Phase III Study of RAD001 Adjuvant Therapy in Poor Risk Patients With Diffuse Large B-Cell Lymphoma (DLBCL) of RAD001 Versus Matching Placebo After Patients Have Achieved Complete Response With First-line Rituximab-chemotherapy

Phase 3

Completed

Conditions: Diffuse Large B-cell Lymphoma

Interventions: Drug: Everolimus
Drug: Everolimus Placebo

Registration Number: NCT00790036

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: Phase III study of RAD001 adjuvant therapy in poor risk patients with Diffuse Large B-Cell Lymphoma (DLBCL) of RAD001 versus matching placebo after patients had achieved complete response with first-line rituximab-chemotherapy

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 742

Inclusion Criteria

Patients with previous histologically confirmed Stage III-IV (or Stage II bulky disease, defined as any tumor mass more than 10 cm in longest diameter), at time of original diagnosis, diffuse large B cell lymphoma (pathology report based on original tumor tissue/lymph node is acceptable for meeting inclusion criteria, but tumor tissue (slides/block) must be available to be sent for central pathology to confirm diagnosis).
Patients defined as poor risk with IPI of 3, 4, or 5 at time of original diagnosis.
Patients age ≥ 18 years old.
Patients must have achieved complete remission (CR) based on the revised IWRC (Cheson et al 2007) following first line R-chemotherapy treatment. Radiation therapy (RT) during or after R-chemotherapy is acceptable provided: 1) it ends 4 weeks prior to start of study drug and, 2) in case of consolidation RT targeted at initial bulky tumor mass, administered after R-chemotherapy, patient is already in CR before initiating RT. Complete remission from R-chemotherapy must be confirmed by clinical and radiologic evaluation along with bone marrow confirmation (if bone marrow was involved by lymphoma before the R-chemotherapy treatment). Local pathology report on the bone marrow biopsy is acceptable. If bone marrow was not involved by lymphoma before R-chemotherapy treatment, then bone marrow confirmation after R-chemotherapy is not required.
Patients who received a minimum 5 cycles of R-chemotherapy treatment and maximum 8 cycles of R-chemotherapy treatment. Any variation of CHOP (R-CHOP-14, R-CHOP-21) is acceptable. Liposomal doxorubicin, epirubicin, or pirarubicin (also known as therarubicin) is acceptable. R-EPOCH is acceptable.
Patients' last treatment with R-chemotherapy must be 6 to 14 weeks prior to start of study drug.
Patients with ECOG performance status (PS) 0, 1, or 2.
Patients willing to provide a portion of his/her tumor tissue from original diagnosis or lymph node to confirm diagnosis.
The following laboratory values obtained ≤ 21 days prior to start of study drug:
- Absolute neutrophil count ≥ 1000/mm3 (or 1.0 GI/L, SI units)
- Platelet count ≥ 100,000/mm3 (or 100 GI/L, SI units)
- Hemoglobin ≥ 9 g/dL (can be achieved by transfusion)
- Total bilirubin ≤ 2 x ULN (if >2 x ULN direct bilirubin is required and should be ≤1.5 x ULN)
- AST ≤ 3 x ULN
- Serum creatinine ≤ 2 x ULN
Women of childbearing potential must have had a negative serum pregnancy test 14 days prior to the start of study drug plus a negative local urine pregnancy test on Day 1, Cycle 1 prior to treatment and must be willing to use adequate methods of contraception during the study and for 8 weeks after study drug administration.
Patients who give a written informed consent obtained according to local guidelines.
Patients capable of swallowing intact study medication tablets and following directions regarding taking study drug, or have a daily caregiver who will be responsible for administering study drug.

Exclusion Criteria

Patients with evidence of disease according to the revised IWRC (Cheson et al 2007) after completion of the first-line R-chemotherapy treatment, prior to study entry.
Patients receiving ongoing radiation therapy or who received radiation therapy to the residual tumor masses < 4 weeks from start of study drug.
Patients who have previously received systemic mTOR inhibitor (sirolimus, temsirolimus, everolimus, etc).
Patients with evidence of current central nervous system (CNS) involvement with lymphoma. Patients who have only had prophylactic intrathecal chemotherapy against CNS disease are eligible.
Patients with transformed follicular lymphoma.
Patients who received ibritumomab tiuxetan (Zevalin®), in order to avoid potential delayed kidney toxicities.
Patients who had myelosuppressive chemotherapy or biologic therapy < 3 weeks from start of study drug.
Patients receiving chronic systemic immunosuppressive agents. Inhaled and topical steroids are acceptable. Patients may be receiving stable (not increased within the last month) chronic doses of corticosteroids with a maximum dose of 20 mg of prednisone or ≤5 mg of dexamethasone per day, if they are being given for disorders other than lymphoma such as rheumatoid arthritis, polymyalgia rheumatica, adrenal insufficiency or asthma.
Patients with active, bleeding diathesis.
Patients with a known history of HIV seropositivity.
Patients with known hypersensitivity to RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus) or to any of the excipients.
Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
- unstable angina pectoris, symptomatic congestive heart failure (NYHA II, III, IV), myocardial infarction ≤ 6 months prior to first study drug, serious uncontrolled cardiac arrhythmia, cerebrovascular accidents ≤ 6 months before study drug start
- severely impaired lung function as defined as spirometry and DLCO that is ≤ 50% of the normal predicted value and/or O2 saturation that is 88% or less at rest on room air
- poorly controlled diabetes as defined by fasting serum glucose >2.0 x ULN
- any active (acute or chronic) or uncontrolled infection/disorders that impair the ability to evaluate the patient or for the patient to complete the study
- nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by this study drug, such as severe hypertension that is not controlled with medical management and thyroid abnormalities whose thyroid function cannot be maintained in the normal range by medication
- liver disease such as cirrhosis or decompensated liver disease.
Patients who have a history of another primary malignancy ≤ 3 years, with the exception of non-melanoma skin cancer and carcinoma in situ of uterine cervix.
Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. If barrier contraceptives are being used, these must be continued throughout the trial by both sexes.
Patients who are using other investigational agents or who had received investigational drugs ≤ 4 weeks prior to study drug start.
Patients unwilling to or unable to comply with the protocol.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Everolimus	Everolimus	Participants who received Everolimus 10 mg (two 5 mg tablets), daily for 12 months
Placebo	Everolimus Placebo	Participants who received Everolimus placebo 10 mg (two 5 mg tablets), daily for 12 months

