Treatment-related Serious Adverse Events Research Articles

Maintenance with 5-FU/LV-aflibercept after induction with FOLFIRI-aflibercept versus FOLFIRI-aflibercept until progression as second-line treatment in older adults with metastatic colorectal cancer: the AFEMA phase II randomized trial

The combination chemotherapy i.v. 5-fluorouracil (5-FU), irinotecan, and aflibercept (FOLFIRI-A) is a standard second-line treatment of metastatic colorectal cancer (mCRC). The aim was to assess maintenance treatment in second-line setting in older patients (aged ≥70 years) with mCRC. We evaluated FOLFIRI-A given for six cycles followed by maintenance with 5-FU/leucovorin (LV)-A (arm A) or FOLFIRI-A (arm B) until progression in older adults with mCRC in the AFEMA randomized, open-label, non-inferiority phase II trial (EudraCT2016-004076-21/NCT03279289). Patients aged ≥70 years who previously failed oxaliplatin-fluoropyrimidine were randomly allocated (1 : 1) to either arm A (experimental) or arm B (control). After enrolling 35 patients, the FOLFIRI dose was reduced to level 1 in both arms due to toxicity. The primary endpoint was median progression-free survival (PFS); and secondary endpoints were median overall survival, objective response rate, and safety. Non-inferiority required the upper confidence interval (CI) limit to not exceed a hazard ratio (HR) of 1.5 (one-sided α= 0.075, 80% power). A total of 170 patients were randomly allocated to arm A or arm B (n= 85 each). The median follow-up was 12.2 versus 10.9 months in arm A versus arm B. Most patients died (83.5% versus 88.2% in arm A versus arm B), mainly from disease progression. PFS non-inferiority was met (HR= 0.78, 95% CI 0.566-1.076, P= 0.131) with a median PFS of 6.1 versus 5.5 months in arm A versus arm B. Median overall survival was similar in arms A and B (12.2 and 11.5 months, respectively) (HR= 0.89, 95% CI 0.640-1.227, P= 0.467). During the maintenance phase, severe asthenia (4.5% versus 21.6%, P= 0.038), serious adverse events (SAEs) (17.8% versus 37.8%, P= 0.049), and treatment-related SAEs (6.7% versus 10.8%, P= 0.695) were reduced in arm A versus arm B. In older adults, induction with six cycles of FOLFIRI-A plus maintenance with 5-FU/LV-A was non-inferior to FOLFIRI-A until progression. Severe asthenia, SAEs, and treatment-related SAEs were reduced with 5-FU/LV-A maintenance.

Results of a Phase 2 Multicenter Study Evaluating the Safety and Tolerability of VP-315, an Investigational Therapy for Basal Cell Carcinoma

Introduction VP-315 is an intratumorally injected, chemotherapeutic oncolytic peptide in development as a non-surgical immunotherapeutic agent to be utilized as first line therapy in a primary or neoadjuvant setting for patients with basal cell carcinoma (BCC). Objective In Part 2 of this study, the primary objective was to determine the optimal dosing regimen for VP-315 by exploring the effects of various dosing schemes on the safety and tolerability of VP-315 in a larger population of subjects with biopsy proven BCC. Methods Eighty-two (82) subjects with up to 2 target BCC tumors (total 91 tumors) were treated intratumorally with VP-315 for up to 2 weeks. Cohort 3 was not enrolled based on results from Cohorts 1-2. Each 7-day treatment week was comprised of 2 or 3 consecutive treatment days followed by a no-treatment period of at least 4 days. Dosing scheme: Cohort 1: (n=6) Tumor injected 3 days consecutively (3X/week 4 mg loading dose Day 1 followed by 8 mg dose). Cohort 2: (n=3) Tumor injected 3 days consecutively (3X/week 8 mg dose). Cohort 4: (n=36) Each tumor was injected 2 days consecutively (2X/week 8 mg split dose*). Cohort 5: (n=37) Each tumor was injected 3 days consecutively (3X/week 8 mg split dose*). * Dose split into 2 injections, 30% injected initially; 70% injected 15-30 minutes later. Safety and tolerability were assessed by documenting the occurrence of Treatment Related Adverse Events (TRAEs), including those of special interest, Treatment Related Serious Adverse Events (TRSAEs), discontinuations due to AEs and expected treatment-related cutaneous reactions including tumor necrosis. Results All 82 subjects completed one of the VP-315 treatment regimens for BCC. TRAEs were mostly mild to moderate. AEs included injection site pain (mild 13.4%, moderate 12.2%, severe 1.2%), hypertension (mild 4.9%), hypotension (mild 4.9%), erythema (mild 1.2%, moderate 2.4%), and headache (mild 2.4%). Expected cutaneous reactions were observed. No TRSAEs were reported. Conclusion VP-315 treatment was shown to be safe and well-tolerated when administered once daily 2-3 times per week per tumor for up to 2 weeks using a split dose approach. Given its favorable safety profile, VP-315 warrants continued research as a potential non-surgical immunotherapy for BCC as a first line therapy in a primary or neoadjuvant setting. Sponsored by Verrica Pharmaceuticals Inc.

NCOG-07. SAFETY OF ONC201 TREATMENT IN PATIENTS WITH PREVIOUSLY TREATED H3 K27M-MUTANT GLIOMA: RESULTS FROM ONC028, AN ONGOING COMPASSIONATE USE PROGRAM

Abstract PURPOSE H3 K27M-mutant diffuse midline glioma (DMG) has a poor prognosis, with a median overall survival of 1 year and no proven treatments beyond radiotherapy. ONC201 (dordaviprone), a first-in-class imipridone, previously demonstrated durable responses in patients with recurrent H3 K27M-mutant DMG. The present analysis reports safety data from ONC028, a compassionate use program (CUP) for patients with previously treated H3 K27M-mutant glioma. METHODS ONC028 is an expanded access program that provides ONC201 monotherapy to patients with H3 K27M-mutant glioma. Eligible patients are adults or pediatric patients with H3 K27M-mutant glioma, prior therapy including at least radiation, and adequate organ function. Patients must be ineligible for enrollment in other ongoing clinical studies evaluating ONC201. ONC201 is administered orally once weekly at 625 mg or dose-equivalent based on body weight for pediatric patients. MRIs are performed every two 28-day cycles for the initial 12 months, thereafter every 2-3 cycles. Treatment continues until disease progression, unacceptable adverse events (AEs), or withdrawal of consent. Treatment may continue post-progression at the discretion of the treating physician. Bevacizumab use for radiation necrosis or symptom management is acceptable. AEs are assessed by NCI CTCAE v5.0 criteria. RESULTS The 422 enrolled patients include 191 adults (45.2%) and 231 children (54.7%); 87.1% had a performance score ≥60 and the most common tumor location was the pons (57.3%). Any-causality Grade ≥3 AEs have been reported in 200 patients (47.4%). Grade ≥3 treatment-related AEs (TR-AEs) were reported in 19 (4.5%) patients; the commonest was decreased lymphocyte count, occurring in 3 (0.7%) patients. Any-causality serious AEs (SAE) were reported in 43.1% (n=182) patients. There were 10 (2.4%) patients with reports of treatment-related SAEs, the commonest were ascites, nausea, vomiting, and seizure, each occurring in 2 patients (0.2%). CONCLUSIONS ONC028 provides expanded access to ONC201 treatment for patients with previously treated H3 K27M-mutant glioma who are ineligible for enrollment in ongoing trials of ONC201. ONC201 treatment remains well-tolerated.

