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AzTrials

Stage I Mantle Cell LymphomaPhase 2NCT01527149

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

A Phase 2 study testing Autologous Hematopoietic Stem Cell Transplantation, Cyclophosphamide and Cytarabine in people with Stage I Mantle Cell Lymphoma and Stage II Contiguous Mantle Cell Lymphoma, run by Roswell Park Cancer Institute at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

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). Read more about this study

Who is it for?
Ages 18 to 70 years
What is being tested?
Autologous Hematopoietic Stem Cell Transplantation, Cyclophosphamide and Cytarabine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
37 participants
Where
2 sitesUnited States
Study dates
6 Dec 2011to 11 Jan 2024
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 70 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Histologically documented mantle cell lymphoma with co-expression of CD20 and CD5 and lack of CD23 expression by immunophenotyping and at least one of the following confirmatory tests: 1) positive immunostaining for cyclin D1; 2) the presence of t(11;14) on cytogenetic analysis; OR 3) molecular evidence of B-cell leukemia/lymphoma 1 (bcl-1)/immunoglobulin heavy locus (IgH) rearrangement
  • Cases that are CD5-negative and/or CD23-positive will be eligible provided that the histopathology is consistent with mantle cell lymphoma AND positive for cyclin D1, t(11;14), or bcl-1/IgH rearrangement
  • A tissue block or unstained slides (10 - 20 slides) will be submitted to the Roswell Park Cancer Institute (RPCI) Pathology Department for central pathology review
  • A diagnosis based on peripheral blood or bone marrow aspirate is allowed; if the diagnosis is based only on blood, in addition to the immunophenotype and molecular confirmation above, a peripheral blood smear must be available for central pathology review; if the diagnosis is based on a bone marrow, the bone marrow core biopsy or aspirate clot tissue block will be submitted to the RPCI Pathology Department: if the tissue block is not available please submit the diagnostic smears for review
  • Extent of disease: stage I - IV; patients with nodular histology mantle cell lymphoma must have Ann Arbor stage III or IV disease to be eligible
  • Patients with mantle zone type histology will not be eligible
Show all 36Show fewer
  • Patients with other mantle cell histologies are eligible regardless of stage
  • Measurable or assessable disease is required; measurable tumor size (at least one node measuring 2.25 cm^2 in bidimensional measurement)
  • No active central nervous system (CNS) disease defined as symptomatic meningeal lymphoma or known CNS parenchymal lymphoma; a lumbar puncture demonstrating mantle cell lymphoma at the time of registration to this study is not an exclusion for study enrollment
  • Patients must be previously untreated
  • No prior radiation therapy for mantle cell lymphoma
  • >= 2 weeks since major surgery
  • No known hypersensitivity to murine products
  • No medical condition requiring chronic use of high dose systemic corticosteroids (i.e., doses of prednisone higher than 10 mg/day or equivalent)
  • No human immunodeficiency virus (HIV) infection; patients with a history of intravenous drug abuse or any behavior associated with an increased risk of HIV infection should be tested for exposure to the HIV virus; patients who test positive or who are known to be infected are not eligible; an HIV test is not required for entry on this protocol, but is required if the patient is perceived to be at risk
  • Non-pregnant and non-nursing; women and men of reproductive potential should agree to use an effective means of birth control
  • Patients who test positive for hepatitis C antibody (Ab) are eligible provided all of the following criteria are met: 1) total bilirubin =< 2 x upper limit of normal; 2) AND aspartate aminotransferase (AST) =< 3 x upper limit of normal; AND 3) liver biopsy (pathology) demonstrates =< grade 2 fibrosis and no cirrhosis
  • Specific guidelines will be followed regarding inclusion of MCL based on hepatitis B serological testing as follows:
  • Hepatitis B surface antigen (HBsAg) negative, hepatitis B core antibody (HBcAb) negative, hepatitis B surface antibody (HBsAb) positive MCL patients are eligible
  • Patients who test positive for HBsAg are ineligible (regardless of other hepatitis B serologies)
  • For MCL patients with HBsAg negative, but HBcAb positive (regardless of HBsAb status), should have hepatitis B virus (HBV) deoxyribonucleic acid (DNA) testing done and protocol eligibility determined as follows:
  • If HBV DNA is positive the subject is excluded
  • If HBV DNA is negative, patient may be included but must undergo at least every 2 months HBV DNA polymerase chain reaction (PCR) testing from the start of treatment throughout the duration the study
  • Monitoring during the study is required at least every 2 months and during follow-up at a minimum of every 2-3 months up to 6 months after the last dose
  • Prophylactic antiviral therapy with lamivudine (3TC) or investigator's preferred antiviral regimen throughout protocol therapy and for 6-12 months thereafter may be initiated at the discretion of the investigator
  • If the patients' HBV DNA becomes positive during the study, the investigator should manage the clinical situation as per the standard of care of participating institution; the investigator should weigh the risks and benefits of continuing ofatumumab or discontinuing ofatumumab before appropriate treatment decisions are made for that individual patient
  • Patients must not have a history of cardiac disease, defined as New York Heart Association class II or greater or clinical evidence of congestive heart failure (CHF)
  • No known hypersensitivity to ofatumumab, humanized antibodies or chemotherapy agents throughout the protocol
  • Left ventricular ejection fraction (LVEF) by multi gated acquisition scan (MUGA) or echocardiogram (ECHO) >= 45%
  • Neutrophils > 1000/uL
  • Platelets >= 75,000/uL (unless significant bone marrow involvement with MCL)
  • Creatinine =< 2.0 mg/dL
  • Total bilirubin =< 2.0 mg/dL (unless MCL related or attributable to Gilbert's disease)
  • Urine or serum beta-human chorionic gonadotropin (HCG) or serum HCG = negative (if female patient of childbearing potential)
  • Patient or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure
  • Consult with a physician experience in care and management of subjects with hepatitis B to manage/treat subjects who are anti-hepatitis B core antibody (HBc) positive

