Browsing by Subject "Protein kinase inhibitors"
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Item Adjuvant Palbociclib for Early Breast Cancer: The PALLAS Trial Results (ABCSG-42/AFT-05/BIG-14-03)(American Society of Clinical Oncology, 2022) Gnant, Michael; Dueck, Amylou C.; Frantal, Sophie; Martin, Miguel; Burstein, Hal J.; Greil, Richard; Fox, Peter; Wolff, Antonio C.; Chan, Arlene; Winer, Eric P.; Pfeiler, Georg; Miller, Kathy D.; Colleoni, Marco; Suga, Jennifer M.; Rubovsky, Gabor; Bliss, Judith M.; Mayer, Ingrid A.; Singer, Christian F.; Nowecki, Zbigniew; Hahn, Olwen; Thomson, Jacqui; Wolmark, Norman; Amillano, Kepa; Rugo, Hope S.; Steger, Guenther G.; Hernando Fernández de Aránguiz, Blanca; Haddad, Tufia C.; Perelló, Antonia; Bellet, Meritxell; Fohler, Hannes; Metzger Filho, Otto; Jallitsch-Halper, Anita; Solomon, Kadine; Schurmans, Céline; Theall, Kathy P.; Lu, Dongrui R.; Tenner, Kathleen; Fesl, Christian; DeMichele, Angela; Mayer, Erica L.; PALLAS groups and investigators; Medicine, School of MedicinePurpose: Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor approved for advanced breast cancer. In the adjuvant setting, the potential value of adding palbociclib to endocrine therapy for hormone receptor-positive breast cancer has not been confirmed. Patients and methods: In the prospective, randomized, phase III PALLAS trial, patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer were randomly assigned to receive 2 years of palbociclib (125 mg orally once daily, days 1-21 of a 28-day cycle) with adjuvant endocrine therapy or adjuvant endocrine therapy alone (for at least 5 years). The primary end point of the study was invasive disease-free survival (iDFS); secondary end points were invasive breast cancer-free survival, distant recurrence-free survival, locoregional cancer-free survival, and overall survival. Results: Among 5,796 patients enrolled at 406 centers in 21 countries worldwide over 3 years, 5,761 were included in the intention-to-treat population. At the final protocol-defined analysis, at a median follow-up of 31 months, iDFS events occurred in 253 of 2,884 (8.8%) patients who received palbociclib plus endocrine therapy and in 263 of 2,877 (9.1%) patients who received endocrine therapy alone, with similar results between the two treatment groups (iDFS at 4 years: 84.2% v 84.5%; hazard ratio, 0.96; CI, 0.81 to 1.14; P = .65). No significant differences were observed for secondary time-to-event end points, and subgroup analyses did not show any differences by subgroup. There were no new safety signals for palbociclib in this trial. Conclusion: At this final analysis of the PALLAS trial, the addition of adjuvant palbociclib to standard endocrine therapy did not improve outcomes over endocrine therapy alone in patients with early hormone receptor-positive breast cancer.Item Biomarker Changes in Response to Tofacitinib Treatment in Patients With Polyarticular-Course Juvenile Idiopathic Arthritis(Wiley, 2024) Ogbu, Ekemini A.; Brunner, Hermine I.; Eloseily, Esraa; Aviel, Yonatan Butbul; Nanda, Kabita; Schmeling, Heinrike; Tory, Heather; Uziel, Yosef; Viola, Diego Oscar; Wahezi, Dawn M.; Tarvin, Stacey E.; Sproles, Alyssa; Chen, Chen; Ruperto, Nicolino; Huang, Bin; Grom, Alexei; Thornton, Sherry; Investigators of the PRINTO and PRCSG Networks; Pediatrics, School of MedicineObjective: We examine levels of candidate blood-based biomarkers (CBBs) in patients with juvenile idiopathic arthritis (JIA) treated with tofacitinib. Methods: Patients with JIA who participated in clinical trial NCT02592434 received tofacitinib from baseline to week 18. Serial serum samples were assayed for CBBs (S100A8/9, S100A12, interleukin-18 [IL-18], serum amyloid A, resistin, vascular endothelial growth factor, angiopoietin-1, angiopoietin-2, matrix metalloproteinase 8 [MMP8], MMP2, tissue inhibitor of metalloproteinases 1, leptin, chemokine [C-X-C motif] ligand 9, soluble IL-2 receptor, intercellular adhesion molecule 1, soluble tumor necrosis factor receptor, IL-6, IL-23, monocyte chemotactic