P1086: EFFICACY AND SAFETY OF ZANDELISIB ADMINISTERED BY INTERMITTENT DOSING IN JAPANESE PATIENTS WITH RELAPSED/REFRACTORY INDOLENT B-CELL NON-HODGKIN’S LYMPHOMA: PRIMARY ANALYSIS OF THE PHASE 2 STUDY MIRAGE
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SUBMITTER: Kumode T
PROVIDER: S-EPMC10430995 | biostudies-literature | 2023 Aug
REPOSITORIES: biostudies-literature
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Project description:In this global phase 2 study in patients with relapsed/refractory follicular lymphoma (FL), zandelisib was administered on intermittent dosing to mitigate immune-related adverse events and infections that have been reported with oral PI3Kδ inhibitors administered daily continuously. Eligible patients with measurable disease and progression after at least two prior therapies were administered zandelisib until disease progression or intolerability. The primary efficacy endpoint was objective response rate (ORR) and the key secondary efficacy endpoint was duration of response (DOR). We report on 121 patients with FL administered zandelisib on intermittent dosing after 8 weeks of daily dosing for tumor debulking. The median number of prior therapies was 3 (range, 2-8) and 45% of patients had refractory disease. The ORR was 73% (95% confidence interval [CI], 63.9-80.4), the complete response (CR) rate was 38% (95% CI, 29.3-47.3), and the median DOR was 16.4 months (95% CI, 9.5-not reached). With a median follow-up of 14.3 months (range, 1-30.5), the median progression-free survival was 11.6 months (95% CI, 8.3-not reached). Twenty-one patients (17%) discontinued therapy due to an adverse event. Grade 3-4 class-related toxicities included 6% diarrhea, 5% lung infections, 3% colitis (confirmed by biopsy or imaging), 3% rash, 2% AST elevation, and 1% non-infectious pneumonitis. Zandelisib achieved a high rate of durable responses in heavily pretreated patients with relapsed/refractory FL. The intermittent dosing resulted in a relatively low incidence of severe class-related toxicities, which supports the evaluation of zandelisib as a single agent and in combination with indolent B-cell malignancies.
| S-EPMC11302793 | biostudies-literature
Project description:The selective phosphatidylinositol 3-kinase δ inhibitor zandelisib demonstrated favorable safety and efficacy [objective response rate (ORR) 79%] in patients with B-cell malignancies in a phase 1b study in the US and Switzerland. In this phase 1 dose-escalation study (NCT03985189), 9 Japanese patients with relapsed/refractory indolent non-Hodgkin's lymphoma (R/R iNHL) received zandelisib on a continuous daily schedule (45 or 60 mg) until progressive disease/unacceptable toxicity. No dose-limiting toxicities were observed. The maximum tolerated dose was not reached. At a median follow-up of 17.5 months, Grade ≥ 3 treatment-emergent adverse events that occurred in 2 or more patients were neutrophil count decreased (55.6%; 5/9) and diarrhea (33.3%; 3/9). Immune-related toxicities, including hepatobiliary disorder, aspartate/alanine aminotransferase increased, diarrhea/colitis, organizing pneumonia, stomatitis, and rash, led to zandelisib discontinuation in 4 patients. The investigator-assessed ORR, based on modified Lugano criteria, was 100%, including 2 complete responses (22.2%; in follicular lymphoma patients receiving 60 mg/day). Median duration of response, progression-free survival, and time to response were 7.9, 11.1, and 1.9 months, respectively. Zandelisib demonstrated a manageable safety profile at 60 mg, the recommended phase 2 dose (RP2D) in Japanese patients. The RP2D resulted in favorable pharmacokinetics and anti-tumor efficacy in Japanese patients with R/R iNHL.Trial registration. NCT03985189 (ClinicalTrials.gov).
| S-EPMC9668928 | biostudies-literature
Project description:Zandelisib, a selective, potent PI3Kδ inhibitor, demonstrated favourable outcomes in patients with relapsed or refractory follicular lymphoma in a global phase II study. This phase II study evaluated the efficacy and safety of zandelisib for relapsed or refractory follicular lymphoma or marginal zone lymphoma. Sixty-one patients received zandelisib orally at 60 mg daily continuously in the first two 28-day cycles, followed by intermittent dosing on Days 1-7 following each cycle until progressive disease or unacceptable toxicity. Objective and complete response rates were 75.4% (95% confidence interval [CI], 62.7%-85.5%) and 24.6% (95% CI, 14.5%-37.3%) respectively. Median time to response was 58 days; 70.5% (43/61) of patients achieved their first response by Week 8. At least one Grade ≥ 3 treatment-emergent adverse event (TEAE) occurred in 55.7% of patients: transaminase elevation (8.2%); cutaneous reactions (3.3%); and diarrhoea, enterocolitis and lung infection (1.6% each), defined as adverse events of special interest. The discontinuation rate due to any TEAE was 14.8%. No zandelisib-related death occurred. Zandelisib showed favourable efficacy and tolerability in Japanese patients with relapsed or refractory indolent non-Hodgkin B-cell lymphoma. This unique dosing schedule may maintain efficacy while mitigating the safety issues observed with other PI3Kδ inhibitors (ClinicalTrials.gov number, NCT04533581).
