Clinical trial NCT01781572: A Phase Ib/II Study of LEE011 in Combination With MEK162 in Patients With NRAS Mutant Melanoma
Official title: A Phase Ib/II, Multicenter, Open Label, Study of LEE011 in Combination With MEK162 in Adult Patients With NRAS Mutant Melanoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Locally Advanced or Metastatic NRAS Mutant Melanoma
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2013-02-01
Enrollment: 102
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

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.

Primary outcomes:
measure: Number of Dose Limiting Toxicities (Phase Ib)
timeFrame: first 28 days of treatment
measure: Objective Response Rate (ORR) (Phase II)
timeFrame: Approximately 12 months after the FPFV
Secondary outcomes:
measure: Plasma Concentration-time Profile (AUCtau) of LEE011 (Phase Ib)
timeFrame: Cycle 1 Day 1
measure: Plasma Concentration-time Profile (AUCtau) of MEK162 (Phase Ib)
timeFrame: Cycle 1 Day 1
measure: Plasma Concentration-time Profile (AUCtau,ss) of LEE011 (Phase Ib)
timeFrame: 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
measure: Plasma Concentration-time Profile (AUCtau,ss) of MEK162 (Phase Ib)
timeFrame: 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
measure: Plasma Concentration-time Profile (Cmin,ss) of LEE011 (Phase Ib)
timeFrame: 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
measure: Plasma Concentration-time Profile (Cmin,ss) of MEK162 (Phase Ib)
timeFrame: 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
measure: Plasma Concentration-time Profile (Cmax) of LEE011 (Phase Ib)
timeFrame: Cycle 1 Day 1
measure: Plasma Concentration-time Profile (Cmax) of MEK162 (Phase Ib)
timeFrame: Cycle 1 Day 1
measure: Plasma Concentration-time Profile (Cmax,ss) of LEE011 (Phase Ib)
timeFrame: 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
measure: Plasma Concentration-time Profile (Cmax,ss) of MEK162 (Phase Ib)
timeFrame: 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
measure: Plasma Concentration-time Profile (Tmax) of LEE011 (Phase Ib)
timeFrame: Cycle 1 Day 1
measure: Plasma Concentration-time Profile (Tmax) of MEK162 (Phase Ib)
timeFrame: Cycle 1 Day 1
measure: Plasma Concentration-time Profile (Tmax,ss) of LEE011 (Phase Ib)
timeFrame: 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
measure: Plasma Concentration-time Profile (Tmax,ss) of MEK162 (Phase Ib)
timeFrame: 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
measure: Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of LEE011 (Phase Ib)
timeFrame: 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
measure: Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of MEK162 (Phase Ib)
timeFrame: 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
measure: Plasma Concentration-time Profile (T1/2,ss) of LEE011 (Phase Ib)
timeFrame: 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
measure: Plasma Concentration-time Profile (T1/2,ss) of MEK162 (Phase Ib)
timeFrame: 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
measure: Plasma Concentration-time Profile (CL/F) of LEE011 (Phase Ib)
timeFrame: Cycle 1 Day 1
measure: Plasma Concentration-time Profile (CL/F) of MEK162 (Phase Ib)
timeFrame: Cycle 1 Day 1
measure: Number of Participants With Adverse Drug Reactions
timeFrame: Approximately 12 months after FPFV
measure: Duration of Response (DoR) - Phase 2
timeFrame: Approximately 12 months after the FPFV
measure: Time to Progression (TTP) - Phase 2
timeFrame: Approximately 12 months after the FPFV
measure: Progression Free Survival (PFS) - Phase 1b and Phase 2
timeFrame: Approximately 12 months after the FPFV
measure: Overall Survival (OS) - Phase ll
timeFrame: Approximately 12 months after the FPFV
measure: Best Overall Response (BOR) - Phase II
timeFrame: Approximately 12 months after the FPFV
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California, Dept of Oncology
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center Onc Dept
state: California
city: Detroit
country: United States
facility: Karmanos Cancer Institute Dept of Oncology
state: Michigan
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center Dept Oncology
state: New York
city: New York
country: United States
facility: Columbia University Medical Center- New York Presbyterian Onc Dept.
state: New York
city: Nashville
country: United States
facility: Vanderbilt University Medical Center SC - Dept of Oncology .
state: Tennessee
city: Houston
country: United States
facility: University of Texas/MD Anderson Cancer Center Dept of Onc.
state: Texas
city: North Sydney
country: Australia
facility: Pfizer Investigative Site 1003
state: New South Wales
city: Westmead
country: Australia
facility: Pfizer Investigative Site 1002
state: New South Wales
city: East Melbourne
country: Australia
facility: Pfizer Investigator Site 1001
state: Victoria
city: Essen
country: Germany
facility: Pfizer Investigative Site 1050
city: Gera
country: Germany
facility: Pfizer Investigative Site 1053
city: Hannover
country: Germany
facility: Pfizer Investigative Site 1052
city: Muenchen
country: Germany
facility: Pfizer Investigative Site 1051
city: Napoli
country: Italy
facility: Pfizer Investigative Site 1101
city: Utrecht
country: Netherlands
facility: Pfizer Investigative Site 1151
state: The Netherlands
city: Nijmegen
country: Netherlands
facility: Pfizer Investigative Site 1150
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: 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.