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Chronic Lymphocytic LeukemiaPhase 2NCT01024010

Ofatumumab, Pentostatin, and Cyclophosphamide in Treating Patients With Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

A Phase 2 study testing Cyclophosphamide, Laboratory Biomarker Analysis and Ofatumumab in people with Chronic Lymphocytic Leukemia and Stage 0 Chronic Lymphocytic Leukemia, run by Mayo Clinic at 4 sites in United States.

Completed

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

Official record
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Trial summary

This phase II trial studies how well giving ofatumumab together with pentostatin and cyclophosphamide works in treating patients with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. Monoclonal antibodies, such as ofatumumab, can block the ability of cancer cells to grow and spread. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Cyclophosphamide, Laboratory Biomarker Analysis and Ofatumumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
82 participants
Where
4 sitesUnited States
Study dates
Mar 2010to 28 Sep 2017
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 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Diagnosis of CLL according to the National Cancer Institute (NCI) criteria or SLL according to the World Health Organization (WHO) criteria, including previous documentation of:
  • Biopsy-proven SLL
  • Diagnosis of CLL according to NCI working group criteria as evidenced by all of the following:
  • Peripheral blood lymphocyte count of > 5,000/mm^3 consisting of small to moderate size lymphocytes, with < 55% prolymphocytes
  • Immunophenotyping consistent with CLL defined as:
  • The predominant population of lymphocytes share both B-cell antigens (CD19, CD20 [typically dim expression], or CD23) as well as CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc.)
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  • Clonality as evidenced by kappa or lambda light chain expression (typically dim immunoglobulin expression)
  • Note: splenomegaly, hepatomegaly, or lymphadenopathy are not required for the diagnosis of CLL
  • Before diagnosing CLL or SLL, mantle cell lymphoma must be excluded by demonstrating a negative FISH analysis for t(11;14)(immunoglobulin heavy [IgH]/cyclin D1 [CCND1]) on peripheral blood or tissue biopsy or negative immunohistochemical stains for CCND1 on involved tissue biopsy
  • Patients must be previously untreated and meet at least one of the following indications for chemotherapy:
  • Evidence of progressive marrow failure as manifested by the development of or worsening anemia (=< 11 g/dl) and/or thrombocytopenia (=< 100,000/mm^3) not due to autoimmune disease
  • Symptomatic or progressive lymphadenopathy, splenomegaly or hepatomegaly
  • One or more of the following disease-related symptoms:
  • Weight loss > 10% within the previous 6 months
  • Extreme fatigue attributed to CLL
  • Fevers > 100.5 degree Fahrenheit for 2 weeks without evidence of infection
  • Drenching night sweats without evidence of infection
  • Progressive lymphocytosis due to CLL with an increase of > 50% over a two-month period or an anticipated doubling time of less than six months
  • Prior chemotherapy or monoclonal antibody based therapy for treatment of CLL will be considered prior therapy; nutraceutical treatments with no established benefit in CLL (such as epigallocatechin gallate [EGCG], found in green tea or other herbal treatments) will not be considered "prior treatment"
  • Marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of the above criteria for active disease are not sufficient for protocol therapy
  • Serum creatinine =< 1.5 x upper normal levels (UNL)
  • Total bilirubin =< 1.5 x UNL unless due to Gilbert's disease; if total bilirubin is > 1.5 x UNL, a direct bilirubin should be performed and must be < 1.5 mg/dL for Gilbert's to be diagnosed
  • Aspartate aminotransferase (AST) =< 3.0 x UNL and alanine aminotransferase (ALT) =< 3.0 x UNL (unless due to hemolysis or CLL)
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0, 1, or 2
  • Willingness to provide blood samples as required
  • Able to adhere to the study visit schedule and other protocol requirements

Who cannot join

  • Any of the following comorbid conditions:
  • New York Heart Association Class III or IV heart disease
  • Recent myocardial infarction (< 1 month)
  • Uncontrolled infection
  • Infection with the human immunodeficiency virus (HIV/acquired immunodeficiency syndrome [AIDS])
  • Infection with known chronic, active Hepatitis C
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  • Positive serology for hepatitis B (HB) defined as a positive test for HB surface antigen (HBsAg); in addition, if negative for HBsAg but HB core antibody (HBcAb) positive (regardless of HBsAb status), a HB deoxyribonucleic acid (DNA) test will be performed and if positive the subject will be excluded
  • Pregnant women
  • Nursing women
  • Men or women of childbearing potential who are unwilling to employ adequate contraception
  • Other active primary malignancy requiring treatment or limiting survival to =< 2 years
  • Any radiation therapy =< 4 weeks prior to registration
  • Any major surgery =< 4 weeks prior to registration
  • Current use of corticosteroids; EXCEPTION: low doses of steroids (< 10 mg of prednisone or equivalent dose of other steroid) used for treatment of non-hematologic medical conditions; Note: previous use of corticosteroids is allowed
  • Active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment; patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from participation

Trial locations and contacts

4 sites in 1 country.

