Frequent Treatment-emergent Adverse Events Research Articles

P405 Long-term safety of 3 years of ozanimod in moderately to severely active ulcerative colitis: an interim analysis of the True North open-label extension

Abstract Background The phase 3, randomised True North (TN) study demonstrated the efficacy and safety of ozanimod for up to 52 weeks in patients (pts) with moderately to severely active ulcerative colitis (UC). The ongoing TN open-label extension (OLE) aims to assess the long-term efficacy and safety of ozanimod in UC. This analysis evaluated the cumulative long-term safety of ozanimod in these studies, which included pts with up to ~3 years of treatment exposure. Methods In TN, pts were randomised to once-daily ozanimod 0.92 mg or placebo, or to open-label ozanimod for a 10-week induction period. Ozanimod clinical responders were rerandomised at Week 10 to ozanimod or placebo in the maintenance period through Week 52. TN pts were eligible to enrol in the OLE and receive ozanimod if they did not achieve clinical response at the end of induction (Week 10), lost response during maintenance, or completed maintenance at Week 52. This interim analysis of the TN OLE (data cutoff: 10 January 2022) included all pts who entered the OLE from TN (n=823). Safety was monitored from the first dose of ozanimod in TN and throughout the subsequent OLE. Exposure-adjusted incidence rates per 100 patient-years (PY) were calculated. Results The average age of TN OLE study participants was 41.7 years (±13.6), 41% were female, 62% had left-sided UC disease, and 35% had prior exposure to tumor necrosis factor inhibitors. Total PY exposure to ozanimod was 2219 years (mean [SD] exposure = 2.7 [1.6]). The most frequent treatment-emergent adverse events (TEAEs) reported through OLE Week 94 (up to 146 weeks of continuous treatment) are listed in the Table. Most TEAEs were nonserious; TEAEs leading to discontinuation were uncommon. Bradycardia was reported in 3 pts (0.4%; EAIR 0.1/100 PY; 2 in TN and 1 in OLE; no pts were discontinued from treatment). Macular edema was reported in 2 (0.2%; EAIR 0.1/100 PY) pts. Reductions in ALC were common (470 [57.1%] had ALC < 500 cells/mm3), as previously described, but ALC reductions were not associated with the occurrence of TEAEs. Malignancies were uncommon (n=13 [1.6%]; EAIR 0.6/100 PY), and included 6 basal cell carcinomas and 3 colorectal neoplasms. Two deaths were reported: 1 due to COVID-19 and 1 sudden death. Investigators deemed both to be unrelated to treatment. Ozanimod was not associated with an increased risk of ischemic heart disease or thromboembolic events. Conclusion Long-term exposure to ozanimod for up to 3 years was well tolerated in pts with moderately to severely active UC. No new safety signals were observed with long-term ozanimod use in UC (2219 PY exposure). Safety findings are consistent with previous reports from the UC and multiple sclerosis development programs (>16,512 PY exposure).

Efficacy and safety of bimekizumab in axial spondyloarthritis: results of two parallel phase 3 randomised controlled trials

ObjectivesAxial spondyloarthritis (axSpA) is a complex disease with diverse manifestations, for which new treatment options are warranted. BE MOBILE 1 (non-radiographic (nr)-axSpA) and BE MOBILE 2 (radiographic axSpA (r-axSpA)) are...

Phase 1 Study of the Selective c-MET Inhibitor, HS-10241, in Patients With Advanced Solid Tumors

Introductionc-MET is an important therapeutic target for various cancers; however, the People’s Republic of China currently retails only one specific c-MET inhibitor. Our preclinical study has revealed the high selectivity of HS-10241 to suppress c-MET. This phase 1 study aims to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of the selective c-MET inhibitor (HS-10241) in patients with advanced solid tumors. MethodsPatients with locally advanced or metastatic solid tumors orally received a single or multiple dose of HS-10241 once daily or twice daily for 21 consecutive days, which included the following six regimens: 100 mg once daily, 200 mg once daily, 400 mg once daily, 600 mg once daily, 200 mg twice daily, and 300 mg twice daily. The treatment continued until disease progression, unacceptable toxicity, or treatment termination. The primary end point was the incidence of dose-limiting toxicity and maximal tolerated dose (MTD). Secondary end points included safety, tolerability, pharmacokinetics, and pharmacodynamics. ResultsA total of 27 patients with advanced NSCLC received HS-10241, and dose-limiting toxicity was observed in three patients after 600 mg once-daily HS-10241 treatment. For once-daily dosing, MTD was 400 mg, and for twice-daily dosing, the maximal safe escalated dose was 300 mg, and MTD was not reached. Nausea (48.1%, 13 of 27), fatigue (37.0%, 10 of 27), and anemia (33.3%, 9 of 27) are the three most frequent treatment-emergent adverse events. At 400 mg once daily, Css,max was 5076 ng/mL and steady state area under the curve was 39,998 h × ng/mL. Patients (n = 5) with positive MET (MET exon 14-skipping, MET amplified, and MET immunohistochemistry 3+) had confirmed partial responses (n = 1) or stable disease (n = 3), with a disease control rate of 80.0%. ConclusionsThe selective c-MET inhibitor HS-10241 was well tolerated and had clinical activity in advanced NSCLC, especially in patients with positive MET. Furthermore, this study expounds on the therapeutic potential of HS-10241 in patients with cancer.

Lipid-lowering efficacy and safety of alirocumab in a real-life setting in France: Insights from the ODYSSEY APPRISE study

BackgroundRecently, a multicentre, prospective, single-arm, phase 3b, open-label trial was conducted to determine the safety and efficacy of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, in a real-life setting. This study enrolled patients at high cardiovascular risk, with heterozygous familial hypercholesterolaemia (HeFH) or non-familial hypercholesterolaemia (non-FH). Results showed that alirocumab was well tolerated and resulted in a clinically significant reduction in low-density lipoprotein cholesterol (LDL-C). AimThis ancillary analysis aimed to describe the characteristics of the French patients enrolled in the study, the main results observed in this population according to their familial hypercholesterolaemia status, and adherence to treatment. MethodsFrench data were analysed separately from the original dataset of the study. ResultsAmong 215 French patients in the ODYSSEY APPRISE trial, 63.7% had non-FH, with a mean LDL-C concentration of 5.0±1.8mmol/L at baseline. The mean duration of alirocumab exposure was 72.4±42.5 weeks, with only 48.4% of patients receiving statins concomitantly. At week 12, a mean reduction in LDL-C of 56.5±17.8% was observed: 51.2±22.8% in HeFH; 59.5±13.2% in non-FH. This improvement in LDL-C started from week 4 and remained stable and sustained until week 120 in both populations. The overall incidence of severe treatment-emergent adverse events (TEAEs) was 33.5%. The most frequent TEAEs were myalgia (15.8%) and asthenia (15.3%). No tolerance or efficacy differences were observed between patients with or without established coronary artery disease or other cardiovascular disease, whatever the age of these events or considering the concomitant use of other lipid-lowering therapies. ConclusionsIn the French setting, alirocumab was well tolerated, safe and highly effective at reducing LDL-C. These findings support the use of alirocumab to manage hypercholesterolaemia in patients at high cardiovascular risk.