protein 1, chemokine [C-C motif] ligand 18 [CCL18], and CCL20). Association of CBBs with JIA response to treatment from baseline to week 18 were assessed. Results: This study included 166 patients with polyarticular-course JIA. Paired serum samples from 143 patients were available at both baseline and week 18. Thirty-five percent (50 of 143) of patients had a JIA-American College of Rheumatology 90 (JIA-ACR90) level improvement, whereas 90, 121, and 137 (63%, 85%, and 96%) achieved JIA-ACR70, 50, and 30 improvement at week 18. Despite small numerical differences by JIA category, there were no baseline CBB values that independently predicted a decrease in Juvenile Arthritis Disease Activity Score (JADAS-27) or JIA-ACR90 response by week 18. Decrease in resistin level (baseline to week 18) was significantly associated with week 18 improvement in JADAS-27 and JIA-ACR90 response after adjusting for age, sex, JIA disease duration, and baseline resistin (r2 0.79, SE 0.070, P < 0.01, and odds ratio [95% confidence interval] 1.134 [1.018-1.264]). HLA-B27 positivity was significantly associated with not achieving a JIA-ACR90 response at week 18 (P = 0.0097). Conclusion: Among the CBBs included, only resistin was significantly associated with treatment response, and no CBB was identified that forecasts JIA improvement after initiation of tofacitinib. The association of HLA-B27 positivity with lower response to tofacitinib in JIA is intriguing and merits further study.Item Combined CDK4/6 and ERK1/2 inhibition enhances anti-tumor activity in NF1-associated plexiform neurofibroma(American Association for Cancer Research, 2023) Flint, Alyssa C.; Mitchell, Dana K.; Angus, Steven P.; Smith, Abbi E.; Bessler, Waylan; Jiang, Li; Mang, Henry; Li, Xiaohong; Lu, Qingbo; Rodriguez, Brooke; Sandusky, George E.; Masters, Andi R.; Zhang, Chi; Dang, Pengtao; Koenig, Jenna; Johnson, Gary L.; Shen, Weihua; Liu, Jiangang; Aggarwal, Amit; Donoho, Gregory P.; Willard, Melinda D.; Bhagwat, Shripad V.; Clapp, D. Wade; Rhodes, Steven D.; Pediatrics, School of MedicinePurpose: Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options remain limited. To identify novel therapeutic targets for PNF, we applied an integrated multi-omic approach to quantitatively profile kinome enrichment in a mouse model that has predicted therapeutic responses in clinical trials for NF1-associated PNF with high fidelity. Experimental design: Utilizing RNA sequencing combined with chemical proteomic profiling of the functionally enriched kinome using multiplexed inhibitor beads coupled with mass spectrometry, we identified molecular signatures predictive of response to CDK4/6 and RAS/MAPK pathway inhibition in PNF. Informed by these results, we evaluated the efficacy of the CDK4/6 inhibitor, abemaciclib, and the ERK1/2 inhibitor, LY3214996, alone and in combination in reducing PNF tumor burden in Nf1flox/flox;PostnCre mice. Results: Converging signatures of CDK4/6 and RAS/MAPK pathway activation were identified within the transcriptome and kinome that were conserved in both murine and human PNF. We observed robust additivity of the CDK4/6 inhibitor, abemaciclib, in combination with the ERK1/2 inhibitor, LY3214996, in murine and human NF1(Nf1) mutant Schwann cells. Consistent with these findings, the combination of abemaciclib (CDK4/6i) and LY3214996 (ERK1/2i) synergized to suppress molecular signatures of MAPK activation and exhibited enhanced antitumor activity in Nf1flox/flox;PostnCre mice in vivo. Conclusions: These findings provide rationale for the clinical translation of CDK4/6 inhibitors alone and in combination with therapies targeting the RAS/MAPK pathway for the treatment of PNF and other peripheral nerve sheath tumors in persons with NF1.Item Imatinib therapy for patients with recent-onset type 1 diabetes: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial(Elsevier, 2021) Gitelman, Stephen E.; Bundy, Brian N.; Ferrannini, Ele; Lim, Noha; Blanchfield, J. Lori; DiMeglio, Linda A.; Felner, Eric I.; Gaglia, Jason L.; Gottlieb, Peter