Safety and Efficacy of RAD001 in Participants With Mantle Cell Lymphoma Who Are Refractory or Intolerant to Velcade® Therapy

Study Overview
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Brief Summary
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This study was to evaluate the safety and efficacy of a daily, oral dose of 10 mg RAD001 in participants with Mantle Cell Lymphoma who were refractory or intolerant to Velcade® therapy and who had received at least one prior antineoplastic agent other than Velcade®, either separately or in combination with Velcade® (see inclusion criteria). Intolerance to Velcade® therapy was determined by the study investigator based on clinical evaluations. Participants were considered refractory to Velcade® if they have documented radiological progression on or within 12 months of the last dose of Velcade® when given alone or, on or within 12 months of the last dose of the last component of a combination therapy which included Velcade®.

Official Title
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An Open-Label, Single-Arm, Phase II Study of RAD001 in Patients With Mantle Cell Lymphoma Who Are Refractory or Intolerant to Velcade® (Bortezomib)

Conditions
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Lymphoma, Mantle- Cell

Intervention / Treatment
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* Drug: Everolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult participants (≥18 years old) with Mantle Cell Lymphoma that has been confirmed by central pathology review (archival diagnostic tumor specimen required). Participants with mantle cell lymphoma who have documented refractory disease to Velcade® (bortezomib) or who have documented intolerance to Velcade® therapy. Intolerance to Velcade® is determined by the study investigator based on clinical evaluations. Participants are considered refractory to Velcade® if they have documented radiological progression on or within 12 months of last dose of Velcade® when given alone or, on or within 12 months from the last dose of the last component of a combination therapy which included Velcade®. Participants are considered refractory to Velcade®, if Velcade® is part of a combination treatment for the disease. Participants must have received at least one prior antineoplastic agent, other than Velcade® either separately or in combination with Velcade® (bortezomib). At least one site of measurable nodal disease at baseline >2.0 cm in the longest transverse diameter and clearly measurable in at least two perpendicular dimensions, as determined by computer tomography (CT) scan (or magnetic resonance imaging (MRI), only if CT scan can not be performed). Eastern Cooperative Oncology Group (ECOG) performance status = 0, 1 or 2. Life expectancy ≥3 months. Adequate bone marrow, liver and renal function. Platelets ≥75 x 10^9/L (untransfused platelets). Exclusion Criteria: Participants who are currently receiving anticancer therapies or have received anticancer therapies within 4 weeks of the start of study drug (including chemotherapy, radiation, antibodies, targeted therapy etc.) are not eligible. Previous treatment with mammalian target of rapamycin (mTOR) inhibitors (e.g. everolimus, sirolimus, temsirolimus, etc). Participants with prior allogeneic stem cell transplant. Grade 3 or 4 unresolved toxicity from prior antineoplastic therapies. Currently taking other investigational agents or received other investigational drugs within 4 weeks of the start of study drug. Participants with central nervous system (CNS) lymphoma are not eligible; head magnetic resonance imaging (MRI) (or computer tomography (CT) if MRI is not available) is required prior to study entry. Use of chronic, systemic corticosteroids or another immunosuppressive agent, except prednisone ≤20 mg daily (or equivalent) for adrenal insufficiency (must have been on a stable dosage regimen for ≥4 weeks prior to the first treatment with RAD001). HIV positive participants are not eligible; (human immunodeficiency virus (HIV) testing is not required for study entry; review of previous medical records is required). Uncontrolled hyperlipidemia (≥Grade 3 hyperlipidemia despite optimal supportive medical therapy). Active, bleeding disorders or major surgery within 4 weeks of starting study drug. Severe and/or uncontrolled medical conditions such as symptomatic congestive heart failure (New York Heart Association Class III or IV), unstable angina, myocardial infarction within 6 months or study start, severely impaired lung function, cirrhosis, chronic active/persistent hepatitis. History of another primary malignancy ≤3 years prior to study entry.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 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: Everolimus<br>Participants received everolimus tablets, 10 mg, orally, once daily during each 28 day cycle until determination of objective tumor progression or unacceptable toxicity, or death, or consent withdrawal, or discontinuation from the study for any other reason. | Drug: Everolimus<br>* Everolimus tablets<br>* Other names: RAD001;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | Overall response rate was defined as the percentage of participants with a best overall disease response of complete response (CR) or partial response (PR). CR was defined as complete disappearance of all extranodal lesions. PR was defined as at least a 50% decrease in the sum of the product of diameter (SPD) of all index nodal and extranodal lesions. | From date of enrollment up to disease progression or death (approximately 3.8 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate (DCR) | Disease Control Rate was defined as the percentage of participants with best overall disease response of CR or PR or stable disease (SD). CR was defined as complete disappearance of all extranodal lesions. PR was defined as at least a 50% decrease in SPD of all index nodal and extranodal lesions. SD was defined failure to attain the criteria needed for CR or PR and failure to fulfill the criteria for at least a 50% increase in the SPD of all index nodal and extranodal (including splenic and/or hepatic nodules) lesions, taking as reference the smallest sum of the product of the diameters of all index lesions recorded at or after baseline. | From date of start of treatment up to disease progression or death (approximately up to 3.8 years) | 
| Duration of Response | Duration of response was defined as the time from the date of first documented disease response (CR or PR) to the date of first documented progression or death due to lymphoma. CR was defined as complete disappearance of all extranodal lesions. PR was defined as at least a 50% decrease in SPD of all index nodal and extranodal lesions. | From date of start of treatment up to disease progression or death (approximately up to 3.8 years) | 
| Progression Free Survival (PFS) | PFS was defined as 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. | From date of start of treatment up to disease progression or death (approximately up to 3.8 years) | 
| Overall Survival | Overall survival was defined as the time from the date of start of study treatment to the date of death due to any cause. | From date of start of treatment up to disease progression or death (approximately up to 3.8 years) | 
| Number of Participants With At Least One Adverse Event (AE) and Serious Adverse Event (SAE) | An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A SAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. | From the start of the study and 28 days after study drug discontinuation (approximately up to 18 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mantle Cell Lymphoma, Lymphoma, B-Cell Lymphoma, Mantle Zone Lymphoma, Refractory Lymphoma, Aggressive Lymphoma, PILLAR-1