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Therapy targeting Bruton's tyrosine kinase (BTK) with ibrutinib has transformed the treatment of chronic lymphocytic leukaemia. However, patients who are refractory to or relapse after ibrutinib therapy have poor outcomes. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 active in previously treated patients with relapsed or refractory chronic lymphocytic leukaemia. In this study, we assessed the activity and safety of venetoclax in patients with chronic lymphocytic leukaemia who are refractory to or relapse during or after ibrutinib therapy. In this interim analysis of a multicentre, open-label, non-randomised, phase 2 trial, we enrolled patients aged 18 years or older with a documented diagnosis of chronic lymphocytic leukaemia according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and an Eastern Cooperative Oncology Group performance score of 2 or lower. All patients had relapsed or refractory disease after previous treatment with a BCR signalling pathway inhibitor. All patients were screened for Richter's transformation and cases confirmed by biopsy were excluded. Eligible patients received oral venetoclax, starting at 20 mg per day with stepwise dose ramp-up over 5 weeks to 400 mg per day. Patients with rapidly progressing disease received an accelerated dosing schedule (to 400 mg per day by week 3). The primary endpoint was overall response, defined as the proportion of patients with an overall response per investigator's assessment according to IWCLL criteria. All patients who received at least one dose of venetoclax were included in the activity and safety analyses. This study is ongoing; data for this interim analysis were collected per regulatory agencies' request as of June 30, 2017. This trial is registered with ClinicalTrials.gov, number NCT02141282. Between September, 2014, and November, 2016, 127 previously treated patients with relapsed or refractory chronic lymphocytic leukaemia were enrolled from 15 sites across the USA. 91 patients had received ibrutinib as the last BCR inhibitor therapy before enrolment, 43 of whom were enrolled in the main cohort and 48 in the expansion cohort recruited later after a protocol amendment. At the time of analysis, the median follow-up was 14 months (IQR 8–18) for all 91 patients, 19 months (9–27) for the main cohort, and 12 months (8–15) for the expansion cohort. 59 (65%, 95% CI 53–74) of 91 patients had an overall response, including 30 (70%, 54–83) of 43 patients in the main cohort and 29 (60%, 43–72) of 48 patients in the expansion cohort. The most common treatment-emergent grade 3 or 4 adverse events were neutropenia (46 [51%] of 91 patients), thrombocytopenia (26 [29%]), anaemia (26 [29%]), decreased white blood cell count (17 [19%]), and decreased lymphocyte count (14 [15%]). 17 (19%) of 91 patients died, including seven because of disease progression. No treatment-related deaths occurred. The results of this interim analysis show that venetoclax has durable clinical activity and favourable tolerability in patients with relapsed or refractory chronic lymphocytic leukaemia whose disease progressed during or after discontinutation of ibrutinib therapy. The durability of response to venetoclax will be assessed in the final analysis in 2019. AbbVie, Genentech.

The effect of posaconazole, a strong cytochrome P450 3A (CYP3A) inhibitor and commonly used antifungal agent, on the pharmacokinetic properties of venetoclax, a CYP3A substrate, was evaluated in patients with acute myeloid leukemia to determine the dose adjustments needed to manage this potential interaction. Twelve patients received 20- to 200-mg ramp-up treatment with oral venetoclax and 20 mg/m2 of intravenous decitabine on days 1 through 5, followed by 400 mg of venetoclax alone on days 6 through 20. On days 21 through 28, patients received 300 mg of posaconazole plus reduced doses of venetoclax (50 or 100 mg) to account for expected increases in venetoclax plasma concentrations. Blood samples were collected before dosing and up to 24 hours after the venetoclax dose on days 20 and 28. Compared with a venetoclax dose of 400 mg when administered alone (day 20), coadministration of venetoclax at a 50-mg dose with multiple doses of posaconazole increased mean venetoclax Cmax and AUC0–24 by 53% and 76%, respectively, whereas coadministration of venetoclax at a 100-mg dose with posaconazole increased mean venetoclax Cmax and AUC0–24 by 93% and 155%, respectively. When adjusted for different doses and nonlinearity, posaconazole was estimated to increase venetoclax Cmax and AUC0–24 by 7.1- and 8.8-fold, respectively. Both the 50- and 100-mg venetoclax doses administered with posaconazole were well tolerated. The results are consistent with inhibition of CYP3A-mediated metabolism of venetoclax. Posaconazole can be used for antifungal prophylaxis in patients with acute myeloid leukemia receiving venetoclax after reducing the venetoclax dose by at least 75%. ClinicalTrials.gov identifier: NCT02203773.