Incidence and type of adverse events in patients with cirrhosis receiving terlipressin: A systematic review and meta-analysis.

Terlipressin has been widely used for various cirrhosis-related complications, but its safety profile remains controversial. Herein, this issue was systematically evaluated. All studies reporting adverse events (AEs) of terlipressin in cirrhosis were screened. Incidences were pooled using a random-effects model. Subgroup analyses were performed according to the patient's characteristics and treatment regimens. Interaction among subgroups was evaluated. Seventy-eight studies with 7257 patients with cirrhosis were included. The pooled incidences of any AEs, treatment-related AEs, any serious AEs (SAEs), treatment-related SAEs, treatment withdrawal due to AEs, and treatment withdrawal due to treatment-related AEs were 31%, 22%, 5%, 5%, 4%, and 4% in patients with cirrhosis receiving terlipressin, respectively. Patients with hepatorenal syndrome had higher incidences of any SAEs (29% vs. 0% vs. 0%, pinteraction = 0.01) and treatment-related SAEs (8% vs. 1% vs. 7%, pinteraction = 0.02) than those with variceal bleeding or ascites. Patients who received terlipressin with human albumin had higher incidences of any SAEs (18% vs. 1%, pinteraction = 0.04) and treatment-related SAEs (7% vs. 0%, pinteraction = 0.09) than those without albumin. Patients with total bilirubin level >4.3mg/dL had higher incidences of any AEs (69% vs. 24%, pinteraction = 0.02), any SAEs (64% vs. 0%, pinteraction < 0.01), and treatment-related SAEs (8% vs. 1%, pinteraction = 0.04) than those ≤4.3mg/dL. AEs are common in patients with cirrhosis receiving terlipressin and influenced by clinical scenarios, combination with albumin, and bilirubin levels.

Efficacy and safety of immune checkpoint inhibitors plus platinum-etoposide vs. platinum-etoposide in the first-line treatment of extensive-stage small cell lung cancer: a systematic review and a meta-analysis.

Currently, immune checkpoint inhibitors (ICIs) combined with platinum-etoposide (EP) are gradually becoming the first-line standard treatment for extensive-stage small cell lung cancer (ES-SCLC). This meta-analysis aims to compare the efficacy and safety of ICIs combined with EP vs. EP alone in the first-line treatment of ES-SCLC. We searched PubMed, Embase, and Cochrane Library databases for phase II/III randomized controlled trials (RCTs) that met inclusion criteria from January 2016 to November 2023. Outcome measures included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), treatment-related adverse events (TRAEs), treatment-related serious adverse events (TRSAEs), and immune-related adverse events (IRAEs). The effect analysis statistics of the outcome indicators were expressed with hazard ratio (HR) and odds ratio (OR) and their 95% confidence interval (CI). This study included nine RCTs with a total of 4,711 patients. Compared to EP, ICIs plus EP improved patients' PFS (HR =0.71; 95% CI: 0.64-0.79; P<0.001), OS (HR =0.79; 95% CI: 0.74-0.84; P<0.001), and ORR (OR =1.27; 95% CI: 1.12-1.44; P=0.001), but increased the incidence of adverse events (AEs): TRAEs (OR =1.45; 95% CI: 1.20-1.76; P<0.001), IRAEs (OR =3.97; 95% CI: 2.49-6.32; P<0.001), and grade 3-4 IRAEs (OR =6.17; 95% CI: 2.36-16.15; P<0.001). However, there was no significant difference in the incidence of grade 3-4 TRAEs (OR =1.05; P=0.54), TRSAEs (OR =1.40; P=0.13), and grade 3-4 TRSAEs (OR =1.17; P=0.72). Subgroup analysis found that patients with brain metastasis did not benefit from ICIs combined with EP therapy, and patients with programmed cell death ligand 1 (PD-L1) expression ≥1% had poorer survival benefits compared to patients with PD-L1 expression <1%. In the first-line treatment of ES-SCLC, compared to EP chemotherapy, ICIs with EP can benefit patients in terms of PFS, OS, and ORR, but it will increase the occurrence of AEs.

A phase Ib/IIa trial to evaluate the safety and efficacy of PM8002, a bispecific antibody targeting PD-L1 and VEGF-A, as a monotherapy in patients with advanced NSCLC.

8533 Background: The combination of immune checkpoint inhibitors with chemotherapy has become the first-line treatment for advanced non-squamous NSCLC with negative driver genes, but not for driver gene-positive tumors. PM8002 is a bispecific antibody targeting both PD-L1 and VEGF-A. Previous published data indicated that PM8002 has a tolerable safety profile and potential anti-tumor activity in a variety of solid tumors (SITC2022 abstract #725 and ASCO2023 abstract #2536). Here, we report results of PM8002 in advanced NSCLC patients in an ongoing Phase Ib/IIa trial. Methods: Patients with previously untreated advanced non-squamous NSCLC (EGFR/ALK wild-type and PD-L1+; Cohort 6), advanced non-squamous with EGFR mutations who had failed prior EGFR-TKI treatment (Cohort 7), or EGFR/ALK wild-type who had failed anti-PD-1/L1 therapy and platinum-based chemotherapy regiments (NSCLC IO- and PBC-treated) were enrolled into a Phase I/IIa trial. All patients received PM8002 until observations of unacceptable toxicity, disease progression, or consent withdrawal. Tumor responses were evaluated every 6 weeks. The primary endpoint was objective response rate (ORR), with disease control rate (DCR), progression-free survival (PFS), and safety, as secondary endpoints. Results: As of Dec 20, 2023, 61 patients with advanced NSCLC were enrolled and had at least one tumor assessment. Among 61 evaluable patients 16 partial response (PR) and 32 stable diseases (SD) were observed (all cohorts; see individual cohorts in the table below). Any-grade treatment-related adverse events (TRAEs) occurred in 85.2% patients (52/61) with those ≥ Grade 3 at 18% (11/61). Immune-related AEs (irAEs) occurred in 37.7% patients (23/61). Serious adverse events (SAEs) and treatment-related SAEs were observed in 23% (14/61) and 9.8% (6/61) of patients, respectively. The most common TRAEs (≥15%) were hypertension, hypothyroidism, proteinuria, hypoalbuminemia, hypocalcemia, aspartate aminotransferase increase, and lactate dehydrogenase increase. 8.2% (5/61) of patients discontinued PM8002 due to TRAEs. Conclusions: PM8002 showed preliminary antitumor activity and acceptable safety in patients with advanced NSCLC. Monotherapy and combination trials with chemotherapy for different indications are still ongoing. Clinical trial information: NCT05918445 . [Table: see text]

A phase I dose escalation and expansion trial of the next-generation oral SERD camizestrant in women with ER-positive, HER2-negative advanced breast cancer: SERENA-1 monotherapy results

