Pharmacokinetics and Exposure-Response Analysis of Venetoclax + Obinutuzumab in Chronic Lymphocytic Leukemia: Phase 1b Study and Phase 3 CLL14 Trial.

INTRODUCTION: This study aims to investigate pharmacokinetics (PK) and exposure-response parameters of the 400 mg once-daily venetoclax dose regimen in combination with obinutuzumab, which was approved for the first-line (1L) treatment of chronic lymphocytic leukemia (CLL) based on data from the phase 3 CLL14 study and the phase 1b dose-finding GP28331 study. METHODS: Parameter estimates and uncertainty, which were estimated by a previously developed population PK (popPK) model, were used as informative priors for this analysis. They were re-estimated, and then used to evaluate additional covariate effects, describe venetoclax PK when administered with obinutuzumab, and provide empirical Bayes estimates of PK parameters and exposure. Exposure-progression-free survival (PFS) and exposure-safety relationships were assessed using data from CLL14, with steady-state nominal venetoclax exposure (CmeanSS,nominal) as the predictor variable. Exposure-safety analyses were conducted using logistic regression for selected treatment-emergent grade ≥ 3 adverse events (AEs) and serious AEs (SAEs). Dose intensities were summarized by tertiles of CmeanSS,nominal. RESULTS: PK data from 274 patients (CLL14, n = 194; GP28331, n = 80) were included. The final model provided good fit of the observed data. Obinutuzumab co-administration, history of prior treatments, and disease severity at baseline had no appreciable influence on venetoclax steady-state exposure. No significant correlations were observed between venetoclax exposure and PFS, or between venetoclax exposure and the probability of treatment-emergent grade ≥ 3 neutropenia, grade ≥ 3 thrombocytopenia, grade ≥ 3 infections, and SAEs. Median dose intensities for venetoclax and obinutuzumab remained similar across venetoclax exposure tertiles. CONCLUSION: PopPK and exposure-efficacy, exposure-safety, and exposure-tolerability analyses support the 400 mg once-daily venetoclax dose plus obinutuzumab for 1L treatment in patients with CLL. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifiers NCT02242942 and NCT02339181.

Minimal Residual Disease Dynamics after Venetoclax-Obinutuzumab Treatment: Extended Off-Treatment Follow-up From the Randomized CLL14 Study.

PURPOSE: The CLL14 study has established one-year fixed-duration treatment of venetoclax and obinutuzumab (Ven-Obi) for patients with previously untreated chronic lymphocytic leukemia. With all patients off treatment for at least three years, we report a detailed analysis of minimal residual disease (MRD) kinetics and long-term outcome of patients treated in the CLL14 study. PATIENTS AND METHODS: Patients were randomly assigned to receive six cycles of obinutuzumab with 12 cycles of venetoclax or 12 cycles of chlorambucil (Clb-Obi). Progression-free survival (PFS) was the primary end point. Key secondary end points included rates of undetectable MRD and overall survival. To analyze MRD kinetics, a population-based growth model with nonlinear mixed effects approach was developed. RESULTS: Of 432 patients, 216 were assigned to Ven-Obi and 216 to Clb-Obi. Three months after treatment completion, 40% of patients in the Ven-Obi arm (7% in the Clb-Obi arm) had undetectable MRD levels < 10-6 by next-generation sequencing in peripheral blood. Median MRD doubling time was longer after Ven-Obi than Clb-Obi therapy (median 80 v 69 days). At a median follow-up of 52.4 months, a sustained significant PFS improvement was observed in the Ven-Obi arm compared with Clb-Obi (median not reached v 36.4 months; hazard ratio 0.33; 95% CI, 0.25 to 0.45; P < .0001). The estimated 4-year PFS rate was 74.0% in the Ven-Obi and 35.4% in the Clb-Obi arm. No difference in overall survival was observed (hazard ratio 0.85; 95% CI, 0.54 to 1.35; P = .49). No new safety signals occurred. CONCLUSION: Appearance of MRD after Ven-Obi is significantly slower than that after Clb-Obi with more effective MRD reduction. These findings translate into a superior long-term efficacy with the majority of Ven-Obi-treated patients remaining in remission.

