Glyco-Polypeptides (Comosain) in Treating of Various Types of Late-Stage Refractory Solid Carcinoma in Humans - A DoubleBlind Study-Case Report of 126 Patients

Glyco-polypeptides (Comosain, Bromelain) induced leucocyte binding ability to tumor surface antigens, such as interleukin 2, 6, 8, and TNFs, is known as an immuno-target therapy. Using different concentration of Bromelain proteinases in 6 types of cancer cell, it resulted in hydrolysis, fibrinolysis, necrosis, and anti-metastatic effects in tumor cells. Anti-cancer effects were achieved in carcinoma of lung, breast, colon, ovary, cervix, and uterus. Investigation of anti-metastatic effects in Bromelain were carried out in a double-blind study: low dose cohort was on 10 mg/kg/day and a high dose cohort which was on 50 mg/kg/day for a period of over six months. A total of 83 patients with 3rd and 4th stage of refractory solid tumors were enrolled, whom at least previously failed on two regimens of chemotherapy and/or failed on radiation therapy. The rates of Complete Response (CR) and Partial Responses (PR) in high dose cohort are astonishing with 52% and 27% respectively. The Progress Disease (PD) was 10%, and the Stable Disease (SD) was 11%. The implications and results of the findings are discussed with in view of the reported anti-metastatic activity of orally administrated Bromelain.

Standard- versus intermediate-dose enoxaparin for anti-factor Xa guided thromboprophylaxis in critically ill patients with COVID-19

The prevalence of venous thromboembolism (VTE) is high in critically ill patients with COVID-19. Dosing of Low Molecular Weight Heparin (LMWH) for thromboprophylaxis in patients with severe COVID-19 is subject to ongoing debate.In this brief report, we describe our study where we retrospectively examined the efficacy of standard- versus intermediate-dosing of enoxaparin in attaining and maintaining accepted prophylactic levels of anti-Factor Xa (anti-FXa) in critically ill patients with COVID-19.We collected data for all patients with confirmed COVID-19 who were treated with enoxaparin for thromboprophylaxis in a single Intensive Care Unit (ICU) in the United Kingdom between 31st March and 16th November 2020. Standard-dose of enoxaparin was 40 mg subcutaneously once daily for patients with normal renal function and body weight between 50 and 100 kg; the intermediate-dose was 40 mg subcutaneously twice daily. Anti-FXa peak concentrations between 0.2-0.4 IU/ml were considered appropriate for thromboprophylaxis.Age, sex, weight, Body Mass Index, APACHE II score, ICU length of stay, initial P/F ratio and creatinine were not statistically significantly different between standard- and intermediate-dose thromboprophylaxis cohorts. In the standard-dose group, the median initial anti-FXa level was 0.13 (interquartile range 0.06-0.18) compared to 0.26 (0.21-0.33) in the intermediate-dose cohort (p < 0.001). On repeated measurement, in the standard dose cohort, 44 of 95 (46%) anti-FXa levels were < 0.2 IU/ml compared with 24 of 132 (18%) levels in the intermediate-dose cohort even after dose-adjustment. There was one radiologically confirmed pulmonary embolism (PE) on computed tomography pulmonary angiogram during hospital admission in each cohort.Our study supports starting intermediate-dose thromboprophylaxis for critically ill patients with COVID-19 to achieve anti-FXa levels in the accepted thromboprophylactic range although further study is required to investigate whether anti-FXa guided thromboprophylaxis is safe and effective in reducing the incidence of VTEs in critically ill patients with COVID-19.

Recombinant ADAMTS13 for Patients with Sickle Cell Disease: Design of a Phase 1 Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study