Who cannot join

  • Prior history of HIV-positivity (routine HIV testing is not required pre-treatment)
  • Positive serology for hepatitis B (HB) defined as a positive test for HBsAg; in addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a hepatitis B DNA test will be performed and if positive the patient will be excluded
  • Serious non-malignant disease (e.g., active uncontrolled bacterial, viral, or fungal infections) or other medical conditions (including psychiatric) which, in the opinion of the Principal Investigator (PI) would compromise other protocol objectives
  • Presence of symptomatic CNS lymphoma
  • Pregnant or lactating females
  • Prior history of radiation or chemotherapy for MCL
Show all 14Show fewer
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to ofatumumab or other agents used in study
  • Patients with a "currently active" second malignancy, other than non-melanoma skin cancer or in situ carcinoma of the cervix or breast; patients are not considered to have a "currently active" malignancy if they have completed anti-cancer therapy, are considered by their physician to be at less than 30% risk of relapse and at least 2-5 years have lapsed
  • Major surgery, other than diagnostic surgery, within 2 weeks
  • Patients with non-Hodgkin lymphoma (NHL) other than MCL
  • Patients must not have a history of cardiac disease, defined as New York Heart Association class II or greater or clinical evidence of congestive heart failure; all patients must have a MUGA scan or 2-dimensional (D) echocardiogram indicating an ejection fraction of >= 45% within 42 days prior to registration; the method used at baseline must be used for later monitoring
  • Unwilling or unable to follow protocol requirements
  • Any condition which in the Investigator's opinion deems the patient an unsuitable candidate to receive study drug
  • Received an investigational agent within 30 days prior to enrollment

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • Roswell Park Cancer Institute

    Buffalo, New York, 14263

  • Vanderbilt University/Ingram Cancer Center

    Nashville, Tennessee, 37232

Other trials in United States

About this study

Official title: 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

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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:

  1. 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.

  1. 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.

  1. 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.

Being tested
Autologous Hematopoietic Stem Cell Transplantation, Cyclophosphamide, Cytarabine, Dexamethasone, Doxorubicin Hydrochloride
Medical subject headings
Lymphoma, Mantle-Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Autologous Hematopoietic Stem Cell TransplantationProcedure or surgery

    Also called Autologous Stem Cell Transplantation

    Undergo autologous HDC-ASCT

  • CyclophosphamideDrug

    Also called (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida

    Given IV

  • CytarabineDrug

    Also called .beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine

    Given IV

  • DexamethasoneDrug

    Also called Aacidexam, Adexone, Aknichthol Dexa, Alba-Dex

    Given IV or PO

  • Doxorubicin HydrochlorideDrug

    Also called 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI), ADM, Adriacin, Adriamycin

