Required Dose Interruption Research Articles

INNV-07. IVOSIDENIB AND BEVACIZUMAB IN HEAVILY PRETREATED PATIENTS WITH IDH1 MUTANT GLIOMAS

Abstract Isocitrate dehydrogenase 1 (IDH1) inhibitors are transforming the treatment of patients with non-enhancing IDH1 mutant gliomas that have only undergone surgical resection. Questions remain on the utility of IDH1 inhibitors in patients that have received prior therapies such as radiation therapy (RT) and chemotherapy (e.g. temozolomide (TMZ)) and have progressive disease. We evaluated the safety and efficacy of ivosidenib, an oral IDH1 inhibitor, in combination with bevacizumab (BEV), a monoclonal antibody targeting VEGF-A, in IDH1 mutant glioma patients that were heavily pretreated. Fourteen patients received combination ivosidenib and bevacizumab starting between February 2021 to July 2023. In our small cohort, patient age range was 26 to 73 years with seven female patients and seven male patients. Diagnoses represented were astrocytoma, IDH1 mutant (n=10) and oligodendroglioma, IDH1 mutant (n=4). At the time of IDH1 therapy initiation, the majority of patients (n=10) had a grade 3 tumor. All patients (n=14) had canonical IDH1 mutation (p.Arg132His) and had enhancing disease. Therapies initiated prior to ivosidenib therapy included: prior RT (n=12), prior TMZ (n=14) and prior BEV (n=10). The median number of progressions prior to initiation of ivosidenib combination therapy was 3 (range 2 to 6). All patients received ivosidenib dosed at 500 mg daily with bevacizumab doses varying from 5 to 15 mg/kg IV dosed every 2 to 3 weeks. Combination therapy was well tolerated with minimal patients experiencing toxicities requiring dose interruptions; diarrhea (n=2), creatine phosphokinase elevations (n=1), QTc prolongation (n=1), and thrombocytopenia (n=1). The median treatment duration on ivosidenib combination therapy was 4.42 months (range 0.69 to 11.4 months). In this cohort, the combination of ivosidenib and bevacizumab was well tolerated. More information is needed on the benefit of ivosidenib in combination with other therapies and in heavily pretreated patients with IDH1 mutant gliomas.

Abemaciclib dose escalation to maintain intensity (ADE-MI).

TPS618 Background: Abemaciclib is a an oral CDK4/6 inhibitor that is FDA-approved as adjuvant therapy for certain patients with early-stage HR+HER2- breast cancer in combination with endocrine therapy. The major toxicity of abemaciclib is diarrhea, which often occurs within the first 6-8 days of treatment initiation. Across several registrational trials, roughly 25% of patients with diarrhea from abemaciclib treatment required dose interruptions with roughly 20% required dose reductions. Because diarrhea happens early in the treatment course, one concern is this might dissuade people from continuing on or being fully adherent to adjuvant therapy. Incorporating strategies to minimize diarrhea may improve adherence and permit more patients to stay on the target recommended dose of 150mg BID for the full 2 years of adjuvant therapy. Our trial-in-progress evaluates dose escalation to address diarrhea as a cause of dose interruptions, reductions, and discontinuations, a strategy that has worked with other therapeutic agents. Specifically, our study tests the hypothesis that gradual up-titration of abemaciclib dose over a course of 4 weeks will decrease the rate of grade 3 or worse diarrhea. Methods: This is a post-marketing, single arm, phase IV trial for patients with high-risk early-stage HR+HER2- breast cancer who are eligible for treatment with adjuvant abemaciclib in combination with endocrine therapy. Fifty (50) subjects will be enrolled. Patients will gradually up-titrate the dose of abemaciclib over the course of 4 weeks before reaching the FDA recommended dose of 150mg BID (Table). The primary objective of this study is to increase the proportion of patients on the FDA recommended dose of abemaciclib at 3 months of treatment. At the significance level of 0.05, a minimum of 43 patients will achieve a power of at least 80% to detect the improvement (80% vs the historical control of 60%), using a two sized exact binomial test. Additional objectives are determining the number of days with greater than grade 1 diarrhea in the first month of treatment, determining rates of grade 3 or greater diarrhea, determining DFS and OS, and to assess patient reported outcomes regarding adverse events. The trial opened to enrollment on 12/21/2023. The first patient on the study was enrolled 1/25/2024. Clinical trial information: NCT06169371 . [Table: see text]

Efficacy and toxicity of KIT targeted therapy in elderly patients with melanoma.