United States4 sites

  • Duke University Medical Center

    Durham, North Carolina, 27710

  • Mayo Clinic in Florida

    Jacksonville, Florida, 32224-9980

  • Mayo Clinic

    Rochester, Minnesota, 55905

  • Mayo Clinic in Arizona

    Scottsdale, Arizona, 85259

Other trials in United States

About this study

Official title: Phase II Trial of Pentostatin, Cyclophosphamide, and Ofatumumab for Previously Untreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL)

This phase II trial studies how well giving ofatumumab together with pentostatin and cyclophosphamide works in treating patients with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. Monoclonal antibodies, such as ofatumumab, can block the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as pentostatin and cyclophosphamide, 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 pentostatin and cyclophosphamide may be a better way to block cancer growth.

Read the detailed description

PRIMARY OBJECTIVES:

  1. Arm A: To assess the rate of complete response using pentostatin, cyclophosphamide, and ofatumumab in patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) requiring therapy.

II. Arm B: To assess the treatment-free survival rate at 18 months using pentostatin, cyclophosphamide, and ofatumumab induction therapy followed by ofatumumab consolidation in patients with previously untreated CLL or SLL requiring therapy.

SECONDARY OBJECTIVES:

  1. Arm A and Arm B: To assess the rate of overall response in patients with previously untreated CLL or SLL requiring therapy and to determine the proportion of patients who achieve a minimal residual disease (MRD) negative state as assessed by flow cytometry in each arm independently.

II. Arm A and Arm B: To monitor and assess toxicity in patients with previously untreated CLL or SLL in each arm independently.

III. Arm A and Arm B: To determine the progression-free survival, treatment-free survival, and duration of response in each arm independently.

IV. Arm A and Arm B: To determine if molecular prognostic parameters (zeta-chain-associated protein [ZAP]-70, cluster of differentiation [CD]38, cytogenetic abnormalities identified by fluorescence in situ hybridization [FISH], immunoglobulin heavy-chain variable-region [IgVH] mutation status, etc) relate to response to therapy in each arm independently.

  1. Arm B: To assess the rate of complete response using pentostatin, cyclophosphamide, and ofatumumab induction followed by ofatumumab consolidation in patients with previously untreated CLL or SLL requiring therapy.

VI. Arm B: To evaluate whether consolidation therapy with ofatumumab after pentostatin, cyclophosphamide, and ofatumumab (PCO) induction improves the depth of response.

TERTIARY OBJECTIVES:

  1. Arm A and Arm B: To assess the complete and overall response as well as treatment free survival in each arm as compared to a historic control of patients treated with pentostatin, cyclophosphamide, and rituximab in an exploratory manner.

II. Arm A and Arm B: To assess the complete and overall response as well as treatment free survival of patients treated with PCO induction followed by ofatumumab consolidation (Arm B) as compared to patients treated with PCO induction who did not receive ofatumumab consolidation (Arm A) in an exploratory manner.

III. Arm A and Arm B: Assess the mechanisms of ofatumumab induced cell death and explore methods to enhance ofatumumab cytotoxicity.

OUTLINE: Patients are assigned to 1 of 2 treatment arms.

ARM A (closed to accrual as of 8/23/2011): Patients receive induction therapy comprising ofatumumab intravenously (IV) on day 1 (days 1-2 of course 1 only), pentostatin IV over 30 minutes on day 1, and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive induction therapy as in Arm A. Patients then receive consolidation therapy comprising ofatumumab IV on day 1. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 90 days for 1 year.

Being tested
Cyclophosphamide, Laboratory Biomarker Analysis, Ofatumumab, Pentostatin
Medical subject headings
Leukemia, Lymphocytic, Chronic, B-Cell

What participants receive

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

  • CyclophosphamideDrug

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

    Given IV

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • OfatumumabBiological

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

    Given IV

  • PentostatinDrug

    Also called (R)-3-(2-Deoxy-.beta.-D-erythro-pentofuranosyl)-3,6,7, 8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol, 2'-Deoxycoformycin, CI-825, Co-Vidarabine

    Given IV

Study groups in NCT01024010
Study groupRoleWhat they receive
Arm A (PCO, closed to accrual as of 8/23/2011)ExperimentalPatients receive induction therapy comprising ofatumumab IV on day 1 (days 1-2 of course 1 only), pentostatin IV over 30 minutes on day 1, and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
Receives: Drug: Cyclophosphamide; Other: Laboratory Biomarker Analysis; Biological: Ofatumumab; Drug: Pentostatin
Arm B (PCO with ofatumumab consolidation)ExperimentalPatients receive induction therapy as in Arm A. Patients then receive consolidation therapy comprising ofatumumab IV on day 1. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.
Receives: Drug: Cyclophosphamide; Other: Laboratory Biomarker Analysis; Biological: Ofatumumab; Drug: Pentostatin