Background Sickle cell disease (SCD) is an autosomal recessive hemoglobinopathy associated with chronic hemolysis and vaso-occlusive crises (VOCs) resulting in pain, organ damage, and a shortened lifespan. Current treatment options are limited, and many individuals with SCD continue to experience VOCs despite receiving therapy. Although the precise cause of VOCs is not clear, evidence suggests that cell adhesion is involved. Von Willebrand factor (VWF) is a multimeric glycoprotein that mediates the adhesion of platelets to each other and to other cell types, including vascular endothelium and leukocytes. An emerging hypothesis is that VWF contributes to the pathophysiology of VOCs through the formation of hyper-adhesive ultra-large VWF multimers. VWF activity is regulated by the metalloprotease ADAMTS13, which specifically cleaves ultra-large VWF multimers in an extended conformation. Patients with SCD have been shown to have higher levels of VWF multimers and lower levels of ADAMTS13 activity during VOCs. This imbalance could be caused either by the increased generation and release of ultra-large VWF multimers or by the inhibition of ADAMTS13 activity by plasma free hemoglobin or thrombospondin-1. Increasing the plasma concentration of ADAMTS13 using a recombinant ADAMTS13 (rADAMTS13; TAK-755, Takeda Development Center Americas, Inc., Lexington, MA, USA) may be therapeutically beneficial by enhancing cleavage of ultra-large VWF multimers. Here, we report the design and enrollment status of the Recombinant ADAMTS13 In Sickle Cell Disease (RAISE-UP) study (NCT03997760), the first clinical study of a recombinant ADAMTS13 in patients with SCD. Study Design and Methods This phase 1, randomized, double-blind, placebo-controlled, multicenter, ascending single dose study will assess the safety (including immunogenicity), tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of rADAMTS13 in patients with SCD. This study is planned to be conducted in 2 parts (part A and part B). Here we present the study design for part A which is being conducted initially and will enroll approximately 20 patients aged between 18 and 65 years with a documented history of SCD (HbSS or HbSβ 0 thalassemia). Concurrent treatment with a stable dose of hydroxyurea is allowed. Exclusion criteria include an acute VOC in the preceding 21 days and a blood transfusion either within the last 30 days or on ≥2 occasions in the last 90 days. Ethics committee approval and patient consent were obtained. Patients will be randomized 3:1 to receive a single intravenous infusion of either rADAMTS13 or placebo in 3 sequential dose cohorts. Patients in cohort 1 (n=4) will receive a 40 IU/kg dose, cohort 2 (n=8) will receive an 80 IU/kg dose, and cohort 3 (n=8) will receive a 160 IU/kg dose (Figure). In cohorts 2 and 3, 6 patients will receive rADAMTS13 and 2 patients will receive placebo. The first 3 patients enrolled in each cohort will be dosed with a separation time of at least 14 days. Enrollment into the next higher dose cohort will only be allowed following review of safety data and authorization by a dose escalation committee. Enrollment will be paused if anaphylaxis, binding or inhibitory antibodies, a life-threatening condition, or death are reported. All patients will complete an end-of-study visit on day 28 following infusion. Primary safety endpoints include adverse events, serious adverse events (SAEs), adverse changes in vital signs and laboratory parameters, and incidence of binding and inhibitory antibodies against rADAMTS13 occurring during the study. A secondary objective is to assess the PK of single-dose rADAMTS13 in each dose cohort, including an assessment of ADAMTS13 antigen and ADAMTS13 activity. Secondary PD objectives are to assess the effect of rADAMTS13 on VWF and platelet count and to study the correlation of plasma free hemoglobin and thrombospondin-1 with rADAMTS13 activity and VWF. Enrollment has been completed for cohort 1. In the review of safety data by the dose escalation committee, no drug-related SAEs were reported and no binding or inhibitory antibodies to ADAMTS13 were observed. On the basis of these findings, cohort 2 has been opened for enrollment. Figure 1 Figure 1. Disclosures Patwari: Takeda Development Center Americas, Inc.,: Current Employment. Nguyen: Takeda Development Center Americas, Inc.,: Current Employment. Bhattacharya: Takeda: Current equity holder in publicly-traded company; Takeda Development Center Americas, Inc.: Current Employment. Jain: Takeda Development Center Americas, Inc.,: Current Employment; Takeda: Current equity holder in publicly-traded company.

