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Imprime PGG, Alemtuzumab, and Rituximab in Treating Patients With High Risk Chronic Lymphocytic Leukemia

Primary Purpose

B-cell Chronic Lymphocytic Leukemia, Refractory Chronic Lymphocytic Leukemia, Stage 0 Chronic Lymphocytic Leukemia

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

alemtuzumab

rituximab

PGG beta-glucan

flow cytometry

laboratory biomarker analysis

DNA analysis

fluorescence in situ hybridization

polymerase chain reaction

polymorphism analysis

mutation analysis

About this trial

This is an interventional treatment trial for B-cell Chronic Lymphocytic Leukemia focused on measuring Imprime PGG

Eligibility Criteria

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

Inclusion Criteria:

Diagnosis of CLL (Hallek, Cheson et al. 2008) manifested by: Minimum threshold peripheral lymphocyte count of 5 x 10^9/L AND immunophenotypic demonstrations of a population of B lymphocytes (as defined by CD19+) which are monoclonal (light chain exclusion); CLL will be diagnosed if these cells have >= 3 of the following characteristics: CD5+, CD23+, dim surface light chain expression, dim surface CD20 expression AND fluorescence in situ hybridization (FISH) analysis is negative for IGH/CCND1 and/or immunostaining is negative for cyclin D1 expression
>= 1 of the following poor prognosis factors: unmutated IGHV (< 2%) AND CD38 expression (>= 30% cells positive on flow cytometry); unmutated IGHV (< 2%) AND ZAP-70 expression (>= 20% cells positive on flow cytometry); use of VH3-21 gene segment irrespective of mutation status AND CD38 expression (>= 30% cells positive on flow cytometry); use of VH3-21 gene segment irrespective of mutation status AND ZAP-70 expression (>= 20% cells positive on flow cytometry); 11q22-; 17p13-
Rai classification Stage 0, I or II that does not meet standard NCI-IWCLL criteria for treatment of CLL (Hallek, Cheson et al. 2008)
Limited CLL disease burden with no lymph nodes > 5 cm in any diameter and splenomegaly < 6 cm below left costal margin in midclavicular line at rest
Creatinine =< 1.5 x upper normal limit (UNL)
Total bilirubin =< 3.0 x UNL; if total is elevated, a direct bilirubin should be performed and should be =< 1.5 x UNL
AST =< 3.0 x UNL
Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0, 1, or 2
Negative serum pregnancy test done =< 7 days prior to registration, for women of childbearing potential only
Provide informed written consent
Willing to return to a Lymphoma Specialized Program of Research Excellence (SPORE) enrolling institution for follow-up
Willing to provide blood samples for correlative research purposes

Exclusion Criteria:

Pregnant women
Nursing women
Men or women of childbearing potential who are unwilling to employ adequate contraception
New York Heart Association Class III or IV heart disease
Recent myocardial infarction (< 1 month)
Uncontrolled infection
Infection with the human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), serological evidence of active hepatitis B infection (HBsAg or HBeAg positive) or positive hepatitis C serology, as further severe immunosuppression with this regimen may occur
Evidence of active autoimmune hemolytic anemia, immune thrombocytopenia, or pure red blood cell aplasia
Other active primary malignancy requiring treatment or limits survival to =< 2 years
Any major surgery =< 4 weeks prior to registration
Any previous chemotherapy or monoclonal antibody treatment for CLL
Current use of corticosteroids; NOTE: previous corticosteroids are allowed

Sites / Locations

Mayo Clinic

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Arm I

Arm Description

Patients receive PGG beta-glucan IV over 2-4 hours on days 1, 5, 10, 17, 24, and 31; alemtuzumab subcutaneously on days 3, 4, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 31, and 33; and rituximab IV on days 10, 17, 24, and 31. Treatment continues in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Maximum Tolerated Dose (MTD) of PGG Beta Glucan in Combination With Alemtuzumab and Rituximab Assessed by Analyzing the Number of Dose-limiting Toxicity Events (Phase I)

MTD is defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of a maximum of 6 new patients). A total of 6 patients treated at the MTD will be sufficient to identify common toxicities at the MTD. Three patients will be treated at a given dose level combination for at least 5 weeks to assess toxicity. If dose-limiting toxicity (DLT) is not seen in any of the 3 patients, 3 new patients will be accrued and treated at the next higher dose level. If DLT is seen in 2 or 3 of 3 patients treated at a given dose level, then the next 3 patients will be treated at the next lower dose level, if only 3 patients were enrolled and treated at this lower dose level. We tabulate the number of patients reporting a DLT.

