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Mantle Cell Lymphoma

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COURSES 1, 3, and 5 (O-HyperCVAD): Patients receive ofatumumab IV on day 1, cyclophosphamide IV over 2 hours every 12 hours for 6 doses on days 3-5, doxorubicin hydrochloride IV continuously over 72 hours on days 6-8, vincristine sulfate IV on days 6 and 13, and dexamethasone IV or PO on days 3-6 and 13-16.

COURSES 2, 4, and 6 (O-HD-MA): Patients receive ofatumumab IV on day 1, methotrexate IV continuously over 24 hours on day 3, and cytarabine IV over 2 hours every 12 hours on days 4-5.

All courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Eligible patients then undergo standard HDC-ASCT.

Autologous Hematopoietic Stem Cell Transplantation

Doxorubicin Hydrochloride

Laboratory Biomarker Analysis

Vincristine Sulfate

Francisco Hernandez-ILizaliturri

This phase II trial studies how well ofatumumab in combination with cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and dexamethasone alternating with ofatumumab in combination with cytarabine and methotrexate works in treating patients with newly diagnosed mantle cell lymphoma (MCL). Monoclonal antibodies, such as ofatumumab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, dexamethasone, cytarabine, and methotrexate, 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. Giving ofatumumab together with alternating regimens of combination chemotherapy may kill more cancer cells.

PRIMARY OBJECTIVES:

I. To determine the overall response rate (ORR), and in particular, the complete remission rate (CRR) in previously untreated MCL treated with ofatumumab in combination with aggressive chemo-immunotherapy.

SECONDARY OBJECTIVES:

I. To determine the high sensitivity flow cytometry (HSFCM) complete remission rate (HSFCM-CRR) in previously untreated MCL treated with ofatumumab in combination with aggressive chemo-immunotherapy +/- high dose chemotherapy and autologous stem cell transplant (HDC-ASCT).

II. To determine the time-to-progression (TTP), progression-free survival (PFS) and overall survival (OS) of patients with previously untreated MCL treated with ofatumumab and aggressive chemoimmunotherapy +/- HDC-ASCT.

III. To determine the toxicity profiles of ofatumumab in combination with high dose cytarabine chemoimmunotherapy +/- HDC-ASCT.

IV. To correlate minimal residual disease (MRD) at different time intervals with TTP, PFS, and OS.

V. To correlate surface cluster of differentiation (CD)20 levels, Ki67, and additional cytogenetic abnormalities in pretreatment tumor biopsies with respect to ORR, CRR, TTP, PFS, or OS.

VI. To determine the relationship between proliferation signature and clinical outcome using quantitative real-time reverse-transcriptase polymerase chain reaction (RT-PCR).

VII. To determine changes in surface CD20 levels, Ki67, or gain of additional cytogenetic abnormalities in relapsed/refractory tumor specimens.

VIII. To correlate serum component (C)3, C4, and hemolytic complement (CH)50 levels measured at baseline and at the end of first ofatumumab infusion with ORR, CRR, median response rate (MRR), TTP, PFS and OS.

IX. Evaluate the ability of the induction and consolidation therapy to get 70% of patients to autologous stem cell transplantation.

X. Evaluate the tolerability and CD34+ cell yield following therapy with patient and hyper-fractionated cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and dexamethasone (HyperCVAD)/high-dose cytarabine and methotrexate (HD-MA).

XI. To compare differences in response rate in patients with MCL treated with ofatumumab + HyperCVAD/HD-MA according Cheson and Modified Cheson Criteria.

OUTLINE:

COURSES 1, 3, and 5 (O-HyperCVAD): Patients receive ofatumumab intravenously (IV) on day 1, cyclophosphamide IV over 2 hours every 12 hours for 6 doses on days 3-5, doxorubicin hydrochloride IV continuously over 72 hours on days 6-8, vincristine sulfate IV on days 6 and 13, and dexamethasone IV or orally (PO) on days 3-6 and 13-16.

