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

Study Overview
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Brief Summary
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This phase I/II trial studies the side effects and best dose of temsirolimus when given together with cladribine and rituximab and to see how well it works in treating patients with newly diagnosed mantle cell lymphoma. Monoclonal antibodies, such as rituximab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as cladribine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Temsirolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving temsirolimus together with cladribine and rituximab may kill more cancer cells.

Detailed Description
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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.

Official Title
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Phase I/II Trial of Rituximab, Cladribine, and Temsirolimus (RCT) Therapy in Newly Diagnosed Mantle Cell Lymphoma (MCL)

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: rituximab
* Drug: cladribine
* Drug: temsirolimus
* Biological: Filgrastim
* Biological: Pegfilgrastim


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (rituximab, cladribine, temsirolimus)<br>Patients receive rituximab 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 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. | Biological: rituximab<br>* Give IV<br>Drug: cladribine<br>* Give IV<br>Drug: temsirolimus<br>* Give IV<br>Biological: Filgrastim<br>* Give SC<br>Biological: Pegfilgrastim<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of dose limiting toxicity incidents as per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 3.0 (Phase I) |  | 28 days | 
| Proportion of complete tumor responses defined as complete remission (CR) as the objective status (Phase II) |  | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  | up to 5 years | 
| Progression-free survival (PFS) |  | up to 5 years | 
| Time to disease progression |  | up to 5 years | 
| Duration of response, defined as date at which the patient's objective status is first noted to be either a CR or partial remission to the date progression is documented |  | Up to 5 years | 
| Survival time |  | Up to 5 years | 
| Frequency and severity of adverse events assessed by CTCAE v3.0 |  | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I mantle cell lymphoma, Stage II Contiguous Mantle Cell Lymphoma, Stage II Non-Contiguous Mantle Cell Lymphoma, Stage III Mantle Cell Lymphoma, Stage IV Mantle Cell Lymphoma