e23269 Background: Most cases of malignant melanoma are cutaneous, with ≈50% having a BRAF driver mutation that predicts response to MAPK pathway inhibitors. A small minority of melanoma cases harbor an activating KIT mutation, most notably in mucosal and acral melanomas (15-20%) and occasionally in those arising from chronic sun-damaged skin (2-3%). Only about a third of KIT mutated melanomas respond to targeted therapy with Imatinib, yet data is scarce and limited, especially in older patients. We sought to characterize the efficacy and toxicity of Imatinib in KIT-mutated melanoma patients over 65. Methods: We identified electronic medical records of patients over 65 that were treated with Imatinib for KIT mutated melanoma at our institution over the years 2017-2023. Data was retrospectively collected including demographics, disease characteristics, response patterns and toxicity. Results: 10 patients were identified, 50% were males. The median age at treatment initiation was 75 years (71-100). 3 patients had cutaneous primary, 3 had Vulvar/vaginal primary, 3 had acral primary and 1 had anal canal primary. All patients had normal Lactate dehydrogenase at treatment initiation and ECOG performance status was 0-2 (median 0). 9 patients received Imatinib for stage IV disease with an overall response rate (ORR) of 55% (44% partial response, 11% complete response). Median duration of response was 4 months. Responses were seen in acral melanoma (67%), vulvar/vaginal melanoma (67%) and cutaneous melanoma (33%). Median Progression free survival was 4.3 months (1.8-44), median overall survival from treatment initiation was 22.6 months (4-64). 6 patients were treated as 2nd line with an ORR of 67% and 3 were treated as 3rd line with an ORR of 33%. There was one patient with M1d disease who did not respond to treatment either systematically or intracranially. 6 patients had Exon 11 mutations (V560D/G/E, N564S and L576P) of which 4 responded (67%). 2 had Exon 17 mutations (N822C/K) of which 1 responded (50%) and the 2 others had an Exon 14 (F681I) and Exon 13 (K642E) mutation that did not respond to treatment at all. Toxicity was moderate with 90% of patients experiencing any grade AE, yet only 1 experienced toxicity requiring dose interruption with two Grade 3 toxicities - Pneumonitis and decreased neutrophil count, leading to temporary treatment interruption, dose reduction and a course of corticosteroids. The rest of the patients experienced only Grade 1-2 toxicity. 4 patients needed dose reductions, there were no treatment discontinuations due to toxicity. Conclusions: Treatment with Imatinib for elderly KIT mutated melanoma patients is safe and well tolerated with no treatment discontinuations recorded. The response rate is encouraging yet seems to vary according to the KIT mutation present as previously reported. The duration of response is usually short-lived and alternative/combination treatments are still needed for this patient population.

Safety and efficacy of non-reduced use of caspofungin in patients with Child–Pugh B or C cirrhosis: a real-world study

Background and purposeThe need for dose adjustment of caspofungin in patients with hepatic impairment is controversial, especially for those with Child–Pugh B or C cirrhosis. The purpose of this study was to investigate the safety and efficacy of standard-dose caspofungin administration in Child–Pugh B and C cirrhotic patients in a real-world clinical setting.Patients and methodsThe electronic medical records of 258 cirrhotic patients, including 67 Child–Pugh B patients and 191 Child–Pugh C patients, who were treated with standard-dose of caspofungin at the Second Affiliated Hospital of Chongqing Medical University, China, from March 2018 to June 2023 were reviewed retrospectively. The white blood cells (WBC), hepatic, renal and coagulation function results before administration and post administration on days 7, 14 and 21 were collected, and the efficacy was assessed in all patients at the end of caspofungin therapy.ResultsFavorable responses were achieved in 137 (53.1%) patients while 34 (13.2%) patients died. We observed that some patients experienced an increase of prothrombin time (PT) or international normalized ratio (INR), or a decrease of WBC, but no exacerbation of hepatic or renal dysfunction were identified and no patient required dose interruption or adjustment because of an adverse drug reaction during treatment with caspofungin.ConclusionsStandard-dose of caspofungin can be safely and effectively used in patients with Child–Pugh B or C cirrhosis, and we appealed to re-assess the most suitable dosing regimen in this population to avoid a potential subtherapeutic exposure.

Increase in creatinine levels associated with niraparib maintenance therapy in ovarian cancer.

In Japan, Niraparib maintenance therapy for primary and recurrent ovarian cancer was approved in September 2020 and is expected to improve the prognosis of ovarian cancer. However, the safety of niraparib maintenance therapy in Japanese patients has not been fully evaluated. Patients with ovarian cancer (including fallopian tube and peritoneal cancer) treated with niraparib at Jichi Medical University Hospital from September 2020 to August 2022 were enrolled in this study. Patient background, starting dose, rates of interruption, reduction, or discontinuation, adverse events (AEs) during treatment, and estimated glomerular filtration rate (eGFR) trends were retrospectively analyzed. Twenty-nine patients received niraparib maintenance therapy during the study period, including 21 with primary cancer and 8 patients with recurrent cancer. Seventeen patients (58.6%) required dose interruptions and 16 patients (55.2%) required dose reductions. Only two patients (6.9%) discontinued treatment due to fatigue and nausea. The most frequent AE was creatinine increases in 18 patients (62.1%, all grades). Although eGFR levels decreased significantly after niraparib therapy compared to before niraparib therapy (59.3 vs. 50.3 mL/min/1.73 m2 , p < 0.001), the levels returned to pre-niraparib initiation levels after discontinuation of niraparib (64.6 vs. 64.6 mL/min/1.73 m2 , p = 0.96). Multivariate regression analysis showed that diabetes was independently associated with decreased eGFR (p = 0.013). Niraparib maintenance therapy frequently increased serum creatinine, but the change was reversible. Further studies are needed to determine the effects of niraparib on renal function in Japanese patients.

