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Ofatumumab and Dinaciclib in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or B-Cell Prolymphocytic Leukemia

Primary Purpose

Chronic Lymphocytic Leukemia, Prolymphocytic Leukemia, Recurrent Small Lymphocytic Lymphoma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Dinaciclib
Laboratory Biomarker Analysis
Ofatumumab
Pharmacological Study
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

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:

  • Patients must have histologically confirmed B-cell chronic lymphocytic leukemia (B-CLL)/small lymphocytic lymphoma (SLL) or a B-cell prolymphocytic leukemia (B-PLL) according to 2008 World Health Organization (WHO) diagnostic criteria
  • Patients must meet one or more of the following modified indications for treatment as described in the 2008 International Workshop on chronic lymphocytic leukemia (CLL) (IWCLL) guidelines for the diagnosis and treatment of CLL:

    • Progressive disease or marked splenomegaly and/or lymphadenopathy or disease requiring de-bulking for future allogeneic transplantation
    • Anemia (hemoglobin < 11 mg/dL) or thrombocytopenia (platelets < 100,000/μL)
    • Unexplained weight loss exceeding 10% of body weight over the preceding 6 months
    • Cancer Therapy Evaluation Program (CTEP) active version of the Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or 3 fatigue
    • Fevers > 100.5 º F or night sweats for greater than 2 weeks without evidence of infection
    • Progressive lymphocytosis, with an increase exceeding 50% over a 2-month period or a doubling time of less than 6 months
    • Need for cytoreduction prior to allogeneic stem cell transplant
  • Patients must have received at least one prior therapy that includes either fludarabine or equivalent nucleoside analogue, or an alternative regimen if there was a contraindication (i.e. autoimmune hemolytic anemia) or patient elected not to receive fludarabine
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Life expectancy >= 12 weeks
  • Absolute neutrophil count >= 1,000/μL in absence of bone marrow involvement
  • Platelets >= 30,000/μL in absence of bone marrow involvement
  • Total bilirubin =< 1.5 X institutional upper limit of normal (ULN) unless secondary to Gilbert's
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal (ULN) unless due to infiltration of the liver
  • Creatinine =< 2.0 mg/dL OR creatinine clearance >= 50 mL/min/1.73 m^2 for patients(Cockcroft-Gault estimated)
  • Patients with a history of current/previous infection with hepatitis B virus will be eligible if receiving appropriate antiviral prophylaxis
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier; corticosteroids alone will not be considered prior therapy, but must be discontinued at least 24 hours prior to the first day of therapy unless continued for indications other than the primary malignancy
  • Patients who are receiving any other investigational agents
  • Patients who have received prior treatment with dinaciclib will not be eligible; patients previously treated with ofatumumab will be eligible as long as their disease responded to previous treatment (defined as achieving at least stable disease by consensus criteria) and did not subsequently progress < 3 months from completing treatment
  • Patients with known brain metastases should be excluded from this clinical trial
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition as dinaciclib
  • History of anaphylactic reaction to rituximab or other anti-cluster of differentiation (CD)20 monoclonal antibody
  • Because dinaciclib is metabolized by the cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) liver enzyme, the eligibility of patients taking medications that are potent inducers or inhibitors of that enzyme will be determined following a review of their case by the principal investigator; every effort should be made to switch patients taking such agents or substances to other medications; any identified agent needs to be stopped at least 2 weeks prior to study registration; use of aprepitant will be permitted, however, based on drug-drug interaction study performed by the manufacturer showing no effect on dinaciclib pharmacokinetics (PK)
  • Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency are excluded
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant and/or breast-feeding women are excluded from this study; breastfeeding should be discontinued if the mother is treated with dinaciclib
  • Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject is considered by his or her physician to have a 2 year survival expectation
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible

Sites / Locations

  • Ohio State University Comprehensive Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (ofatumumab, dinaciclib)

Arm Description

Patients receive ofatumumab IV over 4-6 hours on days 1, 8, 15, and 22 of courses 1-2, and on day 1 of courses 4-7. Beginning on course 2, patients also receive dinaciclib IV over 2 hours on days 2, 8, and 15 of course 2, and on days 1, 8, and 15 of courses 3-7. Treatment repeats every 28 days for up to 7 courses in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Maximum-tolerated Dose of Dinaciclib When Given in Combination With Ofatumumab, Defined as a Dose Level Where at Most One of 6 Evaluable Patients Has a Dose Limiting Toxicity (Phase Ia)
Graded according to the National Cancer Institute (NCI) CTCAE version (v)4.0. Assessed using the continuous variables as the outcome measures (primarily nadir and percent change from baseline values) as well as categorization.
Number of Patients With Dose-limiting Toxicity Incidents Graded According to the NCI CTCAE v4.0 (Phase I)
Hematologic dose-limiting toxicity measures will be assessed using the continuous variables as the outcome measures (primarily nadir and percent change from baseline values) as well as categorization via CTCAE version 4 standard toxicity grading. Non-hematologic dose-limiting toxicities such as dyspnea and renal will be evaluated via the ordinal CTCAE standard toxicity grading only.
Percentage of Patients Who Achieve an Overall Response, Defined as Achieving a Complete Response, an Unconfirmed Complete Response (SLL Only), or a Partial Response (Phase II)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Secondary Outcome Measures