Treatment with an Allogeneic Leukemia-Derived Dendritic Cell Vaccine in AML Patients Shows MRD Conversion and Improved Survival

Background. Persistence of measurable residual disease (MRD) is a poor prognostic factor and predicts relapse in acute myeloid leukemia (AML). In a phase I study, the allogeneic leukemia-derived dendritic cell vaccine, DCP-001, has shown safety and humoral and cellular immune responses (A.A. van de Loosdrecht, et al. Cancer Immunol. Immunother. 2018;67:1505). In the current phase II study, (Clintrials.gov: NCT03697707) we report on progress and evaluation of MRD conversion, as primary endpoint, relapse free and overall survival. Methods. AML-patients, ineligible at screening for HSCT, who are in first complete remission (CR1) but with MRD receive 4 biweekly doses of 25e6 or 50e6 cells per vaccination (cells/vc) followed by 2 doses of 10e6 cells/vc as boosts at week 14 and 18. MRD is assessed at 4 timepoints (baseline, week 14, 20 and 32) by flow cytometry and/or molecular analyses. Primary endpoints are the effect of vaccination on MRD status and safety and tolerability of the two vaccination schedules. Secondary endpoints include relapse free, overall survival and immunological response evaluation. Results. As of 28 th July 2021, 19 patients have been enrolled, of which 10 patients have been given at least 4 vaccinations with 25e6 cells/vc and 9 with 50e6 cells/vc. No serious adverse events (AE) or severe AE (grade 3 or higher) related to DCP-001 have been reported. AE's related to DCP-001 are mainly injection site reactions, occurring within 48 hours after intradermal administration. In the 25e6 cells/vc cohort all patients have completed the treatment phase up to week 32, allowing full assessment of MRD response. Three patients have converted to MRD negative, 4 patients relapsed (followed by HSCT for 1 patient), 3 patients remained MRD positive, of which 2 patients underwent HSCT immediately after completion of the full dosing schedule. In this cohort 2 patients eventually died during follow up. Treatment is still ongoing in the 50e6 dose cohort, with thus far one additional MRD conversion reported and two relapses, 3 patients with stable MRD levels, and 3 have no MRD data available yet. Median follow-up of patients in the 25e6 cells/vc cohort was 288 days (range 148 - 546). Median RFS and OS have not yet been reached, but estimated RFS and OS at 12 months is calculated at 57% and 79%, respectively (Figure 1). MRD converted patients after DCP-001 vaccination, showed improved survival, compared to patients without MRD conversion (Figure 2). All 4 patients who converted to MRD negative are still in CR and alive (FU median 423.5 days (range 140 - 546). Immunological monitoring of patients is currently being performed. As previously reported (abstract #168, ASH2020), 3 of 4 evaluable patients show at least 1 or more responses against tumor-associated antigens known to be present in DCP-001 in IFNy ELISPOT assay. Conclusion/discussion. Four patients have shown MRD conversion (3 in the 25e6 dose cohort, and 1 in the 50e6 dose cohort). Six patients remained in complete remission with stable or declining levels of MRD, 6 patients relapsed and for 3 patients no MRD data is available yet. Median RFS and OS have not yet been reached. MRD conversion showed improved relapse free and overall survival. Treatment with DCP-001 is very well tolerated, with limited side effects mainly related to intradermal administration. Immunological analyses for specific tumor-associated antigen responses and general immune profiling are currently being performed. Preliminary data from this study shows that the relapse vaccine DCP-001 is a promising treatment for patients with AML in complete remission but with residual disease aiming to deepen responses and prolong survival. Its excellent safety profile allows for future combination therapy. Figure 1 Figure 1. Disclosures Van de Loosdrecht: Novartis: Consultancy; Alexion: Consultancy; Roche: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Research Funding. Cloos: Takeda: Research Funding; Novartis: Consultancy, Other, Research Funding; Navigate: Patents & Royalties; Merus: Other, Research Funding; Janssen: Research Funding; Helsinn: Other; Genentech: Research Funding; DC-One: Other, Research Funding; Astellas: Speakers Bureau. Platzbecker: AbbVie: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Celgene/BMS: Honoraria; Geron: Honoraria; Takeda: Honoraria. Holderried: Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; MSD: Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Therakos: Other: Travel support; Abbvie: Other: Travel support; Medac: Other: Travel support; Eurocept Pharmaceuticals: Other: Travel support; Janssen: Other: Travel support; Daiichi Sankyo: Other: travel support. Giagounidis: Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. van Zeeburg: Immunicum AB: Current Employment; Kiadis: Ended employment in the past 24 months. Rovers: Immunicum AB: Current Employment. Gjertsen: KinN Therapeutics: Current holder of stock options in a privately-held company; Alden Cancer Therapy: Current holder of stock options in a privately-held company; Pfizer Inc.: Consultancy; BerGenBio: Consultancy; Novartis: Consultancy.

