Two Currently Recruiting Randomized Phase III Trials: COMMODORE 1 and 2 Evaluating Crovalimab Vs Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria with or without Current Anti-Complement Therapy

Background Crovalimab is a novel anti-complement C5 antibody currently being studied as a treatment for paroxysmal nocturnal hemoglobinuria (PNH), a life-threatening disease associated with hemolytic anemia and thrombosis. Treatment with approved C5 inhibitors eculizumab or ravulizumab is effective, but can be limited by breakthrough hemolysis due to unsustained C5 inhibition, inadequate efficacy in patients with C5 mutational variants, and the requirement of regular intravenous infusions. Crovalimab is unique in that its properties allow for subcutaneous injections once every 4 weeks (Q4W) that can be self-administered. Additionally, crovalimab binds to C5 mutational variants. Promising results were obtained in the Phase I/II COMPOSER trial (NCT03157635; Röth et al, Blood. 2020) conducted in patients with PNH, with or without prior anti-C5 treatment. The efficacy and safety of crovalimab vs eculizumab will be evaluated in two Phase III, randomized, open-label trials in patients with PNH, with or without current complement C5 inhibition. Study Design and Methods COMMODORE 1 (NCT04432584) will enroll patients who are currently receiving complement C5 inhibitor therapy. This trial is divided into two parts (Figure). Patients aged ≥ 18 years will be randomized 1:1 to receive either crovalimab (Arm A) or eculizumab (Arm B) and will contribute to the primary efficacy analysis. Patients aged < 18 years can be enrolled in an exploratory descriptive arm (Arm C). Arm A and C patients will receive crovalimab loading and subsequent subcutaneous Q4W maintenance dosing from Week 5. Arm B patients will receive eculizumab intravenous maintenance dosing from Day 1, Q2W for a total of 24 weeks. Patients in Arm A and Arm C can continue to receive crovalimab, and patients in Arm B can switch to crovalimab after 24 weeks of treatment, as determined by the treating physician. The primary efficacy objective is to determine the non-inferiority of crovalimab vs eculizumab based on percentage change in lactate dehydrogenase levels from baseline, averaged over weeks 21, 23, and 25. Secondary efficacy objectives are to determine the proportion of patients who experience breakthrough hemolysis, achieve transfusion avoidance or hemoglobin stabilization, as well as determine mean change in fatigue according to the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire from baseline to Week 25. Safety and tolerability of crovalimab vs eculizumab will also be evaluated along with pharmacokinetic, immunogenicity, biomarker, and health status utility objectives. COMMODORE 2 (NCT04434092) will enroll patients not currently treated with C5 complement inhibitors. This trial is also divided into two parts (Figure). Patients aged ≥ 18 years will be randomized 2:1 to receive either crovalimab (Arm A) or eculizumab (Arm B) and will contribute to the primary efficacy analysis. Patients aged < 18 years will be enrolled in an exploratory descriptive arm (Arm C). Arm A and C patients will receive crovalimab loading and subsequent subcutaneous Q4W maintenance dosing from Week 5. Arm B patients will receive induction doses of eculizumab intravenously QW for 4 weeks followed by maintenance dosing Q2W up to 24 weeks. Patients in Arm A and Arm C can continue to receive crovalimab, and patients in Arm B can switch to crovalimab, after 24 weeks of treatment, as determined by the treating physician. The primary efficacy objective is to determine the non-inferiority of crovalimab vs eculizumab, based on the proportion of patients who 1) achieve transfusion avoidance from baseline to Week 25 and 2) with hemolysis control from Week 5-25 (co-primary efficacy endpoints). Safety and tolerability of crovalimab vs eculizumab will also be evaluated along with pharmacokinetic, immunogenicity, biomarker, and health status utility objectives. Figure 1 Figure 1. Disclosures Kulasekararaj: F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; Akari: Consultancy, Honoraria, Speakers Bureau; Biocryst: Consultancy, Honoraria, Speakers Bureau; Achilleon: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria, Speakers Bureau; Ra Pharma: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Alexion, AstraZeneca Rare Disease Inc.: Consultancy, Honoraria, Other: Travel support. Risitano: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Research Funding, Speakers Bureau; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA Pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Achillion: Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees; Jazz: Other: Lecture fees, Speakers Bureau; F. Hoffmann-La Roche Ltd.: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Lecture fees, Speakers Bureau; Apellis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Speakers Bureau. Roeth: Novartis: Consultancy, Honoraria; Bioverativ, a Sanofi company: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Apellis Pharmaceuticals: Consultancy, Honoraria; Kira: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria. He: LongBio Pharma: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd.: Consultancy. Pu: University of Arizona: Current Employment; Pennsylvania State University: Patents & Royalties; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees. Wright: Genentech, Inc.: Current Employment. Appius: F. Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company. Sostelly: F. Hoffmann-La Roche Ltd: Current Employment. Sreckovic: F. Hoffmann-La Roche Ltd.: Current Employment. Stanzel: F. Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company. Munir: F. Hoffmann-La Roche: Consultancy; Alexion: Honoraria. Nishimura: Apellis: Consultancy; Novartis: Consultancy; Chugai: Consultancy; Sanofi: Consultancy; Alexion: Consultancy; Roche: Consultancy; Biocryst: Consultancy.