Phase 1 dose escalation study of SL-172154 (SIRPα-Fc-CD40L) in platinum-resistant ovarian cancer.

5544 Background: SIRPα-Fc-CD40L is a hexameric, bi-functional fusion protein consisting of SIRPα linked to CD40L via an inert Fc linker. This molecule competitively inhibits CD47 to enhance tumor cell phagocytosis and activates CD40 to increase antigen processing and cross-presentation by antigen presenting cells (APCs) to CD8 T cells, thus bridging innate and adaptive immunity. Methods: This first-in-human, Phase 1 dose escalation study evaluated SL-172154 in patients (pts) with advanced platinum resistant ovarian, fallopian tube and primary peritoneal cancers (PROC). SL-172154 was administered intravenously across 5 dose levels (0.1, 0.3, 1.0, 3.0, 10mg/kg). Dose escalation followed a modified toxicity probability interval 2 design. Objectives included evaluation of safety, dose-limiting toxicity (DLT), recommended phase 2 dose, pharmacokinetic and pharmacodynamic (PD) parameters, and antitumor activity per RECIST 1.1. Results: As of 3 Jan 2023, 27 pts (median age 66 years [range 33-85]; median of 4 prior systemic therapies [range 2-9]) with ovarian (70%), fallopian tube (15%) or primary peritoneal (15%) cancer were dosed. Treatment-emergent AEs (&gt;15%) regardless of grade (G) included infusion related reaction (IRR) (67%), fatigue (44%), nausea (33%), back pain (26%), constipation, diarrhea (both 22%), decreased appetite and pruritus (both 19%). There was one DLT of G3 ALT increased at 10mg/kg requiring dose interruption for resolution. A maximum tolerated dose was not reached. G3/4 treatment-related AEs (&gt;1pt) were AST increased (G3) and lymphopenia (G4), each in 2 pts (7%); all were fully resolved with no dose modifications. There were no fatal AEs, no AEs that led to drug discontinuation and no events of cytokine release syndrome. The frequency of IRR events increased with increasing dose, and slowing the rate of infusion was utilized for mitigation. SL-172154 Cmax and AUC increased with dose with greater than proportional exposure noted at 3 and 10mg/kg potentially due to target saturation. These findings were supported by dose-dependent target engagement of CD47 and CD40 on CD4 T cells and B cells respectively, approaching 100% by 3 mg/kg. Rapid dose-dependent egress of CD40+ B cells was maximal at ≥3mg/kg. SL-172154 induced dose-dependent responses in IL-12, CXCL-8, CXCL-10, IL-10, CCL2, CCL20, and CCL22, which also approached a plateau at ≥3mg/kg. Analysis of peripheral and tumor immunophenotypes and anti-drug antibodies in response to SL-172154 is ongoing and will be presented. Best response was stable disease in 6/27 response evaluable (22%) pts. Conclusions: SL-172154 is well tolerated in heavily pretreated PROC pts. IRRs were readily manageable. Maximal CD47 and CD40 target engagement and CD40-dependent PD effects were observed with ≥3mg/kg SL-172154. 3mg/kg is a safe, tolerable, and pharmacologically active dose for evaluation in combination studies in pts with PROC. Clinical trial information: NCT04406623 .

Combination Therapy of Eltrombopag and Cyclosporine a Improves Hematopoiesis in Patients with Lower-Risk Myelodysplastic Syndrome