Selective BCL2 inhibition with venetoclax has substantial activity in patients with relapsed or refractory chronic lymphocytic leukaemia. Combination therapy with rituximab enhanced activity in preclinical models. The aim of this study was to assess the safety, pharmacokinetics, and activity of venetoclax in combination with rituximab. Adult patients with relapsed or refractory chronic lymphocytic leukaemia (according to the 2008 Modified International Workshop on CLL guidelines) or small lymphocytic lymphoma were eligible for this phase 1b, dose-escalation trial. The primary outcomes were to assess the safety profile, to determine the maximum tolerated dose, and to establish the recommended phase 2 dose of venetoclax when given in combination with rituximab. Secondary outcomes were to assess the pharmacokinetic profile and analyse efficacy, including overall response, duration of response, and time to tumour progression. Minimal residual disease was a protocol-specified exploratory objective. Central review of the endpoints was not done. Venetoclax was dosed daily using a stepwise escalation to target doses (200–600 mg) and then monthly rituximab commenced (375 mg/m2 in month 1 and 500 mg/m2 in months 2–6). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for adverse events version 4.0. Protocol-guided drug cessation was allowed for patients who achieved complete response (including complete response with incomplete marrow recovery) or negative bone marrow minimal residual disease. Analyses were done per protocol for all patients who commenced drug and included all patients who received at least one dose of venetoclax. Data were pooled across dose cohorts. Patients are still receiving therapy and follow-up is ongoing. The trial is registered at ClinicalTrials.gov, number NCT01682616. Between Aug 6, 2012, and May 28, 2014, we enrolled 49 patients. Common grade 1–2 toxicities included upper respiratory tract infections (in 28 [57%] of 49 patients), diarrhoea (27 [55%]), and nausea (25 [51%]). Grade 3–4 adverse events occurred in 37 (76%) of 49 patients; most common were neutropenia (26 [53%]), thrombocytopenia (eight [16%]), anaemia (seven [14%]), febrile neutropenia (six [12%]), and leucopenia (six [12%]). The most common serious adverse events were pyrexia (six [12%]), febrile neutropenia (five [10%]), lower respiratory tract infection, and pneumonia (each three [6%]). Clinical tumour lysis syndrome occurred in two patients (resulting in one death) who initiated venetoclax at 50 mg. After enhancing tumour lysis syndrome prophylaxis measures and commencing venetoclax at 20 mg, clinical tumour lysis syndrome did not occur. The maximum tolerated dose was not identified; the recommended phase 2 dose of venetoclax in combination with rituximab was 400 mg. Overall, 42 (86%) of 49 patients achieved a response, including a complete response in 25 (51%) of 49 patients. 2 year estimates for progression-free survival and ongoing response were 82% (95% CI 66–91) and 89% (95% CI 72–96), respectively. Negative marrow minimal residual disease was attained in 20 (80%) of 25 complete responders and 28 (57%) of 49 patients overall. 13 responders ceased all therapy; among these all 11 minimal residual disease-negative responders remain progression-free off therapy. Two with minimal residual disease-positive complete response progressed after 24 months off therapy and re-attained response after re-initiation of venetoclax. A substantial proportion of patients achieved an overall response with the combination of venetoclax and rituximab including 25 (51%) of 49 patients who achieved a complete response and 28 (57%) of 49 patients who achieved negative marrow minimal residual disease with acceptable safety. The depth and durability of responses observed with the combination offers an attractive potential treatment option for patients with relapsed or refractory chronic lymphocytic leukaemia and could allow some patients to maintain response after discontinuing therapy, a strategy that warrants further investigation in randomised studies. AbbVie Inc and Genentech Inc.