A phase 2 study of tislelizumab monotherapy in patients with previously treated, locally advanced unresectable ormetastatic microsatellite instability-high/mismatch repair deficient solid tumors.

2569 Background: Tislelizumab is an anti-programmed cell death protein 1 antibody engineered to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis. In early phase clinical studies, tislelizumab monotherapy was generally well tolerated and had antitumor activity in patients (pts) with solid tumors, including microsatellite instability-high (MSI-H) or mismatch-repair-deficient (dMMR) solid tumors such as colorectal cancer (CRC). Methods: This single-arm, multicenter, open-label, phase 2 study evaluated the efficacy and safety of tislelizumab monotherapy in adult Chinese pts with previously treated, locally advanced, unresectable or metastatic histologically confirmed MSI-H/dMMR solid tumors by central lab. Pts received tislelizumab 200 mg intravenously every 3 weeks until disease progression, unacceptable toxicity, or withdrawal. Radiological imaging was performed at 9 weeks then every 6 weeks for the first year of therapy and every 12 weeks thereafter. The primary efficacy analysis set was all pts who received any dose of tislelizumab with measurable disease per independent review committee (IRC) at baseline. The primary endpoint was IRC-assessed overall response rate (ORR; RECIST v1.1). Secondary endpoints included duration of response (DoR) and disease control rate. Using a binomial exact test, the null hypothesis of ORR=10% (historical rate) was rejected if 1-sided p≤0.025. Results: Between Sep 2018-Aug 2020, 80 pts were enrolled (median age 53 years; range 19-81 years) and 74 were included in the primary efficacy analysis set. At median study follow-up of 11.78 months, ORR by IRC was 45.9% (n=34/74; 95% CI 34.3, 57.9) in all tumor types (1-sided p<0.0001), including 4 complete responses (CR) and 30 partial responses (PR). Observed ORR by IRC was 39.1% (n=18/46; 95% CI 25.1, 54.6) in CRC pts and 57.1% (n=16/28; 95% CI 37.2, 75.5) in non-CRC pts. Of 74 pts, 53 (71.6%) had disease control and 39 (52.7%) achieved CR, PR or durable stable disease by IRC ≥24 weeks. Median DoR by IRC has not been reached; no disease progression was reported in the 34 responders (CR+PR), with 33 responders still on treatment (12-month DoR rate=100%). Treatment-emergent adverse events (TEAEs) ≥Grade 3 occurred in 47.5% (n=38/80) pts, of which 21.3% (n=17/80) were lab abnormalities. Immune-mediated TEAEs ≥Grade 3 were 5% (n=4/80). Conclusions: Tislelizumab achieved statistical significance and demonstrated clinically meaningful improvement in ORR in pts with previously treated locally advanced unresectable or metastatic MSI-H or dMMR solid tumors. Treatment effect was consistent and durable across tumor types and endpoints. Tislelizumab was generally well tolerated and no new safety signals were identified. The data support tislelizumab as a new treatment option in this population. Clinical trial information: NCT03736889.

Personalized ANtibodies for GastroEsophageal Adenocarcinoma (PANGEA): Primary efficacy analysis of the phase II platform trial (NCT02213289).