Objective: Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal myeloid disorders characterized by ineffective hematopoiesis and cytopenias, with variable risks of progression to acute myelogenous leukemia (AML). Peripheral blood cytopenias are the major sources of morbidity and mortality for lower-risk MDS (LR-MDS) pts.The strategies guided by risk stratification tools are different for HR- and LR-MDS. The treatment options for cytopenias in IST non-responders, especially thrombocytopenia, are limited. Such pts are prone to a high risk of bleeding. Eltrombopag (EPAG) is an orally administered nonpeptide thrombopoietin (TPO) receptor agonist. The single-agent activity of EPAG was demonstrated in 44-47% of pts with LR-MDS . In this study, we investigated the efficacy and safety of the combination of EPAG and CysA in LR-MDS in a non-randomized phase II investigator-initiated trial. Method(s):Pts with a diagnosis of LR-MDS by WHO 2016 classification and IPSS-R as low to intermediate-risk group with hemoglobin (Hb) <9.0 g/dL, or RBC transfusion-dependence (at least four units of RBC at 8 weeks prior to enrollment); platelet count <20×109/L or platelet transfusion dependence; were enrolled. http://www.chictr.org.cn/ identifier: ChiCTR2000035473. The primary objective of this IIT was to evaluate the response to this regimen based on IWG-MDS 2006 criteria. Results All the 31 pts were evaluated for response at the primary endpoint. Among them, 21 (67.7%) pts achieved treatment response in at least one eligible lineage with an objective response rate (ORR), 4 (12.9%) pts achieved a CR, 5 (16.1%) pts achieved bi-lineage responses (HI-PE R), 11 (24.3%) pts achieved platelet lineage responses (HI-P R), and 1 (3.2%) patient achieved erythroid lineage response (HI-E R). ANC did not increase significantly at the primary endpoint compared to the baseline; however, altered ANC was a response of CR pts. The median time to response was 8 (range, 2-24) weeks, irrespective of whether the pts had a platelet or erythroid response.Of the 21 pts eligible for an erythroid lineage response,10 pts (47.6%) had responded by the endpoint and the platelet response rate was 64.5% (20/31). The median increase in Hb levels and platelets was from 60.4±18.2 g/L to 68.0±21.2 g/L (P=0.015) and from 12.3±11.2×109/L to 32.5±37.3×109/L (P=0.003) (Figure 1). The median DORs of HI-E and HI-P were not achieved, but the response rates of erythroid and platelet lineages in 20 months were 80.0% and 70.6%, respectively (Figure 2). The RBC and platelet transfusion-dependent rate decreased from 42.9% (9/21) to 28.6% (6/21) (P=0.334) and from 58.0% (18/31) to 25.8% (8/31)We also performed targeted next-generation exome sequencing of 80 genes associated with myeloid malignancies in 21 pts. Among them, 18 showed a total 19 somatic mutations (Figure 3). TET2,and ANKRD11 were detected in 3 responding pts,and KMT2D was detected in 3 responding pts. Pts with adverse prognostic genes, such as ASXL1, ARSR2, U2AF1, KIT, and ETV6, did not exhibit a hematological response. Somatic mutations in DHX9 and ROBO1 were associated with BM failure, as detected in responding pts. All 31 pts were evaluated for toxicity, and the treatment was found to be well-tolerated. The most commonly reported adverse events (AEs) of any grade were nausea (6/31,19.4%), elevated liver transaminases (4/31,12.9%), and headache (3/31,9.7%); no severe AEs had been reported until the cutoff date. One MDS-SLD patient who received CR at 3 weeks experienced deep venous thrombosis of the lower extremity after 9 months of medication, thereby requiring dose interruption. After anticoagulant therapy, the platelet count was still 65×109/L. One MDS-U case who received HI-P had increased BM blasts from 3.2% to 15.4% for 4 months. Another MDS-U case received HI-E and HI-P, and the chromosome was changed from normal karyotype to -7/del (20q) chimeric karyotype for 9 months after administration of the drugs. However, the hematological response was maintained for 16 months until the cutoff date for data collection. Conclusions: Our results indicated that the addition of Epag to CysA is well-tolerated and is an effective treatment for LR-MDS. These ORR are better than CysA monotherapy, especially HI-P. Also, the hematological responses are durable, although continued Epag administration might be necessary. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A phase 1, open-label, dose-escalation study of selinexor plus ruxolitinib in patients with treatment-naïve myelofibrosis.

7060 Background: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by unregulated, clonal proliferation of a hematopoietic stem cells in the bone marrow and is commonly associated with gene mutations in JAK2, CALR, or MPL. Front-line therapy may include the JAK1/2 inhibitor ruxolitinib (RUX), resulting in spleen volume reductions and improvement in MF-related symptoms. Despite the therapeutic effect of RUX, most patients (pts) eventually progress and thus novel combinations are required to increase responses and delay progression. Selinexor (SEL) is an oral selective inhibitor of nuclear export (SINE) compound, specifically inhibiting exportin-1 (XPO1), and currently approved for treatment of multiple myeloma and diffuse large B-cell lymphoma. Significant activity of SEL in combination with RUX has been shown in preclinical studies, and SEL monotherapy in MF refractory to JAK inhibitors demonstrated robust clinical activity and a tolerable safety profile (NCT03627403). Here, we present the initial results of a phase 1 dose escalation study of the combination SEL and RUX in treatment-naïve MF. Methods: The ongoing multicenter, open-label, Phase 1/2 study (NCT04562389) is evaluating the efficacy and safety of SEL plus RUX in JAKi-naïve MF pts. Two dose levels of SEL were evaluated, 40mg and 60mg once-weekly (QW) plus RUX twice daily (BID) as per label in 28-day cycles, using a 3+3 design. All pts received 5-HT3 antagonist for nausea prophylaxis. Primary objectives include safety, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and preliminary efficacy. Secondary objectives include spleen, symptom, and anemia response, and OS. Results: As of 31 Jan 2022, 10 pts have been dosed in 2 dose levels (40mg (n = 3), and 60mg (n = 7) SEL QW plus RUX). RUX starting dose was 20 mg in 8 pts, 15 mg in one patient and 10 mg in one patient. The median age was 64 (range 45-76). Seven pts had primary MF and 3 had post-ET MF. DIPSS risk category was int-1 (n = 4), int-2 (n = 4) and high risk (n = 2). No dose limiting toxicities have been reported at either dose levels of SEL. One patient required dose interruption due to dizziness and later discontinued treatment due to new onset of atrial fibrillation and pulmonary hypertension (unrelated to SEL and RUX) after 5 months of therapy. All other pts remain on study. There was no grade 3 neutropenia or thrombocytopenia observed. Hemoglobin level was maintained without any significant worsening. The most common treatment-emergent adverse event was low grade nausea (30%). All pts experienced improvement in their white blood cell count. Four of the first 5 evaluable pts demonstrated ≥35% spleen volume reduction at week 12. Conclusions: The combination of SEL and RUX has been well-tolerated and with a manageable side effect profile. No dose limiting toxicities were observed in pts with treatment-naïve MF in cohort 1 of once weekly oral SEL 40 and 60 mg with RUX. Clinical trial information: NCT04562389.

