LEE011 for Patients With CDK4/6 Pathway Activated Tumors (SIGNATURE) (SIGNATURE)

Modular Phase II Study to Link Targeted Therapy to Patients With Pathway Activated Tumors: Module 8 - LEE011 for Patients With CDK4/6 Pathway Activated Tumors

The purpose of this signal seeking study was to determine whether treatment with LEE011 demonstrates sufficient efficacy in CDK4/6 pathway activated solid tumors and/or hematologic malignancies to warrant further study.

Study Overview

• Status: Completed
• Conditions: Tumors With CDK4/6 Pathway Activation
• Intervention / Treatment: Drug: LEE011

• Study Type: Interventional
• Enrollment (Actual): 106
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • University of Alabama at Birmingham
  • Alaska
    • Anchorage, Alaska, United States, 99503
      • Alaska Clinical Research
  • Arizona
    • Phoenix, Arizona, United States
      • Arizona Oncology Associates Dept. Of Onc.
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas/ Arkansas Cancer Research Center UA Medical Sciences
  • California
    • Pismo Beach, California, United States, 93449
      • PCR Oncology
    • Sacramento, California, United States, 95817
      • University of California Davis Cancer Center UC Davis Cancer (3)
  • Colorado
    • Denver, Colorado, United States, 80218
      • Sarah Cannon Research Institute
  • Connecticut
    • Danbury, Connecticut, United States, 06810
      • Danbury Hospital
    • New Haven, Connecticut, United States, 06520
      • Yale University School Of Medicine Smilow Cancer Hospital
    • Norwalk, Connecticut, United States, 06856
      • Whittingham Cancer Center Norwalk Hospital
    • Stamford, Connecticut, United States, 06902
      • Stamford Hospital Med. Oncology Hematology Res.
  • Florida
    • Orlando, Florida, United States, 32804
      • Florida Hospital Cancer Institute
  • Georgia
    • Marietta, Georgia, United States, 30060
      • NorthWest Georgia Oncology Centers NW Georgia Oncology
    • Rome, Georgia, United States, 30165
      • Harbin Clinic Medical Oncology Clin. Res.
  • Hawaii
    • Honolulu, Hawaii, United States, 96817
      • Queen's Medical Center Queens Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Medicine Developmental Therapeutics Institute
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Indiana Univ. - Purdue Univ.
    • South Bend, Indiana, United States, 46617
      • Northern Indiana Cancer Research Consortium No. Indiana Cancer Res.
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals & Clinics Regulatory Contact 2
  • Maine
    • Scarborough, Maine, United States, 04074
      • New England Cancer Specialists
  • Maryland
    • Baltimore, Maryland, United States, 21229
      • St. Agnes Hospital St. Agnes Hospital (2)
  • Michigan
    • Ann Arbor, Michigan, United States, 48109 5271
      • Michigan Medicine University of Michigan Int. Medicine Oncology
    • Grand Rapids, Michigan, United States, 49546
      • Cancer and Hematology Centers of West Michigan Dept. of Oncology
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Saint Luke's Hospital/Marion Bloch Neuroscience Institute St. Luke's Hospital (4)
    • Kansas City, Missouri, United States, 64132
      • Research Medical Center Research Med Center (2)
  • Nevada
    • Las Vegas, Nevada, United States, 89109
      • Comprehensive Cancer Centers of Nevada CCC of Nevada- Southwest (2)
  • New Jersey
    • Camden, New Jersey, United States, 08103
      • Cooper Health System Cooper Health System (5)
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • New Mexico Cancer Care Alliance
    • Albuquerque, New Mexico, United States
      • Cancer Center at Presbyterian
  • New York
    • Johnson City, New York, United States, 13790
      • Broome Oncology Broome Oncology (2)
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7600
      • University of N C at Chapel Hill Physician Office Building
    • Hickory, North Carolina, United States, 28602
      • Carolina Oncology Specialists, PC
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Baptist Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • Oncology Hematology Care Inc Oncology Hematology Care 2
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation Taussig Cancer Institute
    • Columbus, Ohio, United States, 43221
      • Ohio State University Medical Center Comprehensive Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University Oregon Health & Science U (56)
    • Salem, Oregon, United States, 97309
      • Salem Health
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center Dept of Medical Oncology
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital Rhode Island Hosp. (2)
  • South Carolina
    • Greenville, South Carolina, United States, 29615
      • Greenville Health System ITOR - Cancer Institute
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57104
      • Sanford University of South Dakota Medical Center Sanford Health
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Chattanooga Oncology and Hematology Assoicates, PC Chattanooga Oncology
    • Memphis, Tennessee, United States, 38120
      • The West Clinic Dept. of the West Clinic
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology Tennessee Oncology (3)
  • Texas
    • Corpus Christi, Texas, United States, 78404
      • Coastal Bend Cancer Center
    • Houston, Texas, United States, 77024
      • Oncology Consultants Oncology Group
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center/University of Texas MD Anderson Cancer Center (3)
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio Cancer Therapy & Research Ctr.
  • Utah
    • Murray, Utah, United States, 84157
      • Intermountain Medical Center Intermountain Healthcare
    • Salt Lake City, Utah, United States, 84106
      • Utah Cancer Specialists Utah Cancer Specialists (11)
  • Virginia
    • Winchester, Virginia, United States, 22601
      • Shenandoah Oncology Shenadoah Oncology (2)
  • Washington
    • Kennewick, Washington, United States, 99336
      • Kadlec Clinic Hematology and Oncology Kadlec Clinic Hematology & Onc
    • Olympia, Washington, United States, 98502
      • Vista Oncology Inc. PS
    • Tacoma, Washington, United States, 98405
      • MultiCare Research Institute
    • Tacoma, Washington, United States, 98405
      • Northwest Medical Specialties Rainier Physicians, PC
    • Walla Walla, Washington, United States, 98057
      • Providence St. Mary Regional Cancer Center
    • Wenatchee, Washington, United States, 98801
      • Wenatchee Valley Medical Center Wenatchee Valley
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin Cancer Center
    • Milwaukee, Wisconsin, United States, 53226
      • Aurora Research Institute Aurora Health Care

