Trial Review

Please note that the ANZCTR website will be unavailable from 1:00pm until 2:00pm (AEST) on Thursday 10th of April for website maintenance. Please be sure to log out of the system in order to avoid any loss of data. Thank you and apologies for any inconvenience caused.


The ANZCTR website is back online for trial registration and updates. We apologise for any inconvenience caused while the site was inactive.


With activity expected to increase on the ANZCTR again, there may be extended wait times while we process pending studies, with priority being given to those trials submitted in February. Thank you for your patience.


Reset your password and enable multi-factor authentication (MFA)


For ANZCTR account holders: to help ensure the cyber safety of your account, you’ll need to reset your password and set-up multi-factor authentication (MFA) as per the instructions below.


  1. Go to the Login page, click ‘reset password’ and follow the instructions.
  2. Check your email for the link to set a new password.
  3. Create a new password that meets requirements.
  4. Return to the Login page and enter your new password. A verification code will be sent to your email.
  5. Check your email for the code and enter it on the Login page. If the code is entered incorrectly, you can re-enter the correct one or request a new one.

Learn more about MFA and its importance on the Australian Signals Directorate website.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT01781572




Registration number
NCT01781572
Ethics application status
Date submitted
24/01/2013
Date registered
1/02/2013
Date last updated
7/12/2020

Titles & IDs
Public title
A Phase Ib/II Study of LEE011 in Combination With MEK162 in Patients With NRAS Mutant Melanoma
Scientific title
A Phase Ib/II, Multicenter, Open Label, Study of LEE011 in Combination With MEK162 in Adult Patients With NRAS Mutant Melanoma
Secondary ID [1] 0 0
C4211005
Secondary ID [2] 0 0
CMEK162X2114
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Locally Advanced or Metastatic NRAS Mutant Melanoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Malignant melanoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - LEE011
Treatment: Drugs - MEK162

Experimental: Phase Ib - The phase Ib is the dose escalation part where successive cohorts of 3-6 newly enrolled patients receiving various dose pairs considering the recommendation from an adaptive BLRM incorporating the EWOC principle until MTD(s)/RP2D is defined. If multiple alternate dosing schedules are explored in parallel, the allocation of patients will proceed in an alternating fashion. Approximately 40 patients are expected to be treated during the phase Ib part of the study.

Dosing Schedule 1: MEK162 administered orally twice daily on a continuous dosing schedule. LEE011 administered orally once daily for 21 days followed by a 1 week break (28-day cycle).

Dosing Schedule 2: MEK162 administered orally twice daily and LEE011 administered orally once daily for 3 weeks followed by a 1 week break (28-day cycle).

Dosing Schedule 3: MEK162 administered orally twice daily and LEE011 administered once daily for 2 weeks followed by a 1 week break (21-day cycle).

Experimental: Phase II - The Phase II part will begin once the MTD(s)/RP2D have been determined in the Phase Ib in order to assess antitumor activity of the LEE011and MEK162 combination. Patients enrolled in the Phase II part of the study are required to have measurable disease. Approximately 40 patients will be treated in this part.

Phase II part will begin at the RP2D on the chosen schedule in order to assess antitumor activity of the LEE011 and MEK162 combination.