Phase 2 Study of Zanubrutinib in BTK Inhibitor-Intolerant Patients (Pts) with Relapsed/Refractory B-Cell Malignancies

Phase 2 Study of Zanubrutinib in BTK Inhibitor-Intolerant Patients (Pts) with Relapsed/Refractory B-Cell Malignancies

Clinical Outcomes of Anti PD-1 Immunotherapy in Patients with Relapsed/Refractory Non Hodgkin Lymphomas

Introduction: Immune checkpoint blockade with anti PD-1 antibodies in Hodgkin Lymphoma has been transformative, changing the standard of care in the relapsed/refractory settings. Limited prospective data exist to support a role for anti PD-1 monotherapy for patients (pts) with diffuse large B cell lymphoma (DLBCL) and T cell lymphomas (ORR 36% DLBCL, n=11 ORR 17% T cell lymphomas, Lesokhin et al, JCO 2016). However, in clinical practice, agents such as pembrolizumab and nivolumab are sometimes administered to non-Hodgkin lymphoma (NHL) pts who are without other conventional treatment options. We performed an analysis of all NHL pts treated with anti PD-1 antibodies at our institution to assess activity and safety of anti PD-1 antibodies in the management of relapsed/refractory NHL.Patients and Methods: We conducted a retrospective cohort study of all adult pts receiving pembrolizumab or nivolumab for management of NHL at the University of Pennsylvania between 1/2014 and 6/2017. Demographics, duration of therapy, reason for discontinuation, overall response rates, survival, and toxicity were examined. The primary endpoint was progression-free survival (PFS) defined as the time of immune checkpoint blockade start to progression, death, or last-follow-up via Kaplan Meier (KM) method. All other analyses were descriptive.Results: We identified 23 NHL pts for this analysis. NHL subtypes included DLBCL (86%) and peripheral T-cell lymphomas (14%). Median age at time of initiation of PD-1 inhibitor was 65 years old (Range: 21-79). Pts had an Ann Arbor Stage 2 or greater (78%) and median ECOG performance status of 1 (Range: 0-3). High risk features, defined as C-myc rearrangement, Ki-67>80%, high IPI, or ABC subtype, were observed in 15 pts (65%). Majority of pts had no history of autoimmune disease (91%). Pts had a median of 5 prior therapies (Range: 1-14, 91% ≥ 3 prior therapies) including 7 pts who had a prior autologous stem cell transplant (30%). Time to initiating PD-1 inhibitor from last active therapy was 2 months (Ranging from 0.5 to 15 months). In our cohort, 14 pts (61%) received pembrolizumab and 9 pts (39%) received nivolumab. The majority (%) of both groups were administered weight based dosing given in standard frequencies according to each respective package label. Median time on immunotherapy was 1 month ranging from 0.5 to 19 months. Pts most commonly discontinued PD-1 therapy for progression or lymphoma associated mortality (73.4%), and 5 pts (21.7%) remain on active therapy. Overall response rate (ORR) for the entire cohort was 23% (9% CR) and ORR in DLBCL of 26% (N=19). Median PFS for the entire cohort and DLBCL subset was 2 months (median follow-up of 2 months, figure 1). Of the responders (n=5), the median duration of response was 17 months (median of 6 prior therapies).No pt experienced opportunistic infections while on anti PD-1 therapy. Roughly 47.8% experienced at least 1 toxicity. There were 3 pts (13%) who were documented with at least two concomitant adverse events (AEs). Observed AEs included: pneumonitis (30%), elevated liver function tests (LFT's) (7%), diarrhea/colitis (7%), infusion related reactions (7%), nausea (7%), sepsis (7%), tumor flare (7%), graft versus host disease (GVHD) exacerbation (7%), headache (7%), idiopathic thrombocytopenic purpura (ITP) (7%), and rash (7%). Only 2 (14%) pts required dose interruptions and 57% of AEs resolved, with standard management of immune mediated AEs.Conclusion: Our results are consistent with the published literature in that we identified a subset of heavily pre-treated multi-refractory NHL pts who achieved durable responses to anti PD-1 antibody monotherapy. While the median PFS / OS for the entire cohort is 2 months, responders, with 6 median prior therapies, achieved a median PFS of 17 months. These results underscore the importance of immune check point blockade in some lymphomas and the critical need to identify biomarkers of response to anti PD-1 therapies so that this therapeutic approach can be delivered to the appropriate pts. A multicenter analysis with correlative studies is in progress. [Display omitted] DisclosuresSvoboda:Kite: Consultancy; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding; BMS: Consultancy, Research Funding; Celgene: Research Funding. Schuster:Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Research Funding; Nordic Nanovector: Consultancy; Seattle Genetics: Consultancy. Landsburg:Curis: Consultancy, Research Funding; Takeda: Research Funding. Dwivedy Nasta:Incyte: Research Funding; Takeda: Research Funding; Immunogen: Research Funding. Mato:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; Portola: Research Funding; Janssen: Consultancy; AstraZeneca: Consultancy; Regeneron: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Kite: Consultancy; AbbVie: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees.