What is being measured

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

  1. Arm A: Percentage of Complete Responses

    In Arm A: PCO, the primary endpoint of this trial is the percentage of complete responses. The NCI Working Group criteria was used to assess response to therapy:

    A Complete Response (CR) is briefly defines as the absence of lymphadenopathy, no heptomegaly nor splenomegaly, neutrophils greater than 1500/ul, platelets > 100,000/ul, hemoglobin >11.0 gm/dl, and peripheral blood lymphocytes <4000uL.

    Measured: 7 months

  2. Arm B: Treatment-free Survival at 18 Months

    The primary endpoint Arm B: PCO+O is treatment-free survival rate at 18 months. An event for treatment-free survival will be defined as initiation of subsequent therapy for CLL or death due to any cause. All patients meeting the eligibility criteria who have signed a consent form and have begun treatment will be evaluable for event-free survival at 18 months. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success proportion will be calculated.

    Measured: 18 months

Secondary outcomes (3)

  1. Overall Response Rate

    The overall response rate will be estimated by the total number of complete or partial responses (CCR, CR, CRi, nPR, or PR) divided by the total number of evaluable patients. Responses will be evaluated using NCI Working Group criteria. Minimum requirements for a Partial Response (PR) requires:

    • 50% decrease in peripheral blood lymphocyte count from the baseline
    • 50% reduction in the sum of the products of the largest measured node or nodal masses on physical examination.
    • 50% reduction in size of liver and/or spleen
    • 50% improvement in neutrophils, platelets and hemoglobin

    Measured: 14 months

  2. Depth of Response After Ofatumumab Consolidation

    The proportion of patients with an improvement in depth of response with the addition of ofatumumab consolidation after PCO induction will be estimated by the number of patients with improvement in response from the time of response evaluation at the completion of PCO to the time of response evaluation at the completion of ofatumumab consolidation divided by the total number of evaluable patients. The hierarchy for depth of response will be in the following increasing order: SD, PR, nPR, CR/CRi with MRD+, CR/CRi with MRD-. An improvement in depth of response will be defined as an improvement of at least one level in the hierarchy. Exact binomial 95% confidence intervals for the true overall improvement rate will be calculated.

    Measured: 14 months

  3. Treatment-free Survival

    Treatment-free survial is defined as the time from registration to the date of initiation of subsequent treatment for CLL or death due to any cause. The distribution of treatment-free survival will be estimated using the method of Kaplan-Meier.

    Measured: up to 5 years from registration

Timeline

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

  1. First posted2 Dec 2009 (estimated)
  2. Study startMar 2010
  3. Primary completionMay 2013
  4. Study completion28 Sep 2017

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
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
82 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01024010
Sponsor's protocol ID
MC0983
Other IDs
NCI-2009-01437, MC0983, P30CA015083
Status last verified
Sep 2017
First submitted
1 Dec 2009
Last updated
18 Sep 2018
Data monitoring committee
Yes

Publications

  • Strati P, Lanasa M, Call TG, Leis JF, Brander DM, LaPlant BR, Pettinger AM, Ding W, Parikh SA, Hanson CA, Chanan-Khan AA, Bowen DA, Conte M, Kay NE, Shanafelt TD. Ofatumumab monotherapy as a consolidation strategy in patients with previously untreated chronic lymphocytic leukaemia: a phase 2 trial. Lancet Haematol. 2016 Sep;3(9):e407-14. doi: 10.1016/S2352-3026(16)30064-3. Epub 2016 Aug 1.

    PubMed 27570087

  • Baig NA, Taylor RP, Lindorfer MA, Church AK, LaPlant BR, Pettinger AM, Shanafelt TD, Nowakowski GS, Zent CS. Induced resistance to ofatumumab-mediated cell clearance mechanisms, including complement-dependent cytotoxicity, in chronic lymphocytic leukemia. J Immunol. 2014 Feb 15;192(4):1620-9. doi: 10.4049/jimmunol.1302954. Epub 2014 Jan 15.

    PubMed 24431228

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Cyclophosphamide, Laboratory Biomarker Analysis and Ofatumumab in people with Chronic Lymphocytic Leukemia and Stage 0 Chronic Lymphocytic Leukemia, run by Mayo Clinic at 4 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 26 inclusion and 15 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 18 Sep 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 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 18 Sep 2018). 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?

Arm A: Percentage of Complete Responses (time frame: 7 months). The study lists 2 primary outcomes in all. 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 NCT01024010, 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 18 Sep 2018.

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