Mitapivat (AG-348) Demonstrates Safety, Tolerability, and Improvements in Anemia, Hemolysis, Oxygen Affinity, and Hemoglobin S Polymerization Kinetics in Adults with Sickle Cell Disease: A Phase 1 Dose Escalation Study

Abstract Background. Hemoglobin S (HbS) polymerization causes red cell sickling, hemolysis, and vaso-occlusion, key pathological features of sickle cell disease (SCD). Mitapivat (AG-348) has potential as an oral anti-sickling agent in SCD via increasing glycolytic activity, which reduces intracellular levels of 2,3-diphosphoglycerate (2,3-DPG) in parallel with increasing adenosine triphosphate (ATP). Reducing 2,3-DPG decreases HbS polymerization, while increasing ATP improves red cell membrane integrity. Here, we report the complete results of our single-center Phase 1 study of multiple ascending doses of mitapivat in subjects with SCD. Methods. We enrolled adult subjects (age ≥ 18 years) with confirmed SCD (HbSS) and baseline Hb ≥ 7 g/dL; with no recent transfusions, erythropoietin therapy, or changes in SCD-specific therapies including hydroxyurea (HU) and L-glutamine. Subjects received either 3 or 4 ascending dose levels of mitapivat (5 mg BID, 20 mg BID, 50 mg BID, 100 mg BID) for 2 weeks' duration each, followed by a 12-15 day drug taper. Safety and tolerability were assessed by frequency and severity of adverse events (AEs) and changes in hemoglobin (Hb) level and hemolytic markers. For each dose level, pharmacokinetics (PK), pharmacodynamics (PD; 2,3-DPG and ATP levels), and markers of oxygen (O 2) affinity (p50) and HbS polymerization (t50) were assessed pre-dose, post-dose, at end of taper, and at end of study. p50 is the partial pressure of O 2 at which 50% of the hemes in the Hb molecule have O 2 bound; t50 is the time at which 50% of erythrocytes are sickled in response to gradual deoxygenation with nitrogen to a final O 2 partial pressure of 38 torr. Results. Out of 17 subjects enrolled, 16 escalated to 50 mg BID. One subject, withdrawn 3 days after starting the study for a pre-existing pulmonary embolus, was not evaluable for response. After a protocol amendment, 9/10 eligible subjects completed the 100 mg BID dose level; 1 subject self-discontinued treatment after completing 3 dose levels. Mean age of the 17 subjects was 39 years (range 23-55 years); 11 were male, and 12 were on HU. Mitapivat was well tolerated; the most commonly reported drug-related AEs were insomnia (n=6 subjects, Grades 1-2), arthralgia (n=3, Grades 1-2), and hypertension (n=3, Grades 1-3). Six serious AEs (SAEs) were reported in 6/17 subjects, including 4 vaso-occlusive crises (VOCs), 1 non-VOC-related pain, and 1 pre-existing pulmonary embolism; 2/6 SAEs were deemed possibly drug-related. Of the 4 VOCs, 2 occurred during drug taper and were possibly drug-related, and 2 occurred during the 28-day safety follow up post-treatment in the setting of known VOC triggers. In 16 evaluable subjects, a dose-dependent decrease in mean 2,3-DPG levels and increase in mean ATP levels were consistently observed, followed by a return to near baseline by end of study (Figure 1A-B). There was a mean decrease in p50 and increase in t50 (Figure 1D-E), indicating increased oxygen affinity and slower sickling, respectively. The mean Hb increase at the 50 mg BID dose level was 1.2 g/dL (range -0.3-2.9 g/dL; Figure 1C). Over half (9/16, 56.3%) of subjects achieved a Hb response, defined as a ≥ 1 g/dL increase in Hb at any dose level compared to baseline. Subjects also experienced a mean reduction in the hemolytic markers of lactate dehydrogenase, total serum bilirubin, absolute reticulocyte count, and aspartate aminotransferase during the dose escalation period (Figure 1F-I), though responses were variable. Mean corpuscular volume (MCV) and HbF levels remained relatively stable throughout the study, supporting the notion that hydroxyurea exposure remained stable throughout the treatment period. Conclusion. During a 6-8 week treatment period, mitapivat demonstrated an acceptable safety and tolerability profile at multiple ascending dose levels in subjects with SCD. Mitapivat improved anemia, reduced markers of hemolysis, decreased 2,3-DPG and increased ATP levels, improved oxygen affinity, and decreased sickling rate, signaling its potential to improve clinically meaningful outcomes in SCD. Long-term disease modifying effects of mitapivat treatment in SCD are being evaluated in an ongoing extension study (ClinicalTrials.gov NCT04610866). Figure 1 Figure 1. Disclosures Iyer: Novartis: Current equity holder in publicly-traded company; Agios Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Mangus: Agios Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Kung: Agios Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Dang: Agios Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Kosinski: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Hawkins: Bristol-Myers Squibb: Current equity holder in publicly-traded company; Agios: Current equity holder in publicly-traded company.