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient had a confirmed diagnosis of a select solid tumor (except breast cancer (however, triple negative was included), liposarcoma, CRPC, melanoma and teratoma) or hematological malignancy (except mantle cell lymphoma).
• Patient must have been pre-identified as having a tumor with CDK4 amplification or mutation, CDK6 amplification or mutation, Cyclin D1 (CCND1) amplification, Cyclin D3 (CCND3) amplification, or p16 (CDKN2A) mutation
• Patient had received at least one prior treatment for recurrent, metastatic and /or locally advanced disease and for whom no standard therapy options are anticipated to result in a durable remission.
• Patient had progressive and measurable disease as per RECIST 1.1. or other appropriate hematological guidelines.
• Patient had an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1

Exclusion Criteria:

• Patients had received prior treatment with LEE011.
• Patient had clinically significant resting bradycardia (heart rate < 50 at rest), tachycardia (heart rate > 90 at rest), PR interval > 220 msec, QRS interval > 109 msec, or QTcF > 450 msec.
• Patients had primary CNS tumor or CNS tumor involvement
• Patient had received chemotherapy or anticancer therapy ≤ 4 weeks prior to starting study drug

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LEE011; LEE011 600 mg (hard gelatin capsules) was administered orally once daily for 3 weeks on/1 week off. A complete treatment cycle was defined as 28 days.	Drug: LEE011; Study drug was provided in 200 mg and 50 mg hard gelatin capsules to be taken orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Solid Tumor Response ≥ 16 Weeks for Based Upon Local Investigator Assessments	Clinical benefit (CB) for patients with solid tumors were assessed using RECIST 1.1 and included responses of Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) for ≥ 16 weeks. CR and PR (for solid tumors) required a confirmation at least 4 weeks after the initial response observation. For hematologic tumors other appropriate hematological response criteria was applied. CR=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have had reduction in short axis to <10 mm, PR=At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study, PD=At least a 20% increase in the sum of diameter of all measured target lesions and also demonstrate an absolute increase of at least 5 mm. FAS	Baseline up ≥16 weeks up to approximately 36 months
Clinical Benefit Rate (CBR) of ≥ 16 Weeks FAS	CBR was determined by local, Investigator assessment for each tumor assessment and defined as responses of CR + PR + SD for ≥ 16 weeks. CR and PR (for solid tumors) required a confirmation at least 4 weeks after the initial response observation. For hematologic tumors other appropriate hematological response criteria was applied. CR=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have had reduction in short axis to <10 mm, PR=At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study, PD=At least a 20% increase in the sum of diameter of all measured target lesions and also demonstrate an absolute increase of at least 5 mm FAS	Baseline and ≥ 16 weeks up to approximately 36 months
Overall Response Rate (ORR) ≥ 16 Weeks. FAS	ORR was determined by local, Investigator assessment for each tumor assessment and defined as responses of CR+PR ≥ 16 weeks. FAS	Baseline and ≥ 16 weeks up to approximately 36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	Progression-free survival (PFS) is the time from the date of start of treatment to the date of event defined as the first documented progression or death due to any cause within 30 days of the last dose. If a subject has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Progressive disease is defined as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm (Note: the appearance of one or more new lesions is also considered progression)	Every 8 weeks until death, assessed up to 24 months
Overall Survival (OS)	Number of participants Overall survival (OS) is defined as the time from the date of first dose to the date of death due to any cause.	Baseline up to approximately 36 months
Number of Days for Duration of Response for Responders	Duration of response (DOR) is defined as time from the first documented response to the date first documented disease progression or relapse or death due to any cause. For patients with solid tumors the assessment criteria will be RECIST 1.1 and will include responses of CR and/or PR.	Baseline up to approximately 36 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): August 25, 2014
• Primary Completion (Actual): January 17, 2018
• Study Completion (Actual): January 17, 2018

Study Registration Dates

• First Submitted: July 9, 2014
• First Submitted That Met QC Criteria: July 9, 2014
• First Posted (Estimate): July 11, 2014

Study Record Updates

• Last Update Posted (Actual): July 18, 2019
• Last Update Submitted That Met QC Criteria: July 16, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Lymphoma; Breast cancer; Ovarian cancer; Leukemia; LEE011; Mesothelioma; Tumor; Mutations; CDK4/6; CDK4; CDK6; Hematologic malignancy; Cyclin D1; CDKN2A; Solid malignancy; Amplifications; Signature; CCND,; Cyclin D3; p16 mutation; Pancreatic neuroendocrine
• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: CLEE011XUS03

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No