Somatrogon in paediatric growth hormone deficiency: a profile of its use in the EU

Somatrogon (NGENLA®), a modified long-acting form of recombinant human growth hormone (rhGH), is a valuable new option for the treatment of paediatric patients aged ≥ 3 years with growth disturbance due to insufficient GH secretion in the EU, and offers the convenience of once-weekly administration. In a phase 3 randomized trial, once-weekly somatrogon was non-inferior to once-daily somatropin (rhGH; standard therapy) in increasing height velocity in paediatric patients with GH deficiency (GHD). Once-weekly somatrogon was associated with a lower treatment burden than once-daily somatropin in another phase 3 randomized trial. Somatrogon is generally well tolerated, with injection site pain being the most frequent treatment-emergent adverse event. Somatrogon is available as a multi-dose prefilled pen for subcutaneous injection.

Efficacy and Safety of Bosutinib Vs Imatinib By Charlson Comorbidity Index in Newly Diagnosed Patients with Chronic Myeloid Leukemia

Introduction: The efficacy and safety of bosutinib (BOS) vs imatinib (IMA) in patients with newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML) was assessed in the phase 3 BFORE trial (NCT02130557) after 5 years of follow-up (Brümmendorfet al., J Clin Oncol, 2022). Here we analyze the impact of comorbidities on efficacy and safety, reporting the results by Charlson Comorbidity Index (CCI) score. Methods: Patients with newly diagnosed CP CML were randomized 1:1 to receive BOS or IMA (starting dose: 400 mg QD). Outcomes were assessed after 5 years (240 weeks) of follow-up (database lock: June 12, 2020) according to the CCI score without the age component (mCCI). Patients were grouped by mCCI scores of 2 (BOS, n=195; IMA, n=196 [2 untreated]) and >2 (BOS, n=73; IMA, n=72 [1 untreated]). Efficacy was assessed in all randomized patients (intent-to-treat population) and safety in patients who received >1 dose of study medication (safety population). Results: In patients with mCCI 2 and >2, the median treatment duration was 55.1 and 53.4 months with BOS vs 55.0 and 55.1 months with IMA; respective median (range) dose intensity was 396.4 (39−583) and 367.2 (74−573) mg/day with BOS vs 400.0 (240−765) and 400.0 (189−754) mg/day with IMA. Permanent treatment discontinuations in patients with mCCI 2 and >2, respectively, were reported in 36.4% and 50.7% of patients with BOS vs 45.4% and 32.4% of patients with IMA. The most common primary reasons for permanent discontinuation were adverse events (AEs) in the BOS arm (BOS: mCCI 2, 21.0%; mCCI >2, 35.6%; IMA: mCCI 2, 13.9%; mCCI >2, 8.5%) and lack of efficacy (suboptimal response, treatment failure, or disease progression) in the IMA arm (BOS: mCCI 2, 6.7%; mCCI >2, 2.7%; IMA: mCCI 2, 20.6%; mCCI >2, 9.9%). In both treatment arms, the majority of permanent discontinuations due to AEs occurred in year 1 (BOS: mCCI 2, 11.3%; mCCI >2, 20.5%; IMA: mCCI 2, 7.7%; mCCI >2, 5.6%). Among patients with mCCI 2 and >2, respectively, the proportion who achieved an early molecular response (BCR::ABL1 ≤10% at 3 months) was 79.4% and 83.8% with BOS vs 56.5% and 71.0% with IMA (Table 1). Cumulative response rates according to mCCI score and treatment arm are shown in the Table 1. There were 14 deaths during the study period in both the BOS- (mCCI 2, n=7; mCCI >2, n=7) and IMA (mCCI 2, n=9; mCCI >2, n=5) arms; 3 and 4 deaths, respectively, were assessed by investigators as CML-related (all in patients with mCCI 2). Treatment-emergent AEs (TEAEs) occurred in ≥98.5% of patients in each treatment arm and across CCI subgroups. In patient with CCI 2 and >2, respectively, the most common (≥30% in either subgroup) TEAEs with BOS were diarrhea (79.5% and 63.0%), thrombocytopenia (37.4% and 31.5%), nausea (35.9% and 41.1%), increased alanine aminotransferase ([ALT] 34.4% and 31.5%), and fatigue (17.9% and 30.1%). Most common TEAEs with IMA were diarrhea (37.1% and 49.3%), nausea (41.2% and 45.1%), muscle spasms (33.0% and 23.9%), and anemia (17.5% and 36.6%). Among patients with CCI 2 and >2, respectively, grade 3/4 TEAEs were observed in 69.2% and 84.9% with BOS vs 55.2% and 62.0% with IMA. The most frequently reported grade 3/4 TEAEs are shown in Table 2. TEAEs resulting in death in the BOS arm (n=3) were acute cardiac failure, myocardial ischemia, and renal failure (all in patients with CCI >2). TEAEs leading to death in the IMA arm (n=4) were sepsis and CML in patients with CCI 2, and pneumonia and cerebrovascular accident in patients with CCI >2. Conclusions: After 5 years of follow-up in the BFORE study, a substantial proportion of patients across mCCI scores achieved molecular responses with BOS or IMA. In the BOS arm, there was a trend toward a higher rate (>10% difference) of MR4 in patients with CCI 2 vs CCI >2, with a similar proportion of patients achieving MMR and MR4.5 in both subgroups. Molecular response rates by 60 months were higher with BOS vs IMA in patients with CCI 2 and similar in patients with CCI >2. Safety data were consistent with the known safety profiles of BOS and IMA. Discontinuations due to AEs were higher (>10% difference) in patients with CCI >2 in the bosutinib arm and similar across CCI groups in the imatinib arm. However, in both treatment arms, there were no relevant differences in the frequency of TEAEs across the most commonly occurring AEs between patients with CCI 2 and CCI >2. These results support the use of 400 mg once daily BOS in patients with newly diagnosed CP CML irrespective of baseline comorbidities. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase I Study of TQB3455, a Selective Inhibitor of IDH2 with Favorable Safety and More Potent Efficacy to IDH2-R172K Mutation, for Acute Myeloid Leukemia and Myelodysplastic Syndrome