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Phase 1 Multiple Ascending Dose Study of Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics of Mitapivat (AG-348) in Subjects with Sickle Cell Disease

Blood ◽

10.1182/blood-2020-137716 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 21-22

Author(s):

Julia Z. Xu ◽

Anna Conrey ◽

Ingrid Frey ◽

James Nichols ◽

Laurel A Menapace ◽

...

Keyword(s):

Sickle Cell Disease ◽

Study Drug ◽

Dependent Manner ◽

Red Cell ◽

Cell Disease ◽

Publicly Traded ◽

Atp Levels ◽

Dose Levels ◽

Dose Dependent ◽

2,3 Dpg

Background. Sickle cell disease (SCD) is a devastating disorder initiated by polymerization of the deoxy-hemoglobin S (HbS) to form fibers that distort (sickle) erythrocytes. Increased intracellular 2,3- diphosphoglycerate (2,3-DPG) stabilizes fibers and promotes sickling, while decreased intracellular adenosine triphosphate (ATP) levels can lead to hemolysis. Mitapivat (AG-348) is an oral, small molecule, allosteric activator capable of activating both mutant and wild type red cell pyruvate kinase (PKR), thus decreasing 2,3-DPG and increasing ATP levels in red cells and potentially acting as an anti-sickling agent. The safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of multiple ascending doses of mitapivat were assessed in subjects with SCD in a Phase I study. Methods. Subjects aged ≥ 18 years with a confirmed diagnosis of SCD (HbSS), adequate organ function, baseline Hb ≥ 7 g/dL, and no transfusions or erythropoietin therapy in the prior 3 months were eligible. Concomitant stable hydroxyurea (HU) and/or L-Glutamine therapy was permitted on study. Subjects received either 3 or 4 ascending dose levels of mitapivat (5 mg BID, 20 mg BID, 50 mg BID, 100 mg BID) for 2 weeks' duration each, followed by a 12-15-day drug taper. The primary endpoint was safety and tolerability as assessed by frequency and severity of adverse events (AEs) and laboratory parameters. Secondary endpoints included changes in hematological parameters, 2,3-DPG and ATP levels, and markers of Hb S polymerization (p50 and t50). Results. Nine subjects have been enrolled as of July 2020. One patient discontinued treatment early and was lost to follow-up. Results pertain to the 8 subjects who completed study: mean age was 43.6 years (range 34-55 years), 5 were male, and 7 were stabilized on HU. The initial 6 subjects escalated to a maximum dose of 50 mg BID, and the subsequent 2 subjects escalated up to a 100 mg BID dose following a protocol amendment. All 8 subjects reported AEs; the most common treatment related AEs were hypertension (n=3, Grades 1-3), insomnia (n=3, Grade 2), and asymptomatic heart rate increase on vital signs (n=3, Grade 1). 5 serious AEs (SAEs) were reported in 4 subjects, with only 1 SAE possibly attributable to study drug - a vaso-occlusive crisis (VOC) during drug taper, after which the protocol was amended to increase the length of taper from 9 to 12 days for the 50 mg BID dose and 15 days for the 100 mg BID dose. No VOCs have occurred during core period or on the prolonged drug taper. The SAEs not attributable to study drug included a VOC at the end of study, VOC-related transaminitis (Grade 2), a non-VOC-related pain episode, and a pre-existing pulmonary embolism discovered shortly after study drug initiation. Table 1 details the PD and clinical laboratory measures. Mean 2,3-DPG levels decreased and ATP levels increased in a dose-dependent manner. ATP levels remained elevated immediately following drug taper in 5/8 subjects. Both ATP and 2,3-DPG levels returned to near baseline by 4 weeks after drug taper. Decreases in p50 and increases in t50 at various dose levels support an anti-sickling effect of mitapivat in a subset of subjects, though responses were highly variable. Mitapivat increased Hb levels in a dose-dependent manner with a concomitant decrease in hemolytic markers. Mean change in Hb from baseline for all 8 subjects at the 50 mg BID dose level was 1.2 g/dL (range -0.3-2.7 g/dL), followed by near return to mean Hb baseline after drug taper. Hemolytic markers similarly returned to near baseline after drug taper. 3/8 and 5/8 subjects achieved a Hb increase of ≥ 1 g/dL at the 20 and 50 mg BID dose levels, respectively. A small dose-dependent increase in mean corpuscular volume (MCV) was also observed, suggesting a potential alternative mechanism of mitapivat, acting through the ATP-dependent Gardos channel to increase red cell hydration, decrease hemolysis, and improve red cell survival in SCD. Conclusion. Mitapivat demonstrated an acceptable safety profile across the tested dose levels in 8 subjects with SCD. Analyses of data show promising evidence of efficacy in terms of Hb increase from baseline with concomitant decreases in hemolytic markers. The accompanying changes in metabolites and sickling studies are consistent with the proposed mechanism of the drug. The study is ongoing with a planned sample size of 15 subjects completing 6-8 weeks of treatment. Additional data including PK will be presented. Disclosures Iyer: Novartis: Current equity holder in publicly-traded company; Agios Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Mangus:Agios Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Kung:Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Dang:Agios Pharmaceuticals Inc.: Current Employment, Current equity holder in publicly-traded company. Kosinski:Agios Pharmaceuticals Inc: Current Employment, Current equity holder in publicly-traded company. Hawkins:Infinity Pharmaceuticals: Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current equity holder in publicly-traded company; Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company; Jazz Pharmaceuticals: Current equity holder in publicly-traded company.