Proteins of the BCL-2 family regulate clonal selection and survival of lymphocytes, and are frequently overexpressed in lymphomas. Navitoclax is a targeted high-affinity small molecule that inhibits the anti-apoptotic activity of BCL-2 and BCL-XL. We aimed to assess the safety and antitumour activity of navitoclax in patients with lymphoid tumours, and establish the drug's pharmacokinetic and pharmacodynamic profiles. In this phase 1 dose-escalation study, patients (aged ≥18 years) with relapsed or refractory lymphoid malignancies were enrolled and treated at seven sites in the USA between November, 2006, and November, 2009. A modified Fibonacci 3+3 design was used to assign patients to receive oral navitoclax once daily by one of two dosing schedules: intermittently for the first 14 days of a 21-day cycle (14/21) at doses of 10, 20, 40, 80, 110, 160, 225, 315, or 440 mg/day; or continuously for 21 days of a 21-day cycle (21/21) at doses of 200, 275, 325, or 425 mg/day. Study endpoints were safety, maximum tolerated dose, pharmacokinetic profile, pharmacodynamic effects on platelets and T cells, and antitumour activity. This trial is registered with ClinicalTrials.gov, number NCT00406809. 55 patients were enrolled (median age 59 years, IQR 51–67), 38 to receive the 14/21 dosing schedule, and 17 to receive the 21/21 dosing schedule. Common toxic effects included grade 1 or 2 anaemia (41 patients), infection (39), diarrhoea (31), nausea (29), and fatigue (21); and grade 3 or 4 thrombocytopenia (29), lymphocytopenia (18), and neutropenia (18). On the intermittent 14/21 schedule, dose-limiting toxic effects were hospital admissions for bronchitis (one) and pleural effusion (one), grade 3 increase in aminotransferases (one), grade 4 thrombocytopenia (one), and grade 3 cardiac arrhythmia (one). To reduce platelet nadir associated with intermittent 14/21 dosing, we assessed a 150 mg/day lead-in dose followed by a continuous 21/21 dosing schedule. On the 21/21 dosing schedule, two patients did not complete the first cycle and were excluded from assessment of dose-limiting toxic effects; dose-limiting toxic effects were grade 4 thrombocytopenia (one), grade 3 increase in aminotransferases (one), and grade 3 gastrointestinal bleeding (one). Navitoclax showed a pharmacodynamic effect on circulating platelets and T cells. Clinical responses occurred across the range of doses and in several tumour types. Ten of 46 patients with assessable disease had a partial response, and these responders had median progression-free survival of 455 days (IQR 40–218). Navitoclax has a novel mechanism of peripheral thrombocytopenia and T-cell lymphopenia, attributable to high-affinity inhibition of BCL-XL and BCL-2, respectively. On the basis of these findings, a 150 mg 7-day lead-in dose followed by a 325 mg dose administered on a continuous 21/21 dosing schedule was selected for phase 2 study. Abbott Laboratories, Genentech, and National Cancer Institute, National Institutes of Health.

An oral inhibitor of BCL2 produces substantial responses in the majority of patients with refractory chronic lymphocytic leukemia. The agent is so effective that precautions are necessary to protect patients against the tumor lysis syndrome at therapy initiation. The landscape of treatment for relapsed chronic lymphocytic leukemia (CLL) has recently changed with the introduction of agents that inhibit intracellular B-cell receptor signaling. 1 , 2 Ibrutinib monotherapy 3 , 4 and idelalisib in combination with rituximab 5 induce responses in the majority of patients in whom chemoimmunotherapy has failed, and these patients have improved outcomes. Treatment is given indefinitely, and complete remission is uncommon, particularly in the first 2 years after the initiation of therapy. Persistent disease is a concern because of the potential development of resistance. 6 – 8 Although many responses are durable and may deepen over time, relapses accumulate with ongoing follow-up, . . .

In a trial involving patients with relapsed or refractory chronic lymphocytic leukemia, the BCL2 inhibitor venetoclax in combination with rituximab resulted in a higher 2-year rate of progression-free survival than bendamustine in combination with rituximab (85% vs. 36%).

Deletion of chromosome 17p (del[17p]) in patients with chronic lymphocytic leukaemia confers very poor prognosis when treated with standard chemo-immunotherapy. Venetoclax is an oral small-molecule BCL2 inhibitor that induces chronic lymphocytic leukaemia cell apoptosis. In a previous first-in-human study of venetoclax, 77% of patients with relapsed or refractory chronic lymphocytic leukaemia achieved an overall response. Here we aimed to assess the activity and safety of venetoclax monotherapy in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia. In this phase 2, single-arm, multicentre study, we recruited patients aged 18 years and older with del(17p) relapsed or refractory chronic lymphocytic leukaemia (as defined by 2008 Modified International Workshop on Chronic Lymphocytic Leukemia guidelines) from 31 centres in the USA, Canada, UK, Germany, Poland, and Australia. Patients started once daily venetoclax with a weekly dose ramp-up schedule (20, 50, 100, 200, 400 mg) over 4–5 weeks. Patients were then given daily 400 mg continuous dosing until disease progression or discontinuation for another reason. The primary endpoint was the proportion of patients achieving an overall response, assessed by an independent review committee. Activity and safety analyses included all patients who received at least one dose of study drug (per protocol). This study is registered with ClinicalTrials.gov, number NCT01889186. Follow-up is ongoing, and patients are still receiving treatment. Between May 27, 2013, and June 27, 2014, 107 patients were enrolled into the study. At a median follow-up of 12·1 months (IQR 10·1–14·2), an overall response by independent review was achieved in 85 (79·4%; 95% CI 70·5–86·6) of 107 patients. The most common grade 3–4 adverse events were neutropenia (43 [40%]), infection (21 [20%]), anaemia (19 [18%]), and thrombocytopenia (16 [15%]). Serious adverse events occurred in 59 (55%) patients, irrespective of their relationship to treatment, with the most common (≥5% of patients) being pyrexia and autoimmune haemolytic anaemia (seven [7%] each), pneumonia (six [6%]), and febrile neutropenia (five [5%]). 11 patients died in the study within 30 days of the last dose of venetoclax; seven due to disease progression and four from an adverse event (none assessed as treatment related). Results of this trial show that venetoclax monotherapy is active and well tolerated in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia, providing a new therapeutic option for this very poor prognosis population. Additionally, in view of the distinct mechanism-of-action of venetoclax, combinations or sequencing with other novel targeted agents should be investigated to further advance treatment of del(17p) chronic lymphocytic leukaemia. AbbVie and Genentech.