Primary Outcome Measures

Name	Time	Method
Disease-free Survival (DFS)	From date of randomization to the date of event defined as the first documented recurrence of the disease, or death due to any cause and up to 6 years	DFS was defined as the time from date of randomization to the date of event defined as the first documented relapse of the disease or death due to any cause. Relapse was based on investigator assessment and was assigned only if: It was documented according to Cheson guidelines by an objective radiological assessment method; It was documented by a biopsy proven lymphoma including new or recurrent bone marrow involvement; A new anticancer therapy for lymphoma started with subsequent confirmation of the relapse within 4 weeks of the start of this anticancer therapy

Secondary Outcome Measures

Name	Time	Method
Overall Survival (OS)	From date of randomization to date of death due to any cause up to around 7 years	OS was defined as the time from date of randomization to date of death due to any cause. If the patient was not known to have died, survival was censored at the date of the last contact.
Lymphoma-specific Survival (LSS)	From randomization to death documented as a result of lymphoma up to 7 years	LSS was defined as time from randomization to death as a result of lymphoma.

Trial Locations

Locations (35): Medical University of South Carolina -Hollings Cancer Center MUSC/HCC (2)
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Charleston, South Carolina, United States
Ironwood Cancer and Research Centers SC
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Chandler, Arizona, United States
Levine Cancer Institute Oncology
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Charlotte, North Carolina, United States
Rocky Mountain Cancer Centers RMCC
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Greenwood Village, Colorado, United States
Indiana University Hospital IU Cancer Center
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Indianapolis, Indiana, United States
Lahey Clinic Dept of Lahey Clinic (3)
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Burlington, Massachusetts, United States
Rush University Medical Center Div. of Hematology & Oncology
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Chicago, Illinois, United States
Baylor College of Medicine Dept.of Baylor College of Med.
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Houston, Texas, United States
University of Vermont Office of Clinical Trials Res.
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Burlington, Vermont, United States
Waukesha Memorial Hospital Cancer Center Dept.ofWaukeshaMemorialHosp.
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Waukesha, Wisconsin, United States
Highlands Oncology Group Dept of Highlands Oncology Grp
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Fayetteville, Arkansas, United States
University Cancer Institute
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Boynton Beach, Florida, United States
University Cancer & Blood Center, LLC
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Athens, Georgia, United States
Columbus Regional
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Columbus, Georgia, United States
Tulane University Health Sciences Center Office of Clinical Research
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New Orleans, Louisiana, United States
University of Texas/MD Anderson Cancer Center Dept of MD Anderson (18)
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Houston, Texas, United States
Dean Health System
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Madison, Wisconsin, United States
Novartis Investigative Site
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Caracas, Distrito Capital, Venezuela
University of Pittsburgh Medical Center SC-3
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Pittsburgh, Pennsylvania, United States
Mayo Clinic - Rochester Dept. of MayoClinic-Rochester
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Rochester, Minnesota, United States
Denver Health & Hospital Authority CACZ885M2301
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Denver, Colorado, United States
University of California San Diego - Moores Cancer Center Dept of Moores Cancer Ctr (3)
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La Jolla, California, United States
Dartmouth Hitchcock Medical Center Dartmouth
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Lebanon, New Hampshire, United States
Blue Ridge Research Center at Roanoke Neurological Center SC
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Roanoke, Virginia, United States
Washington University School of Medicine Div. of Medical Oncology
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Saint Louis, Missouri, United States
University of Tennessee Cancer Institute SC-2
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Memphis, Tennessee, United States
USC/Kenneth Norris Comprehensive Cancer Center Dept.ofNorrisMedicalCenter(4)
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Los Angeles, California, United States
The West Clinic
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Memphis, Tennessee, United States
The Center for Cancer and Blood Disorders Dept. of The Ctr for C & BD
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Fort Worth, Texas, United States
University of Colorado Health
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Colorado Springs, Colorado, United States
Wake Forest University Baptist Medical Center Dept. of WFUHS
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Winston-Salem, North Carolina, United States
Cancer Centers of the Carolinas Cancer Centers of Carolinas (3
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Greenville, South Carolina, United States
Texas A&M HealthSciencesCtr-Scott & White Memorial Hospital CenterForCancerPrevention&Care
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Temple, Texas, United States
South Texas Oncology and Hematology, PA South Texas Oncology (2)
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San Antonio, Texas, United States
University of Virginia Health Systems SC-2
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Charlottesville, Virginia, United States