A.; Long, S. Alice; Mari, Andrea; Mirmira, Raghavendra G.; Raskin, Philip; Sanda, Srinath; Tsalikian, Eva; Wentworth, John M.; Willi, Steven M.; Krischer, Jeffrey P.; Bluestone, Jeffrey A.; Gleevec Trial Study Group; Pediatrics, School of MedicineBackground: Type 1 diabetes results from autoimmune-mediated destruction of β cells. The tyrosine kinase inhibitor imatinib might affect relevant immunological and metabolic pathways, and preclinical studies show that it reverses and prevents diabetes. Our aim was to evaluate the safety and efficacy of imatinib in preserving β-cell function in patients with recent-onset type 1 diabetes. Methods: We did a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Patients with recent-onset type 1 diabetes (<100 days from diagnosis), aged 18-45 years, positive for at least one type of diabetes-associated autoantibody, and with a peak stimulated C-peptide of greater than 0·2 nmol L-1 on a mixed meal tolerance test (MMTT) were enrolled from nine medical centres in the USA (n=8) and Australia (n=1). Participants were randomly assigned (2:1) to receive either 400 mg imatinib mesylate (4 × 100 mg film-coated tablets per day) or matching placebo for 26 weeks via a computer-generated blocked randomisation scheme stratified by centre. Treatment assignments were masked for all participants and study personnel except pharmacists at each clinical site. The primary endpoint was the difference in the area under the curve (AUC) mean for C-peptide response in the first 2 h of an MMTT at 12 months in the imatinib group versus the placebo group, with use of an ANCOVA model adjusting for sex, baseline age, and baseline C-peptide, with further observation up to 24 months. The primary analysis was by intention to treat (ITT). Safety was assessed in all randomly assigned participants. This study is registered with ClinicalTrials.gov, NCT01781975 (completed). Findings: Patients were screened and enrolled between Feb 12, 2014, and May 19, 2016. 45 patients were assigned to receive imatinib and 22 to receive placebo. After withdrawals, 43 participants in the imatinib group and 21 in the placebo group were included in the primary ITT analysis at 12 months. The study met its primary endpoint: the adjusted mean difference in 2-h C-peptide AUC at 12 months for imatinib versus placebo treatment was 0·095 (90% CI -0·003 to 0·191; p=0·048, one-tailed test). This effect was not sustained out to 24 months. During the 24-month follow-up, 32 (71%) of 45 participants who received imatinib had a grade 2 severity or worse adverse event, compared with 13 (59%) of 22 participants who received placebo. The most common adverse events (grade 2 severity or worse) that differed between the groups were gastrointestinal issues (six [13%] participants in the imatinib group, primarily nausea, and none in the placebo group) and additional laboratory investigations (ten [22%] participants in the imatinib group and two [9%] in the placebo group). Per the trial protocol, 17 (38%) participants in the imatinib group required a temporary modification in drug dosing and six (13%) permanently discontinued imatinib due to adverse events; five (23%) participants in the placebo group had temporary modifications in dosing and none had a permanent discontinuation due to adverse events. Interpretation: A 26-week course of imatinib preserved β-cell function at 12 months in adults with recent-onset type 1 diabetes. Imatinib might offer a novel means to alter the course of type 1 diabetes. Future considerations are defining ideal dose and duration of therapy, safety and efficacy in children, combination use with a complimentary drug, and ability of imatinib to delay or prevent progression to diabetes in an at-risk population; however, careful monitoring for possible toxicities is required.Item MYC and HSF1 Cooperate to Drive Sensitivity to Polo-like Kinase 1 Inhibitor Volasertib in High-grade Serous Ovarian Cancer(American Association for Cancer Research, 2025) Williams, Imade; O’Malley, Matthew; DeHart, Haddie; Walker, Bobby; Ulhaskumar, Vrushabh; Jothirajah, Pranav; Ray, Haimanti; Landrum, Lisa