Introduction: Approximately 15% of patients with acute myeloid leukemia (AML) and 5% of patients with myelodysplastic syndrome(MDS) harbor IDH2 mutations (mIDH2). Enasidenib (ENA), the first selective IDH2 inhibitor, was associated with impressive response rates in relapsed/refractory (R/R) AML and was approved by FDA in 2017. TQB3455, a novel selective inhibitor of IDH2, different from ENA, showed stronger inhibitory activity against IDH2-R172K in vitro, and also demonstrated potent antileukemic activity in humans. The current analysis is the first to evaluate the safety and clinical efficacy of TQB3455 monotherapy in pts with mIDH2-positive AML or MDS. Methods: This multicenter, phase 1, open-label, dose-escalation/expansion study enrolled AML or MDS pts with mIDH2, who were RR or not candidate for standard treatment, estimated survival ≥12w and ECOG performance status＜2. Prior allogeneic hematopoietic stem cell transplantation is prohibited. TQB3455 is administered continuously as oral tablets QD in 28-day cycles. Dose levels are 25mg, 50mg, 75mg, 100mg, 150mg, and 300mg.Dose escalation followed a modified 3+3 design. Once the recommended phase 2 dose (RP2D) is determined, subjects will be enrolled into expansion cohort. Primary objectives include safety, tolerability, maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Safety was assessed by treatment-emergent adverse event (TEAE) reporting and TEAEs were graded per CTCAE version 5.0. DLT was defined as any Grade ≥4 hematologic toxicity or Grade ≥3 non-hematologic toxicity（alopecia excluded）occurring within the first 28 days after initiation of treatment. Secondary objectives include pharmacokinetics (PK), preliminary efficacy per International Working Group (IWG) response criteria for AML and MDS. Fisher's exact test was used to assess the association between categorical variables. Results: As of May 31, 38 pts were enrolled in the study and had received at least one dose of TQB3455, 35 with AML and 3 with MDS. Baseline characteristics are detailed in Table 1. Pts received daily TQB3455 doses of 25mg(n=1), 50mg(n=1), 75mg(n=3), 100mg(n=3), 150mg(n=7), 300mg(n=1). When the dose escalated to 300mg, the patient experienced a DLT of pneumonia, then the dose was switched back to 150mg. The 150mg cohort was expanded to 7 evaluable patients and 1 patient experienced a DLT of differentiation syndrome. Therefore, the RP2D of TQB3455 was identified as 100 mg daily. 22 additional pts were enrolled on this dose during the expansion phase. Safety analysis was performed in all patients. The most frequent Grade 3-4 TEAEs in all regimens were 25mg(n=1, 100%), 50mg(n=1, 100%), 75mg(n=2, 66.67%), 100mg(n=13, 68.42%), 150mg(n=7, 87.50%) and 300mg(n=1, 100%). The most frequent TEAEs were pancytopenia(Table 2). 24 pts discontinued treatment, primarily due to progressive disease or relapse (n=17, 44.74%), adverse events (n=1, 2.63%), withdrawal by patient (n=3, 7.89%) or death (n=2, 5.26%). Efficacy was analyzed only in patients with AML. Three pts was not evaluable for response due to withdrawal by patients before the first efficacy evaluation. Of the 32 evaluable pts, overall response rate (ORR) was 40.63 %, including 12 pts (37.5%) in complete remission(CR) or CR with incomplete hematologic recovery (CRi), 1 pts (3.13%) in partial remission (PR). TQB3455 shows more powerful inhibitory effects on IDH2-R172K rather than IDH2-R140Q/W mutation (ORR, 66.67% vs 25.00%, p=0.03; CR, 41.67% vs 15.00%, p=0.12). The presence of FLT3 and/or RAS co-mutations at study entry was significantly associated with lack of response (ORR, 10% vs 45.46%; CR, 10% vs 31.82%). Median duration of response was 9.17 months (95% CI 7.39-not reached). After a median follow up of 5.49 months, the median overall survival (mOS) was 7.43 months (95% CI 5.55- not reached). Conclusion: TQB3455 is well-tolerated for myeloid malignancy at the R2PD of 100 mg qd. It also yield high rates of clinical response in pts with mIDH2AML. Patients with IDH2-R172K mutation fared much better than IDH2-R140Q/W with regard to response, this is in line with outcome of TQB3455 in vitro but different from previous reports of ENA. These encouraging findings have prompted further studies of TQB3455 combination therapy in patients with mIDH2 AML and MDS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Momelotinib (MMB) Long-Term Safety: Pooled Data from Three Phase 3 Randomized-Controlled Trials (RCTs)

Introduction: MMB, an oral JAK1/JAK2/ACVR1 inhibitor, was evaluated in 3 RCTs (SIMPLIFY-1 [S1], SIMPLIFY-2 [S2], and MOMENTUM) in patients (pts) with high- and intermediate-risk myelofibrosis (MF). We conducted an integrated analysis of MMB to characterize its long-term safety, with pooled data from the 3 RCTs, representing a spectrum of MF disease from early (JAK inhibitor-naive) to late (JAK inhibitor-experienced) stages. Methods: Adult pts with high- and intermediate-risk MF were randomized to receive MMB or ruxolitinib (RUX; S1); MMB or best available therapy, which was RUX in 89% (S2) of patients; and MMB or danazol (MOMENTUM). At the end of the 24-week randomized treatment period, pts in the MMB arms could continue treatment with open-label (OL) MMB, and pts in the control arms could cross over to receive OL MMB. Pts from all 3 RCTs continued to receive long-term extended access to MMB in the extended access protocol (XAP) study. Median follow-up time was 20 months in S1, 10 months in S2, and 7 months in MOMENTUM. Results: As of December 3, 2021, across these 3 studies, 725 pts (1261 person-years) with MF received MMB; 12% remained on therapy for ≥5 years, with a median MMB exposure of 11.3 months, and mean (range) MMB exposure of 20.3 (0.1-90.4) months. Nonhematologic treatment-emergent adverse events (TEAEs) were mostly grade 1/2, with diarrhea (26.8% any grade, 2.6% grade ≥3) and nausea (19.4% any grade, 1.1% grade ≥3) the most frequent TEAEs, in the absence of antidiarrheal and antiemetic prophylaxis. The most frequently occurring hematologic any-grade TEAEs included thrombocytopenia (23.4%), anemia (23.0%), and neutropenia (5.7%). Infections occurred in 55.4% of patients, but serious opportunistic infections were rare (1.5%). Study drug discontinuations due to any treatment-related adverse events (AEs) were not common (15.6%). Thrombocytopenia most frequently led to study discontinuation but only occurred in 3.7% of pts. Malignancies (13.4%), including nonmelanoma skin cancer (4.8%), were infrequent. Acute myeloid leukemia (AML), or leukemic transformation, occurred in 3.0% of pts, and led to MMB discontinuation in 2.1% of pts. Peripheral neuropathy was infrequent (14.8% any grade), rarely severe (n=2 (1.2%) grade ≥3, both resolved on MMB withdrawal), mostly sensory, and rarely led to treatment discontinuation. Frequent and clinically important AEs did not increase in incidence over time (Table). Mean baseline hemoglobin and platelet count levels were and 9.9 g/dL and 238.9 x 109/L, respectively. Hemoglobin levels were increased at first on-study assessment (week 2) on MMB and were maintained thereafter. Hemoglobin levels increased in the OL phase in pts who switched to MMB from RUX (Figure A); platelet counts improved or were maintained (Figure B). Conclusion: We report the largest trial safety database to date for a JAK inhibitor in MF. MMB demonstrated a consistent safety profile without unexpected long-term or cumulative toxicity. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Oral Azacytidine in Patients with Relapsed/Refractory Angioimmunoblastic T-Cell Lymphoma: Final Analysis of the Oracle Phase III Study