Proportion of Complete Responses (Dose Level 2)

The number of patients that demonstrate a Complete Response (CR) during treatment on Dose Level 2 divided by the number of eligible patients starting Dose Level 2 treatment. A CR requires all of the following for a period of at least 2 months: Absence of lymphadenopathy by physical examination, no hepatomegaly or splenomegaly, absence of constitutional symptoms, neutrophils >1500/ul, Platelets >100,000/ul, Hemoglobin >11.0 gm/dl, Peripheral blood lymphocytes <4000/uL.

Secondary Outcome Measures

Overall Response Rate (Dose Level 2)

Overall response rate was estimated by the total number of patients receiving Dose Level 2 reporting complete responses or partial responses (CR or PR) divided by the total number of evaluable patients that started Dose Level 2 treatment. A COMPLETE RESPONSE (CR) requires all of the following for a period of at least 2 months: Absence of lymphadenopathy by physical examination, no hepatomegaly or splenomegaly, absence of constitutional symptoms, neutrophils >1500/ul, Platelets >100,000/ul, Hemoglobin >11.0 gm/dl, Peripheral blood lymphocytes <4000/uL. A PARTIAL RESPONSE (PR) requires the patient exhibits at least two of the features: ≥ 50% decrease in peripheral blood lymphocyte count from baseline, ≥ 50% reduction in the sum of the products of the maximal perpendicular diameters of the largest measured node or nodal masses in the right and left cervical, axillary, and inguinal lymph node regions on physical examination.

Time to Disease Progression

Time to disease progression is defined as the time from registration to the earliest date of documentation of disease progression. If a patient dies without a documentation of disease progression, the patient will be considered to have had tumor progression at the time of their death unless there is sufficient documented evidence to conclude no progression occurred prior to death. The distribution of time to disease progression will be estimated using the method of Kaplan-Meier.

Duration of Response for All Evaluable Patients Who Have Achieved an Objective Response

Duration of response is defined for all evaluable patients who have achieved an objective response as the date at which the patient's objective status is first noted to be either a CR or PR to the earliest date progression is documented. The distribution of duration of response will be estimated using the method of Kaplan-Meier.

Time to Subsequent Therapy

Time to subsequent therapy is defined to be the time from the end of active treatment date to the date subsequent therapy is initiated. The distribution of time to subsequent therapy will be estimated using the method of Kaplan-Meier.

Number of Participants With Grade 3+ Adverse Events

Adverse events were collected at the end of each cycle according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The number of grade 3+ events at least possibly related to treatment are recorded. For a complete set of all recorded adverse events, please see the Adverse Events section of this report.

Full Information

NCT ID

NCT01269385

First Posted

December 23, 2010

Last Updated

June 11, 2020

Sponsor

Mayo Clinic

Collaborators

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT01269385

Brief Title

Imprime PGG, Alemtuzumab, and Rituximab in Treating Patients With High Risk Chronic Lymphocytic Leukemia

Official Title

Early Treatment of High Risk Chronic Lymphocytic Leukemia With Alemtuzumab, Rituximab, and PGG Beta-Glucan: A Phase I/II Trial

Study Type

Interventional

2. Study Status

Record Verification Date

August 2018

Overall Recruitment Status

Completed

Study Start Date

January 2011 (undefined)

Primary Completion Date

June 2014 (Actual)

Study Completion Date

June 2015 (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

RATIONALE: Monoclonal antibodies, such as alemtuzumab and rituximab, can kill chronic lymphocytic leukemia (CLL) cells and are effective therapies for this disease. Biological therapies, such as Imprime PGG (poly-(1-6)-beta-glucotriosyl-(1-3)-beta-glucopyranose), may stimulate the immune system in different ways and help monoclonal antibodies kill CLL cells. Giving PGG beta-glucan together with alemtuzumab and rituximab could make therapy with monoclonal antibodies, such as alemtuzumab and rituximab, more effective. PURPOSE: This phase I/II trial is studying the side effects and best dose of PGG beta-glucan when given together with alemtuzumab and rituximab and to see how well it works in treating patients with earlier stage high-risk chronic lymphocytic leukemia.