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Hemoglobin Function in the Horse: The Role of 2,3-Diphosphoglycerate in Modifying the Oxygen Affinity of Maternal and Fetal Blood

Blood ◽

10.1182/blood.v42.3.471.471 ◽

1973 ◽

Vol 42 (3) ◽

pp. 471-479 ◽

Cited By ~ 35

Author(s):

H. Franklin Bunn ◽

Hyram Kitchen

Keyword(s):

Oxygen Saturation ◽

Oxygen Affinity ◽

Fetal Hemoglobin ◽

Red Cells ◽

Red Cell ◽

Fetal Blood ◽

Atp Levels ◽

2,3 Dpg

Abstract The blood of the newborn horse was found to have a higher affinity for oxygen than that of the mother. This difference was due to the fact that the red cells of newborn foals contained 36% lower 2,3-diphosphoglycerate (2,3-DPG) than red cells from their respective mares. The ATP levels of foal and maternal red cells did not differ significantly. Following birth a prompt rise in the foal's red cell 2,3-DPG occurred, approaching normal (maternal) levels within 5 days. Unlike many other species, the hemoglobins of the newborn and adult horse have been shown to be structurally identical. Furthermore, phosphate-free solutions of newborn and maternal hemoglobins had identical oxygen saturation curves in the absence and presence of added 2,3-DPG. This study demonstrates that, in contrast to other species. the increased oxygen affinity of horse fetal red cells is due to a lower level of the cofactor 2,3-DPG rather than to the presence of fetal hemoglobin.

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Phase 1 Single (SAD) and Multiple Ascending Dose (MAD) Studies of the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of FT-4202, an Allosteric Activator of Pyruvate Kinase-R, in Healthy and Sickle Cell Disease Subjects

Blood ◽

10.1182/blood-2019-121889 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 616-616

Author(s):

Theodosia A. Kalfa ◽

Frans A Kuypers ◽

Marilyn J. Telen ◽

Punam Malik ◽

Diamantis G. Konstantinidis ◽

...

Keyword(s):