Population Pharmacokinetic and Exposure-Response Modeling for the EZH1/2 Dual Inhibitor DS-3201b in Patients with Non-Hodgkin Lymphomas

▪Introduction: Epigenetic regulators are an emerging new target class for cancer therapy. Enhancer of zeste homolog 1 (EZH1) and EZH2 are alternative subunits of polycomb repressive complex 2 (PRC2), and catalyze tri-methylation of the 27th lysine residue of histone H3 (H3K27). The tri-methylation of H3K27 (H3K27me3) plays an important role in the repression of genes associated with tumor suppression and cell differentiation. DS-3201b is a dual inhibitor of EZH1/2 with activity against hematological cancer cell lines that include acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), and adult T-cell leukemia-lymphoma (ATL). The first-in-human (FIH) study (NCT02732275) is on-going to assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and potential anti-tumor activity in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), including ATL. This preliminary analysis was aimed to develop a population PK model, to explore the exposure-response (E-R) relationships for key safety and PD endpoints, and to find the optimal dose and schedule for DS-3201b.Methods: As of August 2, 2017, clinical data that include plasma levels of DS-3201a (a free form of DS-3201b) and platelet counts were collected from 15 patients with NHL who were participated in the FIH study. They received DS-3201b oral once-daily dosing ranging from 150 mg to 300 mg in 28-day cycles. Population PK analysis for DS-3201a in plasma was carried out and the potential influence of patient characteristics on the PK of DS-3201a was investigated in a covariate analysis. The PK/PD model for platelet counts was developed using a semi-mechanistic model which consists of compartments that imitate platelet proliferation, maturation, circulation, and a feedback on proliferation. Preliminary E-R analyses were also performed for PD biomarker.Results: A 2-compartment PK model with first order elimination and absorption lag-time best characterized the plasma concentration-time profile of DS-3201a. Serum albumin was a significant covariate for total clearance. In the FIH study, platelet counts decreased to a nadir during the first treatment cycle and it returned to baseline without drug interruption in most patients who received 150 mg or 200 mg doses, whereas all patients who received 300 mg required dose interruption. The PK/PD model with drug effect on platelet proliferation and feedback compartments aptly described the time-course of platelet counts. Model-based simulations showed that up-titration schedule based on each patient's platelet count after cycle 1 treatment could allow administration of higher DS-3201b doses to a subset of patients with low risk of grade ≥3 thrombocytopenia. The results of E-R relationship for the inhibition of H3K27me3 in surrogate tissues will also be presented.Conclusion: We developed preliminary population PK and E-R models for DS-3201b in patients with relapsed or refractory NHL. Model-based simulations suggested that up-titration approach can be effective for DS-3201b to ensure continuity of treatment benefit while minimizing dose-dependent thrombocytopenia. DisclosuresAtsumi:Daiichi Sankyo Co., Ltd.: Employment. Yoshiba:DaiichiSankyo Co., Ltd: Employment. Maruyama:Dai-ichi Sankyo, Chugai, Kyowa Hakko Kirin, Ono, Celgene, Janssen, GSK, Eisai, Mundipharma, Takeda, AbbVie, MSD, Sanofi, Pfizer, Otsuka, Novartis, Solasia, Zenyaku: Research Funding; Chugai, Kyowa Hakko Kirin, Ono, Celgene, Janssen, Eisai, Mundipharma, Takeda: Honoraria. Tobinai:HUYA Bioscience: Honoraria; Janssen: Honoraria, Research Funding; AbbVie: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; Chugai: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Servier: Research Funding; Daiichi Sankyo Co., Ltd: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding. Ishida:Kyowa Hakko Kirin Co., Ltd. Celgene K.K. Bayer Pharma AG: Honoraria, Research Funding. Ishitsuka:Celgene Kyowa Hakko Kirin Bristol-Myers Squibb Chugai Pharmaceutical Takeda Pharmaceutical mundiharma Taiho Daiichi Sankyo Janssen Novartis Pfizer Astellas sanofi Genzyme Alexion Sumitomo Dainippon Eisai Mochida Shire Otsuka Ono Teijin: Honoraria, Research Funding. Tsukasaki:Kyowa-Kirin: Honoraria; Chugai/Roche: Honoraria; DaiichiSankyo: Consultancy; Celgene: Honoraria, Research Funding; Mundypharma: Research Funding; Takeda: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; HUYA: Honoraria. Adachi:Daiichi Sankyo Co., Ltd.: Employment. Fujitani:DaiichiSankyo: Employment. Tachibana:Daiichi Sankyo Co., Ltd: Employment. Yoshihara:Daiichi Sankyo Co., Ltd: Employment. Ishizuka:Daiichi Sankyo Co., Ltd: Employment.