Detailed Description

PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose of PGG beta glucan in combination with alemtuzumab and rituximab. (Phase I) II. Assess the rate of complete response of patients with high-risk, early-intermediate stage CLL who are treated with alemtuzumab, rituximab, and PGG beta glucan before meeting standard National Cancer Institute-International Workshop on Chronic Lymphocytic Leukemia (NCI-IWCLL) criteria (Hallek, Cheson et al. 2008) for treatment. (Phase II) SECONDARY OBJECTIVES: I. To monitor and assess toxicity of this regimen. II. Clinical evaluation of toxicity. III. Serial monitoring of cytomegalovirus (CMV) viral load by polymerase chain reaction (PCR). IV. To assess the rate of overall response in CLL patients using this treatment regimen. V. To determine time to progression, time to next treatment, and duration of response in CLL patients using this treatment regimen. TERTIARY OBJECTIVES: I. To assess the correlation between the individual prognostic markers (17p-, 11q-, unmutated VH gene, use of VH3-21, ZAP70+, CD38+) and clinical outcome. II. To assess response to this combination regimen using an expanded definition of response, including bone marrow studies with immunohistochemical studies for residual CLL cells and sensitive flow cytometry for minimal residual disease in patients in complete clinical remission. OUTLINE: This is phase I, dose-escalation study of PGG beta-glucan followed by a phase II study. Patients receive PGG beta-glucan intravenously (IV) over 2-4 hours on days 1, 5, 10, 17, 24, and 31; alemtuzumab subcutaneously (SC) on days 3, 4, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 31, and 33; and rituximab IV on days 10, 17, 24, and 31. Treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up monthly for 3 months, every 3 months for 1 year, and then every 6 months for 5 years.

6. Conditions and Keywords

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

B-cell Chronic Lymphocytic Leukemia, Refractory Chronic Lymphocytic Leukemia, Stage 0 Chronic Lymphocytic Leukemia, Stage I Chronic Lymphocytic Leukemia, Stage II Chronic Lymphocytic Leukemia

Keywords

Imprime PGG

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

22 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm I

Arm Type

Experimental

Arm Description

Intervention Type

Biological

Intervention Name(s)

alemtuzumab

Other Intervention Name(s)

anti-CD52 monoclonal antibody, Campath-1H, MoAb CD52, Monoclonal Antibody Campath-1H, Monoclonal Antibody CD52

Intervention Description

Given subcutaneously

Intervention Type

Biological

Intervention Name(s)

rituximab

Other Intervention Name(s)

IDEC-C2B8, IDEC-C2B8 monoclonal antibody, Mabthera, MOAB IDEC-C2B8, Rituxan

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

PGG beta-glucan

Other Intervention Name(s)

Imprime PGG

Intervention Description

Given IV

Intervention Type

Other

Intervention Name(s)

flow cytometry

Intervention Description

Correlative studies

Intervention Type

Other

Intervention Name(s)

laboratory biomarker analysis

Intervention Description

Correlative studies

Intervention Type

Genetic

Intervention Name(s)

DNA analysis

Intervention Description

Correlative studies

Intervention Type

Genetic

Intervention Name(s)

fluorescence in situ hybridization

Other Intervention Name(s)

fluorescence in situ hybridization (FISH)

Intervention Description

Correlative studies

Intervention Type

Genetic

Intervention Name(s)

polymerase chain reaction

Other Intervention Name(s)

PCR

Intervention Description

Correlative studies

Intervention Type

Genetic

Intervention Name(s)

polymorphism analysis

Intervention Description

Correlative studies

Intervention Type

Genetic

Intervention Name(s)

mutation analysis

Intervention Description

Correlative studies

Primary Outcome Measure Information:

Title

Maximum Tolerated Dose (MTD) of PGG Beta Glucan in Combination With Alemtuzumab and Rituximab Assessed by Analyzing the Number of Dose-limiting Toxicity Events (Phase I)

Description

Time Frame

First cycle of treatment (35 days)

Title

Proportion of Complete Responses (Dose Level 2)

Description

Time Frame

3 months after the completion of treatment, up to 5 years

Secondary Outcome Measure Information:

Title

Overall Response Rate (Dose Level 2)

Description

Time Frame

3 months after the completion of treatment, up to 5 years

Title

Time to Disease Progression

Description

Time Frame

Up to 5 years

Title

Duration of Response for All Evaluable Patients Who Have Achieved an Objective Response

Description

Time Frame

Up to 5 years

Title

Time to Subsequent Therapy

Description

Time Frame

Up to 5 years

Title

Number of Participants With Grade 3+ Adverse Events

Description

Time Frame

up to 5 years of treatment

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Diagnosis of CLL (Hallek, Cheson et al. 2008) manifested by: Minimum threshold peripheral lymphocyte count of 5 x 10^9/L AND immunophenotypic demonstrations of a population of B lymphocytes (as defined by CD19+) which are monoclonal (light chain exclusion); CLL will be diagnosed if these cells have >= 3 of the following characteristics: CD5+, CD23+, dim surface light chain expression, dim surface CD20 expression AND fluorescence in situ hybridization (FISH) analysis is negative for IGH/CCND1 and/or immunostaining is negative for cyclin D1 expression >= 1 of the following poor prognosis factors: unmutated IGHV (< 2%) AND CD38 expression (>= 30% cells positive on flow cytometry); unmutated IGHV (< 2%) AND ZAP-70 expression (>= 20% cells positive on flow cytometry); use of VH3-21 gene segment irrespective of mutation status AND CD38 expression (>= 30% cells positive on flow cytometry); use of VH3-21 gene segment irrespective of mutation status AND ZAP-70 expression (>= 20% cells positive on flow cytometry); 11q22-; 17p13- Rai classification Stage 0, I or II that does not meet standard NCI-IWCLL criteria for treatment of CLL (Hallek, Cheson et al. 2008) Limited CLL disease burden with no lymph nodes > 5 cm in any diameter and splenomegaly < 6 cm below left costal margin in midclavicular line at rest Creatinine =< 1.5 x upper normal limit (UNL) Total bilirubin =< 3.0 x UNL; if total is elevated, a direct bilirubin should be performed and should be =< 1.5 x UNL AST =< 3.0 x UNL Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0, 1, or 2 Negative serum pregnancy test done =< 7 days prior to registration, for women of childbearing potential only Provide informed written consent Willing to return to a Lymphoma Specialized Program of Research Excellence (SPORE) enrolling institution for follow-up Willing to provide blood samples for correlative research purposes Exclusion Criteria: Pregnant women Nursing women Men or women of childbearing potential who are unwilling to employ adequate contraception New York Heart Association Class III or IV heart disease Recent myocardial infarction (< 1 month) Uncontrolled infection Infection with the human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), serological evidence of active hepatitis B infection (HBsAg or HBeAg positive) or positive hepatitis C serology, as further severe immunosuppression with this regimen may occur Evidence of active autoimmune hemolytic anemia, immune thrombocytopenia, or pure red blood cell aplasia Other active primary malignancy requiring treatment or limits survival to =< 2 years Any major surgery =< 4 weeks prior to registration Any previous chemotherapy or monoclonal antibody treatment for CLL Current use of corticosteroids; NOTE: previous corticosteroids are allowed

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Steven Ansell, M.D.

Organizational Affiliation

Mayo Clinic

Official's Role

Study Chair

Facility Information:

Facility Name

Mayo Clinic

City

Rochester

State/Province

Minnesota

ZIP/Postal Code

55905

Country

United States

12. IPD Sharing Statement

Learn more about this trial

Imprime PGG, Alemtuzumab, and Rituximab in Treating Patients With High Risk Chronic Lymphocytic Leukemia

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