Single Dose ◽

Healthy Subjects ◽

Research Funding ◽

Phase 1 ◽

Oxygen Affinity ◽

Post Dose ◽

Dose Levels ◽

2,3 Dpg ◽

Allosteric Activator

Background: The hallmark of sickle cell disease (SCD) is hemoglobin S (HbS) polymerization upon deoxygenation, resulting in red blood cell (RBC) sickling, oxidative damage, membrane damage, hemolysis, chronic anemia, vaso-occlusions and inflammation. Exacerbating the pathogenesis of SCD, the HbS RBC has 1) increased (↑) 2,3-DPG with decreased (↓) oxygen affinity (↑ P50) and 2) ↓ RBC ATP. FT-4202 is a novel, small molecule allosteric activator of erythrocyte pyruvate kinase (PKR) that increases the activity of both wild type and mutated PKR enzymes, resulting in ↓ 2,3-DPG levels and ↑ ATP levels in RBC. In preclinical safety studies, FT-4202 had no effect on steroidogenesis, low risk of drug-to-drug interactions (DDI) and was well tolerated in vivo at the maximum doses administered. In vitro FT-4202 treatment of RBCs from patients with SCD increased oxygen affinity and shifted the point of sickling by oxygen scan. After 1-week of dosing in vivo Berkeley SCD mouse-models, FT-4202 increased the oxygen affinity of HbS RBC, resulting in reduction of sickling and improved hemoglobin. Based on these results, a first-in-human Phase 1 study evaluating FT-4202 in healthy subjects and subjects with SCD was initiated. The key objectives of this randomized, double-blind, placebo-controlled single (SAD), multiple ascending dose (MAD), and food effects (FE) study are to evaluate the safety and pharmacokinetics/pharmacodynamics (PK/PD) of FT-4202, in healthy and SCD subjects [NCT03815695]. Herein we report the effects of FT-4202 on healthy subjects in this ongoing study. Methods: SAD cohorts were randomized to receive a single oral dose of FT-4202 or placebo (P). Four healthy SAD cohorts were evaluated (n=8 each; 6 FT-4202, 2 P), at increasing doses of 200, 400, 700, and 1000 mg. Four healthy MAD cohorts (n=12 each; 9 FT-4202, 3 P) received 200 to 600 mg total daily dose for 14 days at QD or BID dosing. In the FE cohort, 10 subjects received 200 mg FT-4202 QD with and without food. Safety assessments included adverse events (AEs), vital signs, ECGs and laboratory parameters. Rich PK/PD blood sampling was performed on Day1 (SAD/MAD/FE) and Day 14 (MAD), up to 72h after the last dose and at the end of study visit. PD parameters included 2,3-DPG, ATP, and P50. Safety data are summarized in a blinded fashion pending enrollment of SCD subjects. To maintain study blind, PK/PD analysis was performed by an unblinded pharmacologist using dummy subject identifiers. Results: No serious adverse events (SAEs) or AEs leading to withdrawal were reported. In the SAD cohorts, 32 subjects (20 males [M] and 12 females [F]; median age 46 yrs) were enrolled and completed the study. A total of 7 treatment-emergent AEs occurred in 6/32 (19%) subjects during the study: 3 Grade (Gr) 1 and 3 Gr 2 in severity while 1 subject in the 1000 mg FT-4202/P dose cohort experienced an isolated, asymptomatic lipase increase (Gr 3 AE) that occurred 4 days post dose and normalized within 24 hrs. In the MAD cohorts, 48 subjects (28 M; 20 F; median age 46 yrs), were enrolled and completed dosing. 18/48 (38%) of subjects receiving FT-4202/P experienced 31 Gr 1 AEs with the most frequent AE of headache (n=12). In PK assessments, FT-4202 was rapidly absorbed with a median Tmax of 1 hr post-dose. Single dose exposure increased in greater than dose-proportional manner at doses ≥700 mg. In multiple-doses delivered BID or QD, linear PK was observed across all dose levels (100-300 mg BID, 400 mg QD), and exposure remained steady up to day 14, without cumulative effect. FT-4202 exposure under fed/fasted conditions was similar. PD activity was demonstrated at all dose levels evaluated in FT-4202-treated subjects (Table 1). Within 24 hr of a single dose of FT-4202, ↓ 2,3-DPG with a corresponding ↓ P50 was observed. After 14 days of FT-4202 dosing these PD effects were maintained along with ↑ ATP over baseline. PK/PD modeling demonstrated that exposures achieved with FT-4202 150-200 mg BID will result in maximum/sustained PD effect. Conclusions: FT-4202 has a favorable safety profile in healthy subjects based on preliminary analysis of subjects receiving a single dose up to 1000 mg or multiple doses up to 600 mg/day for 14 days. FT-4202 demonstrated linear and time-independent PK with proof of mechanism (POM) demonstrated based on PD effects. Studies in SCD subjects are ongoing to confirm safety and POM of FT-4202 at doses predicted to achieve maximum PD effect (↓ 2,3-DPG/↓ P50 and ↑ ATP) in the HbS RBC. Disclosures Kalfa: FORMA: Other: sponsored research agreement; Agios: Other: local PI of clinical research trial. Kuypers:FORMA Therapeutics: Research Funding. Telen:Forma Therapeutics: Research Funding; Novartis: Other: Member of a safety monitoring committee; Pfizer: Other: Member of a clinical trial steering committee. Estepp:Global Blood Therapeutics, FORMA Therapeutics, Pfizer, Eli Lilly and Co: Research Funding; Daiichi Sankyo, Esperion, Global Blood Therapeutics: Consultancy; ASH, NHLBI: Research Funding. Saraf:Pfizer: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wilson:FORMA Therapeutics: Employment. Ribadeneira:FORMA Therapeutics: Employment. Forsyth:FORMA Therapeutics: Employment. Schroeder:FORMA Therapeutics: Employment. Drake:FORMA Therapeutics: Employment. Polyanskaya:FORMA Therapeutics: Employment. Kelly:FORMA Therapeutics: Employment. Biernat:Medpace, Inc.: Employment.

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17-BI-1206-02 Phase 1/2a Clinical Trial of BI-1206, a Monoclonal Antibody to Fcgriib, in Combination with Rituximab in Subjects with Indolent B-Cell Non-Hodgkin Lymphoma That Has Relapsed or Is Refractory to Rituximab

Blood ◽

10.1182/blood-2020-140219 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 36-37

Author(s):

Mats Jerkeman ◽

Andres McAllister ◽

Carl Roos ◽

Marie Lindell Andersson ◽

Ingrid Karlsson ◽

...