COURSES 2, 4, and 6 (O-HD-MA): Patients receive ofatumumab IV on day 1, methotrexate IV continuously over 24 hours on day 3, and cytarabine IV over 2 hours every 12 hours on days 4-5.

Treatment repeats every 21 days for 6\* courses in the absence of disease progression or unacceptable toxicity.

Eligible patients then undergo standard high dose chemotherapy and autologous stem cell transplant (HDC-ASCT). Patients achieving a high sensitivity flow cytometry complete remission (HSFCM-CR) after 2 courses may proceed to HDC-ASCT after completing 4 courses of treatment.

After completion of study treatment, patients are followed up every 4 months for 2 years, every 6 months for 3 years, and then as clinically instructed.

Ofatumumab in Combination With Cyclophosphamide, Doxorubicin Hydrochloride, Vincristine Sulfate, and Dexamethasone Alternating With Ofatumumab in Combination With Cytarabine and Methotrexate in Treating Patients With Newly Diagnosed Mantle Cell Lymphoma

Ofatumumab (O) in Combination With Chemotherapy: Hyper-Fractionated Cyclophosphamide, Doxorubicin, Vincristine and Dexamethasone (O-HyperCVAD) Alternating With Ofatumumab High-Dose Cytarabine and Methotrexate (O-MA) for Patients With Newly Diagnosed Mantle Cell Lymphoma

Evaluated according to the International Working Group Response criteria as reported by Cheson et al. and the revised Cheson criteria.

Complete response is defined as complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. Typically FDG-avid lymphoma: in patients with PET scan positive before therapy, a posttreatment residual mass of any size is permitted as long as it is PET negative. Variably FDG-avid lymphomas/FDG avidity unknown: in patients with a negative pretreatment PET scan, all lymph nodes and nodal masses must have regressed on CT to normal size (1.5 cm in their greatest transverse diameter for nodes 1.5 cm before therapy). Previously involved nodes that were 1.1 cm to 1.5 cm in their long axis and more than 1)

Estimated using simple relative frequencies. The corresponding 95% confidence intervals will be computed using the method proposed in Clopper and Pearson.

Mean change from baseline in Percentage of Cells Positive for Ki67 by patient response.

Median serum C20 MFI (mean fluorescence intensity)

Evaluated using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Minimal residual disease (MRD) in peripheral blood samples at baseline.

Minimal residual disease (MRD) in and bone marrow biopsy/aspiration samples at baseline.

Estimated distributions obtained using the Kaplan-Meier method. Estimates of quantities such as median survival will be obtained. Corresponding confidence intervals using the methodology of Brookmeyer and Crowley will be computed.

Relationship between proliferation signature and clinical outcome will be compared using the log-rank test. Cox proportional hazards model regression will be utilized for multivariate analyses.

Established when all CR criteria are met and negative flow cytometry examination of peripheral blood and bone marrow biopsy/aspiration collected at baseline, before courses 3 and 5, within 3 weeks after course 6, on day 100 (if HDC-ASCT eligible), and then every 6 months for 3 years.

Estimated percentage of patients that progressed at 3 years. Time to Progression distributions obtained using the Kaplan-Meier method. Corresponding confidence intervals using the methodology of Brookmeyer and Crowley will be computed.

National Comprehensive Cancer Network

Roswell Park Cancer Institute

COURSES 1, 3, and 5 (O-HyperCVAD): Patients receive ofatumumab IV on day 1, cyclophosphamide IV over 2 hours every 12 hours for 6 doses on days 3-5, doxorubicin hydrochloride IV continuously over 72 hours on days 6-8, vincristine sulfate IV on days 6 and 13, and dexamethasone IV or PO on days 3-6 and 13-16.

COURSES 2, 4, and 6 (O-HD-MA): Patients receive ofatumumab IV on day 1, methotrexate IV continuously over 24 hours on day 3, and cytarabine IV over 2 hours every 12 hours on days 4-5.

All courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Eligible patients then undergo standard HDC-ASCT.