M.; Delaney, Joe R.; Nephew, Kenneth P.; Carpenter, Richard L.; Obstetrics and Gynecology, School of MedicineWe show that HSF1 and MYC genes are co-amplified in more than 30% of HGSOC and demonstrate that HSF1 and MYC functionally cooperate to drive the growth of HGSOC cells. This work provides the foundation for HSF1 and MYC co-amplification as a biomarker for treatment efficacy of the polo-like kinase 1 inhibitor volasertib in HGSOC.Item PERK Inhibition by HC-5404 Sensitizes Renal Cell Carcinoma Tumor Models to Antiangiogenic Tyrosine Kinase Inhibitors(American Association for Cancer Research, 2023) Stokes, Michael E.; Calvo, Veronica; Fujisawa, Sho; Dudgeon, Crissy; Huang, Sharon; Ballal, Nupur; Shen, Leyi; Gasparek, Jennifer; Betzenhauser, Matthew; Taylor, Simon J.; Staschke, Kirk A.; Rigby, Alan C.; Mulvihill, Mark J.; Bose, Nandita; Lightcap, Eric S.; Surguladze, David; Biochemistry and Molecular Biology, School of MedicinePurpose: Tumors activate protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK, also called EIF2AK3) in response to hypoxia and nutrient deprivation as a stress-mitigation strategy. Here, we tested the hypothesis that inhibiting PERK with HC-5404 enhances the antitumor efficacy of standard-of-care VEGF receptor tyrosine kinase inhibitors (VEGFR-TKI). Experimental design: HC-5404 was characterized as a potent and selective PERK inhibitor, with favorable in vivo properties. Multiple renal cell carcinoma (RCC) tumor models were then cotreated with both HC-5404 and VEGFR-TKI in vivo, measuring tumor volume across time and evaluating tumor response by protein analysis and IHC. Results: VEGFR-TKI including axitinib, cabozantinib, lenvatinib, and sunitinib induce PERK activation in 786-O RCC xenografts. Cotreatment with HC-5404 inhibited PERK in tumors and significantly increased antitumor effects of VEGFR-TKI across multiple RCC models, resulting in tumor stasis or regression. Analysis of tumor sections revealed that HC-5404 enhanced the antiangiogenic effects of axitinib and lenvatinib by inhibiting both new vasculature and mature tumor blood vessels. Xenografts that progress on axitinib monotherapy remain sensitive to the combination treatment, resulting in ∼20% tumor regression in the combination group. When tested across a panel of 18 RCC patient-derived xenograft (PDX) models, the combination induced greater antitumor effects relative to monotherapies. In this single animal study, nine out of 18 models responded with ≥50% tumor regression from baseline in the combination group. Conclusions: By disrupting an adaptive stress response evoked by VEGFR-TKI, HC-5404 presents a clinical opportunity to improve the antitumor effects of well-established standard-of-care therapies in RCC.Item Phase Ib/II Study of Enzalutamide with Samotolisib (LY3023414) or Placebo in Patients with Metastatic Castration-Resistant Prostate Cancer(American Association for Cancer Research, 2022) Sweeney, Christopher J.; Percent, Ivor J.; Babu, Sunil; Cultrera, Jennifer L.; Mehlhaff, Bryan A.; Goodman, Oscar B.; Morris, David S.; Schnadig, Ian D.; Albany, Costantine; Shore, Neal D.; Sieber, Paul R.; Guba, Susan C.; Zhang, Wei; Wacheck, Volker; Donoho, Gregory P.; Szpurka, Anna M.; Callies, Sophie; Lin, Boris Kin; Bendell, Johanna C.; Medicine, School of MedicinePurpose: To report efficacy and safety of samotolisib (LY3023414; PI3K/mTOR dual kinase and DNA-dependent protein kinase inhibitor) plus enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) following cancer progression on abiraterone. Patients and methods: In this double-blind, placebo-controlled phase Ib/II study (NCT02407054), following a lead-in segment for evaluating safety and pharmacokinetics of samotolisib and enzalutamide combination, patients with advanced castration-resistant prostate cancer with progression on prior abiraterone were randomized to receive enzalutamide (160 mg daily)/samotolisib (200 mg twice daily) or placebo. Primary endpoint was progression-free survival (PFS) assessed