Background: Angioimmunoblastic T-cell Lymphoma (AITL) and nodal lymphomas of follicular helper T-cell origin have in common frequent mutations affecting genes regulating DNA methylation and hydroxymethylation such as TET2, DNMT3A and IDH2. Preliminary studies suggested efficacy of the hypomethylating agent 5-azacytidine (Blood. 2018; 132(21):2305-09) in relapsed/refractory AITL patients. We present here the final results of the ORACLE study (NCT03593018), a phase III trial comparing CC-486, an oral form of 5-azacytidine, to single agent treatment chosen by the investigator. Patients & methods: Eighty-six patients with relapsed/refractory AITL or nodal follicular helper T-cell lymphoma were randomized between CC-486 (n=42) and investigator's choice (gemcitabine, n=24, bendamustine n=16, romidepsin n=4) between November 2018 and February 2021. CC-486 was given at a daily dose of 300 mg/day (200 mg/day in Asian patients, based on previous phase I pharmacokinetics results) every day for 14 days out of 28 day-cycles, until progression or unacceptable toxicity. Gemcitabine and bendamustine were both administered for 6 cycles, while romidepsin was administered until progression. Patients were evaluated for response using 2014 international working group CT-based criteria. The primary endpoint was progression-free survival (PFS) based on local assessment of progressive disease, and overall survival was a key secondary endpoint in this study. Main secondary endpoints were PFS based on central review, overall response rate (ORR), complete response (CR) rate and safety. Statistical hypotheses were built on a PFS of 12 months in the experimental arm vs 5 months in the standard arm (HR=0.417), with a one-sided alpha risk of 0.025 and 90% power. Results: Median age was 69 years (IQR 62-76), and the male/female ratio was 1.4. Patients had received a median of 2 (IQR 1-2) previous lines of treatment, 90.6% of them had advanced stage (III-IV), 57% had elevated LDH, 23.3% had an ECOG performance status >1, 31.4% had an IPI score 4-5 and 35.8% had a bone marrow involvement. Patients received a median number of 5.5 (IQR 2;14) cycles of CC486, and respectively 2 (1-4), 3.5 (2-6) and 13.5 (5-25) cycles of gemcitabine, bendamustine and romidepsin. The primary endpoint was analysed after a follow-up of 14.4 months. Median PFS in the CC-486 arm was 5.6 (95%CI, 2.66-8.11) months vs 2.8 (95%CI, 1.87-4.83) months in the standard arm (stratified log-rank test p=0.0421), with a hazard ratio of 0.634 (95%CI, 0.38; 1.07), which did not reach the required significance of p<0.025. Median overall survival was 18.4 months (95%CI, 12.9-31.5) in the CC-486 arm vs 10.3 (95%CI, 4.2-13.5) in the standard arm, with a hazard ratio of 0.557 (95%CI, 0.323-0.961). Best overall response and complete response rates at 3 months in the CC-486 arm were 33.3% (95%CI, 19.6%-49.5%) and 11.9% (95%CI, 4%-25.6%) respectively, vs 43.2% (95%CI, 28.3%-59.0%) and 22.7% (95%CI, 11.5%-37.8%) in the standard arm. The most frequent (>40%) treatment emergent adverse events (TEAEs) for the CC-486 versus (vs) standard arm respectively were: blood and lymphatic system disorders (76.2% vs 93%) [neutropenia (42.9% vs 58.1%) and thrombocytopenia (23.8% vs 48.8%)], infections (35.7% vs 67.4%), gastrointestinal disorders (71.4% vs 55.8%). At least one grade 3/4 TEAE occurred in 76.2% patients in CC-486 arm vs 97.7% in the standard arm, and at least one serious TEAE occurred in 26.2% patients in CC-486 arm vs 44.2% patients in the standard arm. Central pathological review confirmed the diagnosis of AITL and TFH PTCL in 69 and 9 cases. We detected TET2, RHOA, DNMT3A and IDH2 mutations in 68/77 (88%), 51/75 (68%), 24/75 (32%) and 25/75 (33%) samples. None of these mutations were associated with PFS or OS of the whole population or the 5-azacytidine treated patients. Conclusion: The trial did not meet its primary endpoint, most likely due to an optimistic hypothesis of PFS improvement, resulting in a study including 86 patients which could be underpowered to detect a clinically meaningful difference. 5-azacytidine had a favourable safety profile compared to standard of care and was associated with prolonged overall survival, suggesting that this drug might have a role in the treatment of TFH PTCL and could be investigated in combination with other agents. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A First-in-Human Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Polyethylene Glycol-Erythropoietin Injection, RD01, in Healthy Volunteers

