BRAF Inhibitor, LGX818, Utilizing a Pulsatile Schedule in Patients With Stage IV or Unresectable Stage III Melanoma Characterized by a BRAFV600 Mutation

• Sponsor: Memorial Sloan Kettering Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01894672
• Collaborator: Array BioPharma (Industry)
• Enrollment: 7
• Locations: 5
• Arm: 1
• Duration (Months): 32.5
• Patients Per Site: 1.4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this phase II study is to find out if an investigational drug called LGX818 can stop the melanoma from growing.

Condition or Disease	Intervention/Treatment	Phase
Melanoma	Drug: LGX818	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 7 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Trial of the BRAF Inhibitor, LGX818, Utilizing a Pulsatile Schedule in Patients With Stage IV or Unresectable Stage III Melanoma Characterized by a BRAFV600 Mutation
• Study Start Date: Jul 1, 2013
• Actual Primary Completion Date: Mar 17, 2016
• Actual Study Completion Date: Mar 17, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: LGX818 LGX818 capsules will be administered orally on a once -daily schedule (QD) dosing at a dose of 300 mg/day, 2 weeks on followed by a 2 week break. This schedule of 2 weeks on, followed by 2 weeks off, will continue for the duration of time the patients remains on the clinical trial. After the follow up visit patients will be contacted approximately every 12 weeks until they have received a subsequent therapy or until they have been off treatment for a year to monitor their survival.

Drug: LGX818

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Response According to RECIST v1.1 Criteria [1.5 years]

   Efficacy for all patients will be evaluated by the study sites using RECIST v1.1 and response criteria based on contrast-enhanced CT. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Progression must also involve an increase in size of measurable lesions by at least 5 mm, to minimize the possibility that small changes in a small number of target lesions is falsely interpreted as progression.Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.

Secondary Outcome Measures

1. Response Rate [1.5 years]

   Response rate (defined as complete + partial response) and 95% confidence interval will be estimated.

Other Outcome Measures

1. Overall Survival [1.5 years]

   Overall survival will be calculated for the start of treatment to the date of last death or follow-up.

2. Pharmacokinetic (PK) Analysis: Geometric Mean of Maximum Observed Concentration (Cmax) of LGX818 at Steady State [Cycle 1 - Day 1, 15; Cycle 2 - Day 15; Cycle 3 - Day 1, Day 15]

   PK parameters will be determined on PK profiles after the first dose and at steady-state using non-compartmental method(s) using WinNonlin

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Stage IV, or unresectable stage III melanoma that harbors a BRAFV600 mutation

• Any prior therapy allowed except a BRAF or MEK inhibitor,.

• Patients must provide written informed consent prior to any screening procedures.

• Age 18 years or older.

• Willing and able to comply with scheduled visits, treatment plan and laboratory tests

• Patient is able to swallow and retain oral medication

• Measurable disease according to RECIST v1.1

• ECOG performance status ≤ 1

Exclusion Criteria:

• Brain metastasis or leptomeningeal disease

• Known acute or chronic pancreatitis

• Prior colectomy

• Clinically significant cardiac disease including any of the following:

• CHF requiring treatment (NYHA Classification ≥ 2) in which patients have a history of LVEF < 45% as determined by MUGA scan or ECHO, or uncontrolled hypertension (please refer to WHO-ISH guidelines)

• History or presence of clinically significant ventricular arrhythmias or atrial fibrillation

• Clinically significant resting bradycardia

• Unstable angina pectoris ≤ 3 months prior to starting study drug

• Acute Myocardial Infarction (AMI) ≤ 3 months prior to starting study drug

• QTcF> 480 msec

• Patients with any of the following laboratory values at Screening/baseline:

• Absolute neutrophil count (ANC) <1,500/mm3 [1.5 x 109/L]

• Platelets <100,000/mm3 [100 x 109/L]

• Hemoglobin < 9.0 g/dL

• Serum creatinine>1.5 x ULN

• Serum total bilirubin >1.5 x ULN

• AST/SGOT and/or ALT/SGPT > 2.5 x ULN

• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral LGX818 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).

• Previous or concurrent malignancy. Exceptions: adequately treated basal cell or squamous cell skin cancer; in situ carcinoma of the cervix, treated curatively and without evidence of recurrence for at least 3 years prior to study entry; or other solid tumor treated curatively, and without evidence of recurrence for at least 3 years prior to study entry.

• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL).

Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, are not allowed to participate in this study UNLESS they are using highly effective methods of contraception throughout the study and for 3 months after study drug discontinuation. Highly effective contraception methods include:

Total abstinence or

• Male or female sterilization

• Combination of any two of the following (a+b or a+c or b+c)

1. Use of oral, injected, or implanted hormonal methods of contraception

2. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

3. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository

• Post-menopausal women are allowed to participate in this study. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum Follicle-Stimulating Hormone (FSH) levels > 40 mIU/mL or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to screening. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.

Sexually active males must use a condom during intercourse while taking the drug and for 5 T1/2 after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.

History of thromboembolic or cerebrovascular events within the last 6 months, including transient ischemic attack, cerebrovascular accident, deep vein thrombosis, or pulmonary embolism.

• Patients who have undergone any major surgery within the last 2 weeks prior to starting study drug or who would not have fully recovered from previous surgery.

• Known Human Immunodeficiency Virus (HIV) infection

• Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or that may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for the study.

• Treatment with a prior BRAF or MEK inhibitor

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Memorial Sloan Kettering Cancer Center at Basking Ridge	Basking Ridge	New Jersey	United States
2	Memorial Sloan Kettering Cancer Center at Commack	Commack	New York	United States	11725
3	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
4	Memorial Sloan Kettering Cancer Center at Mercy Medical Center	Rockville Centre	New York	United States	11570
5	Memorial Sloan Kettering Cancer Center at Phelps Memorial Hospital Center	Sleepy Hollow	New York	United States	10591

Sponsors and Collaborators

• Memorial Sloan Kettering Cancer Center
• Array BioPharma

Investigators

• Principal Investigator: Paul Chapman, MD, Memorial Sloan Kettering Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Memorial Sloan Kettering Cancer Center

Publications

None provided.

• Responsible Party: Memorial Sloan Kettering Cancer Center
• ClinicalTrials.gov Identifier: NCT01894672
• Other Study ID Numbers: 13-053
• First Posted: Jul 10, 2013
• Last Update Posted: Jun 14, 2021
• Last Verified: Dec 1, 2019

• Keywords provided by Memorial Sloan Kettering Cancer Center: LGX818; BRAF Inhibitor; Stage IV melanoma; unresectable stage III melanoma; BRAFV600 mutation; 13-053
• Additional relevant MeSH terms: Melanoma

Study Results

Participant Flow

Recruitment Details	Protocol Open to Accrual 07/03/2013 Protocol Closed to Accrual 03/24/2015 Primary Completion Date 03/17/2016 Recruitment Location is the medical clinic

Arm/Group Title	LGX818
Arm/Group Description	Patients With Stage IV or Unresectable Stage III Melanoma Characterized by a BRAFV600 Mutation will receive LGX818 capsules orally on a once -daily schedule (QD) dosing at a dose of 300 mg/day, 2 weeks on followed by a 2 week break. This schedule of 2 weeks on, followed by 2 weeks off, will continue for the duration of time the patients remains on the clinical trial. After the follow up visit patients will be contacted approximately every 12 weeks until they have received a subsequent therapy or until they have been off treatment for a year to monitor their survival.
Period Title: Overall Study
STARTED	7
COMPLETED	7
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	LGX818
Arm/Group Description	Patients With Stage IV or Unresectable Stage III Melanoma Characterized by a BRAFV600 Mutation will receive LGX818 capsules orally on a once -daily schedule (QD) dosing at a dose of 300 mg/day, 2 weeks on followed by a 2 week break. This schedule of 2 weeks on, followed by 2 weeks off, will continue for the duration of time the patients remains on the clinical trial. After the follow up visit patients will be contacted approximately every 12 weeks until they have received a subsequent therapy or until they have been off treatment for a year to monitor their survival.
Overall Participants	7
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	4 57.1%
>=65 years	3 42.9%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	58
Sex: Female, Male (Count of Participants)
Female	2 28.6%
Male	5 71.4%
Region of Enrollment (Count of Participants)
United States	7 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Response According to RECIST v1.1 Criteria
Description	Efficacy for all patients will be evaluated by the study sites using RECIST v1.1 and response criteria based on contrast-enhanced CT. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Progression must also involve an increase in size of measurable lesions by at least 5 mm, to minimize the possibility that small changes in a small number of target lesions is falsely interpreted as progression.Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.
Time Frame	1.5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	LGX818
Arm/Group Description	Patients With Stage IV or Unresectable Stage III Melanoma Characterized by a BRAFV600 Mutation will receive LGX818 capsules orally on a once -daily schedule (QD) dosing at a dose of 300 mg/day, 2 weeks on followed by a 2 week break. This schedule of 2 weeks on, followed by 2 weeks off, will continue for the duration of time the patients remains on the clinical trial. After the follow up visit patients will be contacted approximately every 12 weeks until they have received a subsequent therapy or until they have been off treatment for a year to monitor their survival.
Measure Participants	7
Stable Disease	2 28.6%
Partial Response	2 28.6%
Complete Response	2 28.6%
Progressive Disease	1 14.3%