Keyword(s):

Clinical Trial ◽

Monoclonal Antibody ◽

Clinical Response ◽

Clinical Benefit ◽

Phase 1 ◽

Publicly Traded ◽

Dosing Interval ◽

Non Linear ◽

Dose Levels ◽

Receptor Saturation

Introduction BI-1206 is a fully-human IgG1 monoclonal antibody that exquisitely recognizes and blocks FcγRIIB. BI-1206 enhances the activity of anti-CD20 antibodies such as rituximab by preventing interaction with FcγRIIB and may thus overcome resistance to those treatments. BI-1206 is currently in clinical investigation in combination with rituximab for the treatment of indolent NHL. This report presents a preliminary pharmacokinetic evaluation of the data generated in the trial. Methods The safety and tolerability profile of BI-1206 in combination with rituximab is currently investigated in the Phase 1/2a clinical trial 17-BI-1206-02. The study population includes patients with follicular lymphoma (FL), marginal zone lymphoma (MZL), and mantle cell lymphoma (MCL) who have relapsed or are refractory to rituximab. BI-1206 and rituximab are administered as i.v. infusions once per week for four weeks. In Phase 1a, a 3+3 study design is used, with escalating doses of BI-1206 and a fixed dose of rituximab (375 mg/m2), with the aim of selecting the RP2D of BI-1206 for an expansion cohort in Phase 2a. Patients showing clinical benefit, are eligible for continued maintenance therapy with dosing of BI-1206 and rituximab every 8 weeks. The assessment of the pharmacokinetics (PK) of BI-1206 included non-compartmental analysis (NCA), and the assessment of the pharmacodynamics (PD) included receptor occupancy (RO%). PK modelling was conducted to further characterize the PK behavior and to provide predictions of upcoming dose levels. In addition, the effect of BI-1206 on the PK of rituximab was investigated by comparing PK parameters of rituximab to literature values of rituximab monotherapy. Results Up to 100 mg BI-1206 has been administered in combination with rituximab (375 mg/m2). Increasing doses of BI-1206 from 30 mg to 70 or 100 mg gave rise to a supra-proportional increase in Cmax as well as an increase in the half-life of BI-1206. A trend of accumulation after consecutive doses was also seen. When comparing the serum-concentrations against the associated RO% of FcγRIIB there is a trend that higher doses almost fully saturate the receptors immediately after dosing and for up to 72 hours. It is likely that increasing the dose further, will give rise to full receptor saturation, which should be maintained for an extended period. Clinical response, assessed by reduction of tumour size, has been observed at the 70 mg cohort. This at a dose which typically does not saturate receptors for the entire dose interval. It may therefor be speculated that doses which enable full RO% over the entire dosing interval, may show additional clinical benefit for patients. PK modelling showed that there was a significant contribution of a non-linear component on the elimination of BI-1206, which may be attributed to receptor binding. A two-compartment model with linear (non-saturating) and non-linear (saturating) elimination best describes the data. Using the model for predictions of upcoming doses revealed that doses close to the ones already administered may be sufficient for full receptor saturation during the entire dosing interval. Finally, the Cmax after one dose of rituximab was in the same range as previously reported values, indicating no substantial effect on the PK of rituximab. Consequently, at the current dose levels, there is no apparent need for dose-adjustments for rituximab. Conclusions This report presents preliminary data of the clinical trial 17-BI-1206-02, where BI-1206 is combined with rituximab. The presented data is encouraging, both in terms of first clinical response against tumors, as well as showing signs of overcoming target-mediated drug disposition, which may allow weekly or even less frequent dosing at clinically relevant dose levels. Disclosures Jerkeman: Roche:Research Funding;Celgene:Research Funding;Gilead:Research Funding;Abbvie:Research Funding;Janssen:Research Funding.McAllister:BioInvent International AB:Current Employment, Current equity holder in publicly-traded company.Roos:BioInvent International AB:Current Employment.Lindell Andersson:BioInvent International AB:Current Employment.Karlsson:BioInvent International AB:Current Employment.Borggren:BioInvent International AB:Current Employment.Abrisqueta:Celgene:Consultancy, Honoraria;Janssen:Consultancy, Honoraria, Speakers Bureau;AbbVie:Consultancy, Honoraria, Speakers Bureau;Roche:Consultancy, Honoraria, Speakers Bureau.Teige:BioInvent International AB:Current Employment, Current equity holder in publicly-traded company.Frendéus:BioInvent International AB:Current Employment, Current equity holder in publicly-traded company.

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What is the Clinical Importance of Alterations of the Hemoglobin Oxygen Affinity in Preserved Blood - Especially as Produced by Variations of Red Cell 2,3 DPG Content?

Vox Sanguinis ◽

10.1159/000467572 ◽

1978 ◽

Vol 34 (2) ◽

pp. 111-127 ◽

Cited By ~ 2

Author(s):

J.C. Bakker ◽

Ernest Beutler ◽

John A. Collins ◽

R. Ben Dawson ◽

Lars Garby ◽

...