Results of an ongoing phase 1/2a dose escalation study of HPN424, a tri-specific half-life extended PSMA-targeting T-cell engager, in patients with metastatic castration-resistant prostate cancer (mCRPC).

5013 Background: HPN424 is a prostate-specific membrane antigen (PSMA)-targeting T cell engager designed to redirect T cells to kill PSMA-expressing prostate cancer cells; engineered with three binding domains: anti-PSMA for tumor cell engagement, anti-albumin for half-life extension and anti-CD3 for T cell engagement. HPN424 is optimized for small size and increased stability compared to other bispecific platforms. Methods: This Ph1/2a study is evaluating HPN424 in mCRPC patients (pts) who have received > 2 prior systemic therapies. Primary endpoints are safety, tolerability and determination of MTD/RP2D. Secondary objectives are pharmacokinetics (PK), pharmacodynamics, immunogenicity and preliminary anti-tumor activity. HPN424 is administered IV once weekly. Tumor assessments include PSA, CT and bone scans every 9-weeks. Results: As of 2/8/21, 80 pts were dosed in 15 cohorts with target doses ranging from 1.3 to 160ng/kg fixed dose, and up to 300ng/kg with step dosing to the target dose after initial priming dose. Pts had received a median of 6 prior systemic regimens, 75% received prior chemotherapy for mCRPC. Median age was 70 (43 – 91). Most common grade > 3 TEAEs were AST increase (18%), anemia (11%) and ALT increase (11%). DLTs include CRS G3 (n = 3), elevated lipase G3 (n = 1) and seizure G3 (n = 1). These events did not limit escalation, MTD has not been reached and escalation continues. All grade CRS occurred in 63% of pts, 4% grade 3 per ASTCT and no Grade 4/5 CRS. CRS G3 events occurred after first administration of target dose (n = 2 fixed dose, n = 1 step dose). Transaminase elevation occurred predominantly during Cycle 1, was transient and had no clinical sequelae. Disease progression was the primary reason for drug discontinuation; 2 pts (3%) discontinued due to TRAE. Reduction in circulating tumor cells (CTC) was seen in 32 of 56 pts (57%) with measurable CTC at baseline. Fifteen of 62 pts (24%) with > 24 weeks follow-up remained on treatment ≥ 24 weeks. Thirteen of 63 pts (21%) with post-baseline levels had PSA declines from baseline, including 3 PSA50, 2 PSA30 responses. In chemo-naïve pts, 5 of 15 (33%) showed PSA declines post-baseline. In the highest fixed dose cohort (160ng/kg) tested to-date, 3 of 7 evaluable pts had PSA declines from baseline and 1 had a confirmed partial response per RECIST. Conclusions: HPN424, a novel half-life extended PSMA-targeting T cell engager, was well tolerated when administered once weekly. AEs were transient, manageable and consistent with class of agent. Grade 3 CRS was observed in 4% of patients, occurring with first administration of target dose. Evidence of antitumor activity included PSA and CTC reductions and treatment duration > 24 weeks in 15/62 pts. Encouraging signals were seen at the highest fixed dose cohort including a confirmed RECIST partial response. NCT03577028 Clinical trial information: NCT03577028.

Safety and efficacy of letetresgene autoleucel (lete-cel; GSK3377794) in advanced myxoid/round cell liposarcoma (MRCLS) following high lymphodepletion (Cohort 2): Interim analysis.