Background: Polyethylene glycol-erythropoietin injection, also called RD01, is pegylated recombinant human epoetin alfa (rHuEPOα) which stimulates erythropoietin receptors on erythroid progenitor cells to induce the formation of new red blood cells. rHuEPO (both α and ꞵ, which are almost identical to endogenous erythropoietin in the sequence of amino acids, but are distinct in their glycosylation pattern) have short half-life in 6 to 24 hours after intravenous (IV) or subcutaneous (SC) injection (Halstenson 1991; Salmonson 1990), Darbepoetin alfa, which is more highly glycosylated epoetin and has a longer half-life in 24 to 72 hours (Macdougall 2007; Padhi 2006) and CERA is a pegylated rHuEPO ꞵ with a comparable half-life of about 130 hours (Macdougall 2006). However the pharmacokinetics of pegylated rHuEPOα has not been reported. Here we reported the results of the first-in-human study of the safety, tolerability, and pharmacokinetics of RD01 in healthy volunteers. Methods: In this double-blinded, placebo-controlled, dose escalation study, healthy volunteers were randomly assigned (10:2) to receive single dose of RD01 (0.2, 0.4, 0.8, 1.6, 2.4, 3.6, 4.8 μg/kg) or placebo via subcutaneous injection. There were 7 cohorts, and each cohorts consisted of 12 subjects. Study consisted of screening period (up to 14 days), treatment and assessment period (35 days), and an end-of-study visit (at day 35). RD01 pharmacokinetics parameters were estimated using non-compartmental analysis. Safety, tolerability, and immunogenicity were assessed throughout the study. Results: All adverse events (AEs) were of mild to moderate intensity. There were no deaths, serious AEs, or withdrawal from study due to AEs. The most frequent (＞5%) drug-related treatment emergent adverse events (TEAE) were serum iron decreased, serum ferritin decreased, unsaturated iron binding capacity increased, leukocyte count decreased, and diarrhea . No clinically significant findings in vital signs or electrocardiogram were observed. Positive ADA responses to RD01 were observed in 7 of 70 subjects. The exposure (AUC0-∞) and maximum concentration (Cmax) of RD01 were approximately linear in the range of 0.2-4.8 ug/kg dose. The median Tmax was 48~96 hours, while mean t1/2 as 82.4~160.6 hours (Table 1 The PK parameters of RD01). While RD01 of 0.2- 4.8 μg/kg dose-dependently elevated hemoglobin, reticulocyte and hematocrit. In volunteers who received RD01 above 0.8 μg/kg, the mean changes from baseline of hemoglobin concentration increased over 10 g/L within 7 days after dosing. Compared with placebo, RD01 above 0.8 μg/kg also produced greater mean maximum effect (Emax) in hemoglobin, reticulocyte and hematocrit. Conclusion: RD01 (0.2-4.8 μg/kg) was well tolerated by healthy Chinese subjects with a much longer t1/2, that supported further clinical development of RD01 (above 0.8 μg/kg) for patients with anemia. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The effect of a combined indomethacin and levonorgestrel-releasing intrauterine system on short-term postplacement bleeding profile: a randomized proof-of-concept trial

Long-acting reversible contraceptives, including hormonal levonorgestrel-releasing intrauterine systems, are the most effective methods of reversible contraception. However, unfavorable bleeding, particularly during the first months of use, is one of the most important reasons for discontinuation or avoidance. Minimizing this as early as possible would be highly beneficial. Nonsteroidal anti-inflammatory drugs inhibiting prostaglandin synthesis are known to reduce bleeding and pain at time of menses. A levonorgestrel-releasing intrauterine system has been developed with an additional reservoir containing indomethacin, designed to be released during the initial postplacement period. This proof-of-concept study aimed to establish whether the addition of indomethacin to the currently available levonorgestrel-releasing intrauterine system (average invivo levonorgestrel release rate of 8 μg/24 h during the first year of use) reduces the number of bleeding and spotting days during the first 90 days of use compared with the unmodified system. The dose-finding analysis included 3 doses of indomethacin-low (6.5 mg), middle (12.5 mg), and high (15.4 mg)-to determine the ideal dose of indomethacin to reduce bleeding and spotting days with minimal side-effects. This was a multicenter, single-blinded, randomized, controlled phase II trial conducted between June 2018 and June 2019 at 6 centers in Europe. Three indomethacin dose-ranging treatment groups (low-, middle-, and high-dose indomethacin/levonorgestrel-releasing intrauterine system) were compared with the unmodified levonorgestrel-releasing intrauterine system group, with participants randomized in a 1:1:1:1 ratio. The primary outcome was the number of uterine bleeding and spotting days over a 90-day reference (treatment) period. Secondary outcomes were the number of women showing endometrial histology expected for intrauterine levonorgestrel application and the frequency of treatment-emergent adverse events. Point estimates and 2-sided 90% credible intervals were calculated for mean and median differences between treatment groups and the levonorgestrel-releasing intrauterine system without indomethacin. Point and interval estimates were determined using a Bayesian analysis. A total of 174 healthy, premenopausal women, aged 18 to 45 years, were randomized, with 160 women eligible for the per-protocol analysis set. Fewer bleeding and spotting days were observed in the 90-day reference period for the 3 indomethacin/levonorgestrel-releasing intrauterine system dose groups than for the levonorgestrel-releasing intrauterine system without indomethacin group. The largest reduction in bleeding and spotting days was achieved with low-dose indomethacin/levonorgestrel-releasing intrauterine system, which demonstrated a point estimate difference of-32% (90% credible interval,-45% to-19%) compared with levonorgestrel-releasing intrauterine system without indomethacin. Differences for high- and middle-dose indomethacin/levonorgestrel-releasing intrauterine system groups relative to levonorgestrel-releasing intrauterine system without indomethacin were-19% and-16%, respectively. Overall, 97 women (58.1%) experienced a treatment-emergent adverse event considered related to the study drug, with similar incidence across all treatment groups including the unmodified levonorgestrel-releasing intrauterine system. These were all mild or moderate in intensity, with 6 leading to discontinuation. Endometrial biopsy findings were consistent with effects expected for the levonorgestrel-releasing intrauterine system. All 3 doses of indomethacin substantially reduced the number of bleeding and spotting days in the first 90 days after placement of the levonorgestrel-releasing intrauterine system, thus providing proof of concept. Adding indomethacin to the levonorgestrel-releasing intrauterine system can reduce the number of bleeding and spotting days in the initial 90 days postplacement, without affecting the safety profile, and potentially improving patient acceptability and satisfaction.

Pharmacokinetic Profile, Safety, and Tolerability of Topical Berdazimer Gel, 10.3% in Patients With Molluscum Contagiosum.

Berdazimer (SB206), gel 10.3% is a novel, topical, nitric oxide&ndash;releasing agent intended for molluscum contagiosum (MC) treatment. A 12-week, open-label, multicenter trial evaluated the safety, tolerability, and pharmacokinetic (PK) parameters of berdazimer gel, 10.3% applied topically once daily for the treatment of MC. Patients were aged &ge;6 months with &gt;20 molluscum lesions. The primary endpoint was the PK profile of the hydrolyzed N-methylaminopropyl-trimethoxysilane (hMAP3) monomer and nitrate during a 2-week period of once-daily berdazimer gel, 10.3% application (PK period) under maximal use conditions. Safety and tolerability were evaluated throughout the 12-week study period. Half of the 34 enrolled patients (17) were female and most (97.1% [33/34]) were white. Patients were 2 to 12 years old (mean, 5.3 years) with a mean of 50 MC lesions at baseline (mean time since MC awareness, 12.4 months). No patients had quantifiable plasma hMAP3 concentrations on day 1. On day 15, 2 patients had quantifiable plasma hMAP3 concentrations; however, the maximum concentration (33.9 ng/mL) was &gt;10-fold lower than the no observed adverse effect level (NOAEL) in an animal toxicology study. Mean nitrate concentration&ndash;time profiles were similar on days 1 and 15 and remained flat for all patients throughout the 2-week PK period. The highest plasma methemoglobin level observed was 3.2%. Application-site pain (13/34 [38.2%]) and application-site erythema (6/34 [17.6%]) were the most frequent treatment-emergent adverse events (TEAEs), and most TEAEs were mild or moderate. Once-daily berdazimer gel, 10.3% was well-tolerated with minimal systemic absorption. J Drugs Dermatol. 2022;21(10):1104-1110. doi:10.36849/JDD.6938.

