A Study of the Efficacy of ABT-199 in Subjects With Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia With the 17p Deletion
Condition: Chronic Lymphocytic Leukemia; 17p Deletion; Cancer of the Blood and Bone Marrow
MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell
Intervention: ABT-199 (Main Cohort); ABT-199 (Safety Expansion Cohort)
Intervention description: Participants received a test dose of ABT-199 of ≤ 20 mg on Week 1 Day 1 of the Lead-In Period. For those with significant electrolyte and/or lymphocyte changes within 24 hours of the first dose, the 20 mg dose was maintained for 7 days with escalation to 50 mg on Week 2 Day 1. If none of the electrolyte and/or lymphocyte changes occurred within 24 hours from ABT-199 20 mg dose administration, the participant was dose-escalated to 50 mg on Week 1 Day 2. After the first dose of 50 mg, if no laboratory abnormalities occurred, the participant remained on the 50 mg dose through Week 1. After receiving the 50 mg dose for approximately 1 week (6 to 7 days), the following dose escalation proceeded with weekly increases in dose: → 100 mg → 200 mg → 400 mg (or additional lead-in steps to designated 400 mg dose), as tolerated.; Participants received an initial dose of ABT-199 of 20 mg on Week 1 Day 1 of the Lead-In Period. If one or more electrolyte changes (from the 0 hr measurement prior to dosing) suggestive of laboratory tumor lysis syndrome (LTLS) or clinical TLS (CTLS) occurred within 24 hours of the 20 mg dose, no additional doses were administered until resolution. Upon resolution of laboratory abnormalities, the 20 mg dose was continued through Week 1. If no significant findings suggestive of clinical or laboratory TLS occurred within 24 hours, the 20 mg dose was continued through Week 1 Day 7, and escalated to a dose of 50 mg on Week 2 Day 1. Those who had drug interruptions may have been allowed to escalate to and be maintained at 50 mg for 1 week after they had been on a 20 mg dose for at least 1 week (5 - 7 days). After a week at 50 mg, weekly dose escalations were implemented as follows: 100 mg → 200 mg → 400 mg (or additional lead-in steps to designated 400 mg dose) as tolerated.
Intervention MeSH terms: Venetoclax
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 158.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: Chronic Lymphocytic Leukemia; 17p Deletion

Summary:

      This was an open-label, multicenter, global study to determine the efficacy of ABT-199
      (Venetoclax) monotherapy in participants with relapsed/refractory (R/R) or previously
      untreated chronic lymphocytic leukemia (CLL) harboring 17p deletion.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participant must be greater than or equal to 18 years of age.

          -  Participant must have diagnosis of chronic lymphocytic leukemia (CLL) that meets
             published 2008 Modified IWCLL NCI-WG (International Workshop for Chronic Lymphocytic
             Leukemia National Cancer Institute-Working Group) Guidelines.

               -  Participant has an indication for treatment according to the 2008 Modified IWCLL
                  NCI WG Guidelines;

               -  Participant has clinically measurable disease (lymphocytosis > 5 × 10^9/L and/or
                  palpable and measurable nodes by physical exam and/or organomegaly assessed by
                  physical exam);

               -  Participant must be refractory or have relapsed after receiving at least one
                  prior line of therapy (participants that have progressed after 1 cycle of
                  treatment or have completed at least 2 cycles of treatment for a given line of
                  therapy) or previously untreated CLL (previously untreated CLL participants must
                  have received no prior chemotherapy or immunotherapy. Participants with a history
                  of emergency, loco-regional radiotherapy (e.g., for relief of compressive signs
                  or symptoms) are eligible. In addition, participants must meet the CLL diagnostic
                  criteria above and must have > 5 × 10^9/L B-Lymphocytes in the peripheral
                  blood.);

               -  Participants must have 17p deletion, assessed by local laboratory (in bone marrow
                  or peripheral blood) or assessed by central laboratory (peripheral blood).

          -  Participant has an Eastern Cooperative Oncology Group (ECOG) performance score of less
             than or equal to 2.

          -  Participant must have adequate bone marrow function at Screening as follows:

               -  Absolute Neutrophil Count (ANC) greater than or equal to 1000/µL, or

               -  For subjects with an ANC less than 1000/µL at Screening and bone marrow heavily
                  infiltrated with underlying disease (unless cytopenia is clearly due to marrow
                  involvement of CLL), growth factor support may be administered after Screening
                  and prior to the first dose of ABT-199 to achieve the ANC eligibility criteria
                  (greater than or equal to 1000/µL);

               -  Platelets greater than 30,000/mm^3 (without transfusion support within 14 days of
                  Screening, without evidence of mucosal bleeding, without known history of
                  bleeding episode within 3 months of Screening, and without history of bleeding
                  disorder);

               -  Hemoglobin greater than or equal to 8.0 g/dL.

          -  Participant must have adequate coagulation, renal, and hepatic function, per
             laboratory reference range at Screening as follows:

               -  Activated partial thromboplastin time (aPTT) and prothrombin time (PT) not to
                  exceed 1.5 × the upper limit of normal;

               -  Calculated creatinine clearance greater than 50 mL/min using 24-hour Creatinine
                  Clearance or modified Cockcroft-Gault equation (using Ideal Body Mass [IBM]
                  instead of Mass). For participants that have body mass index (BMI) of > 30 kg/m^2
                  or < 19 kg/m^2, 24-hour measured urine creatinine clearance is required;

               -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or
                  equal to 3.0 × the upper normal limit of institution's normal range; Bilirubin
                  less than or equal to 1.5 × upper limit of normal. Participants with Gilbert's
                  Syndrome may have a bilirubin greater 1.5 × upper limit of normal, per
                  correspondence between the investigator and AbbVie medical monitor.

          -  For participants at high risk of tumor lysis syndrome a pre-approval by the AbbVie
             medical monitor is required prior to enrollment.

        Exclusion Criteria:

          -  Participant has undergone an allogeneic stem cell transplant.

          -  Participant has developed Richter's transformation confirmed by biopsy.

          -  Participant has prolymphocytic leukemia.

          -  Participant has active and uncontrolled autoimmune cytopenias (for 2 weeks prior to
             Screening), including autoimmune hemolytic anemia and idiopathic thrombocytopenic
             purpura despite low dose corticosteroids.

          -  Participant has previously received ABT-199.

          -  Participant has received a biologic agent for anti-neoplastic intent within 30 days
             prior to the first dose of study drug.

          -  Participant has received any of the following within 14 days or 5 half-lives as
             applicable prior to the first dose of study drug, or has not recovered to less than
             Common Toxicity Criteria (CTC) grade 2 clinically significant adverse
             effect(s)/toxicity(s) of the previous therapy:

               -  Any anti-cancer therapy including chemotherapy, or radiotherapy;

               -  Investigational therapy, including targeted small molecule agents.

          -  Participant has known allergy to both xanthine oxidase inhibitors and rasburicase.