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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Tumors With CDK4/6 Pathway Activation

Intervention / Treatment
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* Drug: LEE011


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LEE011<br>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<br>* Study drug was provided in 200 mg and 50 mg hard gelatin capsules to be taken orally<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid malignancy, Hematologic malignancy, Mutations, Amplifications, Signature, CDK4, CDK6, CDK4/6, Cyclin D1, CCND,, Cyclin D3, p16 mutation, CDKN2A, LEE011, Breast cancer, Ovarian cancer, Lymphoma, Mesothelioma, Pancreatic neuroendocrine, Leukemia, Tumor