SERENA-1 (NCT03616587) is a Phase 1, multi-part, open-label study of camizestrant in pre- and post-menopausal women with ER+, HER2- advanced breast cancer. Parts A and B aim to determine the safety and tolerability of camizestrant monotherapy and define doses for clinical evaluation. Patients and Methods Women aged 18 years or older with metastatic or recurrent ER+, HER2- breast cancer, refractory (or intolerant) to therapy were assigned 25 mg up to 450 mg once daily (QD; escalation) or 75, 150, or 300 mg QD (expansion). Safety and tolerability, anti-tumor efficacy, pharmacokinetics, and impact on ESR1m circulating tumor (ct)DNA levels were assessed. By 9 March 2021, 108 patients received camizestrant monotherapy at 25-450 mg doses. Of these, 93 (86.1%) experienced treatment-related adverse events (TRAEs), 82.4% of which were grade 1 or 2. The most common TRAEs were visual effects (56%), (sinus) bradycardia (44%), fatigue (26%), and nausea (15%). There were no TRAEs grade 3 or higher, or treatment-related serious adverse events (TRSAEs) at doses ≤150 mg. Median tmax was achieved ∼2-4 hours post-dose at all doses investigated, with an estimated half-life of 20-23 hours. Efficacy was observed at all doses investigated, including in patients with prior CDK4/6 inhibitor and/or fulvestrant treatment, with and without baseline ESR1 mutations, and with visceral disease, including liver metastases. Camizestrant is a next-generation oral SERD and pure ER antagonist with a tolerable safety profile. The pharmacokinetics profile supports once-daily dosing, with evidence of pharmacodynamic and clinical efficacy in heavily pre-treated patients, regardless of ESR1m. This study established 75, 150 and 300 mg QD doses for Phase 2 testing (SERENA-2, NCT04214288 and SERENA-3, NCT04588298).

Protocol for a randomized, placebo-controlled, double-blind phase IIa study of the safety, tolerability, and symptomatic efficacy of the ROCK-inhibitor Fasudil in patients with Parkinson's disease (ROCK-PD).

The Rho-kinase (ROCK) inhibitor Fasudil has shown symptomatic and disease-modifying effects in Parkinson's disease (PD) models in vitro and in vivo. In Japan, Fasudil has been approved for the treatment of subarachnoid haemorrhage since 1995 and shows a favourable safety profile. To investigate the safety, tolerability, and symptomatic efficacy of ROCK-inhibitor Fasudil in comparison to placebo in a randomized, national, multicenter, double-blind phase IIa study in patients with PD. We plan to include 75 patients with at least 'probable' PD (MDS criteria), Hoehn and Yahr stages 1-3, and age 30-80 years in 13 German study sites. Patients must be non-fluctuating and their response to PD medication must have been stable for 6 weeks. Patients will be randomly allocated to treatment with the oral investigational medicinal product (IMP) containing either Fasudil in two dosages, or placebo, for a total of 22 days. As primary analysis, non-inferiority of low/high dose of Fasudil on the combined endpoint consisting of occurrence of intolerance and/or treatment-related serious adverse events (SAEs) over 22 days will be assessed in a sequential order, starting with the lower dose. Secondary endpoints will include tolerability alone over 22 days and occurrence of treatment-related SAEs (SARs) over 22 and 50 days and will be compared on group level. Additional secondary endpoints include efficacy on motor and non-motor symptoms, measured on established scales, and will be assessed at several timepoints. Biomaterial will be collected to determine pharmacokinetics of Fasudil and its active metabolite, and to evaluate biomarkers of neurodegeneration. After positive evaluation by the competent authority and the ethics committee, patient recruitment started in the 3rd quarter of 2023. ROCK-PD is registered with Eudra-CT (2021-003879-34) and clinicaltrials.gov (NCT05931575). Results of this trial can pave way for conducting extended-duration studies assessing both symptomatic efficacy and disease-modifying properties of Fasudil.

Growth hormone treatment in children with Prader-Willi syndrome: safety and effectiveness data from the PATRO Children study.

Recombinant human growth hormone (rhGH, somatropin) therapy is approved in children with Prader-Willi syndrome (PWS). To report safety and effectiveness data for children with PWS treated with biosimilar rhGH (Omnitrope®, Sandoz) in the PAtients TReated with Omnitrope (PATRO) Children study. PATRO Children was a multicenter, non-interventional, postmarketing surveillance study. Children with PWS received Omnitrope according to standard clinical practice. Adverse events (AEs) were monitored for the duration of Omnitrope treatment. Effectiveness outcomes were also assessed, including height standard deviation (SD) scores (HSDS). As of July 2020 (study completion), 235 patients with PWS had been enrolled. At baseline, 95.7% (n = 225) of patients were prepubertal and 86.4% (n = 203) were rhGH treatment-naïve. At analysis, the median (range) treatment duration in the study was 56.8 (2.9-155.8) months. AEs were reported in 192 patients (81.7%) and were suspected as treatment-related in 39 patients (16.6%). Serious AEs (SAEs) were reported in 96 patients (40.9%) and were suspected as treatment-related in 22 patients (9.4%). The most frequent treatment-related SAEs were sleep apnea syndrome (n = 11; 4.7%), tonsillar hypertrophy (n = 4; 1.7%), and adenoidal hypertrophy (n = 4; 1.7%). Development of scoliosis was considered treatment-related in two patients; development of impaired glucose tolerance in one patient and type 2 diabetes mellitus in another patient were considered treatment-related. Effectiveness outcomes were primarily assessed in 153 patients who completed 3 years of treatment. Among the 151 prepubertal patients (135 treatment-naïve), mean (SD) change from baseline in HSDS after 3 years was +1.50 (1.07) across all patients and +1.57 (1.07) for treatment-naïve patients. These data suggest that biosimilar rhGH is well tolerated and effective in patients with PWS managed in real-life clinical practice. Patients with PWS should continue to be closely monitored for well-known safety issues (including respiratory, sleep, and glucose metabolism disorders, and scoliosis) during rhGH treatment.

A Phase II Study of Single Agent Aspacytarabine (BST-236) in Adults Unfit for Intensive Chemotherapy with Relapsed or Refractory Acute Myeloid Leukemia (R/R AML) or Higher Risk Myelodysplastic Syndromes (R/R HR MDS)

