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
Condition: Diffuse Large B-cell Lymphoma
MeSH terms: Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse
Intervention: Everolimus; Everolimus Placebo
Intervention description: Everolimus was formulated as tablets of 5 mg strength, blister-packed under aluminum foil in units of 10 tablets.; Everolimus placebo was formulated as tablets of 5 mg strength, blister-packed under aluminum foil in units of 10 tablets.
Intervention MeSH terms: Everolimus
Phase: Phase 3
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 742.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Diffuse large B cell lymphoma; DLBCL; poor risk; R-IPI 3-5; adjuvant therapy; after R-CHOP or R-EPOCH; after R-CHOP; B-cell lymphoma; lymphoma; b cells; blood cancer; lymph nodes; Hodgkin's; non-Hodgkin

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
    

Eligibility criteria:

        Inclusion Criteria:

          1. 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).

          2. Patients defined as poor risk with IPI of 3, 4, or 5 at time of original diagnosis.

          3. Patients age ≥ 18 years old.

          4. 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.

          5. 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.

          6. Patients' last treatment with R-chemotherapy must be 6 to 14 weeks prior to start of
             study drug.

          7. Patients with ECOG performance status (PS) 0, 1, or 2.

          8. Patients willing to provide a portion of his/her tumor tissue from original diagnosis
             or lymph node to confirm diagnosis.

          9. 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

         10. 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.

         11. Patients who give a written informed consent obtained according to local guidelines.

         12. 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:

          1. 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.

          2. Patients receiving ongoing radiation therapy or who received radiation therapy to the
             residual tumor masses < 4 weeks from start of study drug.

          3. Patients who have previously received systemic mTOR inhibitor (sirolimus,
             temsirolimus, everolimus, etc).

          4. 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.

          5. Patients with transformed follicular lymphoma.

          6. Patients who received ibritumomab tiuxetan (Zevalin®), in order to avoid potential
             delayed kidney toxicities.

          7. Patients who had myelosuppressive chemotherapy or biologic therapy < 3 weeks from
             start of study drug.

          8. 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.

          9. Patients with active, bleeding diathesis.

         10. Patients with a known history of HIV seropositivity.

         11. Patients with known hypersensitivity to RAD001 (everolimus) or other rapamycins
             (sirolimus, temsirolimus) or to any of the excipients.

         12. 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.

         13. 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.

         14. 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.

         15. Patients who are using other investigational agents or who had received
             investigational drugs ≤ 4 weeks prior to study drug start.

         16. Patients unwilling to or unable to comply with the protocol.