Pembrolizumab and Umbralisib in Treating Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia and B-Cell Non-Hodgkin Lymphoma
- Must have histologically confirmed diagnosis of one of the following: * Relapsed or refractory diffuse large B cell lymphoma (DLBCL) who have failed or are not candidates for autologous stem cell transplant * Indolent B cell non-Hodgkin lymphoma who have had at least 2 prior lines of therapy * CLL/SLL who have failed, have contraindications to, or are intolerant to a BTK inhibitor (eg, ibrutinib or acalabrutinib) * CLL/SLL with 17p deletion who have failed, have contraindications to, or are intolerant to a BTK inhibitor (eg, ibrutinib or acalabrutinib) and ventoclax.
- Be willing and able to provide written informed consent for the trial
- Have measurable disease based on standard criteria: * For DLBCL: Lugano criteria. * For indolent non-Hodgkin lymphoma (NHL): Lugano criteria or International Workshops on Waldenström macroglobulinemia (IWWM). * For CLL/SLL: iwCLL.
- Have had at least 1 prior line of standard therapy or 2 prior lines for indolent B cell NHL.
- For patients with Richter’s transformation, one prior line of therapy for either CLL or Richter’s transformation (RT) is required
- Be willing to provide tissue from a bone marrow biopsy if suspected involvement and/or lymph node at enrollment.
- Be willing to repeat bone marrow biopsy (if involved at diagnosis) after 3 cycles of therapy and at the time of progression and/or completion of therapy whichever comes first.
- Have a performance status of 0-1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
- Absolute neutrophil count (ANC) >= 1000/mcL (>= 500 mcL documented bone marrow involvement) (performed within 10 days of treatment initiation)
- Platelets >= 50,000/mcL (>= 30,000/mcL if documented bone marrow involvement) (performed within 10 days of treatment initiation).
- Hemoglobin >= 8 g/dL (performed within 10 days of treatment initiation).
- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (performed within 10 days of treatment initiation) * Creatinine clearance should be calculated per institutional standard.
- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (performed within 10 days of treatment initiation).
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN (performed within 10 days of treatment initiation).
- Albumin >= 2.0 mg/dL (performed within 10 days of treatment initiation).
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range on intended use of anticoagulants (performed within 10 days of treatment initiation).
- Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range on intended use of anticoagulants (performed within 10 days of treatment initiation).
- Female subject of childbearing potential should have a negative urine or serum pregnancy test 3 days prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
- Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
- Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy
- Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
- Has a known history of active TB (Bacillus tuberculosis)
- Hypersensitivity to pembrolizumab or any of its excipients
- Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
- Has had prior radiation therapy or ibrutinib within 14 days, or other targeted small molecule therapy, chemotherapy, or any other therapy within 21 days prior to study day 1.
- 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.
- Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer, or nonmelanomatous skin cancer, 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
- Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs) with the exception of autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura (ITP); replacement therapy (eg. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
- Has a history of non-infectious pneumonitis that required steroids or has current pneumonitis
- Has an active infection requiring systemic therapy
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
- Has known history of hepatitis B or hepatitis C, as defined by hepatitis B surface antigen positivity or hepatitis B polymerase chain reaction (PCR) positivity, or hepatitis C PCR positivity, respectively. Patients with hepatitis B core positivity are included provided PCR negative.
- Has received a live vaccine within 30 days of planned start of study therapy. * Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed.
- Has received prior therapy with a PI3K-inhibitor in the dose escalation study. The expansion cohort will allow participation of patients who have received a prior therapy with a PI3K-inhibitor and were intolerant but have not progressed on it. (Prior therapy with a PI3K-inhibitor is allowed if it was discontinued for intolerance).
- Is pregnant or breast feeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of treatment
- Has known active central nervous system (CNS) disease and/or lymphomatous involvement; subjects with previously treated CNS lymphoma and/or lymphomatous meningitis may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment
I. To determine the maximally tolerated dose of umbralisib (TGR-1202) in combination with pembrolizumab and to determine the recommended phase II dose for this combination for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and B-cell non-Hodgkin lymphoma (NHL).
I. Complete response (CR) and CR rate – defined as the proportion of participants who achieve a confirmed CR by the international workshop on CLL (iwCLL) and the Lugano Response Criteria for NHL.
II. Duration of Response (DOR) – defined as the interval from the first documentation of confirmed CR or partial response (PR) ([by Independent Review Committee (IRC)]) to the first documentation of definitive disease progression or death from any cause.
III. Progression-free survival (PFS) – defined as the interval from the first dose of study drug to the first documentation of definitive disease progression or death from any cause.
IV. Minimal residual disease (MRD) negativity rate for CLL – defined as the proportion of subjects with MRD < 10^-4, assessed by flow cytometry in bone marrow.
V. Nodal response rate – defined as the proportion of subjects who achieve a 50% decrease from baseline in the sum of the products of the greatest perpendicular diameters (SPD) of index lesions.
VI. Overall survival (OS) – defined as the interval from the start of the study treatment to death from any cause.
I. Time to response (TTR) – defined as the interval from the first dose of the study drugs to the first documentation of confirmed CR or PR.
II. Percent change in lymph node area – defined as the percent change from baseline in the sum of the products of the greatest perpendicular diameters (SPD) of index lesions.
III. Splenomegaly response rate – defined as the proportion of subjects with baseline splenomegaly (>= 13 cm) who achieve an on-study normalization or a decrease by 50% (minimum 2 cm) from baseline in the pretreatment enlargement of the vertical splenic dimension by imaging.
OUTLINE: This is a dose-escalation study of umbralisib.
Patients receive umbralisib orally (PO) daily on days 1-21, and beginning cycle 3, patients also receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles repeats every 21 days for up to 10 cycles in the absence of disease progression or unacceptable toxicity. Patients with disease progression may continue on pembrolizumab for up to 6 cycles.
After completion of study treatment, patients are followed up at 28 days, and at 2 years from the date of first study treatment.
Trial Phase Phase I
Trial Type Treatment
University of Chicago Comprehensive Cancer Center
Michael J. Thirman
- Primary ID IRB17-0901
- Secondary IDs NCI-2018-00007
- Clinicaltrials.gov ID NCT03283137