Complete Response Rate
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions
Overall Survival
Distributions will be explored and assessed using the methods of Kaplan and Meier.
Progression Free Survival
95% confidence intervals will be constructed using the methods of Duffy and Santner with the assumption that these rates are binomially distributed. Distributions will be explored and assessed using the methods of Kaplan and Meier.
Time to Treatment Failure
Distributions will be explored and assessed using the methods of Kaplan and Meier.

Full Information

First Posted
January 16, 2012
Last Updated
February 15, 2018
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT01515176
Brief Title
Ofatumumab and Dinaciclib in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or B-Cell Prolymphocytic Leukemia
Official Title
Phase 1b/2 Study of Dinaciclib (SCH 727965) and Ofatumumab in Relapsed and Refractory CLL/SLL/B-PLL
Study Type
Interventional

2. Study Status

Record Verification Date
February 2018
Overall Recruitment Status
Completed
Study Start Date
January 2012 (Actual)
Primary Completion Date
March 4, 2015 (Actual)
Study Completion Date
July 19, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase I/II trial studies the side effects and the best dose of ofatumumab and dinaciclib and to see how well they work in treating patients with relapsed or refractory chronic lymphocytic leukemia, small lymphocytic lymphoma, or B-cell prolymphocytic leukemia. Monoclonal antibodies, such as ofatumumab, can find cancer cells and help kill them. Dinaciclib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving ofatumumab together with dinaciclib may kill more cancer cells.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the tolerable dose of combination therapy with ofatumumab and dinaciclib (phase 1b component) in chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), and B-cell prolymphocytic leukemia (B-PLL). II. To characterize the toxicity of combination therapy with ofatumumab and dinaciclib in CLL/SLL/B-PLL. III. To determine the overall response rate associated with this treatment as assessed by consensus response criteria. (Phase II) SECONDARY OBJECTIVES: I. To estimate progression-free survival (PFS) after combination treatment with ofatumumab and dinaciclib. II. To characterize the pharmacokinetics of dinaciclib when given in combination with ofatumumab. III. To correlate pharmacokinetic features of dinaciclib with response, toxicity (particularly tumor lysis syndrome), and pharmacodynamic endpoints. IV. To perform detailed baseline and serial pharmacodynamic studies of combination therapy with ofatumumab and dinaciclib and correlate these with response to therapy. V. To correlate baseline disease-risk parameters (i.e., zeta-chain-associated protein kinase [ZAP]-70 expression, interphase cytogenetics, immunoglobulin heavy chain variable region [IgVH] mutational analysis, and other clinical prognostic factors) with response to therapy. OUTLINE: This is a phase I, dose-escalation study followed by a phase II study. Patients receive ofatumumab intravenously (IV) over 4-6 hours on days 1, 8, 15, and 22 of courses 1-2, and on day 1 of courses 4-7. Beginning on course 2, patients also receive dinaciclib IV over 2 hours on days 2, 8, and 15 of course 2, and on days 1, 8, and 15 of courses 3-7. Treatment repeats every 28 days for up to 7 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 6 months for up to 3 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Lymphocytic Leukemia, Prolymphocytic Leukemia, Recurrent Small Lymphocytic Lymphoma, Refractory Chronic Lymphocytic Leukemia