| S-EPMC11829137 | biostudies-literature
Project description:Outcomes for marginal zone lymphoma (MZL) and follicular lymphoma (FL) remain suboptimal, owing to the limited number of approved agents and the incurable nature of the diseases. BGB-3111-AU-003 was a phase 1/2, open-label, multicenter, single-agent study of the selective Bruton's tyrosine kinase inhibitor zanubrutinib in 385 patients with B-cell malignancies. Here, we present safety and efficacy outcomes for the 53 enrolled patients with relapsed/refractory MZL (n = 20) and relapsed/refractory FL (n = 33), all of whom were enrolled during the part 2 dose expansion, and therefore received zanubrutinib at the recommended phase 2 dose. Treatment with zanubrutinib was generally well tolerated, with most adverse events being ≤ grade 2. Atrial fibrillation/flutter was not reported. Two patients required dose reduction, and 4 patients discontinued treatment because of adverse events. Response was assessed by an independent review committee for MZL and the investigators for FL, per Lugano 2014 classification for non-Hodgkin lymphoma. In patients with MZL, the overall response rate (ORR) was 80%, and the complete response (CR) rate was 20%. With median follow-up of 33.8 months, median progression-free survival (PFS) was not reached. In patients with FL, the ORR was 36.4%, and the CR rate was 18.2%. After a median follow-up of 33.9 months, median PFS was 10.4 months. In conclusion, the results of this study suggest a favorable benefit-risk profile and support zanubrutinib as a potentially meaningful addition to available therapies for patients with relapsed/refractory MZL and FL. This trial was registered at www.clinicaltrials.gov as #NCT02343120.
| S-EPMC9198905 | biostudies-literature
Project description:BackgroundPhosphatidylinositol 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.MethodsWe 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.FindingsBetween 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.InterpretationZandelisib 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.FundingMEI Pharma.
| S-EPMC11870117 | biostudies-literature
Project description:The safety, efficacy, and pharmacokinetics of copanlisib were evaluated in this phase Ib/II study in Japanese patients with relapsed/refractory indolent non-Hodgkin lymphoma (NHL). The primary endpoint was safety at the recommended dose; efficacy endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival. In phase Ib, patients received copanlisib 45 mg intravenously on days 1, 8, and 15 of a 28-day cycle, and when tolerated, consecutive patients received copanlisib 60 mg. As no dose-limiting toxicities occurred at the 45 mg (n = 3) or 60 mg (n = 7) dose in phase Ib, the recommended dose for Japanese patients was determined to be 60 mg, and this dose was used in phase II (n = 15). Although all patients experienced at least one treatment-emergent adverse event (TEAE), with hyperglycemia being the most common AE, no AE-related deaths were reported. The ORR was 68.0% (17/25 patients), median PFS was 302 (95% CI 231-484) days, and the duration of response was 330 (range 65-659) days. The pharmacokinetic properties of copanlisib were similar between Japanese and non-Japanese patients. Overall, copanlisib 60 mg had an acceptable safety profile and showed promising antitumor activity in Japanese patients with relapsed/refractory indolent NHL.
| S-EPMC9813077 | biostudies-literature
Project description:Of the 142 patients enrolled in Study CHRONOS-1, an open-label, single-arm, Phase II study evaluating the efficacy and safety of single-agent copanlisib in patients with relapsed or refractory, indolent B-cell lymphoma (NCT01660451; Part B), 96 archival formalin-fixed paraffin-embedded tumor tissues were collected under relevant consent and available for tumor macro-dissection, mRNA extraction and gene expression profiling using Affymetrix GeneChip Gene ST 1.0 Arrays (AltheaDx, Inc., San Diego, CA, USA). Of these, only 78 samples were with high quality and passed Affymetrix positive versus negative controls AUC ≥ 0.62. Affymetrix CEL files were processed with RMA (R package affy) using a custom CDF from Brainarray (version 20.0.0). 71 patients with indolent non-Hodgkin lymphoma (iNHL), including 54 with follicular lymphoma (FL), had both response data and evaluable gene expression data with high quality array data sets (array positive versus negative controls AUC ≥ 0.62) and were included in this biomarker analysis. In this study, with the exception of subject # 16349B-53, for which expression values were averaged from three equal aliquots that were amplified and scanned on 3 separate days in order to control for day-to-day batch effect, there was only one sample per subject. Affymetrix raw data (CEL files) and the gene expression matrix generated with RMA for the 78 high quality tumor samples are submitted.