Health-related quality of life with fixed-duration venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: Results from the randomized, phase 3 CLL14 trial.

Chronic lymphocytic leukemia (CLL)-related symptoms impair the well-being of patients, making improvement of health-related quality of life (QoL) a goal of treatment. The CLL14 trial demonstrated higher efficacy of fixed-duration venetoclax-obinutuzumab (Ven-Obi) compared to chlorambucil-obinutuzumab (Clb-Obi) in patients with previously untreated CLL. To assess patients' QoL, the following patient-reported outcomes (PRO) measures were assessed: the M.D. Anderson Symptom Inventory (MDASI) core instrument and CLL module and the EORTC Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). At treatment start, physical functioning (mean 75.9 [standard deviation (SD) ± 20.1] in the Clb-Obi arm and 76.9 [±19.4] in the Ven-Obi arm), role functioning (73.6 [±27.86] and 72.6 [±26.9]) and GHS/QoL (63.6 [±21.0] and 60.3 [±20.5]) were comparable between treatment arms per EORTC QLQ-C30 scale scores. Baseline levels of physical and role functioning were maintained throughout treatment and follow-up, with no relevant improvement or deterioration. On average, patients treated with Ven-Obi showed a meaningful improvement of GHS/QoL during treatment and follow-up by at least eight points at cycle three, whereas improvement was delayed until cycle eight with Clb-Obi. According to MDASI scores, CLL symptoms (1.5 [±1.2] and 1.6 [±1.3]), core cancer symptoms (1.5 [±1.4] and 1.8 [±1.7]) and symptom interference (2.1 [±2.3] and 2.3 [±2.3]) were generally low and comparable between treatment arms at baseline and were maintained throughout treatment and follow-up. This analysis demonstrates that the higher efficacy of Ven-Obi is not associated with QoL impairment and that Ven-Obi achieves early relief of CLL-related symptoms in elderly unfit patients.

Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Venetoclax plus obinutuzumab has been established as a fixed-duration treatment regimen for patients with chronic lymphocytic leukaemia. We compared the long-term efficacy after treatment cessation of the combination of venetoclax plus obinutuzumab with chlorambucil plus obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia. METHODS: CLL14 is a multicentre, randomised, open-label, phase 3 trial done at 196 sites in 21 countries. Eligible patients were aged 18 years or older, had untreated chronic lymphocytic leukaemia, and coexisting conditions with a cumulative illness rating scale greater than 6, a creatinine clearance of 30-69 mL/min, or both. Patients were randomly assigned (1:1) via a web and voicemail system with allocation concealment and based on a computer-generated randomisation schedule with a block size of six and stratified by Binet stage and geographical region. Patients received either venetoclax plus obinutuzumab (oral venetoclax initiated on day 22 of cycle 1 [28-day cycles], with a 5-week dose ramp-up [20 mg, 50 mg, 100 mg, and 200 mg, then 400 mg daily for 1 week], thereafter continuing at 400 mg daily until completion of cycle 12; combined with intravenous obinutuzumab for six cycles starting with 100 mg on day 1 and 900 mg on day 2 [or 1000 mg on day 1], 1000 mg on days 8 and day 15 of cycle 1, and subsequently 1000 mg on day 1 of cycles 2 through 6) or chlorambucil plus obinutuzumab (oral chlorambucil at 0·5 mg/kg bodyweight on days 1 and 15 of each cycle for 12 cycles combined with the same obinutuzumab regimen). The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. Patient enrolment is complete, and the study is registered with ClinicalTrails.gov, NCT02242942. FINDINGS: Between Aug 7, 2015, and Aug 4, 2016, 432 patients were enrolled and randomly assigned to receive either venetoclax plus obinutuzumab (n=216) or chlorambucil plus obinutuzumab (n=216). All patients had been off treatment for at least 24 months at data collection. At a median follow-up of 39·6 months (IQR 36·8-43·0), patients given venetoclax plus obinutuzumab had a significantly longer progression-free survival than did patients given chlorambucil plus obinutuzumab (HR 0·31, 95% CI 0·22-0·44; p<0·0001). Median progression-free survival was not reached (95% CI not estimable to not estimable) in the venetoclax plus obinutuzumab group vs 35·6 months (33·7-40·7) in the chlorambucil plus obinutuzumab group. The most common grade 3 or 4 adverse event in both groups was neutropenia (112 [53%] of 212 patients in the venetoclax plus obinutuzumab group versus 102 [48%] of 214 patients in the chlorambucil plus obinutuzumab group). Serious adverse events occurred in 115 (54%) of 212 patients in the venetoclax plus obinutuzumab group and 95 (44%) of 214 patients in the chlorambucil plus obinutuzumab group. Venetoclax or chlorambucil treatment-related deaths were reported in one (1%) of 212 patients in the venetoclax plus obinutuzumab group (n=1 sepsis) and two (1%) of 214 patients in the chlorambucil plus obinutuzumab group (n=1 septic shock, n=1 metastatic skin squamous carcinoma). INTERPRETATION: 2 years after treatment cessation, venetoclax plus obinutuzumab continues to significantly improve progression-survival compared with chlorambucil plus obinutuzumab, thereby providing a limited duration treatment option for patients with previously untreated chronic lymphocytic leukaemia. FUNDING: F Hoffmann-La Roche and AbbVie.

