this research study is to test the safety of an investigational new drug called PLX3397 when used in combination with Vemurafenib (Zelboraf™) at different dose levels. Vemurafenib has been approved by the United States Food and Drug Administration (FDA)/European Medicines Agency (EMA) for the treatment of a specific category of unresectable or metastatic melanoma.

Condition or Disease	Intervention/Treatment	Phase
V600-mutated BRAF Unresectable Melanoma; V600-mutated BRAF Metastatic Melanoma; Stage III or Stage IV Metastatic Melanoma That Has Not Been Previously Treated With a Selective BRAF Inhibitor	Drug: PLX3397; Drug: vemurafenib	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1b Open Label, Dose Escalation Study to Assess Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of PLX3397 in Combination With Vemurafenib in V600-mutated BRAF Unresectable or Metastatic Melanoma
• Actual Study Start Date: Nov 5, 2013
• Actual Primary Completion Date: Sep 22, 2014
• Actual Study Completion Date: Sep 22, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose extension cohort Patients will take PLX3397 and vemurafenib at the recommended phase 2 dose. This will be determined by the tolerability and safety of these drugs in the previous 3 cohorts.	Drug: PLX3397; Drug: vemurafenib; Other Names: Zelboraf
Experimental: Cohort 3 Patients will take 1000mg/day of PLX3397 and 960mg BID of vemurafenib	Drug: PLX3397; Drug: vemurafenib; Other Names: Zelboraf
Experimental: Cohort 2 Patients will take 800mg/day of PLX3397 and 960mg BID of vemurafenib	Drug: PLX3397; Drug: vemurafenib; Other Names: Zelboraf
Experimental: Cohort 1 Patients will take 800mg/day of PLX3397 and 720mg BID of vemurafenib	Drug: PLX3397; Drug: vemurafenib; Other Names: Zelboraf

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Adverse Events Who Received PLX3397 in Combination With Vemurafenib in V600-mutated BRAF Melanoma [1 year]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female ≥18 years old.

• Patients with histologically confirmed unresectable Stage III or Stage IV metastatic melanoma who have not been previously treated with a selective BRAF inhibitor.

• Presence of a BRAF V600 mutation in the tumor tissue using the cobas BRAF mutation assay or comparable standard of care methodology.

• Measurable disease per RECIST v. 1.1 criteria.

• ECOG performance status 0 or 1.

Exclusion Criteria:

• Radiation therapy within 14 days of C1D1.

• Investigational drug use within 28 days of C1D1.

• Patients with active CNS lesions are excluded (i.e., those with radiographically unstable, symptomatic lesions). However, patients treated with stereotactic therapy or surgery are eligible if they remain without evidence of disease progression in the brain for ≥3 weeks.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCLA	Los Angeles	California	United States	90024
2	University of Colorado, Denver	Aurora	Colorado	United States	80012
3	Vanderbilt University	Nashville	Tennessee	United States	37232
4	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
5	Institute Gustave Roussy	Paris		France
6	University Hospital Essen	Essen		Germany

Sponsors and Collaborators

• Daiichi Sankyo, Inc.
• Plexxikon

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Daiichi Sankyo, Inc.
• ClinicalTrials.gov Identifier: NCT01826448
• Other Study ID Numbers: PLX108-09
• First Posted: Apr 8, 2013
• Last Update Posted: May 28, 2020
• Last Verified: May 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Melanoma; Vemurafenib

Study Results

Participant Flow

Recruitment Details	A total of 13 participants who met all inclusion and none of the exclusion criteria were enrolled in the study.
Pre-assignment Detail	This was an open-label, multicenter, Phase 1b, dose-escalation study, followed by an Extension Phase at the recommended Phase 2 dose (RP2D) of both drugs. During Dose-escalation (planned n=40), cohorts of 3 to 6 participants were enrolled to identify the RP2D of each agent to be administered to patients enrolled in the subsequent Extension Phase.

Arm/Group Title	Cohort 1; PLX3397 800 mg/Day + Vemurafenib 720 mg BID	Cohort 2; PLX3397 800 mg/Day + Vemurafenib 960 mg BID
Arm/Group Description	Participant who received 800 mg/day (400 twice daily [BID]) of PLX3397 and 720 mg BID of vemurafenib.	Participants who received 800 mg/day (400 twice daily [BID]) of PLX3397 and 960 mg BID of vemurafenib.
Period Title: Overall Study
STARTED	4	9
COMPLETED	0	0
NOT COMPLETED	4	9

Baseline Characteristics

Arm/Group Title	Cohort 1; PLX3397 800 mg/Day + Vemurafenib 720 mg BID	Cohort 2; PLX3397 800 mg/Day + Vemurafenib 960 mg BID	Total
Arm/Group Description	Participant who received 800 mg/day (400 twice daily [BID]) of PLX3397 and 720 mg BID of vemurafenib.	Participants who received 800 mg/day (400 twice daily [BID]) of PLX3397 and 960 mg BID of vemurafenib.	Total of all reporting groups
Overall Participants	4	9	13
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	42	60.1	54.5
Sex: Female, Male (Count of Participants)
Female	1 25%	4 44.4%	5 38.5%
Male	3 75%	5 55.6%	8 61.5%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Adverse Events Who Received PLX3397 in Combination With Vemurafenib in V600-mutated BRAF Melanoma
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Adverse events (AEs) were assessed in the modified intent-to-treat population (mITT).