356 Background: 1-yr OS is ~40% for HER2- & ~55% for HER2+ advanced (aGEA). Targeted therapies (tx) have had limited benefit due to molecular heterogeneity. Methods: This phase 2a study of a personalized tx strategy (PTS) enrolled newly diagnosed aGEA pts who then received up to 3 cytotoxic (cx) lines: first line (1L) 5FU + oxaliplatin, 2L 5FU + irinotecan & 3L 5FU + docetaxel. Baseline biomarker profiling (BP) was mandated on primary & metastatic tumors (PT/MT) & progressive disease points (PD1, PD2). Assigned antibody (AN) was added to cx by a predefined prioritized tx algorithm (PTA) (Table) based on the MT BP. At PD1, pts went to 2L cx + initial AN. Upon results of PD1 BP, pts changed AN only if BP evolved per PTA. The same was done at PD2. If AN was unavailable (MET/FGFR2), these pts were tx’d with cx alone (not ITT). The 10 endpt was 1-yr OS of the PTS. Assuming historical 50% 1-yr OS for all aGEA pts, 68 pts tx’d per protocol PTS provided 80% power to detect an HR=0.67, corresponding to a 1-yr OS rate of 63% (under exponential survival), using a 1-sided test at the 0.10 alpha level. 20 endpts: safety, feasibility, PT/MT BP discordance at baseline & over tx line, & OS/PFS/ORR by tx line & BP group. Results: Between 6/2015-5/2019, 80 consecutive pts enrolled at 3 sites: ECOG PS 0-2 40/33/7; Male 80%; median age 60, range 28-81, peritoneal disease 36%. AN assigned by PTA at 1L & 1-yr OS are shown (Table). PT/MT discordance was 37%. Of 68 pts treated by PTS ITT, the 1-yr OS was 69.4% (p<0.001). The mOS was 16.4m [95%CI 13.8-20.8]. Any grade >3 tox thru all 3 tx lines was seen in 32% of pts. 20 analyses will be presented. Conclusions: PANGEA was feasible & met its 10 efficacy objective with observed 1-yr OS of 69.4%, meriting a randomized study. Clinical trial information: NCT02213289 . U.S. National Institutes of Health.[Table: see text]

IQP-VV-102, a Novel Proprietary Composition for Weight Reduction: A Double-Blind Randomized Clinical Trial for Evaluation of Efficacy and Safety

The individual ingredients in IQP-VV-102 have demonstrated promising effects in reducing sugar and starch digestion, which potentially leads to weight loss. The trial objective was to evaluate the safety and efficacy of IQP-VV-102 in reducing body weight in overweight and obese subjects. 120 overweight and obese individuals aged 18 to 60 years were randomly assigned to 2 treatment arms (IQP-VV-102 and placebo). The trial was conducted in 2 study centres in Berlin, Germany. The primary efficacy analysis was conducted on 117 subjects (IQP-VV-102:N=54; placebo:N=59), comparing the weight loss effect at baseline and 12 weeks after randomization. There was a statistically significant reduction in mean body weight of 3.29 kg (SD 2.30) in the IQP-VV-102 group compared to 0.83 kg (SD 2.00) in the placebo groupp<0.001. There were no serious or product-related adverse events that were reported over the combined period of 14 weeks. The findings suggested that IQP-VV-102 is effective and safe in body weight reduction in overweight and obese individuals in the short term. The study is registered under clinicaltrials.gov asNCT01681069.

Defibrotide (DF) in the Treatment of Severe Hepatic Veno-Occlusive Disease (VOD) with Multi-Organ Failure (MOF) Following Stem Cell Transplantation (SCT): Results of a Phase 3 Study Utilizing a Historical Control.

