Ensayos clínicos

Inclusion Criteria

CLL/SLL patients only

• Diagnosis of CLL according to the National Cancer Institute (NCI) criteria or SLL according to the World Health Organization (WHO) criteria
• This includes previous documentation of biopsy-proven small lymphocytic lymphoma or
• Diagnosis of CLL according to NCI working group criteria as evidenced by all of the following:
  • Peripheral blood B cell count of > 5 x 10^9/L consisting of small to moderate size lymphocytes;
  • Immunophenotyping consistent with CLL defined as:
    • The predominant population of lymphocytes share both B-cell antigens;
    • Clonality as evidenced by kappa (κ) or lambda (λ) light chain expression  or other genetic method;
    • 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 fluorescent in situ hybridization (FISH) analysis  on peripheral blood or tissue biopsy or negative immunohistochemical stains for cyclin D1 on involved tissue biopsy.
• Patients must be previously treated with at least one prior line of therapy.
• Prior chemotherapy or biologic novel therapy or anti-cancer 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 or EGCG, found in green tea or other herbal treatments) will not be considered "prior treatment";
  • Prior oral corticosteroid therapy for an indication other than CLL will not be considered "prior treatment."
• Previous use of corticosteroids in the combination with other therapy for treatment of autoimmune complications of CLL does constitute prior therapy for CLL.
• Have progressive disease with any one of the following characteristics based on standard criteria for treatment as defined by the NCI-Working Group (WG) 1996.
• Symptomatic CLL characterized by any one of the following:
  • Weight loss ≥ 10% within the previous 6 months;
  • Extreme fatigue attributed to CLL;
  • Fevers ≥ 100.5*F for 2 weeks without evidence of infection;
  • Drenching night sweats without evidence of infection.
• Evidence of progressive bone marrow failure with hemoglobin ≤ 11 g/dL or platelet count ≤ 100 x 10^9/L.
• Symptomatic or progressive lymphadenopathy, splenomegaly, or hepatomegaly:
  • 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.

Low Grade B-NHL patients only

• Histologically confirmed relapsed (response to last treatment ≥ 6 months duration) or refractory (no response to last treatment or response duration < 6 months) indolent/low grade B cell NHL:
  • If patient has received previous anti-PD-1 or anti-PDL-1 consult with study chair.
• Follicular lymphoma, grades 1, 2 and 3.
• Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type.
• Splenic and nodal marginal zone lymphoma.
• Lymphoplasmacytic lymphoma including Waldenstrom macroglobulinemia.
• Measurable disease (at least 1 lesion of ≥ 1.5 cm in diameter) as detected by computed tomography (CT) or the CT images of the positron emission tomography (PET)/CT:
  • Patients with Waldenstrom macroglobulinemia are not required to have measurable disease by CT or PET/CT if monoclonal protein is detectable by serum protein electrophoresis and/or immunoglobulin M (IgM) level is at least 2 times upper limit of normal.

All patients

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
• Creatinine ≤ 1.5 X upper limit of normal (ULN) OR creatinine clearance ≥ 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN.
• Platelet count ≥ 25 x 10^9/L.
• Absolute neutrophil count ≥ 0.5 X 10^9/L.
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) unless due to Gilbert's disease:
  • If total bilirubin is > 1.5 x ULN, a direct bilirubin should be performed and must be ≤ upper limit of normal.
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 X ULN.
• Negative pregnancy test done ≤ 7 days prior to registration, for women of childbearing potential only.
• Provide informed written consent.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
• Willing to provide bone marrow and blood samples for correlative research purposes.
• Must have failed or be unable to tolerate or refused other available Food and Drug Administration (FDA) approved effective therapies:
  • Patients should not have other treatment options considered curative.

Exclusion Criteria:

• Currently participating in or has participated in a study of an investigational agent or using an investigational device ≤ 28 days prior to registration.
• Receiving systemic steroid therapy or any other form of systemic immunosuppressive therapy ≤ 7 days prior to registration.  Exceptions:
  • Low doses of steroids (≤ 20 mg of prednisone or equivalent dose of other steroid/day) used for treatment of non-hematologic medical conditions;
  • Previous use of corticosteroids is allowed;
  • After initiation of MK-3475 therapy, steroid can be used for management of potential immune mediated adverse events  for less than 8 weeks of therapy;
  • Topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption) are permitted.
• Prior anti-cancer monoclonal antibody < 28 days prior to registration or who has not recovered (i.e., ≤ grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Prior chemotherapy or radiation therapy ≤ 14 days prior to registration or who has not recovered (i.e., ≤ grade 1 or at baseline) from adverse events due to a previously administered agent:
  • Subjects with ≤ grade 2 neuropathy are an exception to this criterion and may qualify for the study;
  • If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Known additional malignancy that is progressing or requires active treatment.  Exceptions:
  • Richter's transformation or Hodgkin's transformation of the CLL are permitted;
  • In situ cervical cancer that has undergone or will undergo potentially curative therapy;
  • Basal cell carcinoma, squamous cell carcinoma, melanoma of the skin that has undergone or will undergo potentially curative therapy.
• Active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease/syndrome difficult to control in the past.  Exceptions:
  • Conditions not expected to recur in the absence of an external trigger are permitted to enroll;
  • Patients with psoriasis not requiring systemic treatment are permitted for participation;
  • Patients who have a positive Coombs test but no evidence of hemolysis are permitted for participation;
  • Subjects with hypothyroidism stable on hormone replacement, diabetes or Sjogren's syndrome are permitted for the study;
  • Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study;
  • Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule.
• Evidence of interstitial lung disease or active, non-infectious pneumonitis.
• Active infection requiring systemic therapy:
  • When the infection is controlled, patients are permitted for this study.
• Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Any of the following:
  • Pregnant women;
  • Nursing women;
  • Men or women of childbearing potential who are unwilling to employ adequate contraception starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
• Known to be human immunodeficiency virus (HIV) positive.
• Known active hepatitis B or hepatitis C:
  • Patients with a positive hepatitis B core antibody but with negative hepatitis B DNA may participate, but must have hepatitis serologies and hepatitis B DNA monitored periodically by the treating physician;
  • Intravenous immunoglobulin (IVIG) can cause a false positive hepatitis B serology. If patients receiving routine IVIG have core antibody or surface antigen positivity without evidence of active viremia (negative hepatitis B DNA) they may still participate in the study, but should have hepatitis serologies and hepatitis B DNA monitored periodically by the treating physician.
• Received a live vaccine ≤ 30 days prior to registration.
• New York Heart Association classification III or IV cardiovascular disease or recent myocardial infarction or unstable angina pectoris or cardiac arrhythmia (< 30 days).
• Active central nervous system (CNS) lymphoma or cerebrospinal fluid involvement with malignant lymphoma cells that requires therapy.
• Has a clinically significant coagulopathy per investigator's assessment.
• Has received an allogeneic stem cell transplant.