Locally Advanced Metastatic BRAF Mutant MelanomaPhase 1/2NCT01777776

Safety and Efficacy of LEE011 and LGX818 in Patients With BRAF Mutant Melanoma.

A Phase 1/2 study testing LEE011 and LGX818 in people with Locally Advanced Metastatic BRAF Mutant Melanoma, run by Array BioPharma at 9 sites in 4 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record

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Trial summary

To evaluate the safety, tolerability and efficacy of LEE011 and LGX818 when administered orally to patients with BRAF mutant melanoma. Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Locally Advanced Metastatic BRAF Mutant Melanoma
What is being tested?: LEE011 and LGX818
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 28 participants
Where: 9 sitesin 4 countries
Study dates: Jul 2013to Apr 2015
Phase: Phase 1/2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Age ≥18 years.
Diagnosis of locally advanced or metastatic melanoma along with written documentation of BRAF V600 mutation.
ECOG performance status of 0 - 2.
Patients enrolled into Phase Ib must have evidence of evaluable and/or measurable disease as determined by RECIST v1.1.
Patients enrolled into Phase II (BRAFi naïve and resistant) must have evidence of measurable disease as determined by RECIST v1.1.
Archival tumor tissue must be obtained for patients enrolled in Phase Ib and Phase II arm 1a/b- BRAFi naïve patients. If an archival tumor tissue is not available, a fresh tumor sample is acceptable.
For patients enrolled in the phase II arm 2, patients must agree to undergo a fresh tumor biopsy unless one was collected prior to study entry but at the time of disease relapse from the most recent BRAFi treatment.

Who cannot join

Symptomatic brain metastases.
Symptomatic or untreated leptomeningeal disease.
Patients with inadequate laboratory values during screening.
In the phase II BRAFi naïve arms (1a/b), prior exposure to CDK4/6 inhibitor (e.g., PD 0332991)
Impaired cardiac function or clinically significant cardiac diseases.
Impairment of gastro-intestinal (GI) function or GI disease that may significantly alter the absorption of LEE011 or LGX818.

Show all 11Show fewer

Patients with concurrent severe and/or uncontrolled concurrent medical conditions.
Previous or concurrent malignancy.
Major surgery < 2 weeks before starting study treatment
Known diagnosis of human immunodeficiency virus (HIV) or hepatitis C.
Other protocol-defined inclusion/exclusion criteria may apply.

Trial locations and contacts

9 sites in 4 countries.

Country

City, postcode or hospital

9 sites in 4 countries

United States5 sites

University of Colorado Dept of Oncology
Aurora, Colorado, 80045
Karmanos Cancer Institute Dept of Oncology
Detroit, Michigan, 48201
Vanderbilt University Medical Center SC - Dept of Oncology .
Nashville, Tennessee, 37232
Memorial Sloan Kettering Cancer Center Dept Oncology
New York, New York, 90033
Oregon Health & Science University Dept. of OHSU (3)
Portland, Oregon, 97239

Other trials in United States

Australia2 sites

Novartis Investigative Site
Westmead, New South Wales, 2145
Novartis Investigative Site
Woodville, South Australia, 5011

Other trials in Australia

Canada1 site

Novartis Investigative Site
Montreal, Quebec, H2X 3J4

Other trials in Canada

Netherlands1 site

Novartis Investigative Site
Utrecht, Netherlands, 3584CX

Other trials in Netherlands

About this study

Official title: A Phase Ib/II, Multicenter, Study of LEE011 in Combination With LGX818 in Adult Patients With BRAF Mutant Melanoma.

To evaluate the safety, tolerability and efficacy of LEE011 and LGX818 when administered orally to patients with BRAF mutant melanoma.

Read the detailed description

In response to developments in the treatment of melanoma, the sponsor reviewed the data from the ongoing study and decided to halt further enrollment of patients in the Phase Ib part of the study. Consequently, the Phase II part of the study was not performed. Early termination of the study was not due to any safety concerns.

Conditions: Locally Advanced Metastatic BRAF Mutant Melanoma
Being tested: LEE011, LGX818
Keywords: Open-label dose escalation, BRAF inhibitor, LEE011, CDK4/6, LGX818, RAF kinase inhibitor, Metastatic melanoma, BRAF, V600
Medical subject headings: Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

LEE011Drug
Also called Ribociclib
LEE011 will be administered orally, once daily for 21 consecutive days followed by a 7-day planned break (28-day cycle).
LGX818Drug
Also called Encorafenib
LGX818 will be administered orally, once daily on a continuous dosing schedule (28-day cycle).

