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Umbralisib for the Treatment of Treatment Naive Chronic Lymphocytic Leukemia

Trial Status: Active

This phase II trial studies how well umbralisib works in treating patients with chronic lymphocytic leukemia that has not been previously treated (treatment naive). Umbralisib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Inclusion Criteria

  • Have a diagnosis of B-cell CLL that has not been previously treated and now warrants treatment consistent with accepted International Workshop Group on CLL (iwCLL) criteria (Hallek 2018) for initiation of therapy. Any one of the following conditions constitute CLL that warrants treatment: * Evidence of progressive marrow failure as manifested by the onset or worsening of anemia and/or thrombocytopenia, or * Massive (i.e., lower edge of spleen >= 6 cm below the left costal margin), progressive, or symptomatic splenomegaly, or * Massive (i.e., >= 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy, or * Progressive lymphocytosis in the absence of infection, with an increase in blood absolute lymphocyte count (ALC) > 50% over a 2-month period or lymphocyte doubling time of < 6 months (as long as initial ALC was >= 30,000/uL), or * Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy, or * Symptomatic or functional extranodal involvement (e.g. skin, kidney, lung, or spine), or * Constitutional symptoms, defined as any one or more of the following disease-related symptoms or signs occurring in the absence of evidence of infection: ** Unintentional weight loss of ≥10% within the previous 6 months, or ** Significant fatigue (>= grade 2), or ** Fevers > 100.5°F or 38.0°C for >= 2 weeks, or ** Night sweats for > 1 month
  • Absolute neutrophil count (ANC) >= 1,000/mm^3 (ANC >= 500/mm^3 permitted if known marrow involvement) Growth factors are permitted at any time during the study, but not to meet eligibility criteria
  • Platelet count >= 30,000/mm^3, (platelet count >= 20,000/mm^3 permitted if known marrow involvement). Growth factors are permitted at any time during the study, but not to meet eligibility criteria
  • Total bilirubin =<1.5 times the upper limit of normal (ULN) (unless diagnosed with Gilbert’s syndrome)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN if no liver involvement or =< 5 x the ULN if known liver involvement
  • Calculated creatinine clearance > 30 mL/min (as calculated by the Cockcroft-Gault or Modification of Diet in Renal Disease (MDRD) formula, 24 hour urine creatinine [Cr] clearance also acceptable)
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Ability to swallow and retain oral medication
  • Female patients who are not of child-bearing potential and female patients of child-bearing potential who have a negative serum pregnancy test within 3 days prior to cycle 1, day 1. Female patients of child-bearing potential and all male partners, and male patients must consent to use a medically acceptable method of contraception throughout the study period and for 30 days after the last dose of study drug
  • Willingness and ability to comply with trial and follow-up procedures, and give written informed consent

