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