Study groups in NCT01777776
Study group	Role	What they receive
Phase Ib	Experimental	Phase Ib will randomize 18 patients with BRAF mutant melanoma, who are naïve or who have progressed on prior therapy to evaluate the safety and tolerability of the combination of LEE011 and LGX818. Receives: Drug: LEE011; Drug: LGX818
Phase II arm 1a	Experimental	Phase II arm 1a will randomize 60 patients that are naïve to prior BRAF inhibitor therapy to LGX818+LEE011 to evaluate the effect of adding LEE011 to a BRAFi in this population. Receives: Drug: LEE011; Drug: LGX818
Phase II arm 1b	Experimental	Phase II arm 1b will randomize 30 patients to LGX818. Single agent anti-tumor activity of LGX818 is comparable to other BRAFi that are either approved or in clinical trials. This single agent anti-tumor activity will be compared to that of the combination (LEE011 + LGX818) in the BRAFi naïve patient population. Receives: Drug: LGX818
Phase II arm 2	Experimental	Phase II arm 2 will evaluate a single arm LEE011+LGX818 in 40 patients resistant to prior BRAF inhibitor therapy. Single agent LGX818 has shown limited activity in patients with melanoma who have failed prior BRAF inhibitor treatment; the contribution of LEE011 in this combination will be evaluated. Receives: Drug: LEE011; Drug: LGX818

What is being measured

The primary outcome is the main question the study is designed to answer.

Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1
Dose Limiting Toxicities (DLTs) during the first 28 days of the combination treatment of LEE011 and LGX818.
Due to the halt of enrollment, no Maximum Tolerated Dose (MTD) was formally declared during the study.
Measured: Cycle 1 (approximately 28 days)
Phase II - Progression Free Survival (PFS)
As per RECIST v1.1, PFS is the time from date of randomization/ start of treatment to the date of event defined as the first documented progression or death due to any cause.
Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to efficacy were not performed.
Measured: Approximately 23 months after enrollment
Phase II - Objective Response Rate (ORR)
As per RECIST v1.1, ORR is defined as the proportion of patients with a best overall response of complete response or partial response.
Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to efficacy were not performed.
Measured: Approximately 23 months after enrollment

Secondary outcomes (12)

Phase I - Number of Subjects Experiencing at Least One Adverse Event (AE).
Measured: Approximately 23 months after enrollment
Phase I - Number of Subjects Experiencing at Least One Serious Adverse Event (SAE).
Measured: Approximately 23 months after enrollment
Phase Ib/II - Plasma Concentration-time Profiles
Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to plasma concentration time profiles were not performed.
Measured: 28-day cycles
Phase Ib/II - Overall Response Rate (ORR)
ORR is defined as the proportion of patients with a best overall response of complete response or partial response.
Due to the halt of enrollment during the Phase Ib part of the study, this analysis was not performed.
Measured: Approximately 23 months after enrollment
Phase Ib/II - Progression Free Survival (PFS)
PFS is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause.
Due to the halt of enrollment during the Phase Ib part of the study, this analysis was not performed.
Measured: Approximately 23 months after enrollment
Phase Ib/II - Duration Of Response (DOR)
DOR is calculated as the time from the date of first documented response (complete response (CR) or partial response (PR)) to the first documented date of progression or death due to underlying cancer.
Due to the halt of enrollment during the Phase Ib part of the study, this analysis was not performed.
Measured: Approximately 23 months after enrollment
Phase II - Overall Survival (OS)
OS is defined as the time from date of randomization/start of treatment to date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of last known date patient alive.
Due to the halt of enrollment during the Phase Ib part of the study, this analysis was not performed.
Measured: Approximately 23 months after enrollment
Phase Ib/II - Pharmacokinetic Parameters: AUCtau
Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed.
Measured: 28-day cycles
Phase Ib/II - Pharmacokinetic Parameters: Cmin
Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed.
Measured: 28-day cycles
Phase Ib/II - Pharmacokinetic Parameters: Cmax
Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed.
Measured: 28-day cycles
Phase Ib/II - Pharmacokinetic Parameters: Tmax
Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed.
Measured: 28-day cycles
Phase Ib/II - Pharmacokinetic Parameters: Racc
Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed.
Measured: 28-day cycles

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Jul 2013Apr 2015

First posted29 Jan 2013 (estimated)
Study startJul 2013
Primary completionApr 2015
Study completionApr 2015

Why it stopped: Study was withdrawn due to scientific and business considerations.