Background-Common treatment approaches for R/R AML and to some extent HR MDS involve intensive chemotherapy regimens, typically combining high dose cytarabine with other drug(s), but these intensive regimens may not be suitable for unfit or elderly patients. To address this issue, a cytarabine prodrug called BST-236 has been developed, which delivers high doses of cytarabine while reducing systemic toxicity, making it a potential option for intensive chemotherapy in older and frail patients. This Phase II study aimed to assess the efficacy and tolerability of BST-236 in unfit patients with R/R AML or HR MDS previously treated with a non-intensive regimen. Methods-This ongoing Phase 2 trial (NCT 04827719) enrolled HR MDS and AML patients (pts) aged ≥ 75 years or with comorbidities incompatible with intensive chemotherapy. MDS pts were refractory or had relapsed to azacytidine (AZA), and AML pts to AZA, low-dose cytarabine (LDAC) or AZA -venetoclax (VEN), given as a first line regimen. Each BST-236 induction and maintenance course consisted of 6 daily 1-hour intravenous infusions at a dose of 4.5 g/m 2/d (containing 3 g/m 2/d of cytarabine). After completing 1 induction cycle, patients with stable disease (SD) or partial response could undergo a second similar cycle, and patients who achieved complete remission (CR) could receive 2 to 4 maintenance cycles at the same schedule. Inclusion of 20 AML and 20 MDS pts was planned. Results-From August 2021 to May 2023, 16 MDS and 20 AML pts from 9 centers were enrolled, with a median follow up of 3 months. MDS: Median age was 74.8 years [IQR, 71.2-76.4] and ECOG was 0- 1 in all but 1 patient . All pts were previously treated with AZA and 4 (29%) had adverse R-IPSS karyotype. 14/16 were evaluable for response after 1 induction: 1 (7%) CR, 2 (14%) marrow CR, 7 (50%) SD. Hematological improvement was observed in 6 (43%) patients. Two serious treatment related adverse events (SAE) - febrile neutropenia and sepsis - occurred in 2 pts. Median duration of hospitalization for the induction cycle was 29.5 days [IQR 25.5-32.5] and 30-day mortality rate was 0%. AML: Median age was 77.6 years [IQR, 73.8-79.4] and all pts had ECOG 0-1. Two pts were previously treated with AZA, 1 with LDAC, 17 with AZA-VEN and 8 (50%) had adverse ELN score. 17/ 20 pts were evaluable for response after 1 induction cycle : 2 (12%) CR including 1 CR with negative MRD, 1 (6%) CRi, 10 (59%) SD. Three SAE- infections and hepatobiliary disorders- occurred in 2 pts. Median duration of hospitalization for the induction cycle was 26 days [IQR 23.2-30.8] and 30-day mortality rate was 10%. Four MDS pts still need to be enrolled, and follow up is ongoing. An update will be presented at the meeting. Conclusion- Response rates with BST-236, in this pretreated older frail R/R AML and MDS population, were modest. Toxicity, including myelosuppression, however appears lower than with conventional intensive chemotherapy, suggesting this treatment could be interesting earlier in the disease course.

Marstacimab, an Anti-Tissue Factor Pathway Inhibitor, in Participants with Hemophilia Α or B, with and without Inhibitors: An Integrated Analysis of Safety

Background: Marstacimab (PF-06741086) targets tissue factor pathway inhibitor (TFPI) to restore hemostasis via the extrinsic pathway of blood coagulation. In phase 1/2 studies, long-term subcutaneous (SC) administration of marstacimab reduced bleeding episodes in adults with severe hemophilia A (HA) or hemophilia B (HB) (factor VIII or factor IX [FIX] ˂1%, respectively), with or without inhibitors. BASIS, the pivotal phase 3 study of marstacimab in adolescents and adults with severe HA (&amp;lt;1%) or moderately severe to severe (FIX ≤2%) HB, is ongoing. Given the potential risk for thrombotic and thromboembolic complications with novel non-factor-based agents, integrated safety analysis of studies of such agents are of interest. Wereport an integrated analysis of marstacimab safety in participants with HA or HB. Methods: Data from participants in the phase 1b/2 study (NCT02974855), its long-term follow-up (LTFU; NCT03363321), the pivotal phase 3 BASIS study (NCT03938792), and its long-term extension (LTE; NCT05145127) were included. In the phase 1b/2 study, male participants (N=26) with severe HA or HB, with or without inhibitors, were assigned to escalating weekly SC doses of marstacimab based on inhibitor status (without inhibitors: 300 mg, a single 300-mg loading dose with subsequent 150-mg doses, or 450 mg; with inhibitors: 300 mg). In the BASIS study, male participants (N=163) with severe HA or moderately severe to severe HB, with or without inhibitors, received a single SC 300-mg loading dose followed by once-weekly 150 mg in the 12-month active treatment phase (ATP). Adverse events (AEs), serious adverse events (SAEs), and AEs of special interest (AESI), including thromboembolic events and injection site reactions (ISRs), were monitored. Results: Overall, 144 unique participants received marstacimab and were included in this analysis: 28 in the phase 1b/2 study (median treatment duration, 2.8 [range, 1.2-3.0] months) and its LTFU (15.0 [1.2-16.4] months) and 116 in the BASIS study (12.1 [0.9-13.1] months) and its LTE (6.4 [1.1-16.1] months; overall BASIS + LTE, 17.3 [0.9-28.2] months). Demographics, baseline characteristics, and marstacimab treatment and dosing ( Table 1) and a summary of safety are shown in Table 2. There were no treatment-related SAEs in the phase 1b/2 study and 1 treatment-related SAE (peripheral swelling) in the BASIS study and its LTE. There were no deaths in any study. There were no AEs related to thromboembolism during treatment in participants with HA or HB across the marstacimab clinical program. Adverse drug reactions were consistent across studies. In the BASIS study and its LTE, ISRs (n=13, 11.2%) tended to be transient and mild in severity and did not lead to discontinuation from the study: other reactions were also mild: pruritus (n=4, 3.4%); rash (n=1, 0.9%) and headache (n=8, 6.9%). One participant, with a history of hemorrhoids, in the BASIS ATP had a grade 2 event of thrombosed hemorrhoids considered related to marstacimab (a local inflammation event, not related to any other thromboembolic event; dose was not interrupted or changed due to this event). No clinically important findings in laboratory values were associated with marstacimab. In the BASIS ATP, antidrug antibodies (ADAs) developed in 23/112 participants (20.5% incidence; titers were low and resolved in 22/23 participants by end of study); 6/23 were positive for neutralizing antibodies (NAbs; titers were transient and resolved by the end of study). In the LTE, ADA developed in 1/44 (2.3%) participants; the ADA titer was negative prior to marstacimab but positive at the end of the main study (titer = 2.48), positive at Day 180 in the LTE (titer = 2.41), and the participant tested negative for NAbs at both timepoints. No differences in the marstacimab safety profile, as determined by AEs, SAEs, AESIs, and discontinuations due to AEs, were reported in ADA positive or negative participants. Across the BASIS study and its LTE, 18 participants had a marstacimab dose escalation from 150 mg to 300 mg; 8/18 (44.4%) had AEs, all mild or moderate in severity and there were no AEs or SAEs leading to treatment discontinuation. Conclusion: Once-weekly SC marstacimab was well tolerated in participants with severe HA or moderately severe to severe HB, without inhibitors, with a low rate and mild severity of ISRs, transient ADAs, and no thromboembolic events with continuous treatment up to 28 months in the phase 3 program.

