E1A10: A Randomized Phase I/II study of Bortezomib, Rituximab, Dexamethasone and Temsirolimus in Patients with Relapsed Waldenstrom's Macroglobulinemia and Relapsed/Refractory Mantle Cell Lymphoma or Follicular Lymphoma (Phase I), and Untreated/Relapsed Waldenstrom's Macroglobulinemia (Phase II)


This randomized phase i/ii trial studies the side effects and the best dose of temsirolimus when given together with bortezomib, rituximab, and dexamethasone and to see how well they work compared to bortezomib, rituximab, and dexamethasone alone in treating patients with untreated or relapsed Waldenstrom Macroglobulinemia or relapsed or refractory mantle cell or follicular lymphoma.

about 3 people will take part in the phase i and phase ii portion of this study at uT Southwestern or Parkland Health and Hospital System. This study is taking place at a number of other medical facilities around the country. Between 3 and 24 patients will take part in the phase i portion of the study. in the Phase ii portion of the study, 144 patients will be divided, with half receiving the study drug Temsirolimus plus the standard 3-drug combination and the other half will receive only the standard 3-drug combination.

Some patients will receive a 30 to 60 minute infusion (iV) of temsirolimus on days 1, 8, 15, and 22; a 30- to 60 minute infusion (iV) of rituximab on days 1, 8, 15, and 22 (of courses one and four only); an infusion (iV) of bortezomib on days 1, 8, and 15 dexamethasone by mouth on days 1, 8, and 15. Treatment may repeat every 4 weeks for up to six courses.

other patients will be randomly assigned (have an equal chance of being placed) to one of two treatment groups.

Patients in group one will receive a 30 to 60 minute infusion (iV) of rituximab on days 1, 8, 15, and 22 (of courses one and four only); an infusion (iV) of bortezomib on days 1, 8, and 15 dexamethasone by mouth on days 1, 8, and 15. Treatment may repeat every 4 weeks for up to six courses .

Patients in group two will receive a 30 to 60 minute infusion (iV) of temsirolimus on days 1, 8, 15, and 22; a 30 to 60 minute infusion (iV) of rituximab on days 1, 8, 15, and 22 (of courses one and four only); an infusion (iV) of bortezomib on days 1, 8, and 15 dexamethasone by mouth on days 1, 8, and 15. Treatment may repeat every 4 weeks for up to six courses.

Patients will complete quality of life questionnaires at baseline and periodically during study treatment.

after finishing treatment, patients will be evaluated every 3 months for the first 2 years from registration, then every 6 months for up to 5 years from registration, and then every year for up to 10 years from study entry.

Participant Eligibility

Each of the criteria in the checklist that follows must be met in order for a patient to be considered eligible for this study.

1. Histologically Proven Diagnosis

* For Phase I portion (ARM A, B, C and D), patients must have one of the following:
o Relapsed Waldenstrom[Single Quote]s macroglobulinemia as defined under section 3.1.2 of the protocol
o Relapsed/refractory follicular lymphoma; Previous treatment with at least one standard regimen and no longer responsive to that regimen.

* For Phase II portion (ARM E and F), patients must have a diagnosis of symptomatic Waldenstrom[Single Quote]s Macroglobulinemia, either untreated or relapsed, confirmed by the presence of all of the following:
o Bone marrow lymphoplasmacytosis with:
a. >= 10% lymphoplasmatic cells (measured within 28 days prior to registration).
b. aggregates or sheets of one of the following: lymphocytes, plasma cells or lymphoplasmacytic cells on the bone marrow biopsy (measured within 28 days prior to registration).

* Measurable disease defined as a quantitative IgM monoclonal protein of >= 1000 mg/dL obtained within 28 days prior to registration.

* CD20 positive bone marrow or lymph node by immunohistochemistry or flow cytometry obtained within 28 days prior to registration.

* Lymph node biopsy must be done <= 28 days prior to registration if used as an eligibility criterion for study entry.