2017-12-01 | E-MTAB-6088 | biostudies-arrayexpress
Project description: Not available
| S-EPMC5161005 | biostudies-literature
Project description:PurposePhosphatidylinositol-3-kinase (PI3K) inhibitors have shown activity in relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). PI3K inhibitors have been hampered by poor long-term tolerability and toxicity, which interfere with continuous use. Umbralisib, a dual inhibitor of PI3Kδ/casein kinase-1ε, exhibits improved selectivity for PI3Kδ compared with other PI3K inhibitors. This phase IIb trial was designed to evaluate the efficacy and safety of umbralisib in patients with R/R iNHL.Patients and methodsIn this multicohort, open-label, phase IIb study, 208 patients with R/R marginal zone, follicular, or small lymphocytic lymphoma (MZL, FL, or SLL) unresponsive to prior treatments (≥ 1 MZL; ≥ 2 FL/SLL), including ≥ 1 anti-CD20-based therapy, were administered umbralisib 800 mg orally once daily until disease progression, unacceptable toxicity, or study withdrawal. Primary end point is overall response rate; secondary end points include time to response, duration of response, progression-free survival, and safety.ResultsThe median follow-up is 27.7 months (efficacy) and 21.4 months (safety). The overall response rate was 47.1%, and tumor reduction occurred in 86.4% of patients. The median time to response was 2.7-4.6 months. The median duration of response was not reached for MZL, 11.1 months for FL, and 18.3 months for SLL. Median progression-free survival was not reached for MZL, 10.6 months for FL, and 20.9 months for SLL. At least one grade ≥ 3 treatment-emergent adverse event (TEAE) was reported in 53.4% of patients. TEAEs led to umbralisib discontinuation in 32 patients (15.4%). A total of 31 patients (14.9%) discontinued because of a treatment-related adverse event. Grade ≥ 3 TEAEs reported in ≥ 10% of patients: neutropenia (11.5%) and diarrhea (10.1%). Increased ALT/AST (grade ≥ 3) occurred in 6.7%/7.2% of patients.ConclusionUmbralisib achieved meaningful clinical activity in heavily pretreated patients with iNHL. The safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and adverse event-related discontinuations.
| S-EPMC8148421 | biostudies-literature
Project description:For patients with indolent non-Hodgkin lymphoma who fail initial anti-CD20-based immunochemotherapy or develop relapsed or refractory disease, there remains a significant unmet clinical need for new therapeutic approaches to improve outcomes and quality of life. 177Lu-lilotomab satetraxetan is a next-generation single-dose CD37-directed radioimmunotherapy (RIT) which was investigated in a phase 1/2a study in 74 patients with relapsed/refractory indolent non-Hodgkin B-cell lymphoma, including 57 patients with follicular lymphoma (FL). To improve targeting of 177Lu-lilotomab satetraxetan to tumor tissue and decrease hematologic toxicity, its administration was preceded by the anti-CD20 monoclonal antibody rituximab and the "cold" anti-CD37 antibody lilotomab. The most common adverse events (AEs) were reversible grade 3/4 neutropenia (31.6%) and thrombocytopenia (26.3%) with neutrophil and platelet count nadirs 5 to 7 weeks after RIT. The most frequent nonhematologic AE was grade 1/2 nausea (15.8%). With a single administration, the overall response rate was 61% (65% in patients with FL), including 30% complete responses. For FL with ≥2 prior therapies (n = 37), the overall response rate was 70%, including 32% complete responses. For patients with rituximab-refractory FL ≥2 prior therapies (n = 21), the overall response rate was 67%, and the complete response rate was 24%. The overall median duration of response was 13.6 months (32.0 months for patients with a complete response). 177Lu-lilotomab satetraxetan may provide a valuable alternative treatment approach in relapsed/refractory non-Hodgkin lymphoma, particularly in patients with comorbidities unsuitable for more intensive approaches. This trial was registered at www.clinicaltrials.gov as #NCT01796171.
| S-EPMC7479948 | biostudies-literature