730MO First-in-human phase I study of INCAGN02390, a TIM-3 monoclonal antibody antagonist in patients with advanced malignancies

TIM-3 is a transmembrane checkpoint receptor expressed on multiple immune cells that promotes an inhibitory tumor microenvironment. INCAGN02390 is a fully human Fc-engineered IgG1κ monoclonal antibody that selectively inhibits TIM-3 ligand interactions. This study is primarily aimed to determine the safety and tolerability and define the MTD or PAD of INCAGN02390 monotherapy. This is a phase 1, multicenter, open-label, dose-escalation study that enrolled pts with locally advanced or metastatic solid tumors that failed available therapies, were intolerant to treatment, or refused noncurative standard treatment. A 3+3 dose-escalation design was used; pts received intravenous INCAGN02390 Q2W in 7 dose levels (DLs): 10 mg, 30 mg, 100 mg, 200 mg, 400 mg, 800 mg, or 1600 mg. The primary endpoint was safety and tolerability. Other endpoints were PK, PD and preliminary efficacy per RECIST v1.1. Forty pts (median age, 63 y) were enrolled; 53% were male and 83% had ECOG PS 1. Lead cancer types were breast (15%), lung (13%), and colorectal (10%). 98% received prior systemic therapy (58% had prior immunotherapy). No DLT was observed and MTD was not reached. Most frequent treatment-emergent adverse events (TEAEs) were anemia (35%), back pain (30%), and fatigue (28%). Drug-related grade ≥3 TEAEs were observed in 7.5% of pts (anemia, adrenal insufficiency, and amylase increased [n=1 each]; all Gr3). One drug-related serious TEAE (adrenal insufficiency) occurred at the 1600 mg DL. One drug-unrelated fatal TEAE (multi-organ failure) occurred in the 800-mg DL. INCAGN02390 trough serum concentrations achieved steady state around Cycles 4 to 6. Maximum concentration and area under the serum concentration-time curve were linear across most DLs. Doses ≥400 mg led to trough TIM-3 receptor occupancy levels of ≥90% in peripheral blood. Disease control rate was 17.5%, with 1 confirmed partial response in a pt with an adenoid cystic carcinoma in lung. INCAGN02390 monotherapy was generally well tolerated, with linear PK. The 400 mg Q2W dose is selected for further investigation in phase 1b/2 studies in combinations with other immunotherapies (NCT04370704, NCT05287113).

Isatuximab plus atezolizumab in patients with advanced solid tumors: results from a phase I/II, open-label, multicenter study

BackgroundThe anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN).Patients and methodsPhase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon’s two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME).ResultsOverall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced ≥1 treatment-emergent adverse event (TEAE), with ≤48.5% being grade ≥3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME.ConclusionsIsa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients.

Participant characteristics and safety outcomes of peanut oral immunotherapy in the RAMSES and ARC011 trials

BackgroundClinical trials (PALISADE [ARC003], ARTEMIS [ARC010]) proving efficacy and safety of peanut (Arachis hypogaea) allergen powder-dnfp (PTAH) have used double-blind, placebo-controlled food challenges (DBPCFCs) to screen for eligibility and to evaluate efficacy. In routine clinical practice, individuals with peanut allergy do not always undergo food challenges to confirm diagnosis or determine candidacy for treatment. ObjectiveTo describe PTAH safety and tolerability in participants selected by clinical history and peanut sensitization parameters not undergoing DBPCFCs during trials and to compare findings with previously published data. MethodsRAMSES (ARC007) was a 6-month, phase 3, randomized, double-blind, placebo-controlled trial in children aged 4 to 17 years with physician-confirmed peanut allergy. ARC011 was the subsequent 6-month follow-on maintenance PTAH study. The primary end point for RAMSES and ARC011 was the frequency of treatment-emergent adverse events (AEs). We descriptively compared baseline characteristics and safety outcomes from RAMSES and ARC011 to participants undergoing DBPCFCs in phase 3 PALISADE and ARTEMIS trials. ResultsIn 506 patients randomized to study treatment, baseline characteristics appeared balanced among groups. Proportion of participants with at least 1 AE was 55% for PTAH vs 33.9% for placebo during initial dose escalation and 98.8% vs 94.0% during updosing, respectively. Most participants with AEs had mild or moderate events. The most common AEs were gastrointestinal. Comparisons to pooled PALISADE and ARTEMIS data revealed higher baseline median peanut-specific immunoglobulin E and skin prick test values for RAMSES participants. Safety outcomes during trial periods were comparable. ConclusionSafety data from clinically selected children with peanut allergy receiving PTAH do not seem different from those in phase 3 trials requiring DBPCFC to enter trials.

Safety and efficacy of tirzepatide as an add-on to single oral antihyperglycaemic medication in patients with type 2 diabetes in Japan (SURPASS J-combo): a multicentre, randomised, open-label, parallel-group, phase 3 trial