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Other trials for Locally Advanced Metastatic BRAF Mutant MelanomaStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1/2
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 28 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01777776
Sponsor's protocol ID: CLEE011X2105
Status last verified: Jul 2016
First submitted: 22 Jan 2013
Last updated: 13 Sep 2016
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No

Study at a glance

From the registry record, last updated by the sponsor on 13 Sep 2016. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Phase Ib/II, Multicenter, Study of LEE011 in Combination With LGX818 in Adult Patients With BRAF Mutant Melanoma.
ClinicalTrials.gov ID: NCT01777776
Acronym / sponsor ID: CLEE011X2105
Conditions: Locally Advanced Metastatic BRAF Mutant Melanoma
Keywords: Open-label dose escalation, BRAF inhibitor, LEE011, CDK4/6, LGX818, RAF kinase inhibitor, Metastatic melanoma, BRAF
Phase: Phase 1/2
Study type: Interventional
Recruitment status: TerminatedReason stopped: Study was withdrawn due to scientific and business considerations.
Enrolment: 28 participants (actual)
Lead sponsor: Array BioPharmaIndustry (pharma, biotech, devices)
Study start: Jul 2013
Primary completion: Apr 2015 (actual)
Study completion: Apr 2015 (actual)
First posted: 29 Jan 2013 (estimated)
Results: Posted 13 Sep 2016

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

To evaluate the safety, tolerability and efficacy of LEE011 and LGX818 when administered orally to patients with BRAF mutant melanoma.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 4

Arm	Type	Receives
Phase Ib	Experimental	Drug: LEE011, Drug: LGX818Phase Ib will randomize 18 patients with BRAF mutant melanoma, who are naïve or who have progressed on prior therapy to evaluate the safety and tolerability of the combination of LEE011 and LGX818.
Phase II arm 1a	Experimental	Drug: LEE011, Drug: LGX818Phase II arm 1a will randomize 60 patients that are naïve to prior BRAF inhibitor therapy to LGX818+LEE011 to evaluate the effect of adding LEE011 to a BRAFi in this population.
Phase II arm 1b	Experimental	Drug: LGX818Phase II arm 1b will randomize 30 patients to LGX818. Single agent anti-tumor activity of LGX818 is comparable to other BRAFi that are either approved or in clinical trials. This single agent anti-tumor activity will be compared to that of the combination (LEE011 + LGX818) in the BRAFi naïve patient population.
Phase II arm 2	Experimental	Drug: LEE011, Drug: LGX818Phase II arm 2 will evaluate a single arm LEE011+LGX818 in 40 patients resistant to prior BRAF inhibitor therapy. Single agent LGX818 has shown limited activity in patients with melanoma who have failed prior BRAF inhibitor treatment; the contribution of LEE011 in this combination will be evaluated.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (7 listed)

Age ≥18 years.
Diagnosis of locally advanced or metastatic melanoma along with written documentation of BRAF V600 mutation.
ECOG performance status of 0 - 2.
Patients enrolled into Phase Ib must have evidence of evaluable and/or measurable disease as determined by RECIST v1.1.
Patients enrolled into Phase II (BRAFi naïve and resistant) must have evidence of measurable disease as determined by RECIST v1.1.

Key exclusion criteria (11 listed)

Symptomatic brain metastases.
Symptomatic or untreated leptomeningeal disease.
Patients with inadequate laboratory values during screening.
In the phase II BRAFi naïve arms (1a/b), prior exposure to CDK4/6 inhibitor (e.g., PD 0332991)
Impaired cardiac function or clinically significant cardiac diseases.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
LEE011Also: RibociclibLEE011 will be administered orally, once daily for 21 consecutive days followed by a 7-day planned break (28-day cycle).	Drug	Phase II arm 1a, Phase II arm 2, Phase Ib
LGX818Also: EncorafenibLGX818 will be administered orally, once daily on a continuous dosing schedule (28-day cycle).	Drug	Phase II arm 1a, Phase II arm 1b, Phase II arm 2, Phase Ib

Primary outcome

Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1
Time frame: Cycle 1 (approximately 28 days)
Dose Limiting Toxicities (DLTs) during the first 28 days of the combination treatment of LEE011 and LGX818. Due to the halt of enrollment, no Maximum Tolerated Dose (MTD) was formally declared during the study.
Phase II - Progression Free Survival (PFS)
Time frame: Approximately 23 months after enrollment
As per RECIST v1.1, PFS is the time from date of randomization/ start of treatment to the date of event defined as the first documented progression or death due to any cause. Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to efficacy were not performed.
Phase II - Objective Response Rate (ORR)
Time frame: Approximately 23 months after enrollment
As per RECIST v1.1, ORR is defined as the proportion of patients with a best overall response of complete response or partial response. Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to efficacy were not performed.