Safety and Efficacy of Relmacabtagene Autoleucel (relma-cel) in Adults with Relapsed/Refractory Mantle Cell Lymphoma (r/r MCL): Updated Results from a Phase II Open-Label Study in China

Background: Mantle cell lymphoma (MCL), an aggressive subtype of B-cell non-Hodgkin lymphoma, predominantly affects elderly males. Poor overall response rates (ORR) and high rates of recurrence are observed for those patients after discontinuation or failure from Bruton 's tyrosine kinase inhibitors (BTKi), with median overall survival (OS) of 6~10 months. A phase II open label study (NCT04718883) for relma-cel reported the first efficacy and safety data in 11 Chinese patients with relapsed/refractory Mantle Cell Lymphoma (r/r MCL) in ASH 2022. This abstract provides the updated data based upon 56 patients. The study is still ongoing. Methods: The study enrolled patients with confirmed diagnosis of MCL, relapsed or refractory after at least 2 lines of prior therapies including anti-CD20 antibody, anthracycline or bendamustine, andBTKi. After lymphodepleting chemotherapy, patients received relma-cel (100×10 6 CAR+ Tcells). Bridging therapy was allowed. Primary endpoint was ORR at month 3 assessed by investigator, and secondary endpoints included complete response rate (CRR) at month 3, duration of response (DoR), progression-free survival (PFS), OS, pharmacokinetics (PK), pharmacodynamics (PD) and safety. Results: As of June 30, 2023, 66 patients enrolled and receivedleukapheresis. Relma-cel was administered in 56 patients (78.6% males; median age of 59.5 years). 42 patients had tumor assessment at month 3 or discontinued treatment due to death, disease progression before evaluation. The study population had poor prognostic factors at baseline: Age: 19 (33.9%) ≥ 65 years oldPathology: 13 (23.2%) with blastoid and 6 (10.7%) with pleomorphic variants30 (53.6%) with extranodal lesions, 4 (7.1%) with gastrointestinal involvement; 28 (50.0%) with spleen involvement, 17 (30.4%) with bone marrow involvementMCL International Prognostic Index (MIPI) score ≥ 4: 27 (48.2%)High tumor burden: 17 (30.4%) had bulky disease ≥ 5 cm Over 65% patients received ≥ 3 lines of prior therapies, including 25.0% patients received ≥ 5 lines. Almost all patients failed to BTKi (29 [51.8%] relapsed and 25 [44.6%] refractory). Seven (12.5%) patients relapsed after hematopoietic stem cell transplantation (HSCT). Twenty-six (46.4%) patients underwent bridging therapy. At month 3, of the 42 efficacy-assessable patients, 27 (64.29%) reached objective responses (OR), and 23 (54. 76%) achieved complete response (CR). Best ORR was 78.57% and best CRR was 66.67%. Based on the safety analysis set of 56 patients, 52 (92.86%) patients had treatment emergent adverse events (TEAE), including 44 (78.57%) with treatment related TEAE of grade ≥ 3. Twenty-five (44.64%) patients had serious adverse events (SAE), and 13 (23.21%) with treatment related SAE. Thirty-one (55.36%) patients had cytokine release syndrome (CRS), 3 (5.36%) with grade ≥ 3. Six (10.71%) patients had neurotoxicities (NT), 4 (7.14%) with grade ≥ 3. Twenty-seven (48.21%) patients had infections, 15 (26.79%) with grade ≥ 3. Forty-seven (83.93%) patients had prolonged cytopenia, 38 (67.86%) with grade ≥ 3. Eighteen (32.1%) deaths occurred, 6 (10.7%) died from disease progression, 8 (14.3%) due to AE, 2 (3.6%) died from treatment related AE, 4 (7.2%) from other reasons or unknown causes. Conclusions: In this phase II study, relma-cel continually demonstrated high response rates (best ORR: 78.57%; best CRR: 66.67%) and good tolerability in patients with r/r MCL.

Emapalumab, a Fully Human Anti-Interferon Gamma Monoclonal Antibody, in Pediatric Patients with Primary Hemophagocytic Lymphohistiocytosis: Long-Term Follow-up of a Phase 2/3 Study

Background: Primary hemophagocytic lymphohistiocytosis (pHLH) is a rare, life-threatening genetically heterogeneous, autosomal recessive disorder, characterized by immune dysregulation and hyperinflammation. Acute treatment of pHLH has traditionally involved immunochemotherapy with glucocorticoids and etoposide to suppress hyperinflammation and facilitate the patient undergoing allogeneic hematopoietic stem cell transplantation (HSCT), the only potentially curative therapy. Emapalumab, a fully human immunoglobulin G1 anti-interferon-γ (IFNγ) monoclonal antibody, binds free and receptor-bound IFNγ, neutralizing its biologic activity. Emapalumab has demonstrated efficacy in patients with pHLH and has a favorable safety profile with no increase in the risk of adverse events (AEs), including infections, with increasing drug exposure prior to patients undergoing HSCT. Objective: To monitor the long-term safety and efficacy of emapalumab in patients with pHLH, including the period after undergoing HSCT. Methods: Long-term follow-up study (NCT02069899) of patients with pHLH who had received ≥1 dose of emapalumab in a multicenter, single-arm, open-label phase 2/3 clinical trial who were followed for 1 year after HSCT or last administration of emapalumab in the parent study (NCT01818492). Patients received emapalumab for 4 to 8 weeks in the parent study, which included a 4-week short-term follow-up period, during which patients could have undergone HSCT. Treatment with emapalumab could continue according to the parent study protocol during follow-up, if a favorable benefit/risk assessment was established. Any concomitant treatment ongoing at the time of study entry was continued as considered necessary by the investigators. Endpoints included safety, 1-year survival, and HSCT outcomes. Results: Overall, 37/45 patients who participated in the phase 2/3 study entered long-term follow-up, with 24 patients (64.9%) completing the study; 13 patients (35.1%) withdrew from the study, most commonly because of AEs (6 patients [46.2%]) and withdrawal of informed consent (2 patients [15.4%]). All patients had ≥1 concomitant medications including systemic corticosteroids and ≥1 systemic antimicrobial. Emapalumab treatment continued during long-term follow-up for 22 patients (59.5%). All patients experienced at least one AE during follow-up ( Table), most commonly infections or infestations (27 patients [73.0%] reported an infection AE). Most AEs were mild or moderate in intensity. Four patients (10.8%) had study drug-related AEs. Overall, 56.8% of patients experienced at least one severe AE. 28 patients (75.7%) experienced at least 1 serious AE (SAE), but only 1 patient (2.7%) had a treatment-related SAE (Coombs positive hemolytic anemia). Infusion-related reactions of rash were observed in 2 patients (5.4%), but these reactions were temporary and resolved without treatment. No patients experienced AEs leading to study drug discontinuation. Nine patients died during the study (4 prior to HSCT conditioning and 5 during the post-conditioning period). No study drug-related deaths were reported. 28 (75.7%) patients were alive at last observation or 1 year after last emapalumab dose and 33 (89.2%) survived to undergo HSCT or until 1 year after last emapalumab dose (whichever came first). 29 patients (78.4%) underwent HSCT, including 18 during long-term follow-up. 24 of the 29 (82.8%) patients who underwent HSCT were alive at last observation or 1 year after last emapalumab dose. Sustained engraftment was achieved in 23 patients (79.3%; 95% confidence interval, 61.6-90.2%). During the follow-up period, 6 patients (20.7%; 95% confidence interval [CI], 9.8-38.4%) experienced primary or secondary graft failure after undergoing HSCT and 7 patients (24.1%; 95% CI, 1.2-42.1%) had acute or chronic graft-versus-host disease. At the 12-months post-transplant visit, 25/26 (96.2%) patients maintained a complete response, while 1 (3.8%) patient was reported to have maintained a partial response. No pHLH reactivation was reported during the study. Conclusions: The long-term outcomes for patients with pHLH treated with emapalumab are consistent with observations made during a phase 2/3 study. A favorable safety profile was maintained, and a high proportion of patients received HSCT and achieved long-term survival.