11521 Background: Cancer testis antigen NY-ESO-1 is expressed in multiple tumor types, including 80‒90% of MRCLS [1,2]. Overall response rates (ORRs) to MRCLS treatment are low (1L, <20%; 2L, <10%) [2]. Lete-cel, an autologous T-cell therapy, targets NY-ESO-1/LAGE-1a+ tumors using a genetically modified, high-affinity T-cell receptor. High-dose lymphodepletion (LD) was linked with better responses in synovial sarcoma [3]; the current study tested this hypothesis in MRCLS. Methods: This open label, pilot study evaluates lete-cel efficacy and safety in advanced MRCLS following low-dose (Cohort 1 [C1]; 30 mg/m2 fludarabine [flu] x 3d + 600 mg/m2 cyclophosphamide [cy] x 3d) or high-dose (Cohort 2 [C2]; 30 mg/m2 flu x 4d + 900 mg/m2 cy x 3d; initiated based on C1 data) LD. Key eligibility: age ≥18 y; HLA-A*02:01; A*02:05, or A*02:06; advanced high-grade NY-ESO-1+ MRCLS (≥30% of cells 2+/3+ by IHC); prior anthracycline; measurable disease; specified washouts; and active/chronic/intercurrent illness restrictions. Stages include screening, leukapheresis, lete-cel manufacture, LD, lete-cel infusion (1– 8 × 109 transduced T cells), follow-up. Response is assessed at wk 4, 8, 12, and 24, then every 3 mo to disease progression/death/withdrawal. The primary efficacy endpoint is investigator-assessed ORR by RECIST v1.1. In C1 (n=10 patients [pts]), lete-cel was well tolerated and linked with 2 confirmed partial responses (PR; ORR, 20%) and stable disease (SD) in 8 pts. Planned interim analysis for C2, shown here, was done once all 10 treated pts had ≥3 post-baseline disease assessments or progressed/died/withdrew. Efficacy data will be correlated with transduced cell kinetics and pharmacodynamics marker profiles. Results: Durable (1.0–7.8 mo) PR (4/10 pts [ORR, 40%]; 2 ongoing) and prolonged (2.7–10.6 mo) SD (5/10 pts; 3 ongoing) with tumor regression were observed. Treatment-emergent cytopenias occurred in all pts. All experienced T-cell related cytokine release syndrome (5 serious adverse events; 30% Grade 3), with onset ≤5d of infusion and median duration 7.5d. Graft-vs-host disease, immune effector cell–associated neurotoxicity syndrome, pancytopenia, or aplastic anemia were not reported. Conclusions: A single lete-cel infusion after high LD showed antitumor activity in advanced MRCLS and a manageable safety profile consistent with other lete-cel studies. The trial is active but no longer recruiting (NCT02992743). MRCLS is included in a separate, ongoing lete-cel study (NCT03967223). References: 1. D’Angelo SP, et al. J Clin Oncol 2018;36:15_suppl, 3005. 2. Pollack SM, et al. Cancer Med 2020;9(13):4593–602. 3. D’Angelo SP, et al. J Immunother Cancer 2020;8:P298. Funding: GSK (208469; NCT02992743). Editorial support was provided by Eithne Maguire, PhD, of Fishawack Indicia, part of Fishawack Health, and funded by GSK. Clinical trial information: NCT02992743.

Design of the ACcomplisH Trial: A Phase 2, Multicenter, Placebo-Controlled, Dose Escalation Trial Evaluating Safety, Efficacy, and Pharmacokinetics of Weekly TransCon CNP in Children With Achondroplasia