Keyword(s):

Oxygen Affinity ◽

Clinical Importance ◽

Red Cell ◽

Hemoglobin Oxygen Affinity ◽

2,3 Dpg

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A Phase 1 Dose Escalation Study of a Fully Human, Antagonist Anti-CD40 Antibody, HCD122 (Formerly CHIR-12.12) in Patients with Relapsed and Refractory Multiple Myeloma.

Blood ◽

10.1182/blood.v108.11.3575.3575 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3575-3575 ◽

Cited By ~ 8

Author(s):

William Bensinger ◽

Sundar Jagannath ◽

Pamela S. Becker ◽

Kenneth C. Anderson ◽

Edward A. Stadtmauer ◽

...

Keyword(s):

Multiple Myeloma ◽

Dose Level ◽

Ex Vivo ◽

Phase 1 ◽

Safety Evaluation ◽

Median Number ◽

Maximum Tolerated Dose ◽

Dose Escalation Study ◽

Myeloma Cells ◽

Dose Levels

Abstract HCD122 is a novel, fully human, IgG1 antagonistic monoclonal antibody targeting the CD40 receptor. This antibody blocks CD40-mediated signaling and is a potent mediator of antibody-dependent cellular cytotoxicity (ADCC). Previous preclinical investigation confirmed expression of CD40 on myeloma cells in the majority of patients and reported antitumor activity of HCD122 against multiple myeloma cells ex vivo (Tai, Y et al. Cancer Res2005; 65(13): 5898–5906). This ongoing phase 1 study will determine the maximum tolerated dose of CHIR-12.12 in multiple myeloma patients (pts) who are relapsed or refractory after at least one prior therapy. Planned dose levels are 1, 3 and 10 mg/kg administered IV once weekly for 4 weeks. Each dose group will enroll 3–6 pts to evaluate safety, pharmacokinetics (PK) and clinical response. To date, 9 pts have been treated at 2 dose levels: 3 pts at 1 mg/kg and 6 pts at 3 mg/kg. Median patient age is 65 yrs (46–81 yrs); median number of prior therapies is 3 (2–12). No dose limiting toxicity (DLT) occurred at the 1mg/kg dose level. At 3 mg/kg, 1 DLT of grade 4 thrombocytopenia occurred in 1 pt. No other grade 3 and 4 lab abnormalities and adverse events have been reported. In 7 pts with available data, infusions were well tolerated, with easily managed grade 1–2 toxicities, primarily chills (5 pts), nausea (3 pts), pyrexia (2 pts), and arthralgia (2 pts) mainly reported during the first infusion. Preliminary PK analysis showed more than dose proportional - increase in Cmax and AUC at the 3 mg/kg dose level compared to the 1 mg/kg dose level. At the 3 mg/kg dose, antibody accumulation occurred week-to-week; the mean Cmax after the fourth infusion on Day 22 was 126.1 mg/mL(range 52 – 195 ug/mL) and HCD122 levels were measurable up to Day 57 and in one patient up to Day 99. One week after the last 3 mg/kg dose, trough levels ranged from 28 to 109 mg/mL. Of the 3 pts at 1 mg/kg, one showed stable disease (SD) for >23 weeks and two had progressive disease (PD) by week 5. Of the 6 pts at 3 mg/kg, one had partial response (PR) at week 9 and was confirmed at week 15, one had SD for > 5 weeks, and 4 had PD at week 5. One pt with PD terminated the study before final safety evaluation, and must be replaced before assessment of the 3mg/kg dose level is complete. Thus, in preliminary studies, HCD122 appears to be safe and well tolerated to date at doses of 1 mg/kg and 3 mg/kg weekly for 4 doses and shows promising anti-myeloma activity. Enrollment is continuing to determine MTD.

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Lenalidomide, Bortezomib, and Dexamethasone (Rev/Vel/Dex) as Front-Line Therapy for Patients with Multiple Myeloma (MM): Preliminary Results of a Phase 1/2 Study.

Blood ◽

10.1182/blood.v110.11.187.187 ◽

2007 ◽

Vol 110 (11) ◽

pp. 187-187 ◽

Cited By ~ 5

Author(s):

Paul Richardson ◽

Sundar Jagannath ◽

Noopur Raje ◽

Andrzej Jakubowiak ◽

Sagar Lonial ◽

...

