Title A Phase 2 Open-Label Study of the Efficacy of ABT-199 (GDC-0199) in Subjects with Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia Harboring the 17p Deletion


CC 13-1173

Hospital Main Campus

Phase Phase 2

Disease Leukemia, Chronic Lymphocytic (CLL)

Drug ABT-199



Primary Objectives
    Main Cohort
    • To evaluate the efficacy of ABT-199 monotherapy in subjects with relapsed or refractory chronic lymphocytic leukemia (CLL) harboring the 17p deletion. Efficacy will be measured by overall response rate (ORR).
    Safety Expansion Cohort
    • To evaluate the safety of ABT-199 in approximately 50 subjects with relapsed/refractory or previously untreated CLL harboring 17p deletion treated per the updated TLS prophylaxis and management measures.
Secondary Objectives
    Main Cohort
    • To evaluate the complete remission rate (CR rate), partial remission rate (PR rate), duration of overall response (DOR), progression-free survival (PFS), event-free survival, time to progression (TTP), time to first response, time to 50% reduction in ALC, overall survival (OS) and percent of subjects who move on to stem cell transplant. The safety and tolerability of ABT-199 in subjects with relapsed or refractory CLL harboring 17p deletion will also be evaluated.
    Safety Expansion Cohort
    • To evaluate ORR, CR rate, PR rate, duration of overall response, progression-free survival, event-free survival, time to progression, time to first response, time to 50% reduction in ALC, overall survival, and percent of subjects who move on to stem cell transplant.
Exploratory Objectives
  • Time to next anti-CLL treatment (TTNT) and minimal residual disease (MRD), assessed in the peripheral blood and/or bone marrow (BM), will be measured.
  • Pharmacokinetics, pharmacogenetics and biomarkers will also be evaluated as exploratory objectives.
  • Health Economic and Patient-Reported Outcome Measures will include the MDASI (measure of subject reported symptoms), the EORTC QLQ-C30 and EORTC QLQ CLL16 (a measure of health related quality of life specific to CLL) and the EQ-5D-5L (measure of general health status) and EQ-5D-VAS.
Inclusion Criteria

Inclusion Criteria

  1. Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures.
  2. Subject must be ≥ 18 years of age.
  3. Subject must have diagnosis of CLL that meets published 2008 Modified IWCLL NCI-WG Guidelines.
    • Subject has an indication for treatment according to the 2008 Modified IWCLL NCI-WG Guidelines;
    • Subject has clinically measurable disease (lymphocytosis > 5 x 109/L and/or palpable and measurable nodes by physical exam and/or organomegally assessed by physical exam);
    • Subject must have relapsed/refractory CLL or previously untreated CLL;
      • Refractory or relapsed CLL subjects must meet the following requirements:
        • Refractory or relapsed after receiving at least one prior line of therapy (subjects that have progressed after 1 cycle of treatment or have completed at least 2 cycles of treatment for a given line of therapy);
      • Previously untreated CLL subjects must meet the following requirements:
        • Received no prior chemotherapy or immunotherapy. Subjects with a history of emergency, loco-regional radiotherapy (e.g., for relief of compressive signs or symptoms) are eligible.
        • CLL diagnostic criteria above and must have > 5 x 109/L B-Lymphocytes in the peripheral blood.
    • Subjects must have 17p deletion, assessed by local laboratory (in bone marrow or peripheral blood) or assessed by central laboratory (peripheral blood). A result obtained prior to study Screening may be used for eligibility. Additionally, a confirmatory sample (peripheral blood) will be sent to the central laboratory.
  4. Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.
  5. Subject must have adequate bone marrow function at Screening as follows:
    • Absolute Neutrophil Count (ANC) ≥ 1000/μL, or
      • For subjects with an ANC < 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 (≥ 1000/μL);
    • Platelets ≥ 30,000/mm3
      • 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 ≥ 8.0 g/dL.
  6. Subject must have adequate coagulation, renal, and hepatic function, per laboratory reference range at Screening as follows:
    • aPTT and PT not to exceed 1.5 x the upper limit of normal (ULN);
    • Calculated creatinine clearance > 50 mL/min using 24-hour Creatinine Clearance or modified Cockcroft-Gault equation (using Ideal Body Mass [IBM] instead of Mass):
      • eCCr = [(140 - Age) x IBM (kg) x [0.85 if Female]]/72 x Serum Creatinine (mg/dL)
      • Or, if serum creatinine is in μmol/L:

      • eCCr = [(140 - Age) x IBM (kg) x [1.23 if Male, 1.04 if Female]]/ Serum Creatinine (μmol/L)
      • Ideal Body Mass should be used:

        IBM (kg) = [(height cm -154) x 0.9] + (50 if Male, 45.5 if Female)