Due to potential ethnic differences in the pathophysiology of type 2 diabetes, new therapeutics need to be evaluated in Japanese patients. We aimed to assess the safety and glycaemic efficacy of tirzepatide as an add-on treatment in Japanese patients with type 2 diabetes who had inadequate glycaemic control with stable doses of various oral antihyperglycaemic monotherapies. This multicentre, open-label, parallel-group, randomised, phase 3 trial was conducted at 34 medical research centres and hospitals in Japan. Eligible participants were aged 20 years or older with inadequately controlled (HbA1c ≥7·0% to <11·0%) type 2 diabetes and were receiving oral antihyperglycaemic monotherapy (sulfonylureas, biguanides, α-glucosidase inhibitors, thiazolidinedione, glinides, or SGLT2 inhibitors) for at least 3 months (stable dose for ≥8 weeks before screening), had a BMI of 23 kg/m2 or higher, and stable bodyweight (±5%) for at least 3 months before screening. After a 2-week screening and 2-week lead-in period, all participants were randomly assigned (1:1:1) to receive 5, 10, or 15 mg of tirzepatide, administered once per week subcutaneously for 52 weeks followed by a 4 week safety follow-up period, using a computer-generated random sequence and interactive web response system, stratified by oral antihyperglycaemic medication group. All participants started receiving 2·5 mg tirzepatide and doses were escalated by 2·5 mg every 4 weeks until the assigned dose was reached. The primary endpoint was safety and tolerability during 52 weeks of treatment, assessed as incidence of treatment-emergent adverse events in the modified intention-to-treat (mITT) population. This trial is registered with ClinicalTrials.gov, NCT03861039. Between March 30, 2019, and Feb 16, 2021, with recruitment and enrolment continuing until Feb 4, 2020, 484 participants were assessed for eligibility and 443 were randomly assigned to receive at least one dose of tirzepatide (148 [33%] in the 5 mg group, 147 [33%] in the 10 mg group, and 148 [33%] in the 15 mg group). 398 (90%) participants completed the study and treatment. Most participants (343 [77%] of 443) had at least one treatment-emergent adverse event. Treatment-emergent adverse events were more frequent in the tirzepatide 15 mg group (125 [84%] of 148) than the 5 mg (109 [74%] of 148) and 10 mg groups (109 [74%] of 147). The most frequent treatment-emergent adverse events with tirzepatide were mild or moderate nasopharyngitis (75 [17%]), nausea (74 [17%]), constipation (54 [12%]), diarrhoea (51 [12%]), and decreased appetite (44 [10%]). At week 52, mean changes from baseline in bodyweight were -3·8 kg (SE 0·5; -5·1% reduction) in the 5 mg group, -7·5 kg (0·5; -10·1% reduction) in the 10 mg group, and -10·2 kg (0·5; -13·2% reduction) in the 15 mg group. Least squares mean HbA1c at baseline reduced from 8·5% (SE 0·1) to 6·0% (0·1) in the 5 mg tirzepatide group, from 8·6% (0·1) to 5·6% (0·1) in the 10 mg group, and from 8·6% (0·1) to 5·6% (0·1) in the 15 mg group at week 52. No adjudication-confirmed deaths were reported. Tirzepatide was well tolerated as an add-on to oral antihyperglycaemic monotherapy in Japanese participants with type 2 diabetes and showed improvement in glycaemic control and bodyweight, irrespective of background oral antihyperglycaemic medication. Tirzepatide is a potential new treatment option for Japanese patients with type 2 diabetes that is inadequately controlled with single oral antihyperglycaemic medication. Eli Lilly and Company. For the Japanese translation of the abstract see Supplementary Materials section.

Efficacy and Safety of Oteseconazole in Recurrent Vulvovaginal Candidiasis

BackgroundManagement of recurrent vulvovaginal candidiasis (RVVC) is an unmet clinical challenge without approved treatment in the United States. Oteseconazole is a novel oral selective inhibitor of fungal CYP51, designed to treat RVVC without off-target toxicities. VIOLET comprised two global, phase 3, multicenter, randomized, double-blind, placebo-controlled trials (CL-011 and CL-012). The primary objective was to evaluate oteseconazole efficacy through week 48. Key secondary objectives evaluated time to first recurrence, safety, and patient-reported outcomes.MethodsWomen with three or more symptomatic acute vulvovaginal candidiasis (VVC) episodes within the previous 12-month period, including the screening episode (in which the VVC episode cleared with fluconazole induction therapy), were randomly assigned 2:1 at baseline (maintenance phase) to 150 mg of oral oteseconazole daily for 7days and then once weekly for 11 weeks or to matching placebo for 12 weeks. Time-to-first-recurrence data were collected during the maintenance phase. Posttreatment follow-up was 36 weeks.ResultsAmong 656 women (326 in CL-011 and 330 in CL-012), the averaged percentage of participants with one or more RVVC episodes through week 48 was 6.7% (range, 6.5 to 7.4%) in CL-011 and 3.9% (3.7 to 4.6%) in CL-012 in the oteseconazole groups versus 42.8% (41.3 to 45.0%) and 39.4% (38.0 to 42.6%) in the corresponding placebo groups (P<0.001). Among oteseconazole-treated participants in CL-011 and CL-012 who experienced an RVVC episode (n=22), the mean time to recurrence was 45.7 and 47.2 weeks versus 27.8 and 33.1 weeks for placebo-treated participants (n=84), respectively (hazard ratio [95% confidence interval], 0.11 [0.06 to 0.21] for CL-011 and 0.08 [0.04 to 0.17] for CL-012; P<0.001). Types and frequencies of treatment-emergent adverse events (TEAEs) were similar between groups in both trials, with no drug-related serious TEAEs or adverse effects on pregnancy outcomes, liver function, or QT interval.ConclusionsOral oteseconazole was effective in preventing acute VVC recurrence and treating RVVC through week 48 in the CL-011 and CL-012 trials, with mostly mild TEAEs. (Funded by Mycovia Pharmaceuticals, Inc., ClinicalTrials.gov numbers, NCT03562156 for CL-011 and NCT03561701 for CL-012.)

Safety profile of lasmiditan in patients with migraine in an Asian population

ABSTRACT Background MONONOFU, a multicenter, randomized, double-blind, placebo-controlled phase 2 study of Japanese patients with migraine, was pivotal for lasmiditan approval in Japan. However, treatment-emergent adverse events (TEAEs) were more common than in global studies. A detailed safety profile would assist patient management. Research design and methods Safety assessments in MONONOFU included specific terms reported, frequency, severity, time to onset, duration, TEAE management, common TEAE risk factors, and TEAE–efficacy associations. Results Of 846 participants, 691 were assessed for safety. The proportion of participants reporting ≥1 TEAE was 23.4% with placebo and 70.9% with lasmiditan; 87.3% of TEAEs with lasmiditan were mild. The most frequent TEAEs with lasmiditan, dizziness (39.4%) and somnolence (19.3%), started ≤1 hour postdose (median durations: 2.5 and 3.3 hours, respectively). Higher lasmiditan dose, but not patient factors including body size, was identified as a clinically meaningful predictor of dizziness and somnolence. There were no adverse consequences of neurological TEAEs, which did not appear to adversely affect lasmiditan efficacy. Conclusions In the MONONOFU study, TEAEs appeared typically mild, transient, and self-limiting. Lasmiditan may represent a useful and well-tolerated acute treatment option for smaller (body mass index <30 kg/m2) patients and Asian patients with migraine.