Abstract 654 Background: Phase 2 clinical trials of DF in the treatment of severe VOD/MOF have demonstrated a complete response (CR) in 36-46% of patients (pts) with encouraging overall survival and tolerability (Richardson Blood 2002; Richardson ASH 2006). Given the life-threatening nature of VOD/MOF, a trial randomizing pts to placebo or best supportive care was considered but rejected. A phase 3 trial, comparing DF in the treatment of VOD/MOF post-SCT to a contemporaneous historical control (HC) was therefore performed. The HC was created using a sequential review of medical charts starting 6 months prior to use of DF at each center. Methods: Eligible pts met Baltimore VOD criteria by D+21 (total bilirubin ≥ 2.0 mg/dL with ≥ 2 of the following: hepatomegaly, ascites or 5% weight gain) and either renal and/or pulmonary failure by D+28. Exclusion criteria: severe GvHD involving liver or gut; clinically significant bleeding; or need for >1 pressors to maintain BP. As this is a non-randomized study, the primary efficacy analysis compared CR by D+100, adjusted by quintiles of propensity score based on 4 stratification variables, at an overall two-sided 0.01 significance level (Koch et al,1989). CR was defined as bilirubin < 2 mg/dL + resolution of MOF; stratification variables were allogeneic/autologous SCT, adult/pediatric, 1 or 2+ SCTs, and ventilator/dialysis dependence. A secondary endpoint was mortality at D+100. DF was given at 6.25 mg/kg IV q6h; treatment duration was recommended for at least 21d. To create the HC, 35 centers sequentially reviewed up to 266 cases. To determine HC eligibility, the Medical Review Committee (MRC, composed of 2 independent expert hematologists) assessed all pts who met VOD criteria with MOF. The MRC were provided data for each pt (a redacted medical chart or pt narrative, depending on the privacy laws for each center) only up to the date on which the pt met inclusion criteria. The MRC remained blinded to outcome data at all times. One interim analysis was planned. Results: For the HC, 6821 medical charts were screened, identifying 123 pts with features consistent with VOD in a setting of renal and/or pulmonary dysfunction that were reviewed for eligibility by the MRC. The MRC selected 32 cases as having an unequivocal diagnosis of VOD whose MOF was secondary to VOD, who met all protocol entry criteria; for all eligible pts, a confounding diagnosis of GvHD was ruled out. In the DF-treated group, 102 pts were enrolled. Following the interim analysis (comparing 61 DF pts to 32 HC pts), the DMC recommended an increase in HC sample size to 51 pts; given the large number of medical charts already reviewed, this was not considered feasible. In the final analysis (comparing 102 DF pts to 32 HC pts), the 2 groups were balanced regarding stratification variables. Baseline demographics (DF vs HC pts): median age 21 vs 18 yrs (43% and 44% pediatric); 63% vs 53% male, 88% vs 84% allogeneic SCT; 13% vs 3% with prior SCT; and 38% vs 38% ventilator/dialysis dependent. Median time post-SCT to VOD diagnosis was 13 and 11 days. Acute leukemia was the underlying diagnosis in 44% and 47%. Median duration of DF therapy was 22 days (range 1-60 days), with a median daily dose of 19 mg/kg/d. For the primary efficacy analysis, D+100 CR rate equaled 24% vs 9% (99%CI difference in CR rate: -1–35%; 95%CI difference in CR rate: 3–30%); p=0.015. D+100 mortality rate equaled 62% vs 75% (95%CI difference in rate -32–3%); p=0.051 by stratified log-rank. Consistent with prior studies, DF in children resulted in higher CR compared with HC (CR 36% vs 7%; p=0.04). Use of DF was associated with improved outcome in less sick pts (D+100 CR for pts without ventilator dependence equaled 40% vs 9%; p=0.051 and for pts without dialysis dependence equaled 34% vs 9 %; p=0.027). For pts receiving autologous SCT (n=12 and 5 pts in DF and HC arms), DF was associated with markedly improved CR (75% vs 0%, p=0.005). Hemorrhagic adverse events (any grade) were similar between the two groups (65% vs 69%); 18% of DF pts experienced a drug-related toxicity that led to discontinuation. D+100 CR strongly correlated with D+100 survival in both DF and HC groups (p<0.0001, p=0.0016). Conclusions: DF improves CR by D+100 in pts with severe VOD/MOF post-SCT with a p value < 0.05. In addition, there was a trend towards improved D+100 survival in this critically ill population. DF-associated toxicities are consistent with prior studies, supporting the observation that DF is generally well tolerated. Disclosures: Richardson: Gentium: Membership on an entity's Board of Directors or advisory committees. Arai:Gentium: Research Funding. Grupp:Gentium: Research Funding. Martin:Gentium: Research Funding. Corbacioglu:Gentium: Consultancy, Research Funding. Holler:Gentium: Consultancy. D'Agostino:Gentium: Membership on an entity's Board of Directors or advisory committees. Massaro:Gentium: Consultancy. Hannah:Gentium: Consultancy. Iacobelli:Gentium: Employment. Soiffer:Gentium: Consultancy, Membership on an entity's Board of Directors or advisory committees.