Keyword(s):

Dose Level ◽

Phase 1 ◽

Single Agent ◽

Safety Data ◽

High Dose ◽

Hematologic Toxicity ◽

Newly Diagnosed ◽

Front Line ◽

Dose Levels ◽

Dose Reductions

Abstract Background: Bortezomib (VELCADE®, Vel) as a single agent and lenalidomide (Revlimid®, Rev) plus dexamethasone (Dex) are approved for the treatment of relapsed MM patients (pts) following ≥1 prior therapy. Rev/Vel±Dex is active and well tolerated in relapsed/refractory MM, and Rev/Dex and Vel/Dex have substantial activity in front-line MM. The aims of this phase 1/2 study were to determine the MTD of Rev/Vel/Dex in newly diagnosed MM pts, and to assess safety and efficacy. Methods: Pts received Rev 15–25 mg on d 1–14, Vel 1.0–1.3 mg/m2 on d 1, 4, 8, 11, and Dex 40/20 mg (cycles 1–4/5–8) on d 1, 2, 4, 5, 8, 9, 11, 12, for up to 8 21-d cycles, initially at 4 planned dose levels (Rev/Vel: 15/1.0, 15/1.3, 20/1.3, 25/1.3). Dose escalation proceeded (3-pt cohorts) depending on DLTs (G≥3 non-hematologic toxicity; G4 thrombocytopenia with platelets <10,000/mm3 on >1 occasion despite transfusion support; G4 neutropenia for >5 d and/or resulting in neutropenic fever; inability to receive cycle 2/d 1 dose due to drug-related toxicity). Based on safety data, dose level 4M was added with a reduced Dex starting dose (Rev/Vel 25/1.3, Dex 20 mg in all cycles). Toxicities were graded by NCI CTCAE v3.0. Pts with G>2 peripheral neuropathy (PNY) were excluded. Responses were assessed by modified EBMT and Uniform criteria. Pts with CR/nCR/VGPR/PR could proceed to ASCT after ≥4 cycles. Results: 33 pts (median age 56 yrs, 55% men, 84% IgG MM, 47% with ISS Stage II/III) have been enrolled to date in dose levels 1–4 and 4M, respectively, including 10 pts enrolled at the maximum planned dose (Dose Level 4M). Pts have received a median of 5 cycles; 9 pts have completed all 8 cycles. Two DLTs of G3 hyperglycemia due to high dose Dex were seen in dose level 4. Dose reductions in cycle 2 and beyond have occurred in dose levels 1–4 for Rev in 9 pts, Vel in 7 pts, and Dex in 17 pts, with 3 dose reductions having occurred in dose level 4M. Toxicities to date have been manageable. Only 1 G4 toxicity (thrombocytopenia) has been reported, plus 1 G3 DVT (reversed with LMWH), and no G≥3 PNY has been seen. The response rate across all dose cohorts (CR/nCR+VGPR+PR: subject to confirmation) is currently 89% in 25/28 evaluable pts, including 35% CR/nCR/VGPR. After median follow-up of 3 mos, median DOR, TTP, PFS, and OS have not been reached; all responders except 1 remain in remission, with 2 pts proceeding to ASCT. Conclusions: Rev/Vel/Dex is very active and well tolerated in newly diagnosed MM pts. The maximum planned dose has been reached at Rev 25 mg, Vel 1.3 mg/m2, and Dex 20 mg, with Phase 1 enrollment now complete using the lower dose of Dex. Enrollment to the Phase 2 component is ongoing.

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Phase 1/2 Trial Of Lenalidomide In Combination With Cyclophosphamide and Prednisone (REP) In Patients With Lenalidomide-Refractory Multiple Myeloma (REPEAT-study)

Blood ◽

10.1182/blood.v122.21.287.287 ◽

2013 ◽

Vol 122 (21) ◽

pp. 287-287 ◽

Cited By ~ 2

Author(s):