Prognostic and predictive impact of genetic markers in patients with CLL treated with obinutuzumab and venetoclax.

Genetic parameters are established prognostic factors in chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy, but are less well studied with novel compounds. We assessed immunoglobulin heavy variable chain (IGHV) mutation status, common genomic aberrations, and gene mutations in 421 untreated patients within the CLL14 trial (NCT02242942), comparing obinutuzumab+chlorambucil (GClb) vs obinutuzumab+venetoclax (VenG). The incidences of genomic aberrations considering the hierarchical model were del(17p) 7%, del(11q) 18%, +12 18%, and del(13q) 35%, whereas IGHV was unmutated in 60% of patients. NOTCH1 mutations were most common (23%), followed by SF3B1 (16%), ATM (13%), and TP53 (10%). Although the overall response rate (ORR) for GClb was lower in patients with del(17p), del(11q), mutated TP53, ATM, and BIRC3, none of these parameters reduced complete remission (CR) rate and ORR with VenG. At a median follow-up of 28 months, del(17p) and mutated TP53 were the only abnormalities with an effect on progression-free survival (PFS) for both treatment groups: GClb (hazard ratio [HR], 4.6 [P < .01]; HR, 2.7 [P < .01], respectively) and VenG (HR, 4.4 [P < .01]; HR, 3.1 [P < .01], respectively). No other factors affected outcome with VenG, whereas for GClb del(11q), BIRC3, NOTCH1, and unmutated IGHV were associated with shorter PFS. Multivariable analysis identified del(17p), del(11q), unmutated IGHV, and mutated TP53, BIRC3, and SF3B1 as independent prognostic factors for PFS with GClb, whereas for VenG, only del(17p) was significant. VenG was superior to GClb across most genetic subgroups. Patients with adverse genetic markers had the strongest benefit from VenG, particularly subjects with unmutated IGHV, which was identified as a predictive factor in a multivariable treatment-interaction analysis.

Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions.