Background: Achondroplasia (ACH) is the most common skeletal dysplasia and the most frequent form of dwarfism. ACH is caused by a gain-of-function mutation in the fibroblast growth factor receptor 3 (FGFR3) gene and results in impairment of the endochondral ossification processes. C-type natriuretic peptide (CNP) promotes chondrocyte development through inhibition of the FGFR3 pathway, specifically through activation of NPRB. CNP is a desirable target as it is known to increase chondrocyte development without off-target effects (Bocciardi, 2007). TransCon CNP is a long-acting prodrug of CNP designed to optimize safety and efficacy with a once-weekly dose. The Phase 1 clinical trial with TransCon CNP demonstrated that doses up to 150 μg CNP/kg were well-tolerated in healthy adult male volunteers, with no clinically significant trends observed in clinical laboratory assessments, vital sign measurements, ECG parameters, or physical examination findings. Methods: The phase 2 ACcomplisH trial will be conducted at over 35 sites worldwide. The primary objective of the trial will be to evaluate the safety and efficacy of once-weekly TransCon CNP compared to placebo at 12 months in prepubertal children, aged 2-10 years old, with ACH. Approximately 60 subjects will be randomized 3:1 to receive either weekly TransCon CNP or placebo. Following screening and verification of clinical ACH with genetic confirmation, subjects will remain within the dose cohort for 52 weeks of treatment. TransCon CNP will be dosed 6 to 100 μg CNP/kg/week across 4 cohorts, with an optional 5th cohort at up to 200 μg CNP/kg/week. An independent Data Monitoring Committee will review safety data prior to initiation of a higher dose cohort. The primary endpoint will evaluate annualized height velocity at 52 weeks of TransCon CNP or placebo. Key secondary endpoints will examine change in upper to lower body segment ratio at week 52, safety, pharmacokinetics (PK), and quality of life associated with weekly TransCon CNP. Conclusion: CNP is targeted specifically to the underlying pathology of ACH through inhibition FGFR3. No effective medicinal product is currently available for the treatment of ACH. TransCon CNP is designed to provide sustained exposure of CNP. This ongoing Phase 2 ACcomplisH trial is designed to assess the efficacy, safety, and PK of TransCon CNP by weekly administration compared to placebo.

Patient Outcomes Following Ketamine Administration for Acute Agitation with a Decreased Dosing Protocol in the Prehospital Setting

Background: Agitated behaviors are frequently encountered in the prehospital setting and require emergent treatment to prevent harm to patients and prehospital personnel. Chemical sedation with ketamine works faster than traditional pharmacologic agents, though it has a higher incidence of adverse events, including intubation. Outcomes following varying initial doses of prehospital intramuscular (IM) ketamine use have been incompletely described. Objective: To determine whether using a lower dose IM ketamine protocol for agitation is associated with more favorable outcomes. Methods: This study was a pre-/post-intervention retrospective chart review of prehospital care reports (PCRs). Adult patients who received chemical sedation in the form of IM ketamine for agitated behaviors were included. Patients were divided into two cohorts based on the standard IM ketamine dose of 4mg/kg and the lower IM dose of 3mg/kg with the option for an additional 1mg/kg if required. Primary outcomes included intubation and hospital admission. Secondary outcomes included emergency department (ED) length of stay, additional chemical or physical restraints, assaults on prehospital or ED employees, and documented adverse events. Results: The standard dose cohort consisted of 211 patients. The lower dose cohort consisted of 81 patients, 17 of whom received supplemental ketamine administration. Demographics did not significantly differ between the cohorts (mean age 35.14 versus 35.65 years; P = .484; and 67.8% versus 65.4% male; P = .89). Lower dose subjects were administered a lower ketamine dose (mean 3.24mg/kg) compared to the standard dose cohort (mean 3.51mg/kg). There was no statistically significant difference between the cohorts in intubation rate (14.2% versus 18.5%; P = .455), ED length of stay (14.31 versus 14.88 hours; P = .118), need for additional restraint and sedation (P = .787), or admission rate (26.1% versus 25.9%; P = .677). In the lower dose cohort, 41.2% (7/17) of patients who received supplemental ketamine doses were intubated, a higher rate than the patients in this cohort who did not receive supplemental ketamine (8/64, 12.5%; P <.01). Conclusion: Access to effective, fast-acting chemical sedation is paramount for prehospital providers. No significant outcomes differences existed when a lower dose IM ketamine protocol was implemented for prehospital chemical sedation. Patients who received a second dose of ketamine had a significant increase in intubation rate. A lower dose protocol may be considered for an agitation protocol to limit the amount of medication administered to a population of high-risk patients.

A phase I/II dose-escalation study of fractionated and multiple dose 225Ac-J591 for progressive metastatic castration-resistant prostate cancer (mCRPC).