2. Secondary Outcome

Title	Response Rate
Description	Response rate (defined as complete + partial response) and 95% confidence interval will be estimated.
Time Frame	1.5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	LGX818
Arm/Group Description	LGX818 capsules will be administered orally on a once -daily schedule (QD) dosing at a dose of 300 mg/day, 2 weeks on followed by a 2 week break. This schedule of 2 weeks on, followed by 2 weeks off, will continue for the duration of time the patients remains on the clinical trial. After the follow up visit patients will be contacted approximately every 12 weeks until they have received a subsequent therapy or until they have been off treatment for a year to monitor their survival. LGX818
Measure Participants	7
Number (95% Confidence Interval) [percentage of participants]	57 814.3%

3. Other Pre-specified Outcome

Title	Overall Survival
Description	Overall survival will be calculated for the start of treatment to the date of last death or follow-up.
Time Frame	1.5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Other Pre-specified Outcome

Title	Pharmacokinetic (PK) Analysis: Geometric Mean of Maximum Observed Concentration (Cmax) of LGX818 at Steady State
Description	PK parameters will be determined on PK profiles after the first dose and at steady-state using non-compartmental method(s) using WinNonlin
Time Frame	Cycle 1 - Day 1, 15; Cycle 2 - Day 15; Cycle 3 - Day 1, Day 15

Outcome Measure Data

Analysis Population Description

Data were not collected

Arm/Group Title	LGX818
Arm/Group Description	Patients With Stage IV or Unresectable Stage III Melanoma Characterized by a BRAFV600 Mutation will receive LGX818 capsules orally on a once -daily schedule (QD) dosing at a dose of 300 mg/day, 2 weeks on followed by a 2 week break. This schedule of 2 weeks on, followed by 2 weeks off, will continue for the duration of time the patients remains on the clinical trial. After the follow up visit patients will be contacted approximately every 12 weeks until they have received a subsequent therapy or until they have been off treatment for a year to monitor their survival.
Measure Participants	0

Adverse Events

Arm/Group Title	LGX818
Arm/Group Description	Patients With Stage IV or Unresectable Stage III Melanoma Characterized by a BRAFV600 Mutation will receive LGX818 capsules orally on a once -daily schedule (QD) dosing at a dose of 300 mg/day, 2 weeks on followed by a 2 week break. This schedule of 2 weeks on, followed by 2 weeks off, will continue for the duration of time the patients remains on the clinical trial. After the follow up visit patients will be contacted approximately every 12 weeks until they have received a subsequent therapy or until they have been off treatment for a year to monitor their survival.
All Cause Mortality
	LGX818
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	LGX818
	Affected / at Risk (%)	# Events
Total	6/7 (85.7%)
Musculoskeletal and connective tissue disorders
Back pain	1/7 (14.3%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Treatment related secondary malignancy	3/7 (42.9%)	3
Nervous system disorders
Facial muscle weakness	1/7 (14.3%)	1
Respiratory, thoracic and mediastinal disorders
Pleural effusion	1/7 (14.3%)	1
Skin and subcutaneous tissue disorders
Skin & subcutaneous tissue disorders Other, spec	1/7 (14.3%)	1
Other (Not Including Serious) Adverse Events
	LGX818
	Affected / at Risk (%)	# Events
Total	7/7 (100%)
Gastrointestinal disorders
Nausea	3/7 (42.9%)
General disorders
Fatigue	1/7 (14.3%)
Musculoskeletal and connective tissue disorders
Arthralgia/myalgia	6/7 (85.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cutaneous squamous cell carcinoma	2/7 (28.6%)
Keratoacanthoma	1/7 (14.3%)
Nervous system disorders
Dysgeusia	1/7 (14.3%)
Bell's Palsy	1/7 (14.3%)
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysesthesia syndrome	6/7 (85.7%)
Hyperkeratosis	3/7 (42.9%)
Pruritus	2/7 (28.6%)
Rash	2/7 (28.6%)

Limitations/Caveats

The protocol was stopped after 7 participants were accrued due to intolerable toxicities.

More Information

Certain Agreements

All Principal Investigators ARE 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.