P1535: SAFETY AND TOLERABILITY OF SINGLE ESCALATING DOSES OF INTRAVENOUS NIPOCALIMAB IN HEALTHY JAPANESE ADULTS: A RANDOMIZED, PHASE 1 PLACEBO-CONTROLLED STUDY

Background: Autoimmune hemolytic anemia (AIHA) is a rare, life-threatening disorder characterized by the destruction of red blood cells (RBCs) by autoantibodies. In Japan, the estimated prevalence of AIHA is 3-10 cases per 1 million person-years. Of these, approximately 90% of patients present with warm AIHA (wAIHA), which occurs when pathogenic IgG antibodies bind to RBCs at a temperature of ~37 °C. There is currently no approved treatment for wAIHA, and patients with severe symptomatic anemia are generally managed with corticosteroids, immunosuppressants, rescue therapies, and immune cell depleting biologic therapies. Nipocalimab is a fully human, effectorless IgG1 monoclonal antibody in clinical development for wAIHA. Nipocalimab targets the IgG binding site on the neonatal Fc receptor (FcRn) to reduce circulating IgG including anti-RBC autoantibodies. In a prior phase 1 study in healthy adults receiving single and multiple ascending doses administered by intravenous (IV) infusion, nipocalimab was well-tolerated with an adverse event profile comparable to placebo. However, the proportion of Asian participants in that study was small, and therefore the safety of nipocalimab required further investigation in this population. Aims: To assess the safety and tolerability of single escalating doses of nipocalimab administered as IV infusions in healthy Japanese adults. Methods: The trial was a randomized, double-blind, placebo-controlled, escalating single dose study. Eligible participants were healthy Japanese males or females aged 18-64 years with no clinically significant medical or physical conditions. Dosing cohorts were: nipocalimab 10 mg/kg, 30 mg/kg, and 60 mg/kg or matching placebo, infused IV over 30 min. Escalation to the next dose level only proceeded following review of safety and tolerability by the principal investigator. Safety was assessed by the frequency of treatment-emergent adverse events (TEAEs), as well as abnormalities in clinical laboratory assessments, physical examinations, or vital signs. Results: A total of 24 Japanese participants (92% female) were randomized, received study drug, and completed the study. A total of 3 participants (12.5%) experienced 1 or more TEAE: 2 in the 30 mg/kg nipocalimab cohort and 1 in the 60 mg/kg nipocalimab cohort (Table). Mild (grade 1) dizziness was the most common TEAE, which was reported by 2 participants, 1 each in the 30 mg/kg and 60 mg/kg nipocalimab cohorts. Mild influenza-like illness was reported by 1 participant who received 30 mg/kg nipocalimab and mild diarrhea was reported by 1 participant who received 60 mg/kg nipocalimab; these TEAEs were considered by the investigator as unrelated to study drug. One participant in the 30 mg/kg nipocalimab cohort discontinued study drug infusion after 22 minutes due to a moderate infusion-related reaction, which was considered to be related to study treatment. This AE was managed with an antihistamine, and the participant received only 22 mg of nipocalimab. There were no clinically significant changes in laboratory parameters or vital signs, no injection site reactions, serious adverse events, or deaths. Image:Summary/Conclusion: Single doses of nipocalimab, administered at doses between 10 mg/kg and 60 mg/kg by IV infusion, were generally safe and well-tolerated in healthy Japanese adults, consistent with the prior phase 1 study in a general population, which included Asian and non-Asian participants.

P1101: PIRTOBRUTINIB, A HIGHLY SELECTIVE, NON-COVALENT (REVERSIBLE) BTK INHIBITOR IN PREVIOUSLY TREATED MANTLE CELL LYMPHOMA: UPDATED RESULTS FROM THE PHASE 1/2 BRUIN STUDY

Background: Covalent BTK inhibitors (BTKi) have transformed the management of mantle cell lymphoma (MCL), but these treatments are not curative and the majority of patients (pts) will require additional treatment. Covalent BTKi share pharmacologic liabilities (e.g. low oral bioavailability, short half-life) that collectively may lead to suboptimal BTK target coverage, for example in rapidly proliferating tumors with high BTK protein turnover such as MCL. To address these limitations, pirtobrutinib, a highly selective, non-covalent (reversible) BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency was developed. Aims: BRUIN is a multicenter phase 1/2 study (NCT03740529) of oral pirtobrutinib monotherapy in pts with advanced B-cell malignancies who have received ≥2 prior therapies. Methods: Pirtobrutinib was dose escalated in a standard 3 + 3 design in 28-day cycles. The primary objective for phase 1 was to determine the recommended phase 2 dose (RP2D) and the primary objective of phase 2 was overall response rate (ORR); secondary objectives included duration of response (DoR), progression-free survival (PFS), overall survival (OS), safety and tolerability, and pharmacokinetics. Efficacy evaluable pts included all dosed pts who underwent their first response evaluation or discontinued therapy. Response was assessed every 8 weeks from cycle 3, and every 12 weeks from cycle 13 and was measured according to Lugano Classification. Safety was assessed in all pts (CLL/SLL and NHL). Results: As of 27 September 2020, 323 pts (170 CLL/SLL, 61 MCL, 26 WM, 26 DLBCL, 13 MZL, 12 FL, 9 RT, and 6 other NHL [other transformation, B-PLL and hairy cell leukemia]) were treated on 7 dose levels (25-300mg QD). Median age was 69 (range 50-87) years for MCL pts. Among the 61 MCL pts, median number of prior lines of therapy was 3 (range, 1-8) and a majority of them had received a prior BTKi (93%), an anti-CD20 antibody (98%) or chemotherapy (92%). No DLTs were reported and MTD was not reached (n=323). 200mg QD was selected as the RP2D. Fatigue (20%), diarrhea (17%) and contusion (13%) were the most frequent treatment-emergent adverse events regardless of attribution or grade seen in ≥10% of pts (n=323). The most common adverse event of grade ≥3 was neutropenia (10%). Treatment-related hemorrhage and hypertension occurred in 5 (2%) and 4 (1%) pts, respectively. Five (1%) pts discontinued due to treatment-related adverse events. At the efficacy cutoff date, 52 prior BTKi treated MCL pts were efficacy evaluable with an ORR of 52% (95% confidence interval 38-66; 13 complete response (CR) [25%], 14 partial response (PR) [27%], 9 stable disease (SD) [17%]), 11 progressive disease (PD) [21%] and 5 [10%] discontinued prior to first response assessment). Median follow up was 6 months (range 0.7-18.3+). Responses were observed in 9/14 pts (64%) with prior autologous or allogeneic stem cell transplant, and 2 of 2 with prior CAR-T cell therapy. Summary/Conclusion: Pirtobrutinib demonstrated promising efficacy in heavily pretreated, poor-prognosis MCL following multiple prior lines of therapy, including a covalent BTKi. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index. Updated data, including approximately 60 new pts with MCL and an additional 10 months since the prior data cut will be presented.