TPS188 Background: Prostate-specific membrane antigen (PSMA)-based targeted radionuclide therapy (TRT) is a promising treatment. PSMA-targeting via large antibodies vs small molecules has different kinetics, biodistribution, and resulting clinical toxicities. Using beta-TRT, 177Lu-J591 has more heme toxicity and 177Lu-PSMA-617 more non-heme toxicity (xerostomia and nausea) [Niaz AUA 2020]. Alpha-emitters are more potent than beta radionuclides, and alpha-PSMA-TRT has efficacy even after beta-PSMA-TRT. In a first-in-human phase I dose-escalation study of 225Ac-J591, patients with mCRPC were treated with a single dose of 225Ac-J591 on seven dose levels, up to 93.3 KBq/kg [Tagawa ASCO 2020]. No maximal tolerated dose (MTD) was achieved. One patient treated at 80 KBq/kg developed dose-limiting toxicity (DLT) of grade 4 anemia and thrombocytopenia, but 0 of 6 at 93.3 KBq/Kg had grade > 3 heme toxicity or grade > 2 non-heme toxicity. Preliminary results indicate 64% had any PSA decline and 41% had > 50% PSA decline (PSA50) across all doses, despite lack of selection for PSMA expression and the majority having been previously treated with 177Lu-PSMA. Methods: Entry criteria include progressive mCRPC by PCWG3 criteria, ECOG PS 0-2, intact organ function (including normal neutrophil and platelet counts), and prior receipt of AR pathway inhibitor and chemotherapy (or refuse/ineligible for chemotherapy). There is no limit to prior lines of therapy except alpha-PSMA-TRT. Phase I includes 2 separate parallel dose-escalation cohorts. In the fractionated-dose cohort, men will receive a single cycle of 225Ac-J591 administered on D1 and D15. In the multiple-dose cohort, 225Ac-J591 will be given every 6 weeks for up to 4 cycles. The phase I component is a 3+3 dose-escalation study design, with the goal of identifying MTD. Each phase II component will treat up to 27 men with PSMA+ PET scans in a Simon 2-stage design with 90% power to exclude the null hypothesis (35% or fewer patients with PSA50). Eligible men with negative PSMA PET scans will be offered treatment with informed consent in an exploratory subgroup, but will not be counted towards phase II efficacy. Secondary outcomes include radiographic response by PCWG modified RECIST 1.1 criteria and PSMA PET, biochemical and radiographic progression-free survival, circulating tumor cell counts, and overall survival. Patient reported outcomes, genomic, and immune analyses are exploratory. Enrollment began in August 2020 (NCT04506567). Clinical trial information: NCT04506567.

An Optimized Dose of Therapeutic Feeding Results in Noninferior Growth in Midupper Arm Circumference Compared with a Standard Dose in Children in Sierra Leone Recovering from Acute Malnutrition

ABSTRACT Background Ready-to-use therapeutic food (RUTF) given at 175 kcal/kg per day throughout severe acute malnutrition (SAM) treatment is recommended. Some treatment programs have diverged from this paradigm in 2 ways: reducing the supplemental food dose to 75 kcal/kg per day when midupper arm circumference (MUAC) is &gt;11.4 cm or simplifying to a fixed-dose regimen. Objective The objective was to determine if transitioning to an optimized, fixed-dose supplementary feeding regimen during SAM treatment when MUAC is &gt;11.4 cm would result in noninferior gain in MUAC compared with standard treatment. Methods Using data from 2 clinical trials conducted in Sierra Leone, a retrospective dual-cohort study was performed. The 2 cohorts included children with SAM who had improved to meet criteria for moderate acute malnutrition (MAM). The standard dose cohort continued to receive weight-based RUTF at 175 kcal/kg per day, while the optimized dose cohort received fixed-dose, 500 kcal/d of supplementary feeding. The primary outcome was a noninferiority margin of 1 mm of MUAC after 4 wk of treatment, while secondary outcomes included rate of anthropometric changes as well as time-to-relapse to SAM or death. Results MUAC after 4 wk was noninferior (Δ: −0.1 mm; 95% CI: −0.05, 0.03; inferiority rejected P = 0.008). Rates of weight gain and MUAC gain were the same in the optimized-dose and standard-dose groups, whereas the rate of length gain was slower in the optimized-dose cohort. Time-to-relapse to SAM or death was not different (HR: 1.05; P = 0.71). Conclusions This study supports the practice of treating children with SAM who have recovered to meet criteria for MAM with a reduced and fixed-dose regimen of RUTF. The results also raise the question of whether this strategy might adversely impact linear growth during SAM treatment.