Autologous Hematopoietic Stem Cell Transplantation: Undergo autologous HDC-ASCT

Cyclophosphamide: Given IV

Cytarabine: Given IV

Dexamethasone: Given IV or PO

Doxorubicin Hydrochloride: Given IV

Laboratory Biomarker Analysis: Correlative studies

Methotrexate: Given IV

Ofatumumab: Given IV

Vincristine Sulfate: Given IV

Treatment (Monoclonal Antibody and Combination Chemotherapy)

Age, Categorical

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Samples were not viable for some of the outcomes the due to inadequate tissue.

Senior Administrator, Compliance - Clinical Research Services

Proportion of Patients Experiencing a Complete Response

Percentage of Participants With Autologous Stem Cell Transplantation

Not CR

All treated and eligible patients that had samples taken after baseline

Change From Baseline in Percentage of Cells Positive for Ki67

Median of Serum Complement CD20 Levels

Number of Participants With at Least One Serious Adverse Event

All treated and eligible patients with available samples

Minimal Residual Disease (MRD) in Peripheral Blood Samples

Minimal Residual Disease (MRD) in Bone Marrow Biopsy/Aspiration Samples

Median Overall Survival (OS)

Median Progression-free Survival (PFS)

Samples were not viable due to inadequate tissue.

Proliferation Signature Using Quantitative Real-time RT-PCR

Proportion of Patients Who Experience Complete Remission as Assessed by HSFCM

Time-to-tumor Progression (TTP) at 3 Years

Overall Study

Rituximab

Lenograstim

Sirolimus

Cladribine

Temsirolimus

MTOR Inhibitors

Antineoplastic Agents, Immunological

Protein Kinase Inhibitors

Clotrimazole

Miconazole

Antifungal Agents

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.

rituximab

cladribine

temsirolimus

Filgrastim

Pegfilgrastim

David J. Inwards, MD

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.

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.

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

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

National Cancer Institute (NCI)

Alliance for Clinical Trials in Oncology

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Ofatumumab in Combination With Cyclophosphamide, Doxorubicin Hydrochloride, Vincristine Sulfate, and Dexamethasone Alternating With Ofatumumab in Combination With Cytarabine and Methotrexate in Treating Patients With Newly Diagnosed Mantle Cell Lymphoma	NCT01527149	Stage I Mantle ... Stage II Contig... Stage II Non-Co... Stage III Mantl... Stage IV Mantle...	Autologous Hema... Cyclophosphamid... Cytarabine Dexamethasone Doxorubicin Hyd... Laboratory Biom... Methotrexate Ofatumumab Vincristine Sul...	18 Years - 70 Years	Roswell Park Cancer Institute
Ofatumumab in Combination With Cyclophosphamide, Doxorubicin Hydrochloride, Vincristine Sulfate, and Dexamethasone Alternating With Ofatumumab in Combination With Cytarabine and Methotrexate in Treating Patients With Newly Diagnosed Mantle Cell Lymphoma	NCT01527149	Stage I Mantle ... Stage II Contig... Stage II Non-Co... Stage III Mantl... Stage IV Mantle...	Autologous Hema... Cyclophosphamid... Cytarabine Dexamethasone Doxorubicin Hyd... Laboratory Biom... Methotrexate Ofatumumab Vincristine Sul...	18 Years - 70 Years	Roswell Park Cancer Institute
Rituximab, Cladribine, and Temsirolimus in Treating Patients With Newly Diagnosed Mantle Cell Lymphoma	NCT00787969	Lymphoma	rituximab cladribine temsirolimus Filgrastim Pegfilgrastim	18 Years -	Alliance for Clinical Trials in Oncology
Rituximab, Cladribine, and Temsirolimus in Treating Patients With Newly Diagnosed Mantle Cell Lymphoma	NCT00787969	Lymphoma	rituximab cladribine temsirolimus Filgrastim Pegfilgrastim	18 Years -	Alliance for Clinical Trials in Oncology

Spots Global Cancer Trial Database for stage ii contiguous mantle cell lymphoma