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

Primary Purpose

Chronic Lymphocytic Leukemia, Stage 0 Chronic Lymphocytic Leukemia, Stage I Chronic Lymphocytic Leukemia

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Cyclophosphamide

Laboratory Biomarker Analysis

Ofatumumab

Pentostatin

About this trial

This is an interventional treatment trial for Chronic Lymphocytic Leukemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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.)
  - 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

Exclusion Criteria:

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
- 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

Sites / Locations

Mayo Clinic in Arizona
Mayo Clinic in Florida
Mayo Clinic
Duke University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Arm A (PCO, closed to accrual as of 8/23/2011)

Arm B (PCO with ofatumumab consolidation)

Arm Description

Patients 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.

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.

Outcomes

Primary Outcome Measures

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.

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.

Secondary Outcome Measures

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

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.

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.

Full Information

NCT ID

NCT01024010

First Posted

December 1, 2009

Last Updated

August 20, 2018

Sponsor

Mayo Clinic

Collaborators

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT01024010

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2017

Overall Recruitment Status

Completed

Study Start Date

March 2010 (Actual)

Primary Completion Date

May 2013 (Actual)

Study Completion Date

September 28, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Mayo Clinic

Collaborators

National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief 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. 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.

Detailed Description

PRIMARY OBJECTIVES: I. 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: I. 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. V. 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: I. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Chronic Lymphocytic Leukemia, Stage 0 Chronic Lymphocytic Leukemia, Stage I Chronic Lymphocytic Leukemia, Stage I Small Lymphocytic Lymphoma, Stage II Chronic Lymphocytic Leukemia, Stage II Small Lymphocytic Lymphoma, Stage III Chronic Lymphocytic Leukemia, Stage III Small Lymphocytic Lymphoma, Stage IV Chronic Lymphocytic Leukemia, Stage IV Small Lymphocytic Lymphoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

82 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm A (PCO, closed to accrual as of 8/23/2011)

Arm Type

Experimental

Arm Description

Arm Title

Arm B (PCO with ofatumumab consolidation)

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide

Other Intervention Name(s)

(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719

Intervention Description

Given IV

Intervention Type

Other

Intervention Name(s)

Laboratory Biomarker Analysis

Intervention Description

Correlative studies

Intervention Type

Biological

Intervention Name(s)

Ofatumumab

Other Intervention Name(s)

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

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

Pentostatin

Other Intervention Name(s)

(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, Covidarabine, DCF, Deoxycoformycin, Nipent, PD-81565, Pentostatine

Intervention Description

Given IV

Primary Outcome Measure Information:

Title

Arm A: Percentage of Complete Responses

Description

Time Frame

7 months

Title

Arm B: Treatment-free Survival at 18 Months

Description

Time Frame

18 months

Secondary Outcome Measure Information:

Title

Overall Response Rate

Description

Time Frame

14 months

Title

Depth of Response After Ofatumumab Consolidation

Description

Time Frame

14 months

Title

Treatment-free Survival

Description

Time Frame

up to 5 years from registration

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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.) 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 Exclusion Criteria: 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 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Tait Shanafelt

Organizational Affiliation

Mayo Clinic

Official's Role

Principal Investigator

Facility Information:

Facility Name

Mayo Clinic in Arizona

City

Scottsdale

State/Province

Arizona

ZIP/Postal Code

85259

Country

United States

Facility Name

Mayo Clinic in Florida

City

Jacksonville

State/Province

Florida

ZIP/Postal Code

32224-9980

Country

United States

Facility Name

Mayo Clinic

City

Rochester

State/Province

Minnesota

ZIP/Postal Code

55905

Country

United States

Facility Name

Duke University Medical Center

City

Durham

State/Province

North Carolina

ZIP/Postal Code

27710

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

27570087

Citation

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.

Results Reference

derived

PubMed Identifier

24431228

Citation

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.

Results Reference

derived

Learn more about this trial

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

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