by Prostate Cancer Clinical Trials Working Group criteria (PCWG2). Secondary and exploratory endpoints included radiographic PFS (rPFS) and biomarkers, respectively. Log-rank tests assessed treatment group differences. Results: Overall, 13 and 129 patients were enrolled in phase Ib and II, respectively. Dose-limiting toxicity was not reported in patients during phase Ib and mean samotolisib exposures remained in the targeted range despite a 35% decrease when administered with enzalutamide. In phase II, median PCWG2-PFS and rPFS was significantly longer in the samotolisib/enzalutamide versus placebo/enzalutamide arm (3.8 vs. 2.8 months; P = 0.003 and 10.2 vs. 5.5 months; P = 0.03), respectively. Patients without androgen receptor splice variant 7 showed a significant and clinically meaningful rPFS benefit in the samotolisib/enzalutamide versus placebo/enzalutamide arm (13.2 months vs. 5.3 months; P = 0.03). Conclusions: Samotolisib/enzalutamide has tolerable side effects and significantly improved PFS in patients with mCRPC with cancer progression on abiraterone, and this may be enriched in patients with PTEN intact and no androgen receptor splice variant 7.Item Treatment Exposure and Discontinuation in the PALbociclib CoLlaborative Adjuvant Study of Palbociclib With Adjuvant Endocrine Therapy for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer (PALLAS/AFT-05/ABCSG-42/BIG-14-03)(American Society of Clinical Oncology, 2022) Mayer, Erica L.; Fesl, Christian; Hlauschek, Dominik; Garcia-Estevez, Laura; Burstein, Harold J.; Zdenkowski, Nicholas; Wette, Viktor; Miller, Kathy D.; Balic, Marija; Mayer, Ingrid A.; Cameron, David; Winer, Eric P.; Ponce Lorenzo, José Juan; Lake, Diana; Pristauz-Telsnigg, Gunda; Haddad, Tufia C.; Shepherd, Lois; Iwata, Hiroji; Goetz, Matthew; Cardoso, Fatima; Traina, Tiffany A.; Sabanathan, Dhanusha; Breitenstein, Urs; Ackerl, Kerstin; Metzger Filho, Otto; Zehetner, Karin; Solomon, Kadine; El-Abed, Sarra; Puyana Theall, Kathy; Lu, Dongrui Ray; Dueck, Amylou; Gnant, Michael; DeMichele, Angela; Medicine, School of MedicinePurpose: The PALLAS study investigated whether the addition of palbociclib, an oral CDK4/6 inhibitor, to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) in early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. In this analysis, we evaluated palbociclib exposure and discontinuation in PALLAS. Methods: Patients with stage II-III HR+, HER2- disease were randomly assigned to 2 years of palbociclib with adjuvant ET versus ET alone. The primary objective was to compare iDFS between arms. Continuous monitoring of toxicity, dose modifications, and early discontinuation was performed. Association of baseline covariates with time to palbociclib reduction and discontinuation was analyzed with multivariable competing risk models. Landmark and inverse probability weighted per-protocol analyses were performed to assess the impact of drug persistence and exposure on iDFS. Results: Of the 5,743 patient analysis population (2,840 initiating palbociclib), 1,199 (42.2%) stopped palbociclib before 2 years, the majority (772, 27.2%) for adverse effects, most commonly neutropenia and fatigue. Discontinuation of ET did not differ between arms. Discontinuations for non-protocol-defined reasons were greater in the first 3 months of palbociclib, and in the first calendar year of accrual, and declined over time. No significant relationship was seen between longer palbociclib duration or ≥ 70% exposure intensity and improved iDFS. In the weighted per-protocol analysis, no improvement in iDFS was observed in patients receiving palbociclib versus not (hazard ratio 0.89; 95% CI, 0.72 to 1.11). Conclusion: Despite observed rates of discontinuation in PALLAS, analyses suggest that the lack of significant iDFS difference between arms was not directly related to inadequate palbociclib exposure. However, the discontinuation rate illustrates the challenge of introducing novel adjuvant treatments, and the need for interventions to improve persistence with oral cancer therapies.Item