Treatment: Drugs: LEE011
LEE011 will be administered orally once daily

Treatment: Drugs: MEK162
MEK162 will be administered orally twice daily
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of Dose Limiting Toxicities (Phase Ib)
Assessment method [1] 0 0
To estimate the maximum tolerate doses (MTDs) and/or identify the RP2D and schedule of LEE011 and MEK162 combination. A dose-limiting toxicity (DLT) was defined as an AE or clinically significant abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurred within the first cycle of treatment with ribociclib and binimetinib.
Timepoint [1] 0 0
first 28 days of treatment
Primary outcome [2] 0 0
Objective Response Rate (ORR) (Phase II)
Assessment method [2] 0 0
ORR is the proportion of patients with best overall response of complete response (CR) or partial response (PR) by month 2 assessed according to RECIST 1.1 criteria. ORR is done to describe the anti-tumor activity of LEE011 and MEK162 combination. The primary analysis of the ORR was based on the Investigator's assessment of overall lesion responses per RECIST 1.1.
Timepoint [2] 0 0
Approximately 12 months after the FPFV
Secondary outcome [1] 0 0
Plasma Concentration-time Profile (AUCtau) of LEE011 (Phase Ib)
Assessment method [1] 0 0
To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).
Timepoint [1] 0 0
Cycle 1 Day 1
Secondary outcome [2] 0 0
Plasma Concentration-time Profile (AUCtau) of MEK162 (Phase Ib)
Assessment method [2] 0 0
To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).
Timepoint [2] 0 0
Cycle 1 Day 1
Secondary outcome [3] 0 0
Plasma Concentration-time Profile (AUCtau,ss) of LEE011 (Phase Ib)
Assessment method [3] 0 0
To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).
Timepoint [3] 0 0
For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14
Secondary outcome [4] 0 0
Plasma Concentration-time Profile (AUCtau,ss) of MEK162 (Phase Ib)
Assessment method [4] 0 0
To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).
Timepoint [4] 0 0
For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14
Secondary outcome [5] 0 0
Plasma Concentration-time Profile (Cmin,ss) of LEE011 (Phase Ib)
Assessment method [5] 0 0
To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).
Timepoint [5] 0 0
For the 28-day schedule the steady-state parameter time frame was predose on Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was predose on Cycle 1 Day 14
Secondary outcome [6] 0 0
Plasma Concentration-time Profile (Cmin,ss) of MEK162 (Phase Ib)
Assessment method [6] 0 0
To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).
Timepoint [6] 0 0
For the 28-day schedule the steady-state parameter time frame was predose on Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was predose on Cycle 1 Day 14
Secondary outcome [7] 0 0
Plasma Concentration-time Profile (Cmax) of LEE011 (Phase Ib)
Assessment method [7] 0 0
To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).
Timepoint [7] 0 0
Cycle 1 Day 1
Secondary outcome [8] 0 0
Plasma Concentration-time Profile (Cmax) of MEK162 (Phase Ib)
Assessment method [8] 0 0
To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).
Timepoint [8] 0 0
Cycle 1 Day 1
Secondary outcome [9] 0 0
Plasma Concentration-time Profile (Cmax,ss) of LEE011 (Phase Ib)
Assessment method [9] 0 0
To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).
Timepoint [9] 0 0
For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14
Secondary outcome [10] 0 0
Plasma Concentration-time Profile (Cmax,ss) of MEK162 (Phase Ib)
Assessment method [10] 0 0
To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).
Timepoint [10] 0 0
For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14
Secondary outcome [11] 0 0
Plasma Concentration-time Profile (Tmax) of LEE011 (Phase Ib)
Assessment method [11] 0 0
To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).
Timepoint [11] 0 0
Cycle 1 Day 1
Secondary outcome [12] 0 0
Plasma Concentration-time Profile (Tmax) of MEK162 (Phase Ib)
Assessment method [12] 0 0
To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).
Timepoint [12] 0 0
Cycle 1 Day 1
Secondary outcome [13] 0 0
Plasma Concentration-time Profile (Tmax,ss) of LEE011 (Phase Ib)
Assessment method [13] 0 0
To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).
Timepoint [13] 0 0
For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14
Secondary outcome [14] 0 0
Plasma Concentration-time Profile (Tmax,ss) of MEK162 (Phase Ib)
Assessment method [14] 0 0
To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).
Timepoint [14] 0 0
For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14
Secondary outcome [15] 0 0
Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of LEE011 (Phase Ib)
Assessment method [15] 0 0
To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).
Timepoint [15] 0 0
For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14
Secondary outcome [16] 0 0
Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of MEK162 (Phase Ib)
Assessment method [16] 0 0
To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).
Timepoint [16] 0 0
For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14
Secondary outcome [17] 0 0
Plasma Concentration-time Profile (T1/2,ss) of LEE011 (Phase Ib)
Assessment method [17] 0 0
To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).
Timepoint [17] 0 0
For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14
Secondary outcome [18] 0 0
Plasma Concentration-time Profile (T1/2,ss) of MEK162 (Phase Ib)
Assessment method [18] 0 0
To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).
Timepoint [18] 0 0
For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14
Secondary outcome [19] 0 0
Plasma Concentration-time Profile (CL/F) of LEE011 (Phase Ib)
Assessment method [19] 0 0
To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).
Timepoint [19] 0 0
Cycle 1 Day 1
Secondary outcome [20] 0 0
Plasma Concentration-time Profile (CL/F) of MEK162 (Phase Ib)
Assessment method [20] 0 0
To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).
Timepoint [20] 0 0
Cycle 1 Day 1
Secondary outcome [21] 0 0
Number of Participants With Adverse Drug Reactions
Assessment method [21] 0 0
Safety and tolerability will be characterized through the incidence and severity of adverse drug reactions, serious adverse drug reactions, changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), dose interruptions, dose reduction and dose intensity.
Timepoint [21] 0 0
Approximately 12 months after FPFV
Secondary outcome [22] 0 0
Duration of Response (DoR) - Phase 2
Assessment method [22] 0 0
To assess clinical safety as per RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer. Please note: As clinicaltrials.gov only allows numerical data entry, the value of 999 indicates "not estimable" for confidence interval.
Timepoint [22] 0 0
Approximately 12 months after the FPFV
Secondary outcome [23] 0 0
Time to Progression (TTP) - Phase 2
Assessment method [23] 0 0
To assess clinical safety as per RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer.
Timepoint [23] 0 0
Approximately 12 months after the FPFV
Secondary outcome [24] 0 0
Progression Free Survival (PFS) - Phase 1b and Phase 2
Assessment method [24] 0 0
To assess clinical safety as per RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer. In the Phase 1b part, patients were combined for purposes of PFS analyses based on schedule received, since too few patients received any individual dose level to allow for valid PFS estimates within the respective dose levels. This is how the data were analyses and presented for the clinical study report.
Timepoint [24] 0 0
Approximately 12 months after the FPFV
Secondary outcome [25] 0 0
Overall Survival (OS) - Phase ll
Assessment method [25] 0 0
To assess clinical safety as per RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer.
Timepoint [25] 0 0
Approximately 12 months after the FPFV
Secondary outcome [26] 0 0
Best Overall Response (BOR) - Phase II
Assessment method [26] 0 0
To assess clinical safety according to RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer.
Timepoint [26] 0 0
Approximately 12 months after the FPFV