Objective Navitoclax is a first-in-class, orally bioavailable, targeted Bcl-2 family protein inhibitor and promotes apoptosis. Thrombocytopenia is a primary dose-limiting toxicity of navitoclax which exhibited a distinct time profile in circulating platelets from that caused by traditional chemotherapies. A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the pharmacokinetic of navitoclax as well as the time course of the platelet counts in cancer patients receiving navitoclax. Methods Data from 256 patients who received oral navitoclax (dose range 10–475 mg) as a 14/21-day schedule or a continuous once daily (QD) schedule were used to construct the model using NONMEM. The PK model was a two-compartmental model with a lag-time and a transit compartment in absorption. The PD model was a semi-physiological model that comprised a progenitor cell compartment, three transition compartments representing the maturation chain in the bone marrow and a peripheral blood compartment. Compared with the previously published models, the model established in this analysis applied a different feedback mechanism and introduced a new concept of progenitor cell “pool”, which describes a large pool of platelet progenitor cells at the beginning of navitoclax treatment. Results The PD model was able to describe a slight downward trend of platelet counts over the long-term navitoclax treatment as observed in around 8 % of the patients and the initial drop in platelets seen in our Phase 1/2a studies. Conclusions We have developed a new semi-physiological platelet model for describing fast drop of platelets after initial navitoclax administration and long-term decline of platelets after continuous administration of navitoclax.

Background Venetoclax is a selective, potent, first-in-class B-cell lymphoma-2 inhibitor that restores apoptosis in cancer cells and has demonstrated efficacy in a variety of hematological malignancies. Objective The objective of this research was to characterize the relationship between venetoclax exposures and efficacy and safety in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Methods A total of 272 and 338 patients from four clinical studies were pooled for the exposure–efficacy and exposure–safety analyses, respectively. Demographics, baseline disease characteristics, and select co-medications were evaluated for their impact on efficacy (lymphocytes, tumor size, objective response [OR]) and safety (neutropenia and infection). Results Higher venetoclax concentrations led to a more rapid decrease in lymphocyte counts and tumor size, which translated into patients more rapidly achieving OR. The 17p deletion somatic mutation was not identified, in any of the analyses, to affect the responsiveness of patients to venetoclax. Model-based simulations of lymphocyte counts and tumor size estimated an OR rate (ORR) of 84.8 % (95 % confidence interval 81.5–88.0 %) at a venetoclax dosage of 400 mg daily, with minimal increase in ORR at higher doses. The safety analyses of the adverse events (grade 3 or higher) of neutropenia and infection indicated that higher average venetoclax concentrations were not associated with an increase in adverse events. Conclusions The exposure–response analyses indicated that a venetoclax dosage regimen of 400 mg daily results in a high (>80 %) probability of achieving OR in R/R CLL/SLL patients, with minimal probability of increasing neutropenia or infection with higher exposures.

Inhibition of prosurvival proteins of the BCL family is a promising anticancer strategy; however, the similarities between the family members make the development of specific agents difficult. Current compounds have been designed to target BCL-2, which is frequently elevated in tumors and is an important prosurvival factor, but also inhibit BCL-X L , which is required for the survival of platelets; thus, thrombocytopenia is a limiting toxic effect in patients. The authors have engineered anti-BCL drugs to generate a more BCL-2–specific compound that has less affinity for BCL-X L and, therefore, reduced platelet toxicity. The compound is effective in several tumor models in vivo and had reduced toxicity in three patients with refractory leukemia, showing a promising activity and safety profile to refine and improve proapoptotic therapy in cancer. Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2–like 1 (BCL-X L ), which has shown clinical efficacy in some BCL-2–dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X L inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2–selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2–dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2–dependent hematological cancers.