Zandelisib with continuous or intermittent dosing as monotherapy or in combination with rituximab in patients with relapsed or refractory B-cell malignancy: a multicentre, first-in-patient, dose-escalation and dose-expansion, phase 1b trial(Elsevier, 2022) Pagel, John M.; Soumerai, Jacob D.; Reddy, Nishitha; Jagadeesh, Deepa; Stathis, Anastasios; Asch, Adam; Salman, Huda; Kenkre, Vaishalee P.; Iasonos, Alexia; Llorin-Sangalang, Judith; Li, Joanne; Zelenetz, Andrew D.; Medicine, School of MedicineBackground: Phosphatidylinositol 3-kinase p110δ (PI3Kδ) inhibitors are efficacious in B-cell malignancies. Immune-related adverse events might be mitigated with intermittent dosing. We aimed to evaluate the safety and antitumour activity of zandelisib, a potent novel PI3Kδ inhibitor, with continuous or intermittent dosing as monotherapy or in combination with rituximab, in patients with relapsed or refractory B-cell malignancy. Methods: We conducted a first-in-patient, dose-escalation and dose-expansion, phase 1b trial at ten treatment centres across Switzerland and the USA. Eligible patients were aged 18 years or older with relapsed or refractory B-cell malignancy (limited to follicular lymphoma or chronic lymphocytic leukaemia during dose escalation) and an Eastern Cooperative Oncology Group performance status of 0-2, and had received at least one previous line of therapy and no previous PI3Kδ inhibitor treatment. In the dose-escalation study, participants received oral zandelisib once daily (60 mg, 120 mg, or 180 mg; we did not evaluate four additional planned dose levels). The 60 mg dose was further evaluated as monotherapy or with intravenous rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 3-6, using a continuous daily schedule or intermittent dosing therapy (days 1-28 of cycles 1-2 and days 1-7 of subsequent cycles) in 28-day cycles. Treatment was continued until evidence of disease progression, intolerance, or withdrawal of consent by the patient. Primary endpoints were safety (dose-limiting toxicities and maximum tolerated dose), minimum biologically effective dose, and a composite endpoint to assess the activity of each dose level, and were analysed by intention to treat. The zandelisib monotherapy and zandelisib-rituximab combination cohorts have completed accrual, but accrual to a cohort evaluating zandelisib with zanubrutinib is ongoing. This study is registered with ClinicalTrials.gov, NCT02914938. Findings: Between Nov 17, 2016, and June 2, 2020, 100 patients were assessed for eligibility and 97 were enrolled and received zandelisib monotherapy (n=56) or zandelisib plus rituximab (n=41), with zandelisib administered on either a continuous schedule (n=38) or with intermittent dosing (n=59). No dose-limiting toxicities were observed, the objective of determining the maximum tolerated dose was abandoned, and antitumour activity was similar across the evaluated doses activity (objective responses in 11 [92%; 95% CI 61·5-99·8] of 12 patients at both 60 mg and 120 mg doses, and in five [83%; 95% CI 35·9-99·6] of six patients at 180 mg). With a median duration of exposure of 15·2 months (IQR 3·7-21·7), the most common grade 3-4 adverse events were neutrophil count decrease (ten [17%] of 59 patients in the intermittent dosing group and four [11%] of 38 in the continuous dosing group), diarrhoea (three [5%] and eight [21%]), pneumonia (one [2%] and six [16%]), alanine aminotransferase increase (three [5%] and two [5%]), and colitis (two [3%] and one [3%]). 26 (44%) of 59 patients in the intermittent dosing group and 29 (76%) of 38 patients in the continuous dosing group had grade 3-4 adverse events. Treatment-related serious adverse events occurred in eight (21%) patients in the continuous dosing group and five (8%) patients in the intermittent dosing group. There were no treatment-related deaths. Interpretation: Zandelisib 60 mg once daily on an intermittent dosing schedule was safe, with low frequency of grade 3 or worse adverse events, warranting the ongoing global phase 2 and phase 3 trials.