Buparlisib in Patients With Relapsed and Refractory Chronic Lymphocytic Leukemia
Condition: Chronic Lymphocytic Leukemia
MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell
Intervention: Buparlisib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 14.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to find out what effects a new drug, buparlisib, has on chronic
      lymphocytic leukemia.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Previously documented CLL that is recurrent or relapsed after previous therapy and
             that requires treatment

          -  Age ≥ 18 years

          -  ECOG Performance Status score of 0, 1 or 2

          -  Patients must have a life expectancy of at least 12 weeks. Those who have previously
             completed curative treatment of a malignancy other than CLL will be eligible

          -  Patients must have at least ONE of: Lymphocyte count ≥ 10 x 10^9/L OR at least one
             pathologically enlarged lymph node (≥ 2 x 2 cm) by CT scan

          -  Previous therapy: Patients must have received at least 1 prior systemic treatment
             regimen (single agent or combination therapy). There is no upper limit on number of
             prior regimens. Patients who have received prior autologous or allogeneic stem cell
             transplantation are eligible.

          -  Patients must have recovered (to ≤ grade 2) from all reversible toxicity related to
             prior systemic therapy, and have adequate washout from prior chemotherapy and
             investigational agents defined as the longest of:

               -  two weeks

               -  standard cycle length of prior regimen (e.g. 28 days for FCR)

               -  5 half-lives for investigational drugs

        Not permitted:

        • prior treatment with buparlisib (BKM120)

          -  Patients may have had radiation, provided a minimum of 21 days has elapsed prior to
             enrollment. Patients must have recovered from any acute toxic effects from radiation
             prior to registration

          -  Previous surgery is permitted provided that wound healing has occurred and at least 14
             days have elapsed if surgery was major

          -  Absolute neutrophil counts (ANC): ≥ 1.0 x 10^9/L

          -  Platelets ≥ 50/min x 10^9/L and more than 5 days since last transfusion

          -  Creatinine clearance* ≥ 50 mL/min

          -  Bilirubin** ≤ 1.5 x upper normal limit (UNL)

          -  Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) ≤ 1.5 x UNL or ≤ 3
             x UNL if hepatic involvement with CLL

          -  Potassium and calcium Within normal limits for laboratory (supplementation permitted)

          -  Glucose (fasting) < 7.8 mmol/L (AND HbA1c ≤ 8% if diabetic)

             * Creatinine clearance as calculated by Cockcroft-Gault formula or by 24 hour urine
             measurement: Females: GFR = 1.04 x (140-age) x weight in kg serum creatinine in μmol/L
             Males: GFR = 1.23 x (140-age) x weight in kg serum creatinine in μmol/L

             ** Direct if patient known to have Gilbert's syndrome

          -  Patient consent must be obtained according to local Institutional and/or University
             Human Experimentation Committee requirements

          -  Patients must be accessible for treatment and follow up. Patients registered on this
             trial must be treated and followed at the participating centre

          -  In accordance with CCTG policy, protocol treatment is to begin within 2 working days
             of patient registration

        Exclusion Criteria:

          -  Progression to high grade lymphoma (Richter's transformation) or myelodysplasia

          -  Patients with known hypersensitivity to the study drug or its excipients

          -  The following are exclusions for enrolment on the study:

               -  Pregnant or lactating women. (N.B. All women of childbearing potential must have
                  a negative serum or urine pregnancy test within 7 days prior to registration).

               -  Men and women of childbearing potential who do not agree to use adequate
                  contraception: prior to study entry; while taking buparlisib and after completion
                  of study therapy for 12 weeks in men and 4 weeks in women.

          -  Serious illness or medical condition which would not permit the patient to be managed
             according to the protocol, including, but not limited to:

               1. active uncontrolled or serious infection (viral, bacterial or fungal);

               2. pulmonary disease requiring oxygen;

               3. known HIV infection or other immune deficiency disorders (except for CLL);

               4. uncontrolled auto-immune hemolytic anemia (AIHA) or auto-immune thrombocytopenia
                  (ITP)

               5. acute or chronic pancreatitis

          -  Uncontrolled or significant cardiovascular disease including:

               -  Myocardial infarction within 12 months

               -  Uncontrolled angina within 6 months

               -  Clinically significant congestive heart failure (eligible if controlled and LVEF
                  ≥ 50%)

               -  Stroke, TIA or other ischemic event within 12 months

               -  Severe cardiac valve dysfunction

               -  Left ventricular ejection fraction < 50% (only required if symptoms suggestive or
                  history of cardiovascular disease)

               -  Uncontrolled hypertension

          -  Patient has any of the following mood disorders:

               -  Medically documented history of or active major depressive episode, bipolar
                  disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of
                  suicidal attempt or ideation, or homicidal ideation (e.g. risk of doing harm to
                  self or others)

               -  Score of ≥ 12 on the PHQ-9 questionnaire

               -  Score of ≥ 15 on the GAD-7 mood scale

               -  ≥ CTCAE grade 3 anxiety

               -  Patient selects a positive response of '1,2,3' to question 9 (suicidal ideation)
                  in the PHQ-9 questionnaire

          -  Patients who have received prior buparlisib (BKM120).

          -  Patients with impairment of gastrointestinal (GI) function or GI disease that may
             significantly alter the absorption of buparlisib (e.g. ulcerative diseases,
             uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel
             resection).

          -  Patients who are unable to swallow capsules

          -  Patients on strong CYP3A inhibitors/inducers or therapeutic doses of warfarin-like
             anticoagulants (must have discontinued > 7 days prior to day 1). Patients may receive
             low molecular weight heparin if indicated. See Appendix VII for a list of prohibited
             medications.

          -  Patients on drugs with a known risk to induce Torsades de Pointes

          -  Patients receiving high dose steroid therapy or another immunosuppressive agent. Note:
             Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways diseases),
             eye drops or local injections (e.g. intra-articular) are allowed. Patients who are on
             stable moderate dose corticosteroid treatment for treatment of conditions other than
             CLL (< dexamethasone 4 mg/day, prednisone 25 mg/day) for at least 14 days before start
             of study treatment are eligible.

          -  Patients with known HIV positivity.

          -  Patients with known CLL involvement of the central nervous system.

          -  Patients with a history of other malignancies, except those which have been curatively
             treated and require no ongoing therapy