BACKGROUND: The BCL2 inhibitor venetoclax has shown activity in patients with chronic lymphocytic leukemia (CLL), but its efficacy in combination with other agents in patients with CLL and coexisting conditions is not known. METHODS: In this open-label, phase 3 trial, we investigated fixed-duration treatment with venetoclax and obinutuzumab in patients with previously untreated CLL and coexisting conditions. Patients with a score of greater than 6 on the Cumulative Illness Rating Scale (scores range from 0 to 56, with higher scores indicating more impaired function of organ systems) or a calculated creatinine clearance of less than 70 ml per minute were randomly assigned to receive venetoclax-obinutuzumab or chlorambucil-obinutuzumab. The primary end point was investigator-assessed progression-free survival. The safety of each regimen was also evaluated. RESULTS: In total, 432 patients (median age, 72 years; median Cumulative Illness Rating Scale score, 8; median creatinine clearance, 66.4 ml per minute) underwent randomization, with 216 assigned to each group. After a median follow-up of 28.1 months, 30 primary end-point events (disease progression or death) had occurred in the venetoclax-obinutuzumab group and 77 had occurred in the chlorambucil-obinutuzumab group (hazard ratio, 0.35; 95% confidence interval [CI], 0.23 to 0.53; P<0.001). The Kaplan-Meier estimate of the percentage of patients with progression-free survival at 24 months was significantly higher in the venetoclax-obinutuzumab group than in the chlorambucil-obinutuzumab group: 88.2% (95% CI, 83.7 to 92.6) as compared with 64.1% (95% CI, 57.4 to 70.8). This benefit was also observed in patients with TP53 deletion, mutation, or both and in patients with unmutated immunoglobulin heavy-chain genes. Grade 3 or 4 neutropenia occurred in 52.8% of patients in the venetoclax-obinutuzumab group and in 48.1% of patients in the chlorambucil-obinutuzumab group, and grade 3 or 4 infections occurred in 17.5% and 15.0%, respectively. All-cause mortality was 9.3% in the venetoclax-obinutuzumab group and 7.9% in the chlorambucil-obinutuzumab group. These differences were not significant. CONCLUSIONS: Among patients with untreated CLL and coexisting conditions, venetoclax-obinutuzumab was associated with longer progression-free survival than chlorambucil-obinutuzumab. (Funded by F. Hoffmann-La Roche and AbbVie; ClinicalTrials.gov number, NCT02242942.).

A phase Ib study to assess the efficacy and safety of vismodegib in combination with ruxolitinib in patients with intermediate- or high-risk myelofibrosis.

BACKGROUND: The JAK inhibitor (JAKi) ruxolitinib is standard treatment for myelofibrosis (MF), but some patients are unresponsive. Pre-clinical and clinical data suggest that addition of a Hedgehog pathway inhibitor (HPI) to ruxolitinib might improve response. Vismodegib is an HPI approved for treatment of locally advanced and metastatic basal cell carcinoma. The MYLIE study assessed the safety and efficacy of combining ruxolitinib with vismodegib in ruxolitinib-naive patients with MF and characterized the pharmacokinetics (PK) of vismodegib in this setting. METHODS: In this phase Ib study, ten patients with intermediate- or high-risk primary or secondary MF received open-label vismodegib (150 mg/day orally) and ruxolitinib (15 or 20 mg orally twice daily, depending on baseline platelet count) for up to 48 weeks, or until withdrawal or discontinuation. PK samples were collected throughout the study for comparison with other patient populations. Efficacy outcomes at week 24 included spleen response (≥ 35% reduction in volume by imaging) and improvement in bone marrow fibrosis by central and investigator assessment, symptom response (≥ 50% reduction in Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom score), and anemia response (per International Working Group for Myeloproliferative Neoplasms Research and Treatment revised response criteria). RESULTS: As of November 17, 2017, eight patients had completed 48 weeks of treatment with vismodegib and ruxolitinib; two discontinued treatment early. At week 24 (± 1 week), three patients experienced a spleen response by central review and no patients showed a 1-grade improvement in bone marrow fibrosis by central review. Five patients experienced symptom response at week 24, and no patients experienced an anemia response. The most common adverse events were muscle spasm (100% of patients), alopecia (70%), dysgeusia (50%), thrombocytopenia (50%), and nausea (40%); these events were predominantly grade 1/2. Three patients experienced a total of six serious adverse events. CONCLUSIONS: The combination of vismodegib and ruxolitinib was tolerable and no new safety signals were seen, but there was no evidence that the addition of vismodegib to ruxolitinib improved any of the efficacy outcome measures assessed. Further evaluation of this combination will not be pursued. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02593760 . Registered November 2, 2015.