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
36 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (ofatumumab, dinaciclib)
Arm Type
Experimental
Arm Description
Patients receive ofatumumab IV over 4-6 hours on days 1, 8, 15, and 22 of courses 1-2, and on day 1 of courses 4-7. Beginning on course 2, patients also receive dinaciclib IV over 2 hours on days 2, 8, and 15 of course 2, and on days 1, 8, and 15 of courses 3-7. Treatment repeats every 28 days for up to 7 courses in the absence of disease progression or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
Dinaciclib
Other Intervention Name(s)
CDK Inhibitor SCH 727965, MK-7965, SCH 727965
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
Other
Intervention Name(s)
Pharmacological Study
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Maximum-tolerated Dose of Dinaciclib When Given in Combination With Ofatumumab, Defined as a Dose Level Where at Most One of 6 Evaluable Patients Has a Dose Limiting Toxicity (Phase Ia)
Description
Graded according to the National Cancer Institute (NCI) CTCAE version (v)4.0. Assessed using the continuous variables as the outcome measures (primarily nadir and percent change from baseline values) as well as categorization.
Time Frame
Day 56
Title
Number of Patients With Dose-limiting Toxicity Incidents Graded According to the NCI CTCAE v4.0 (Phase I)
Description
Hematologic dose-limiting toxicity measures will be assessed using the continuous variables as the outcome measures (primarily nadir and percent change from baseline values) as well as categorization via CTCAE version 4 standard toxicity grading. Non-hematologic dose-limiting toxicities such as dyspnea and renal will be evaluated via the ordinal CTCAE standard toxicity grading only.
Time Frame
Up to day 56
Title
Percentage of Patients Who Achieve an Overall Response, Defined as Achieving a Complete Response, an Unconfirmed Complete Response (SLL Only), or a Partial Response (Phase II)
Description
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame
Up to 28 weeks
Secondary Outcome Measure Information:
Title
Complete Response Rate
Description
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions
Time Frame
Up to 28 weeks
Title
Overall Survival
Description
Distributions will be explored and assessed using the methods of Kaplan and Meier.
Time Frame
Time from study entry to death due to any cause, assessed up to 5 years
Title
Progression Free Survival
Description
95% confidence intervals will be constructed using the methods of Duffy and Santner with the assumption that these rates are binomially distributed. Distributions will be explored and assessed using the methods of Kaplan and Meier.
Time Frame
Time from study entry to documentation of disease progression and/or death, assessed up to 5 years
Title
Time to Treatment Failure
Description
Distributions will be explored and assessed using the methods of Kaplan and Meier.
Time Frame
Time from study entry to the date patients end treatment, up to 28 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must have histologically confirmed B-cell chronic lymphocytic leukemia (B-CLL)/small lymphocytic lymphoma (SLL) or a B-cell prolymphocytic leukemia (B-PLL) according to 2008 World Health Organization (WHO) diagnostic criteria Patients must meet one or more of the following modified indications for treatment as described in the 2008 International Workshop on chronic lymphocytic leukemia (CLL) (IWCLL) guidelines for the diagnosis and treatment of CLL: Progressive disease or marked splenomegaly and/or lymphadenopathy or disease requiring de-bulking for future allogeneic transplantation Anemia (hemoglobin < 11 mg/dL) or thrombocytopenia (platelets < 100,000/μL) Unexplained weight loss exceeding 10% of body weight over the preceding 6 months Cancer Therapy Evaluation Program (CTEP) active version of the Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or 3 fatigue Fevers > 100.5 º F or night sweats for greater than 2 weeks without evidence of infection Progressive lymphocytosis, with an increase exceeding 50% over a 2-month period or a doubling time of less than 6 months Need for cytoreduction prior to allogeneic stem cell transplant Patients must have received at least one prior therapy that includes either fludarabine or equivalent nucleoside analogue, or an alternative regimen if there was a contraindication (i.e. autoimmune hemolytic anemia) or patient elected not to receive fludarabine Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) Life expectancy >= 12 weeks Absolute neutrophil count >= 1,000/μL in absence of bone marrow involvement Platelets >= 30,000/μL in absence of bone marrow involvement Total bilirubin =< 1.5 X institutional upper limit of normal (ULN) unless secondary to Gilbert's Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal (ULN) unless due to infiltration of the liver Creatinine =< 2.0 mg/dL OR creatinine clearance >= 50 mL/min/1.73 m^2 for patients(Cockcroft-Gault estimated) Patients with a history of current/previous infection with hepatitis B virus will be eligible if receiving appropriate antiviral prophylaxis Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier; corticosteroids alone will not be considered prior therapy, but must be discontinued at least 24 hours prior to the first day of therapy unless continued for indications other than the primary malignancy Patients who are receiving any other investigational agents Patients who have received prior treatment with dinaciclib will not be eligible; patients previously treated with ofatumumab will be eligible as long as their disease responded to previous treatment (defined as achieving at least stable disease by consensus criteria) and did not subsequently progress < 3 months from completing treatment Patients with known brain metastases should be excluded from this clinical trial History of allergic reactions attributed to compounds of similar chemical or biologic composition as dinaciclib History of anaphylactic reaction to rituximab or other anti-cluster of differentiation (CD)20 monoclonal antibody Because dinaciclib is metabolized by the cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) liver enzyme, the eligibility of patients taking medications that are potent inducers or inhibitors of that enzyme will be determined following a review of their case by the principal investigator; every effort should be made to switch patients taking such agents or substances to other medications; any identified agent needs to be stopped at least 2 weeks prior to study registration; use of aprepitant will be permitted, however, based on drug-drug interaction study performed by the manufacturer showing no effect on dinaciclib pharmacokinetics (PK) Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency are excluded Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant and/or breast-feeding women are excluded from this study; breastfeeding should be discontinued if the mother is treated with dinaciclib Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject is considered by his or her physician to have a 2 year survival expectation Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kerry Rogers, MD
Organizational Affiliation
Ohio State University Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ohio State University Comprehensive Cancer Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Ofatumumab and Dinaciclib in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or B-Cell Prolymphocytic Leukemia

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