Safety of bendamustine for the treatment of indolent non-Hodgkin lymphoma: a UK real-world experience

AbstractBendamustine is among the most effective chemotherapeutics for indolent B-cell non-Hodgkin lymphomas (iNHL), but trial reports of significant toxicity, including opportunistic infections and excess deaths, led to prescriber warnings. We conducted a multicenter observational study evaluating bendamustine toxicity in real-world practice. Patients receiving at least 1 dose of bendamustine with/without rituximab (R) for iNHL were included. Demographics, lymphoma and treatment details, and grade 3 to 5 adverse events (AEs) were analyzed and correlated. In total, 323 patients were enrolled from 9 National Health Service hospitals. Most patients (96%) received bendamustine-R, and 46%, R maintenance. Overall, 21.7% experienced serious AEs (SAE) related to treatment, including infections in 12%, with absolute risk highest during induction (63%), maintenance (20%), and follow-up (17%) and the relative risk highest during maintenance (54%), induction (34%), and follow-up (28%). Toxicity led to permanent treatment discontinuation for 13% of patients, and 2.8% died of bendamustine-related infections (n = 5), myelodysplastic syndrome (n = 3), and cardiac disease (n = 1). More SAEs per patient were reported in patients with mantle cell lymphoma, poor preinduction performance status (PS), poor premaintenance PS, and abnormal preinduction total globulins and in those receiving growth factors. Use of antimicrobial prophylaxis was variable, and 3 of 10 opportunistic infections occurred despite prophylaxis. In this real-world analysis, bendamustine-related deaths and treatment discontinuation were similar to those of trial populations of younger, fitter patients. Poor PS, mantle cell histology, and maintenance R were potential risk factors. Infections, including late onset events, were the most common treatment-related SAE and cause of death, warranting extended antimicrobial prophylaxis and infectious surveillance, especially for maintenance-treated patients.

Early Initiation of Oral Therapy with Cyclosporine and Eltrombopag for Treatment Naïve Severe Aplastic Anemia: Interim Results of a Phase II Trial

Introduction: Severe aplastic anemia (SAA), a life-threatening bone marrow failure disease, is treated with allogeneic bone marrow transplantation or immunosuppression (IST). Pancytopenia meeting “Camitta” criteria and an empty bone marrow (&amp;lt;30% cellularity) establish the diagnosis of SAA. However, neither diagnosis nor therapeutic interventions are straightforward, resulting in delays of therapy. SAA must be differentiated from hematologic malignancy, and constitutional forms should be excluded by functional or genetic testing. Administration of IST usually occurs at a tertiary care center, and in younger patients' evaluation for BMT is first required. Ongoing immune mediated destruction of stem cells further depletes marrow reserve and increases regenerative stress with such delays. In this phase II study, we tested the feasibility and safety of early initiation of cyclosporine (CSA) to block T cells and eltrombopag (EPAG) to stimulate hematopoiesis followed by standard of care therapies to expedite treatment (NCT04304820). Methods: Twenty-six patients with treatment-naive SAA were enrolled since 2020. Patients were 3 years or older and median age was 35 years. Exclusion criteria included a diagnosis or high clinical suspicion for inherited disease or evidence of myeloid neoplasm. To ensure rapid initiation of therapy, enrollment was not dependent on pending specialized tests (telomere length, chromosomal breakage, cytogenetics, or genomics). Lower dose CSA (2mg/kg) and full dose EPAG were initiated after confirming eligibility. Upon completion of evaluation and confirmation of acquired SAA diagnosis, all subjects received standard IST (horse ATG, CSA, and EPAG; Figure 1A). Primary feasibility endpoint assessed a composite measure of misdiagnosis, non-compliance, and treatment-related serious adverse events (TRSAE) during oral therapy. Secondary endpoints were efficacy at 6 months, relapse, clonal evolution, and overall survival. Results were compared to a historical cohort of 139 patients treated with hATG, CSA, and EPAG initiated the same day (NCT01623167). Results: All patients completed the protocol-defined treatment period, with median time on oral therapy of 17 days (range 0 - 86 days). All subjects ultimately were confirmed to have acquired SAA (no misdiagnoses), all tolerated oral treatment well without any TRSAE, and patients were compliant with local and study-site follow-up. Thus, there were zero events for the primary feasibility endpoint. A single SAE during oral treatment occurred in subject #1, enrolled at the height of the COVID pandemic and was severely ill with persistently positive COVID-19 PCR and recurrent ileitis requiring hospitalization care; his time to standard IST was the longest (86 days). There was significant increase in absolute neutrophil count (ANC; median 0.315x10 3/mL vs 0.570, p=0.041) in a brief interval of oral therapy prior to receiving hATG. There was also a trend towards improvement in absolute reticulocyte count (29x10 3/mL vs. 35.8) and a decrease in absolute lymphocyte count (1.5x10 3/mL vs. 1.3; Figure 1B). Compared to historical cohort, less patients (19% vs 52%) had very SAA (ANC &amp;lt;200 K/uL); age, sex, race, and pre-treatment blood counts were similar in two cohorts. Hematologic response occurred in 68% at 6 months with 45% complete responses, rates similar to the historical cohort (80% and 40%, respectively). Time to platelet and red blood cell transfusion independence was 43 and 51 days, respectively. Only age (18-40 years) was predictive for 6 month response. With median follow-up of 396 days, the cumulative incidence of relapse at 2 years was 17%, lower than in the historical cohort (27%). Clonal evolution to secondary myeloid malignancy was not increased compared to historical cohort; one subject had myelodysplastic syndrome with excess blasts 1 with deletion 20q, and two had transient trisomy 8 without dysplasia. Overall survival was 96.2%; no deaths occurred during study treatment period of oral medications only. Conclusion: Early initiation of CSA and EPAG is a feasible and safe approach to rapidly treat patients with SAA as a bridge to standard therapies and it may lead to improved blood counts, in turn, decreasing early infectious complications. Hematologic response was comparable to our historic cohort. Rates of long-term complications need to be confirmed in a larger cohort with ongoing study enrollment.