12 secondary outcomes

Phase I - Number of Subjects Experiencing at Least One Adverse Event (AE).
Time frame: Approximately 23 months after enrollment
Phase I - Number of Subjects Experiencing at Least One Serious Adverse Event (SAE).
Time frame: Approximately 23 months after enrollment
Phase Ib/II - Plasma Concentration-time Profiles
Time frame: 28-day cycles
Phase Ib/II - Overall Response Rate (ORR)
Time frame: Approximately 23 months after enrollment
Phase Ib/II - Progression Free Survival (PFS)
Time frame: Approximately 23 months after enrollment
Phase Ib/II - Duration Of Response (DOR)
Time frame: Approximately 23 months after enrollment
Phase II - Overall Survival (OS)
Time frame: Approximately 23 months after enrollment
Phase Ib/II - Pharmacokinetic Parameters: AUCtau
Time frame: 28-day cycles
Phase Ib/II - Pharmacokinetic Parameters: Cmin
Time frame: 28-day cycles
Phase Ib/II - Pharmacokinetic Parameters: Cmax
Time frame: 28-day cycles
Phase Ib/II - Pharmacokinetic Parameters: Tmax
Time frame: 28-day cycles
Phase Ib/II - Pharmacokinetic Parameters: Racc
Time frame: 28-day cycles

Results and safety

Results posted to the registry on 13 Sep 2016, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Phase Ib: LEE011 200 mg + LGX818 300 mg (Cohort)	6	0
Phase Ib: LEE011 300 mg + LGX818 200 mg (Cohort)	12	0
Phase Ib: LEE011 400 mg + LGX818 100 mg (Cohort)	6	0
Phase Ib: LEE011 400 mg + LGX818 200 mg (Cohort)	4	0

Primary outcome: Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1

Time frame: Cycle 1 (approximately 28 days). Number. Unit: participants with DLTs

Measure	Phase Ib: LEE011 200 mg + LGX818 300 mg (Cohort) n = 6	Phase Ib: LEE011 400 mg + LGX818 100 mg (Cohort) n = 6	Phase Ib: LEE011 400 mg + LGX818 200 mg (Cohort) n = 4
Myalagia	1	0	0
Elevated Bilirubin	1	0	0
Neuralgia	0	1	0
Maculopapular Rash	0	0	1

Population analysed: Analysis group is comprised of the Safety Set (SS), which includes all patients who received at least one dose of LEE011 or LGX818, and have at least one valid post-baseline safety assessment.

Primary outcome: Phase II - Progression Free Survival (PFS)

Time frame: Approximately 23 months after enrollment

Population analysed: This analysis set would have been the Full Analysis (FAS), which included all patients who received at least one dose of encorafenib or ribociclib.

Primary outcome: Phase II - Objective Response Rate (ORR)

Time frame: Approximately 23 months after enrollment

Population analysed: This analysis set would have been the Full Analysis (FAS), which included all patients who received at least one dose of encorafenib or ribociclib.

12 secondary outcomes are reported in the full results.

Adverse events

Time frame: This study began recruitment on 10-July-2013 and concluded on 13-April-2015. Adverse Events (AEs) were collected throughout the study, approximately 2 years.. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Phase Ib: LEE011 200 mg + LGX818 300 mg (Cohort)	3 of 6 (50%)	6 of 6 (100%)	Not reported
Phase Ib: LEE011 300 mg + LGX818 200 mg (Cohort)	5 of 12 (41.7%)	12 of 12 (100%)	Not reported
Phase Ib: LEE011 400 mg + LGX818 100 mg (Cohort)	3 of 6 (50%)	6 of 6 (100%)	Not reported
Phase Ib: LEE011 400 mg + LGX818 200 mg (Cohort)	1 of 4 (25%)	4 of 4 (100%)	Not reported

Limitations and caveats (from the sponsor): Study recruitment was halted on 07-Aug-2014 during the Phase Ib part of the study. The Phase II part of the study was not performed. Early termination of the study was not due to any safety concerns.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 13 Sep 2016.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Array BioPharma study director

303-381-6604

9 sites in 4 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing LEE011 and LGX818 in people with Locally Advanced Metastatic BRAF Mutant Melanoma, run by Array BioPharma at 9 sites in 4 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 13 Sep 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 9 sites in United States, Australia, Canada, Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 13 Sep 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 (time frame: Cycle 1 (approximately 28 days)). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01777776.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Sep 2016.