Trial Review

Registering a new trial?

To achieve prospective registration, we recommend submitting your trial for registration at the same time as ethics submission.

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)
Timepoint [1] 0 0
first 28 days of treatment
Primary outcome [2] 0 0
Objective Response Rate (ORR) (Phase II)
Timepoint [2] 0 0
Approximately 12 months after the FPFV
Secondary outcome [1] 0 0
Plasma Concentration-time Profile (AUCtau) of LEE011 (Phase Ib)
Timepoint [1] 0 0
Cycle 1 Day 1
Secondary outcome [2] 0 0
Plasma Concentration-time Profile (AUCtau) of MEK162 (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)
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)
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)
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)
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)
Timepoint [7] 0 0
Cycle 1 Day 1
Secondary outcome [8] 0 0
Plasma Concentration-time Profile (Cmax) of MEK162 (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)
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)
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)
Timepoint [11] 0 0
Cycle 1 Day 1
Secondary outcome [12] 0 0
Plasma Concentration-time Profile (Tmax) of MEK162 (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)
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)
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)
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)
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)
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)
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)
Timepoint [19] 0 0
Cycle 1 Day 1
Secondary outcome [20] 0 0
Plasma Concentration-time Profile (CL/F) of MEK162 (Phase Ib)
Timepoint [20] 0 0
Cycle 1 Day 1
Secondary outcome [21] 0 0
Number of Participants With Adverse Drug Reactions
Timepoint [21] 0 0
Approximately 12 months after FPFV
Secondary outcome [22] 0 0
Duration of Response (DoR) - Phase 2
Timepoint [22] 0 0
Approximately 12 months after the FPFV
Secondary outcome [23] 0 0
Time to Progression (TTP) - Phase 2
Timepoint [23] 0 0
Approximately 12 months after the FPFV
Secondary outcome [24] 0 0
Progression Free Survival (PFS) - Phase 1b and Phase 2
Timepoint [24] 0 0
Approximately 12 months after the FPFV
Secondary outcome [25] 0 0
Overall Survival (OS) - Phase ll
Timepoint [25] 0 0
Approximately 12 months after the FPFV
Secondary outcome [26] 0 0
Best Overall Response (BOR) - Phase II
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
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
In the phase Ib, the primary purpose is to establish the maximum tolerated dose (MTD)(s)/recommended phase ll dose (RP2D) and schedule of LEE011 and MEK162 orally administered combination. Once the MTD(s)/RP2D have been determined for each tested schedule, additional patients will be enrolled in the phase II portion of the study at the RP2D on the chosen schedule in order to assess the anti-tumor activity of the combination in addition to continued evaluation of safety.
Trial website
https://clinicaltrials.gov/study/NCT01781572
Trial related presentations / publications
Schuler M, Zimmer L, Kim KB, Sosman JA, Ascierto PA, Postow MA, De Vos FYFL, van Herpen CML, Carlino MS, Johnson DB, Berking C, Reddy MB, Harney AS, Berlin JD, Amaria RN. Phase Ib/II Trial of Ribociclib in Combination with Binimetinib in Patients with NRAS-mutant Melanoma. Clin Cancer Res. 2022 Jul 15;28(14):3002-3010. doi: 10.1158/1078-0432.CCR-21-3872.
Public notes

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



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT01781572