Efficacy, Safety, and Biomarker Analysis of 5 Mg and 7.5 Mg Doses of Crizanlizumab in Patients with Sickle Cell Disease: Primary Analyses from the Phase III STAND Study

Background: Crizanlizumab, a selective, humanized immunoglobulin G2 kappa anti-P-selectin monoclonal antibody, demonstrated positive clinical activity and general tolerability in patients (pts) aged ≥16 years (yrs) with sickle cell disease (SCD) in a phase II SUSTAIN trial at a dose of 5 mg/kg when compared to placebo (PBO). This primary analysis (cutoff: August 31, 2022) from the ongoing multicenter (at 65 sites in 21 countries), Phase III STAND study (NCT03814746) included the comparison of the efficacy, safety, and expression levels of biomarkers, of crizanlizumab (5 &amp; 7.5 mg/kg) vs PBO, over 1-year post randomization, in adolescent and adult pts with SCD. Method: Pts aged ≥12 yrs, with a history of ≥2 vaso-occlusive crises (VOCs), with/without concomitant treatment with hydroxyurea/hydroxycarbamide were randomized (1:1:1) to receive intravenous crizanlizumab 5 mg/kg, 7.5 mg/kg, or PBO, on Day 1 of weeks (wks) 1 and 3, followed by every 4 wks in addition to standard of care therapy. Adverse events (AEs) were evaluated based on MedDRA version 25.1 and severity on CTCAE v5.0. Levels of biomarkers such as soluble P-selectin (sPsel), were evaluated. Results: Overall, 252 SCD pts were enrolled: 85, 84 &amp; 83 pts received PBO, crizanlizumab 5 &amp; 7.5 mg/kg respectively. Mean (SD) age of pts was 27.8 (12) yrs, 54 (21.4%) were adolescents, and 139 (55.2%) were females. Treatment was discontinued in 27 (31.8%), 18 (21.4%), and 15 (18.1%) pts in PBO, crizanlizumab 5 &amp; 7.5 mg/kg arms, respectively, primarily due to pts' (n=30) and physicians' decisions (n=8). Protocol deviations (n=97) were comparable across all arms; deviations due to COVID-19 (n=80) were mostly attributed to missed visits and assessment/procedure changes during lockdown/quarantine of pts. Rate ratios of adjusted annualized rates of VOCs leading to healthcare visits, with crizanlizumab 5 &amp; 7.5 mg/kg vs PBO, were 1.08 (95%CI: 0.76, 1.55; P&amp;gt;0.999) and 0.89 (95%CI: 0.62, 1.27; P&amp;gt;0.999), respectively, indicating no statistically significant difference (Table 1A). Mean (SD) annualized rates of VOCs leading to healthcare visits were similar across PBO (2.1 [2.8]), 5 mg/kg (2.5 [3.0]), and 7.5 mg/kg (1.9 [2.3]) arms. Rate ratios of the adjusted annualized rates of VOCs managed at home and/or leading to a healthcare visit, with crizanlizumab 5 &amp; 7.5 mg/kg vs PBO, were 1.21 (95%CI: 0.87, 1.70) and 0.83 (95%CI: 0.59, 1.17), respectively, suggesting no statistically significant difference (Table 1B). Overall, AEs were reported in 77 (90.6%), 74 (88.1%), &amp; 77 (92.8%) pts with PBO, crizanlizumab 5 &amp; 7.5 mg/kg, respectively (Table 2), the most common being, pyrexia (22 [25.9%], 22 [26.2%], 19 [22.9%]), COVID-19 (17 [20.0%], 18 [21.4%], 27 [32.5%]), and headache (16 [18.8%], 21 [25.0%], 13 [15.7%]). Serious AEs (SAEs) and grade ≥3 AEs were less frequent with PBO (30.6%, 31.8%) and crizanlizumab 7.5 mg/kg (26.5%, 38.6%) than with 5 mg/kg (41.7%, 56.0%). Among AEs of special interest, infections, and infusion-related reactions (all categories) were the most frequent (Table 2). Treatment-related SAEs and AEs leading to discontinuation were rare (&amp;lt;4% pts, all arms). None of the 6 fatal SAEs were related to treatment. Levels of free and total sPsel were measured across time: At Wk 3 Day 1, free sPsel showed a relative change from baseline in geometric mean (CV%, range) of 1.01 (56.2, 0.201-7.37) with PBO vs 0.05 (88.9, 0.00507-0.225) and 0.06 (68.4, 0.0146-0.208) with 5 &amp; 7.5 mg/kg doses, respectively. Relative change from baseline in total sPsel remained close to 0% in the PBO arm at different study visits, while it increased in treatment arms from Wk 3 Day 1 onward, plateauing at Wk 15 Day 1. Conclusion: Unlike the previous phase II PBO-controlled SUSTAIN study, the STAND study did not demonstrate superiority of crizanlizumab (5 or 7.5 mg/kg) over PBO on its primary and key secondary efficacy endpoints, in pts aged ≥12 yrs. These results differ from the previous study results and may be due to various factors, such as geographic differences in healthcare utilization as well as the low VOC rates in all arms, possibly either due to selection of pts with less severe disease, or, more likely due to the lower reporting of VOCs during the pandemic. The safety results were consistent with the known safety profile of crizanlizumab in SCD pts with no new safety concerns. Both treatment arms showed reductions in free sPsel vs PBO, demonstrating crizanlizumab activity on this biological parameter.

Evidence of pre-approval clinical trial supporting the granted conditional approval for novel cancer drugs in China between 2015 and 2022

Accelerated approval (AA) of novel anticancer drugs based on surrogacy has attracted considerable concern globally. China National Medical Products Administration (NMPA) also established a similar conditional approval (CA) program to accelerate the approval of novel drugs to address unmet medical needs. This cross-sectional study aimed to evaluate the pre-approval clinical trial evidence and potential challenge of cancer drugs receiving CA in China from policy implementation to2022. The cancer drugs (initial and supplemental indications) granted CA between January 1, 2015 and December 31, 2022 using the public database of the NMPA were analyzed. The characteristics of the cancer drugs received CA were described. Primary efficacy endpoints and safety derived from the pre-approval clinical trial, including response rates (RR), progression-free survival (PFS), overall survival (OS), treatment-related serious adverse events (SAE) and Grade ≥3 adverse events (AEs) were quantitatively estimated by meta-analysis. Besides, the correlation between the surrogate endpoints and OS was estimated by the reported trial-level correlation analysis. The NMPA approved 72 cancer indications (56 new molecular entities) with CA between 2015 and 2022. 34 indications (47%) were also approved by the FDA or EMA. 74% (53/72) of cancer indications were based on a single-arm trial design while 26% (19/72) for randomized controlled trials. The pooled RR was 0.50 (95% CI: 0.45-0.55, I2=96%) with significant differences across cancer types and targets while the pooled hazard risk was 0.39 (95% CI: 0.28-0.53, I2=89%) for PFS and 0.67 (95% CI: 0.61-0.73, I2=0%) for OS. The pooled treatment-related SAE and Grade ≥3 AEs from single-arm designs resulted in 15% and 25%, respectively. In randomized controlled trials, the pooled treatment-related SAE and Grade ≥3 AEs observed in CA drugs and the control groups were comparable. Surrogate endpoints were widely used as the primary efficacy endpoints in the pre-approval pivotal clinical trials with 75% (54/72) for RR, 10% (7/72) for PFS, and 4% (3/72) for others. Of these, 27% (17/63) of the surrogate endpoints reported a trial-level correlation with OS; three reported high correlation (r≥0.85), two reported moderate correlation (0.70 ≤ r<0.85) and 12 reported low correlation (r<0.70). The majority of novel cancer drugs that received CA were based on RR designed for single-arm trials. The reported correlations of treatment effect between the surrogate endpoints and OS used for CA were limited. Our findings highlighted that the introduction of OS or quality of life based on RCT in confirmatory clinical trials as much as feasible was essential to ensure the clinical benefits for patients. This study was supported by postdoctoral fellowship from Tsinghua-Peking Joint Centers for Life Sciences (CLS).

