Bortezomib, Rituximab, and Dexamethasone With or Without Temsirolimus in Treating Patients With Untreated or Relapsed Waldenstrom Macroglobulinemia or Relapsed or Refractory Mantle Cell or Follicular Lymphoma

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of temsirolimus in combination with
bortezomib, rituximab, dexamethasone in patients with relapsed Waldenstrom's
macroglobulinemia and relapsed/refractory mantle cell, follicular, marginal zone or small
lymphocytic lymphoma. (Phase I) II. To evaluate whether the addition of temsirolimus to the
regimen of bortezomib, rituximab, dexamethasone improves progression-free survival in
patients with previously untreated or relapsed Waldenstrom's macroglobulinemia. (Phase II)

SECONDARY OBJECTIVES:

I. To define and describe the toxicities of temsirolimus in combination with bortezomib,
rituximab, and dexamethasone. (Phase I) II. To evaluate time to progression of bortezomib,
rituximab, dexamethasone +/- temsirolimus in patients. (Phase II) III. To evaluate major and
minor response by 6 cycles of therapy of bortezomib, rituximab, dexamethasone +/-
temsirolimus. (Phase II) IV. To evaluate time to response and duration of response of
bortezomib, rituximab, dexamethasone +/- temsirolimus. (Phase II) V. To evaluate toxicity of
bortezomib, rituximab, dexamethasone +/- temsirolimus. (Phase II) VI. To evaluate time to
next therapy of bortezomib, rituximab, dexamethasone +/- temsirolimus. (Phase II) VII. To
evaluate overall survival of bortezomib, rituximab, dexamethasone +/- temsirolimus. (Phase
II) VIII. To describe treatment-related fatigue, physical and functional well-being during
and after treatment. (Phase II) IX. To compare the change in treatment related fatigue,
physical and functional well-being over 6 cycles of bortezomib, rituximab, dexamethasone +/-
temsirolimus. (Quality of Life) X. To prospectively assess health-related quality of life
longitudinally (pre-treatment to 3 year follow-up assessment) among trial participants.
(Quality of Life) XI. To describe treatment-related peripheral neuropathy associated with
bortezomib neurotoxicity. (Quality of Life)

OUTLINE: This is a phase I, dose-escalation study of temsirolimus followed by a randomized
phase II study.

PHASE I: Patients receive temsirolimus intravenously (IV) over 30-60 minutes on days 1, 8,
15, and 22; rituximab IV over 30-60 minutes on days 1, 8, 15, and 22 (of courses 1 and 4
only); and bortezomib IV or subcutaneously (SC) and dexamethasone orally (PO) on days 1, 8,
and 15. Courses repeat every 28 days for up to 6 courses in the absence of disease
progression or unacceptable toxicity.

PHASE II: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive rituximab IV over 30-60 minutes on days 1, 8, 15, and 22 (of courses
1 and 4 only) and bortezomib IV or SC and dexamethasone PO on days 1, 8, and 15. Treatment
repeats every 28 days for 6 courses in the absence of disease progression or unacceptable
toxicity.

ARM II: Patients receive temsirolimus IV over 30-60 minutes on days 1, 8, 15, and 22 and
rituximab, bortezomib, and dexamethasone as in arm I. Treatment repeats every 28 days for 6
courses in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up every 3 months for 2 years, every
6 months for 3 years, and then yearly for 5 years.

Inclusion Criteria:

- Histologically proven diagnosis

- For phase I portion (Arm A, B, C and D), patients must have of one of the following:

- Relapsed Waldenstrom's macroglobulinemia

- Relapsed/refractory mantle cell lymphoma; previous treatment with at least one
standard regimen and no longer responsive to that regimen

- Relapsed/refractory follicular lymphoma; previous treatment with at least one
standard regimen and no longer responsive to that regimen

- Relapsed/refractory marginal zone lymphoma; previous treatment with at least one
standard regimen and no longer responsive to that regimen

- Relapsed/refractory small lymphocytic 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's macroglobulinemia, either untreated or relapsed, confirmed by the
presence of all of the following:

- Bone marrow lymphoplasmacytosis with

- >= 10% lymphoplasmatic cells (measured within 28 days prior to registration)
OR

- 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 immunoglobulin M (IgM) monoclonal
protein of >= 1000 mg/dL obtained within 28 days prior to registration

- Cluster of differentiation 20 (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

- Serum protein electrophoresis (SPEP) is required to be performed within 28 days
prior to registration

- Additional requirements for Waldenstrom's macroglobulinemia (WM) patients (phase I and
II):

- In addition to measurable disease, patients must have symptomatic disease defined by
one or more of the following:

- Laboratory studies defining eligibility (hemoglobin [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

- Hemoglobin =< 11 g/dL

- 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

- Platelet count < 100,000/mm^3

- Symptomatic lymphadenopathy, splenomegaly, or hepatomegaly

- Constitutional symptoms including fever, night sweats, or unexplained weight loss
(at least 10% of body weight in < 6 months)

- Symptomatic cryoglobulinemia

- Additional requirements for WM patients (phase I):

- Patients must have received previous treatment with at least one standard regimen
and are no longer responsive to that regimen

- There must have been at least 21 days since the last regimen and patient must
have recovered from any previous treatment-related toxicity to =< grade 1

- Additional requirements for WM patients (phase II):

- For previously treated patients, no more than 4 prior regimens are allowed

- If last regimen is with rituximab there must have been at least 6 months since
last rituximab dose, and if without rituximab there must have been at least 3
months since last regimen

- For all phase I patients, there must have been at least 21 days since last regimen and
any previous non-hematologic treatment related toxicity must have resolved to =< grade
1

- Patients must not be receiving concurrent steroids > 10 mg prednisone (or equivalent)
per day

- Prior irradiation is allowed if >= 28 days prior to registration have elapsed since
the date of last treatment

- Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L AND fasting triglycerides =<
2.5 x institutional upper limit of normal (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

- Patients must not have had prior exposure to mammalian target of rapamycin (m-TOR)
inhibitors (sirolimus, temsirolimus, everolimus)

- Women must not be pregnant or breast-feeding; 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)

- 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

- 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

- Platelets >= 75,000 mm^3

- Neutrophils >= 1,000 mm^3

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and
serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x
institutional ULN

- Direct bilirubin =< 1.5 mg/dL

- Serum creatinine =< 2.5 mg/dL

- Patients must be tested for hepatitis B surface antigen (HBsAg) and hepatitis B core
antibody (anti-HBc) within 28 days of registration and will not be eligible if found
to be positive

- 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 diffusing capacity
of the lung for carbon monoxide (DLCO) (corrected for Hgb) that is < 50% of the
normal predicted value and/or oxygen (O2) saturation < 88% at rest on room air

- Active (acute or chronic) or uncontrolled severe infections

- Patients must have Eastern Cooperative Oncology Group (ECOG)-American College of
Radiology Imaging Network (ACRIN) performance status of =< 2

- Patients must not have grade 2 or higher neuropathy

- Patients must not have concurrent use of angiotensin-converting enzyme (ACE)
inhibitors (angioedema), and no concurrent use of strong cytochrome P450, family 3,
subfamily A, polypeptide 4 (CYP3A4) inducers and inhibitors