Arm/Group Title	Cohort 1; PLX3397 800 mg/Day + Vemurafenib 720 mg BID	Cohort 2; PLX3397 800 mg/Day + Vemurafenib 960 mg BID
Arm/Group Description	Participant who received 800 mg/day (400 twice daily [BID]) of PLX3397 and 720 mg BID of vemurafenib.	Participants who received 800 mg/day (400 twice daily [BID]) of PLX3397 and 960 mg BID of vemurafenib.
Measure Participants	4	9
Any primary system organ class	100 2500%	100 1111.1%
Any AE	100 2500%	100 1111.1%
AEs related to both PLX3397 and vemurafenib	100 2500%	55.6 617.8%
AEs related to PLX3397	75 1875%	77.8 864.4%
AEs related vemurafenib	25 625%	77.8 864.4%
AEs leading to withdrawal from any study treatment	25 625%	44.4 493.3%
AEs considered as dose limiting toxicities	25 625%	33.3 370%
Serious adverse events	0 0%	44.4 493.3%
Serious adverse events related to study treatment	0 0%	22.2 246.7%
Adverse events leading to death	0 0%	0 0%

Adverse Events

Time Frame	Adverse events (and serious AEs [SAEs]) were recorded from the time the participant received the first dose of study drug up to 28 days after the last dose, up to 1 year (mITT population).
Adverse Event Reporting Description	Other non-serious adverse events occurring in ≥ 9 participants by system organ class or ≥ 3 participants by preferred term are reported from the mITT population.
Arm/Group Title	Cohort 1; PLX3397 800 mg/Day + Vemurafenib 720 mg BID		Cohort 2; PLX3397 800 mg/Day + Vemurafenib 960 mg BID
Arm/Group Description	Participant who received 800 mg/day (400 twice daily [BID] of PLX3397 and 720 mg BID of vemurafenib.		Participants who received 800 mg/day (400 twice daily [BID]) of PLX3397 and 960 mg BID of vemurafenib.
All Cause Mortality
	Cohort 1; PLX3397 800 mg/Day + Vemurafenib 720 mg BID		Cohort 2; PLX3397 800 mg/Day + Vemurafenib 960 mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/9 (0%)
Serious Adverse Events
	Cohort 1; PLX3397 800 mg/Day + Vemurafenib 720 mg BID		Cohort 2; PLX3397 800 mg/Day + Vemurafenib 960 mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		4/9 (44.4%)
Gastrointestinal disorders
Gastrointestinal haemorrhage	0/4 (0%)		1/9 (11.1%)
General disorders
Pyrexia	0/4 (0%)		1/9 (11.1%)
Infections and infestations
Cellulitis	0/4 (0%)		1/9 (11.1%)
Investigations
Alanine aminotransferase increased	0/4 (0%)		2/9 (22.2%)
Neutrophil count decreased	0/4 (0%)		1/9 (11.1%)
Blood alkaline phosphatase increased	0/4 (0%)		1/9 (11.1%)
Aspartate aminotransferase increased	0/4 (0%)		2/9 (22.2%)
Nervous system disorders
Cerebellar haemorrhage	0/4 (0%)		1/9 (11.1%)
Other (Not Including Serious) Adverse Events
	Cohort 1; PLX3397 800 mg/Day + Vemurafenib 720 mg BID		Cohort 2; PLX3397 800 mg/Day + Vemurafenib 960 mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		9/9 (100%)
Blood and lymphatic system disorders
Anaemia	1/4 (25%)		4/9 (44.4%)
Gastrointestinal disorders
Constipation	0/4 (0%)		3/9 (33.3%)
Diarrhoea	1/4 (25%)		4/9 (44.4%)
Gastrooesophageal reflux disease	0/4 (0%)		3/9 (33.3%)
Nausea	1/4 (25%)		3/9 (33.3%)
Vomiting	2/4 (50%)		3/9 (33.3%)
General disorders
Fatigue	1/4 (25%)		7/9 (77.8%)
Pyrexia	0/4 (0%)		4/9 (44.4%)
Investigations
Alanine aminotransferase increased	1/4 (25%)		2/9 (22.2%)
Aspartate aminotransferase increased	2/4 (50%)		5/9 (55.6%)
Blood alkaline phosphatase increased	1/4 (25%)		4/9 (44.4%)
Blood bilirubin increased	0/4 (0%)		3/9 (33.3%)
Blood creatinine increased	1/4 (25%)		2/9 (22.2%)
Lymphocyte count decreased	2/4 (50%)		1/9 (11.1%)
Weight decreased	2/4 (50%)		1/9 (11.1%)
Metabolism and nutrition disorders
Decreased appetite	2/4 (50%)		3/9 (33.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/4 (25%)		4/9 (44.4%)
Skin and subcutaneous tissue disorders
Photosensitivity reaction	1/4 (25%)		2/9 (22.2%)
Pruritus	1/4 (25%)		3/9 (33.3%)

Limitations/Caveats

This study was terminated due to business decision before the planned sample size was reached; therefore, the planned outcome measure cannot be evaluated.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.