Real-world safety and effectiveness of recombinant porcine sequence factor VIII in acquired haemophilia A: A non-interventional, post-authorization safety study.

Recombinant porcine factor VIII (rpFVIII, susoctocog alfa) is indicated for the treatment of bleeding episodes in adults with acquired haemophilia A (AHA). To provide long-term real-world safety and effectiveness data for rpFVIII in the management of AHA bleeding episodes. US PASS (NCT02610127) was a multicentre, uncontrolled, open-label, post-marketing safety surveillance study conducted in adults with AHA. Data were collected retrospectively or prospectively for 180 days after rpFVIII treatment. The primary outcome was the incidence of treatment-related serious adverse events (SAEs). Secondary outcomes included haemostatic effectiveness of rpFVIII and rpFVIII utilization. Fifty-three patients were enrolled from December 2015 to June 2019 (prospective, n=30; retrospective, n=23). Six patients experienced seven treatment-related SAEs (incidence 12.0%). The most common treatment-related SAE was FVIII inhibition (inhibiting antibodies to rpFVIII; incidence 8.0%, 95% CI: 2.2-19.2). Five patients reported seven thromboembolic events; one was an SAE and possibly related to rpFVIII. Of bleeding events treated with rpFVIII, 80.3% (57/71) of bleeds resolved with rpFVIII. The median (range) dose of rpFVIII per infusion was 50 (10-300) units/kg, with a median (range) of 6.0 (1-140) infusions and a median (range) time from bleed onset to bleed resolution of 14.0 (2.0-132.7)days. In this real-world study of rpFVIII for AHA, no new safety signals were identified compared with previous clinical trial findings. Eighty percent of bleeds resolved with rpFVIII treatment.

Efficacy and Safety of Immune Checkpoint Inhibitors Combined With Chemotherapy as First-line Treatment for Recurrent or Metastatic Nasopharyngeal Carcinoma: A Network Meta-analysis of Randomized Controlled Trials.

Different clinical trials for recurrent or metastatic nasopharyngeal carcinoma have studied different combinations of immuno-oncology in first-line treatment, but the optimal choice has not been determined. To systematically examine and compare the efficacy and safety of different immune checkpoint inhibitors (ICIs) combined with chemotherapy as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma. Several electronic databases were systematically searched up to February 2023. Articles meeting the inclusion criteria were included. Three RCTs were eligible in the study. Compared with placebo plus gemcitabine-cisplatin (GP), toripalimab plus GP (HR = 0.59, 95% CI: 0.37-0.95) was significantly associated with a better OS. Tislelizumab plus GP generated best progression-free survival (PFS) benefit (HR = 0.50, 95% CI: 0.37-0.67), greatest improvement in 1-year PFS rate (RR = 3.00, 95% CI: 1.84-5.22), and objective response rate (ORR) (RR = 1.26, 95% CI: 1.04-1.53) over the placebo plus GP. Furthermore, tislelizumab plus GP appeared to be safer than toripalimab plus GP and camrelizumab plus GP in terms of adverse events (AEs)-grade ≥3, treatment-related AEs (TRAEs)-grade ≥3, serious AEs (SAEs), treatment-related SAEs (TRSAEs), and AEs leading to discontinuation of treatment. In recurrent or metastatic nasopharyngeal carcinoma, programmed death 1 (PD-1) inhibitors plus GP as first-line treatment have better survival outcomes than placebo plus GP with comparable toxicity. Toripalimab plus GP shows the best OS benefit over placebo plus GP, while tislelizumab plus GP generates the best PFS, 1-year PFS rate, ORR, and safety. Tislelizumab plus GP could be the best choice among the ICIs combined with chemotherapy regimens as first-line treatment in recurrent or metastatic nasopharyngeal carcinoma.

Abstract CT174: First-in-class anti-CD200R1 antibody 23ME-00610 in patients with advanced solid malignancies: Phase 1 results

Abstract Background: CD200R1 was identified as a promising immuno-oncology (IO) target from the 23andMe database. Pleiotropic causal variants with opposing effect on risks for cancer and immune diseases, referred to as an IO signature, were observed in 3 components of the CD200R1 pathway. 23ME-00610 is a first-in-class monoclonal antibody that potently inhibits the CD200R1 immune checkpoint (KD less than 0.1 nM). The dose escalation portion of the first-in-human, Phase 1/2a study of 23ME-00610 (NCT05199272) has been completed and we are reporting data for the first time. Methods: Eligible patients were alteast 18 years with histologically diagnosed locally advanced (unresectable), or metastatic carcinoma or sarcoma who have progressed on standard therapies with ECOG 0 or 1. Key exclusion criteria included active autoimmune disease requiring immunosuppressive therapy and Grade 3 or above immune-mediated toxicity related to prior immunotherapy that led to discontinuation. Dose escalation consisted of accelerated titration (2 and 6 mg) followed by a 3+3 design (20, 60, 200, 600 and 1400 mg). Up to 12 participants were included in a PKPD backfill cohort at the recommended phase 2 dose (RP2D) or a previously evaluated dose level. Participants received 23ME-00610 intravenously every 3 weeks (Q3W) infused over 30 minutes. The primary objectives of Phase 1 were determination of the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), safety and tolerability. Key secondary and exploratory objectives included pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of 23ME-00610. Results: Between January 5th, 2022 and November 28, 2022, 21 participants (11/10 male/female; age range: 21-80 years) were enrolled and received ≥ 1 dose of 23ME-00610 across the 2 to 1400 mg cohorts (median duration of exposure: 50 days; range:1-231 days). No dose limiting toxicities, treatment related serious adverse events (TRSAEs) or AEs leading to discontinuation were observed. 14/21 (67%) participants experienced atleast 1 TRAE; the majority were Grade 1 or 2. The most commonly reported TRAEs occurring in atleast 2 participants across all dose levels were headache, fatigue, nausea and pruritis. There was 1 Grade 3 TRAE of increased blood creatinine phosphokinase. Investigator-assessed immune-related AEs including hypothyroidism, pruritis, fatigue and chills were observed at doses 60 mg and above. The PK of 23ME-00610 were dose-proportional at doses 60 mg and above, with a median terminal half-life of ~12 days at 1400 mg. Peripheral saturation of CD200R1 was observed at doses 60 mg and above, as measured by receptor occupancy on T cells and neutrophils, and levels of free soluble CD200R1. Analysis of additional PD data, including cytokines, is ongoing. Conclusion: 23ME-00610 demonstrated an acceptable safety and tolerability profile, with favorable PK and peripheral CD200R1 saturation. Increased immune-related AEs were observed at higher, pharmacologically relevant dose levels. Based on Phase 1 data, 1400 mg 23ME-00610 Q3W will be evaluated in Phase 2a. Citation Format: Shivaani Kummar, Albiruni ABDUL RAZAK, Scott Laurie, Sariah Kell, Dylan Glatt, Sophia R. Majeed, Drew Rasco. First-in-class anti-CD200R1 antibody 23ME-00610 in patients with advanced solid malignancies: Phase 1 results [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT174.