Occurrence and Management of Cataracts in Adult Patients (pts) with Chronic Immune Thrombocytopenia (cITP) during Long-Term Treatment with Eltrombopag (EPAG): Results from the Extend Study

Occurrence and Management of Cataracts in Adult Patients (pts) with Chronic Immune Thrombocytopenia (cITP) during Long-Term Treatment with Eltrombopag (EPAG): Results from the Extend Study

Preliminary Results from an Ongoing Phase 1/2 Study of INCB057643, a Bromodomain and Extraterminal (BET) Protein Inhibitor, in Patients (pts) with Advanced Malignancies

Preliminary Results from an Ongoing Phase 1/2 Study of INCB057643, a Bromodomain and Extraterminal (BET) Protein Inhibitor, in Patients (pts) with Advanced Malignancies

Phase Ib-II Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Ibrutinib, w/ Lenalidomide and Rituximab in Relapsed / Refractory Mantle Cell Lymphoma

Phase Ib-II Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Ibrutinib, w/ Lenalidomide and Rituximab in Relapsed / Refractory Mantle Cell Lymphoma

Evaluating the role of baseline geriatric assessment in predicting adherence to oral targeted therapies and outcomes in older adults with non-Hodgkin lymphoma.

12043 Background: Oral targeted therapies (OTT) have transformed the treatment landscape of Non-Hodgkin lymphoma (NHL). However, measuring, defining and optimizing adherence to OTT remains a challenge. Prior studies have reported variable adherence rates (12-100%) to OTT in cancer patients (pts), with suboptimal adherence associated with inferior outcomes. In older adults (OA), geriatric syndromes (GS) such as polypharmacy and cognitive impairment can impact adherence. While geriatric assessment (GA) can predict chemotherapy-related toxicity in OA, its utility in NHL pts on OTT is unknown. In this pilot study, we evaluate the role of GA in predicting adherence and outcomes in NHL pts on OTT. We also report the feasibility of using MEMS Cap, an electronic event monitoring system, to measure adherence in this population. Methods: Pts ≥70 years (yrs) with NHL, initiating/receiving OTT were included. A GA was performed at baseline; pt, disease, and OTT characteristics were recorded. Pts were followed monthly for the first 3 months (mos), then every 3 mos for 1 year. Primary endpoint was treatment adherence rate, measured using both subjective [brief adherence rating scale (BARS)] and objective (pill counts and MEMS cap) methods. Progression free survival (PFS) was measured from time of therapy initiation to disease progression or death. Results: Of the 54 pts screened, 25 were enrolled. Median age was 77 yrs (71-93 yrs), 21 pts had chronic lymphocytic leukemia, 3 had mantle cell lymphoma and 1 had marginal zone lymphoma. Most frequently used OTT were ibrutinib (n = 17) and venetoclax (n = 5). Most pts (72%) were on OTT at study entry. Median time on therapy was 16.4 mos (1.9-44.6 mos). GS included cognitive impairment (28%), depression (24%), polypharmacy (92%) and recent falls (12%); 48% pts had ≥2 GS. Nine pts (36%) had impaired 4-meter gait speed and/or timed-up-and-go; 20 pts (80%) had an adjusted CIRS-G score of ≥6. So far, pts have completed a median follow up of 3.3 mos. BARS was the most consistent measure of adherence used (63/63 visits, 100%). MEMS Cap and pill counts were used at 13% and 8% visits respectively. Only 5 pts used the MEMS Cap, mostly due to packaging incompatibility (44%-pill box, 32%-blister packs). Median adherence was 100% (range, 70%-100%) with no pts missing &gt; 7 days of prescribed doses. Five pts (20%) required dose interruptions, mostly due to adverse events. Six pts discontinued therapy and 2 pts died of unrelated causes. Median PFS was not reached. Chronological age and presence of a GS were not associated with adherence rate or outcomes. Conclusions: Despite presence of ≥2 geriatric syndromes in 48% of older adults with NHL on OTT, self-reported adherence remains high ( &gt; 99%) in this group. The MEMS Cap device has poor applicability in measuring adherence to OTT due to pill package incompatibility and increasing use of virtual/tele visits.