Eligibility
Key inclusion criteria
* Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1.
* Patients enrolled into phase Ib may be enrolled with evaluable disease only. Patients enrolled into the phase II expansion must have at least one measurable lesion as defined by RECIST 1.1 criteria for solid tumors.
* Patients must have adequate organ function, as defined by the following parameter

1. Absolute Neutrophil Count (ANC) = 1.5 x 109/L.
2. Hemoglobin (Hgb) = 9 g/dL.
3. Platelets = 75 x 109/L without transfusions within 21 days before 1st treatment.
4. PT/INR and aPTT = 1.5 ULN.
5. Serum creatinine =1.5 ULN.
6. Serum total bilirubin = 1.5 x upper limit of normal (ULN).
7. AST and ALT = 3 x ULN, except in patients with tumor involvement of the liver who must have AST and ALT = 5 x ULN.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Presence of any brain metastases detected by MRI or CT with i.v. contrast of the brain at screening.
* Uncontrolled arterial hypertension despite medical treatment
* Impaired cardiac function or clinically significant cardiac diseases, including any of the following:

1. Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition scan (MUGA) or echocardiogram (ECHO).
2. Congenital long QT syndrome or family history of unexpected sudden cardiac death.
3. QTcF corrected with Frederica's or Bazett's formula QTcB >450 ms for males and >470 ms for females on screening ECG.
4. Angina pectoris = 3 months prior to starting study drug
5. Acute myocardial infarction = 3 months prior to starting study drug
6. Clinically significant resting bradycardia
7. History or presence of ventricular tachyarrhythmia
8. Unstable atrial fibrillation (ventricular response >100 bpm)
9. Complete left bundle branch block
10. Right bundle branch block and left anterior hemi block (bifascicular block)
11. Obligate use of a cardiac pacemaker or implantable cardioverter defibrillator
12. Any other clinically significant heart disease
* Patients who are currently receiving treatment with agents that are known to cause QTc prolongation in humans.
* Patients who have neuromuscular disorders that are associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy) or elevated baseline CK levels (= Grade 2)
* Patients who are currently receiving treatment with agents that are metabolized predominantly through CYP3A4 and that have a narrow therapeutic window.
* Patients with concurrent severe and/or uncontrolled concurrent medical conditions that could compromise participation in the study (i.e. uncontrolled diabetes mellitus, clinically significant pulmonary disease, clinically significant neurological disorder, active or uncontrolled infection).
* History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes).

Other protocol related inclusion/exclusion criteria may apply.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/06/2013
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
20/02/2018
Sample size
Target
Accrual to date
Final
102
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
Pfizer Investigative Site 1003 - North Sydney
Recruitment hospital [2] 0 0
Pfizer Investigative Site 1002 - Westmead
Recruitment hospital [3] 0 0
Pfizer Investigator Site 1001 - East Melbourne
Recruitment postcode(s) [1] 0 0
2060 - North Sydney
Recruitment postcode(s) [2] 0 0
2145 - Westmead
Recruitment postcode(s) [3] 0 0
- East Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Michigan
Country [3] 0 0
United States of America
State/province [3] 0 0
New York
Country [4] 0 0
United States of America
State/province [4] 0 0
Tennessee
Country [5] 0 0
United States of America
State/province [5] 0 0
Texas
Country [6] 0 0
Germany
State/province [6] 0 0
Essen
Country [7] 0 0
Germany
State/province [7] 0 0
Gera
Country [8] 0 0
Germany
State/province [8] 0 0
Hannover
Country [9] 0 0
Germany
State/province [9] 0 0
Muenchen
Country [10] 0 0
Italy
State/province [10] 0 0
Napoli
Country [11] 0 0
Netherlands
State/province [11] 0 0
The Netherlands
Country [12] 0 0
Netherlands
State/province [12] 0 0
Nijmegen

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Pfizer
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Pfizer CT.gov Call Center
Address 0 0
Pfizer
Country 0 0
Phone 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Email 0 0
Contact person for scientific queries

No information has been provided regarding IPD availability


What supporting documents are/will be available?

TypeOther DetailsAttachment
Statistical analysis plan
Study protocol



Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results are available at https://clinicaltrials.gov/study/NCT01781572