Exclusion Criteria

  • Has ever received any form of treatment for CLL
  • Corticosteroid therapy of prednisone > 10 mg or equivalent started at least 7 days prior to cycle 1, day 1 is prohibited. Prednisone =< 10 mg daily or equivalent is allowed as clinically warranted. Topical or inhaled corticosteroids are permitted
  • Prior treatment with umbralisib
  • Prior treatment with autologous hematologic stem cell transplant or prior allogeneic hematologic stem cell transplant is excluded.
  • Evidence of chronic active hepatitis B (HBV, not including patients with prior hepatitis B vaccination; or positive serum hepatitis B antibody) or chronic active hepatitis C infection (HCV), active cytomegalovirus (CMV), or known history of human immunodeficiency virus (HIV). If hepatitis B core (HBc) antibody is positive the subject must be evaluated for the presence of HBV deoxyribonucleic acid (DNA) by polymerase chain reaction (PCR). If HCV antibody is positive, the subject must be evaluated for the presence of HCV ribonucleic acid (RNA) by PCR. If the subject is CMV IgG or CMV IgM positive, the subject must be evaluated for the presence of CMV DNA by PCR. Subjects with positive HBc antibody and negative HBV DNA by PCR are eligible. Subjects with positive HCV antibody and negative HCV RNA by PCR are eligible. Subjects who are CMV IgG or CMV IgM positive but who are CMV DNA negative by PCR are eligible. Antiviral prophylaxis should be considered per institutional protocol
  • Known histological transformation from CLL to an aggressive lymphoma (i.e. Richter’s transformation / Hodgkin lymphoma)
  • Evidence of ongoing systemic bacterial, fungal or viral infection, except localized fungal infection of skin/nails * NOTE: Subjects may be receiving prophylactic antiviral or antibacterial therapies at investigator discretion. Use of anti-pneumocystis and antiviral prophylaxis is required
  • Inflammatory bowel disease (such as Crohn’s disease or ulcerative colitis)
  • Malabsorption syndromes
  • Irritable bowel syndrome with greater than 3 loose stools per day as a baseline
  • Any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as: * Symptomatic, or history of documented congestive heart failure (New York [NY] Heart Association functional classification III-IV) * Myocardial infarction within 6 months of enrollment * Concomitant use of medication known to cause QT prolongation or torsades de pointes should be used with caution and at investigator discretion * Angina not well-controlled by medication * Poorly controlled or clinically significant atherosclerotic vascular disease including cerebrovascular accident (CVA), transient ischemic attack (TIA), symptomatic peripheral arterial disease, angioplasty, cardiac/vascular stenting within 6 months of enrollment
  • Malignancy, including myelodysplastic syndromes, within 3 years of study enrollment except for adequately treated basal, squamous cell carcinoma or non-melanomatous skin cancer, carcinoma in situ of the cervix, superficial bladder cancer not treated with intravesical chemotherapy or Bacillus calmette guerin (BCG) within 6 months, localized prostate cancer and prostate specific antigen (PSA) < 1.0 mg/dL on 2 consecutive measurements at least 3 months apart with the most recent one being within 4 weeks of study entry
  • Women who are pregnant or lactating
  • Subjects requiring immediate cytoreductive therapy


Moffitt Cancer Center
Status: ACTIVE
Contact: Javier Pinilla-Ibarz
Phone: 813-745-4748


I. To evaluate the overall response rate (complete response [CR] + partial response [PR]).


I. To determine the progression free survival of umbralisib in patients with chronic lymphocytic leukemia (CLL).

II. To assess safety of umbralisib, tolerability and other efficacy outcomes.

III. To determine the pharmacokinetics and pharmacodynamics of umbralisib.


I. Alterations in T lymphocyte function, including changes in:

Ia. TH1:TH2 polarization, and Treg:TH17 distributions.

Ib. Markers of T cell exhaustion and/or inhibition.

Ic. Alterations in distribution of naive vs. memory.

Id. Cellular activation and cell-mediated cytotoxic capacity.

II. Alterations in B lymphocyte function, including changes in:

IIa. Change in the B cell receptor repertoire, perhaps clonal evolution.

IIb. Quantitative serum immunoglobulin levels and subtyping.

IIc. Fc-receptor (FcR) expression patterns.

III. Alterations in global systemic cytokine patterns: Includes interferon (IFN)-gamma, TNF-alpha, IL-2, IL-4, IL-10, IL-6, IL-17A, allowing discrimination between TH1, TH2, TH17 and Treg profiles.

IV. Alteration in the Myeloid cells, function, including changes in:

IVa-Antigen presentation capacity (functional assay).

IVb-Alterations in the distribution of M1 versus (vs) M2 & N1 vs N2.

V. Pharmacodynamics analysis, including phosphorylated (p)AKT changes in:

Va. T cell compartment.

Vb. B cell compartment.


Patients receive umbralisib orally (PO) once daily (QD) on days 1-28. Cycle repeats every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are every 3-6 months up to 24 months.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Moffitt Cancer Center

Principal Investigator
Javier Pinilla-Ibarz

  • Primary ID MCC-19585
  • Secondary IDs NCI-2019-07955
  • ID NCT04163718