Preliminary results of the phase 2 study of zanubrutinib in patients with previously treated B-cell malignancies intolerant to ibrutinib and/or acalabrutinib.

e19506 Background: Many patients (pts) with B-cell malignancies require continuous treatment with Bruton tyrosine kinase inhibitors (BTKi). Adverse events (AEs) are a common reason for ibrutinib (ibr) or acalabrutinib (acala) discontinuation. Early data from BGB-3111-215 showed zanubrutinib (zanu) was well tolerated in pts with B-cell malignancies intolerant to ibr or acala. We report preliminary results with a median follow-up of 4.2 mo. Methods: Pts meeting protocol criteria for intolerance to ibr, acala or both (without documented progressive disease) were given zanu monotherapy (160 mg twice daily or 320 mg once daily). Recurrence of AEs that led to intolerance of prior BTKi and additional safety measures were assessed based on the Common Terminology Criteria for AEs v5.0. Investigators determined responses using disease status at study entry as baseline. Results: As of November 1, 2020 (cutoff), 44 pts (n=34 chronic lymphocytic leukemia/small lymphocytic lymphoma, n=6 Waldenström macroglobulinemia, n=2 mantle cell lymphoma, n=2 marginal zone lymphoma) were enrolled, received ≥1 dose of zanu, and analyzed for safety. Median age was 70.5 y (range, 49-91); median duration of treatment was 4.2 mo (range, 0.1-12.6). Median number of prior regimens was 2 (range, 1-12). Regarding prior BTKi, 39 pts received ibr only, 4 received ibr and acala, and 1 received acala only. The median number of ibr- or acala-intolerant AEs per pt was 2 (range, 1-5). 83% of ibr and 78% of acala intolerant events did not reccur on zanu; Table. At data cutoff, 43 pts remained on treatment; 1 withdrew consent due to zanu-unrelated grade 3 syncope. Overall, 34 pts (77.3%) reported any AE; most commonly reported AEs were myalgia (n=9; 20.5%), contusion (n=8; 18.2%), dizziness (n=7; 15.9%), fatigue (n=7; 15.9%), and cough (n=5; 11.4%). Grade ≥3 AEs were reported in 6 pts (13.6%), serious AEs in 1 pt (2.3%, febrile neutropenia and salmonella infection), AEs requiring dose interruptions in 6 pts (13.6%), and AEs leading to dose reduction in 2 pts (4.5%). No AEs led to zanu discontinuation. No deaths were reported. All efficacy evaluable pts (26/26 [100%]) maintained (10 [38.5%]) or achieved deepening (16 [61.5%]) of their response. Conclusions: Zanu provides an additional treatment option after intolerance to other BTKi, demonstrating tolerability and sustained or improved efficacy. Updated results will be presented. Recurrence and Severity Change of AEs Leading to Ibr or Acala Intolerance. Clinical trial information: NCT04116437. [Table: see text]

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings

Venetoclax plus azacitidine is indicated in the USA for the treatment of newly diagnosed acute myeloid leukaemia in older patients (≥75years) or those ineligible for induction chemotherapy due to co-morbidities. In this phase 1/2 study (NCT02265731), Japanese patients (≥60years) with untreated (ineligible for induction chemotherapy) or relapsed/refractory acute myeloid leukaemia received oral venetoclax 400mg/day (3-day ramp up in cycle 1) plus subcutaneous or intravenous azacitidine 75mg/m2 on days 1-7 per 28-day cycle until disease progression or unacceptable toxicity. As of 10 December 2019, six patients were enrolled (median age: 75years; untreated: n=5; relapsed/refractory: n=1); median treatment duration: 10.3months (range, 0.7-29.4). Most common grade≥3 adverse events were lymphopaenia and febrile neutropaenia (n=4 each). Four patients reported serious adverse events; only an event of grade 3 fungal pneumonia was considered possibly related to both study drugs, requiring dose interruption of venetoclax and delay of azacitidine. Five (83%) patients had responses (complete remission: n=3). Median time to first response of complete remission/complete remission with incomplete count recovery was 1.0month (range, 0.8-5.5); median overall survival: 15.7months (95% confidence interval: 6.2, not reached). Venetoclax plus azacitidine was well tolerated and showed high response rates in Japanese patients with acute myeloid leukaemia.

Efficacy and Safety Results from ASCEMBL, a Multicenter, Open-Label, Phase 3 Study of Asciminib, a First-in-Class STAMP Inhibitor, vs Bosutinib (BOS) in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Previously Treated with ≥2 Tyrosine Kinase Inhibitors (TKIs

Efficacy and Safety Results from ASCEMBL, a Multicenter, Open-Label, Phase 3 Study of Asciminib, a First-in-Class STAMP Inhibitor, vs Bosutinib (BOS) in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Previously Treated with ≥2 Tyrosine Kinase Inhibitors (TKIs

A Phase I Study of the IDH2 Inhibitor Enasidenib As Maintenance Therapy for IDH2-Mutant Myeloid Neoplasms Following Hematopoietic Cell Transplantation

A Phase I Study of the IDH2 Inhibitor Enasidenib As Maintenance Therapy for IDH2-Mutant Myeloid Neoplasms Following Hematopoietic Cell Transplantation

Venetoclax Has Modest Efficacy in the Treatment of Patients with Relapsed T-Cell Prolymphocytic Leukemia

Venetoclax Has Modest Efficacy in the Treatment of Patients with Relapsed T-Cell Prolymphocytic Leukemia