Rituximab, Cladribine, and Temsirolimus in Treating Patients With Newly Diagnosed Mantle Cell Lymphoma

PRIMARY OBJECTIVES:

I. To assess the efficacy and safety of the combination of rituximab, cladribine, and
temsirolimus for newly diagnosed mantle cell lymphoma.

II. To determine the maximum tolerated dose (MTD) of temsirolimus combined with a fixed dose
and schedule of rituximab and cladribine. (Phase I) III. To assess the efficacy of the
combination of rituximab, cladribine, and temsirolimus for newly diagnosed mantle cell
lymphoma with the proportion of complete responses as the primary endpoint. (Phase II)

SECONDARY OBJECTIVES:

I. To assess other measures of efficacy of the regimen including progression free survival,
duration of response, and overall survival.

II. To assess the toxicity profile of the combination of rituximab, cladribine, and
temsirolimus.

III. To assess efficacy using traditional lymphoma parameters and absolute lymphocyte count.

IV. To assess metabolic markers (hyperglycemia, hyperlipidemia) as markers of mammalian
target of rapamycin (mTOR) inhibition using the glucose and lipid measurements being
performed in the clinical laboratory as part of routine care.

V. To correlate response with serum free light chains, single nucleotide polymorphisms (SNPs)
in host immune genes, vitamin D metabolites, and phosphatidylinositide 3-kinase (PI3K)
pathway member expression.

VI. As part of ongoing research for North Central Cancer Treatment Group (NCCTG) lymphoma
studies, paraffin-embedded tissue blocks/slides and blood products will be banked for future
studies.

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

Patients receive rituximab intravenously (IV) on day 1 and cladribine IV over 2 hours on days
1-5. Patients then receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Patients
also receive filgrastim subcutaneously (SC) on days 6-15 or pegfilgrastim SC on day 6.
Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 4 months for 3 years.

Inclusion Criteria:

- Histologically confirmed mantle cell lymphoma (MCL); the diagnosis must be confirmed
by NCCTG pre-registration pathology review by Dr. Paul Kurtin or his designate; it is
recommended that the biopsy be an excisional biopsy, but adequate core-needle biopsies
will be accepted as long as they are considered adequate for registration by Dr.
Kurtin or his designate; the tumor must be cyclin D-1 positive by immunohistochemistry
or have evidence of a t(11;14) translocation by fluorescence based in situ
hybridization (FISH) or cytogenetics

- Measurable or assessable disease, defined as at least one of the following:

- A lymph node or tumor mass that is >= 2.0 cm in at least one dimension by
positron emission tomography (PET)/computed tomography (CT), CT, magnetic
resonance imaging (MRI), or plain radiograph imaging

- Splenic enlargement may be used as a measurable parameter if the spleen is
palpable >= 3 cm below the left costal margin

- Diffuse infiltration of an organ such as the stomach, bone marrow, peripheral
blood, liver, lungs, or bowel by lymphoma without a discrete mass would
constitute assessable, but not measurable, disease

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, 2, or 3

- Life expectancy >= 12 weeks

- Absolute neutrophil count (ANC) >= 1,500/mm³

- Platelet count (PLT) >= 100,000/mm³

- Serum creatinine =< 2.0 mg/dL

- Serum total bilirubin (or direct bilirubin if total is abnormal) =< institutional
upper limit of normal (ULN) with or without secondary liver involvement

- Serum glutamic oxaloacetic transaminase (SGOT) =< 3 x institutional ULN (exception: if
there is liver involvement, SGOT must be =< 5 x institutional ULN)

- Negative pregnancy test done =< 7 days prior to registration, for women of
childbearing potential only

- Willingness to return to NCCTG enrolling institution for follow-up

- Willingness to provide the blood specimens as required by the protocol

- Willingness to provide tissue specimens as required by the protocol

- Willing to return to NCCTG enrolling institution for follow-up

- Willing to provide blood and tissue specimens as required by the protocol

- Willing to abstain from eating grapefruit or drinking grapefruit juice

- Willingness to abstain from eating grapefruit or drinking grapefruit juice for the
duration of the study

Exclusion Criteria

- Any prior therapy for mantle cell non-Hodgkin lymphoma including radiation therapy;
exception: patient may have undergone a splenectomy for diagnosis, cytopenia, or
systematic splenomegaly

- Active or uncontrolled infection

- Any of the following cardiac conditions:

- Uncontrolled high blood pressure

- Unstable angina

- Active congestive heart failure

- Myocardial infarction =< 6 months

- Serious uncontrolled cardiac arrhythmia

- Known central nervous system (CNS) involvement

- Any of the following:

- Pregnant women or women of reproductive ability who are unwilling to use
effective contraception while taking the drug and for 12 months after stopping
treatment

- Nursing women

- Men who are unwilling to use a condom (even if they have undergone a prior
vasectomy) while having intercourse with any woman, while taking the drug and for
12 months after stopping treatment

- Medical or psychiatric conditions which, in the opinion of the investigator, make the
patient a poor risk for participation

- Known to be human immunodeficiency virus (HIV) positive; HIV testing is not required
but should be done if clinically indicated; HIV-positive patients receiving
combination anti-retroviral therapy are excluded from the study

- Concurrent malignancy =< 5 years ago; exceptions: carcinoma in situ of the cervix,
resected basal cell or squamous cell carcinomas of the skin, or prostate cancer that
is in remission following a radical retropubic prostatectomy or radiation therapy; if
there is a history of prior malignancy, they must not be receiving other specific
treatment (other than hormonal therapy) for their cancer

- Known hypersensitivity to rituximab or its components, or to murine proteins

- Receiving any other investigational agent which would be considered as a treatment for
the primary neoplasm

- Prior treatment with an mTOR inhibitor

- Autologous or allogeneic stem cell transplant planned as part of initial therapy

- Receiving enzyme-inducing antiepileptic drugs (enzyme inducing anti-epileptic drugs
[EIAEDs]; e.g., phenytoin, fosphenytoin, carbamazepine, oxcarbazepine, phenobarbital,
or primidone); any other potent cytochrome P450, family 3, subfamily A, polypeptide 4
(CYP3A4) inducer such as rifampin, glucocorticoids at greater than adrenal replacement
levels, or St. John's wort; or receiving strong CYP3A4 inhibitors * Note: if these
agents are discontinued, temsirolimus therapy can begin >= 7 days after
discontinuation of such agent