    Given IV

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • MethotrexateDrug

    Also called Abitrexate, Alpha-Methopterin, Amethopterin, Brimexate

    Given IV

  • OfatumumabBiological

    Also called Arzerra, GSK1841157, HuMax-CD20, HuMax-CD20, 2F2

    Given IV

  • Vincristine SulfateDrug

    Also called Kyocristine, Leurocristine Sulfate, Leurocristine, sulfate, Oncovin

    Given IV

Study groups in NCT01527149
Study groupRoleWhat they receive
Treatment (monoclonal antibody and combination chemotherapy)ExperimentalCOURSES 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.
Receives: Procedure: Autologous Hematopoietic Stem Cell Transplantation; Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Dexamethasone; Drug: Doxorubicin Hydrochloride; Other: Laboratory Biomarker Analysis; Drug: Methotrexate; Biological: Ofatumumab; Drug: Vincristine Sulfate

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Proportion of Patients Experiencing a Complete Response

    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)

    Measured: 22 weeks

Secondary outcomes (11)

  1. Percentage of Participants With Autologous Stem Cell Transplantation

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

    Measured: Up to 6 weeks after the last dose of ofatumumab-chemotherapy, an average of 4 month

  2. Change From Baseline in Percentage of Cells Positive for Ki67

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

    Measured: Baseline and up to 3 years

  3. Median of Serum Complement CD20 Levels

    Median serum C20 MFI (mean fluorescence intensity)

    Measured: Baseline

  4. Number of Participants With at Least One Serious Adverse Event

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

    Measured: Up to 3 years

  5. Minimal Residual Disease (MRD) in Peripheral Blood Samples

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

    Measured: Up to 3 years

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

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

    Measured: Up to 3 years

  7. Median Overall Survival (OS)

    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.

    Measured: From baseline through study completion, an average of 5 years

  8. Median Progression-free Survival (PFS)

    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.

    Measured: From baseline through study completion, an average of 5 years

  9. Proliferation Signature Using Quantitative Real-time RT-PCR

    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.

    Measured: Baseline

  10. Proportion of Patients Who Experience Complete Remission as Assessed by HSFCM

    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.

    Measured: Up to 3 years

  11. Time-to-tumor Progression (TTP) at 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.

    Measured: From baseline until objective tumor progression, as assessed up to 3 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Feb 2012 (estimated)
  2. Study start6 Dec 2011
  3. Primary completion26 Apr 2018
  4. Study completion11 Jan 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
37 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01527149
Sponsor's protocol ID
I 201611
Other IDs
NCI-2011-03562, I 201611
Status last verified
Feb 2024
First submitted
12 Dec 2011
Last updated
7 Feb 2024
Data monitoring committee
Yes

Publications

  • Torka P, Akhtar OS, Reddy NM, Baysal BE, Kader A, Groman A, Nichols J, Mavis C, Tario JD, Block AW, Sait SNJ, Ghione P, Sundaram S, Przespolewski ER, Mohr A, Lund I, Kostrewa J, McWhite K, DeMarco J, Johnson M, Darrall A, Thomas-Talley RN, Wallace PK, Neppalli V, Hutson A, Hernandez-Ilizaliturri FJ. Ofatumumab plus HyperCVAD/HD-MA induction leads to high rates of minimal residual disease negativity in patients with newly diagnosed mantle cell lymphoma: Results of a phase 2 study. Cancer. 2022 Apr 15;128(8):1595-1604. doi: 10.1002/cncr.34106. Epub 2022 Feb 14.

    PubMed 35157306

  • Barth MJ, Mavis C, Czuczman MS, Hernandez-Ilizaliturri FJ. Ofatumumab Exhibits Enhanced In Vitro and In Vivo Activity Compared to Rituximab in Preclinical Models of Mantle Cell Lymphoma. Clin Cancer Res. 2015 Oct 1;21(19):4391-7. doi: 10.1158/1078-0432.CCR-15-0056. Epub 2015 May 11.

    PubMed 25964296

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Autologous Hematopoietic Stem Cell Transplantation, Cyclophosphamide and Cytarabine in people with Stage I Mantle Cell Lymphoma and Stage II Contiguous Mantle Cell Lymphoma, run by Roswell Park Cancer Institute at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 36 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 7 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 23 Jun 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Proportion of Patients Experiencing a Complete Response (time frame: 22 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01527149, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Feb 2024.

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