* SPEP is required to be performed within 28 days prior to registration.

2. Additional requirements for WM patients (Phase I and II):

* In addition to measurable disease, patients must have symptomatic disease defined by one or more of the following:
o Laboratory studies defining eligibility (Hgb, platelet count, viscosity) must have been obtained within 28 days prior to registration; if more than one test was obtained, the most recent one will be utilized.
o Hemoglobin <= 11 g/dL.
o Hyperviscosity syndrome or measured viscosity level of >= 4 centipoise.

NOTE: For these patients it is strongly recommended that they undergo therapeutic plasmapheresis prior to initiation of therapy.

o Platelet count <100,000/MM3.
o Symptomatic lymphadenopathy, splenomegaly, or hepatomegaly.
o Constitutional symptoms including fever, night sweats, or unexplained weight loss (at least 10% of body weight in < 6 months).
o Symptomatic cryoglobulinemia.

* For previously treated patients, no more than 2 prior regimens are allowed and must have been completed at least 1 year since last regimen.

* Patients must not have received maintenance rituximab or any other anti-CD20 therapy as a maintenance treatment for the last 12 months.

3. Patients must not be receiving concurrent steroids > 10mg prednisone (or equivalent) per day.
4. Prior irradiation is allowed if >= 28 days prior to registration have elapsed since the date of last treatment.
5. Fasting serum cholesterol <= 300 mg/dL OR <= 7.75 mmol/L AND fasting triglycerides <= 2.5x institutional ULN, within 28 days prior to registration.
NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication. Patients cannot be enrolled if they do not meet these criteria on or off lipid lowering medication. Patients must start lipid lowering medication and cholesterol and triglycerides must be below said levels before study entry.

6. Patients must not have had prior exposure to m-TOR inhibitors (sirolimus, temsirolimus, everolimus).
7. Women must not be pregnant or breast-feeding due to the fact that the reproductive risk to humans taking temsirolimus is unknown. All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

Female ? ______ (Yes or No)
Date of blood test or urine study: ___________________

8. Women of childbearing potential and sexually active males must use an accepted and effective method of contraception throughout the study and for 8 weeks following discontinuation of everolimus.

9. Patients must have no history of prior malignancy except for adequately treated basal cell or squamous cell skin cancer or in-situ cervical cancer. The patient may also have had other cancer for which the patient was curatively treated with surgery alone and from which the patient has been disease free for >= 5 years.

10. Patients must have adequate organ function as evidenced by the following criteria. The following Lab values must be obtained <= 28 days prior to registration:

* Platelets >= 75,000mm[CUBED]

* Neutrophils >= 1,000mm[CUBED]

* SGOT (AST) and SGPT (ALT) <= 2.5x institutional ULN

* Direct bilirubin <= 1.5 mg/dL

* Serum creatinine <= 2.5 mg/dL
11. Patients must be tested for Hepatitis B surface antigen (HBsAg) and core antibody (anti-HBc) within 28 days of registration and will not be eligible if found to be positive.
12. Patients must not have any severe and/or uncontrolled medical condition or other conditions that could affect their participation in the study, including, but not restricted to:

* Symptomatic congestive heart failure of New York Heart Association Class III or IV.

* Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 3 months of start of study treatment, serious uncontrolled cardiac arrhythmia or any other clinically significant heart disease.

* Severely impaired lung function as defined as spirometry and DLCO (corrected for Hgb) that is <50% of the normal predicted value and/or O2 saturation <88% at rest on room air.

* Active (acute or chronic) or uncontrolled severe infections.

13. Patients must be >= 18 years old.

14. Patients must have ECOG performance status of <= 2.

15. Patients must not have grade 2 or higher neuropathy.

16. Patients must not have concurrent use of ACE inhibitors (angioedema), and no concurrent use of strong CYP3A4 inducers and inhibitors. (Please see Appendix VI).