      • Note: For subjects that have BMI of > 30 kg/m2 or < 19 kg/m2, 24-hour measuredurine creatinine clearance is required.
    • AST and ALT ≤ 3.0 x the upper normal limit (ULN) of institution's normal range; Bilirubin ≤ 1.5 x ULN. Subjects with Gilbert's Syndrome may have a bilirubin > 1.5 x ULN, per correspondence between the investigator and AbbVie medical monitor.
  7. Female subjects of childbearing potential and non-sterile male subjects must practice at least one of the following methods of birth control with partner(s) beginning with initial study drug administration and continuing to 30 days after the last dose of study drug:
    • Total abstinence from sexual intercourse as the preferred life style of the subject; periodic abstinence is not acceptable;
    • Surgically sterile partner(s); acceptable sterility surgeries are: vasectomy, bilateral tubal ligation, bilateral oophorectomy or hysterectomy;
    • Intrauterine device (IUD);
    • Double-barrier method (contraceptive sponge, diaphragm or cervical cap with spermicidal jellies or cream AND a condom);
    • Hormonal contraceptives (oral, parenteral or transdermal) for at least 3 months prior to study drug administration; If hormonal contraceptives are used, the specific contraceptive must have been used for at least 3 months prior to study drug administration. If the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study from initial study drug administration to 30 days after the last dose of study drug. Any contraception method must be continued for 30 days after the last dose of study drug.
  8. Females of childbearing potential (i.e., not postmenopausal for at least 1 year with no alternative medical reason or surgically sterile) must have negative results for pregnancy test performed:
    • At Screening with a serum sample obtained within 14 days prior to the first study drug administration, and
    • Prior to dosing with a urine sample obtained on Week 1 Day 1 (tested locally), if it has been > 7 days since obtaining the serum pregnancy test results.
  9. Male subjects must agree to refrain from sperm donation, from initial study drug administration until 90 days after the last dose of study drug.
  10. For high risk subjects (as defined in Section 6.7.1) a pre-approval by the AbbVie medical monitor is required prior to enrollment.
Exclusion Criteria

Exclusion Criteria

  1. Subject has undergone an allogeneic stem cell transplant.
  2. Subject has developed Richter's transformation confirmed by biopsy.
  3. Subject has prolymphocytic leukemia.
  4. Subject has active and uncontrolled autoimmune cytopenias (for 2 weeks prior to Screening), including autoimmune hemolytic anemia (AIHA) and idiopathic thrombocytopenic purpura (ITP) despite low dose corticosteroids.
  5. Subject has previously received ABT-199.
  6. Subject is known to be positive for HIV (due to potential drug-drug interactions between anti-retroviral medications and ABT-199, as well as anticipated ABT-199 mechanism based lymphopenia that may potentially increase the risk of opportunistic infections).
  7. Subject has received the following within 30 days prior to the first dose of study drug:
    • A biologic agent (i.e., monoclonal antibodies) for anti-neoplastic intent.
  8. Subject 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 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.
  9. Subject has received the following within 7 days prior to the first dose of study drug:
    • Steroid therapy for anti-neoplastic intent;
    • CYP3A inhibitors (such as fluconazole, ketoconazole, and clarithromycin);
    • Potent CYP3A inducers (e.g., rifampin, phenytoin, carbamazepine or St. John's Wort);
    • Warfarin or requires the use of warfarin (due to potential drug-drug interactions that may potentially increase the exposure of warfarin and complications of this effect);
  10. Subject has consumed the following within 3 days prior to the first dose of study drug.
    • Grapefruit or grapefruit products;
    • Seville oranges (including marmalade containing Seville oranges);
    • Star fruit.
  11. Subject has known allergy to both xanthine oxidase inhibitors and rasburicase.
  12. Subject has a cardiovascular disability status of New York Heart Association Class ≥ 2. Class 2 is defined as cardiac disease in which subjects are comfortable at rest but ordinary physical activity, results in fatigue, palpitations, dyspnea or anginal pain.
  13. Subject exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to:
    • Uncontrolled and/or active systemic infection (viral, bacterial, or fungal).
    • Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: Subjects with serologic evidence of prior vaccination to HBV (i.e., HBs Ag-, anti-HBs+ and anti-HBc-) and positive anti-HBc from IVIG may participate.
    • Febrile neutropenia.
  14. Subject has a significant history of renal, pulmonary, neurologic, psychiatric, endocrinologic, metabolic, immunologic, cardiovascular, or hepatic disease that in the opinion of the investigator would adversely affect his/her participating in this study. For subjects who have required an intervention for any above diseases within the past 6 months, correspondence with the investigator and the AbbVie medical monitor must occur.
  15. A female subject is pregnant or breast-feeding.
  16. Subject has a history of active malignancies other than CLL within the past 2 years prior to study entry, with the exception of:
    • Adequately treated in situ carcinoma of the cervix uteri;
    • Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin;
    • Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent.
  17. Subject has malabsorption syndrome or other condition that precludes enteral route of administration.