Inger S. Nijhof ◽

Sonja Zweegman ◽

Mark-David Levin ◽

Harry R. Koene ◽

Aart Beeker ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Dose Level ◽

Research Funding ◽

Phase 1 ◽

Oral Cyclophosphamide ◽

Phase 2 ◽

Efficacy And Safety ◽

Grade 3 ◽

Dose Levels

Abstract Background The outcome of multiple myeloma (MM) patients who are no longer responding to thalidomide, lenalidomide (LEN) and bortezomib (BORT) is very poor, with a median event-free survival of 5 months and median overall survival (OS) of 9 months (Kumar SK et al, Leukemia 2012; 26;149-157). We have previously shown in a small retrospective study that the combination of continuous low dose oral cyclophosphamide (endoxan) and prednisone combined with lenalidomide (REP) had remarkable activity in heavily pretreated LEN-refractory multiple myeloma patients (median 6 lines of previous chemotherapy) (vd Donk et al; Br J Haematol 2010;148(2):335-7). To determine the optimal dose of lenalidomide with continuous cyclophosphamide and prednisone, we initiated a prospective study to evaluate the maximum tolerated dose (MTD) of the REP regimen and to assess its efficacy and safety in LEN-refractory MM patients. Here we report safety and efficacy data from the phase 1 dose-escalation part of the REPEAT-study (NCT01352338). Patients and Methods Patients aged ≥ 18 years with LEN-refractory MM, ECOG-performance status 0-3 and adequate kidney, liver and hematologic function were included. Five dose levels were evaluated using a standard 3+3 design, based on dose-limiting toxicities (DLTs) occurring in cycle 1. Patients received LEN in doses ranging from 10-25 mg/day on days 1-21 of 28-day cycle, while oral cyclophosphamide (50 or 100 mg) and prednisone (20 mg) were given continuously. Therapy was continued until progression. The MTD for the phase 2 part is defined as the highest dose level with 0 or 1 DLT's observed in 6 patients. Results Up till now, 35 patients were enrolled (22 in phase 1 and 13 in phase 2) from August 2011 to June 2013. The phase 2 part is still recruiting and data are not evaluable yet. One patient in phase 1 was excluded because of study violation and is not included in the analysis. The median age of the 21 evaluable patients in phase 1 was 69 years (range 41-73); 76% were male. The median duration of the disease from diagnosis was 41 months (range 18-96), median number of prior therapies was 3 (range 2-6), and 12 patients (57%) had previously received autologous SCT. All patients were LEN-refractory, 19 (90%) had prior BORT treatment, and 16 (76%) had BORT-refractory MM. Fifty-five % of the patients were considered high risk by FISH. At the time of analysis, 16 of 21 patients in phase 1 have discontinued treatment because of disease progression (13), alternative treatment (allo-SCT) (1), or adverse events (2). The MTD was defined as LEN 25 mg days 1-21 of a 28-day cycle, combined with oral cyclophosphamide 50 mg and prednisone 20 mg continuously (dose level 4), based on three patients experiencing a DLT: two developed pneumonia (in dose levels 4 and 5; CTC grade 3), and one patient at dose level 5 experienced CTC grade 3 dyspnea. Neutropenia (18%) and thrombocytopenia (18%) were the most common grade 3 hematological adverse events (AEs), which were managed with growth factor support and/or dose modification. There were no grade 4 hematologic AEs. Grade 3 respiratory tract infections (29%) and grade 2 fatigue (19%) were the most common non-hematological AEs. Venous thromboembolism occurred in 1 patient. Figure 1 shows a waterfall plot of the responses of the patients that participated in the phase 1 part of the study. Overall response rate (≥ PR) was 67% with 6 out of 21 (29%) patients achieving at least VGPR. In addition 2 patients achieved MR (≥ MR: 76%). Median PFS and OS were 6.3 and 15.5 months respectively. Similar results were achieved in the subset of patients with LEN- and BORT-refractory disease. Interestingly, laboratory experiments with purified myeloma cells from these patients suggest synergism between LEN and cyclophosphamide. Conclusions The REP regimen induces high response rates and prolonged PFS and OS in LEN-refractory patients with acceptable toxicity. The MTD is defined as LEN 25 mg days 1-21 of a 28-day cycle, combined with oral cyclophosphamide 50 mg and prednisone 20 mg continuously. Phase 2 is enrolling patients and evaluates efficacy and safety of the REP regimen at the MTD. REP should be considered a valuable salvage option for LEN-refractory MM patients. We will present an updated follow-up at ASH. Disclosures: Sonneveld: Onyx: Research Funding; Millenium: Research Funding; Janssen-Cilag: Research Funding; Onyx: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Celgene: Research Funding. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria. van de Donk:Celgene: Research Funding.

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Survival of patients considered for participation to contemporary dose-seeking phase trial: Matter of tumour burden, nature of treatment or of dose-levels?

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.2549 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 2549-2549

Author(s):

Juliette Bouchet ◽

Nicolas Isambert ◽

Philippe Alexandre Cassier ◽

Carlos Alberto Gomez-Roca ◽

Stephanie Clisant ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factor ◽

Phase I ◽

Dose Level ◽

Cox Model ◽

Phase 1 ◽

Single Agent ◽

Cytotoxic Agents ◽

Phase 1 Trial ◽

Dose Levels

2549 Background: We have analyzed the survival of pts considered for participation to contemporary phase 1 trial. Methods: All consecutive pts having signed the PIS/IC have been analyzed. OS have been measured using Kalan-Meier method. RMS had been calculated, RMS (0 to 3) is sum of the following prognostic factors: LDH>ULN, met. sites>2 and albumin <35 g/L. Comparisons have been done with Log-rank tests and Cox model. Results: OS of the entire cohort was 448 days. 73.4% of pts having been enrolled. Among not enrolled pts, 74.1% of pts received another treatment. The OS was 497, 247 and 110 days, in pts enrolled in phase I trial, in pts not enrolled but receiving another treatment and in non-treated pts (p=0.001). After adjustment to RMS and with pts not enrolled but receiving other treatment as reference, the HR was 0.47 (95-CI:0.34-0.66; p=0.0001) in pts enrolled in phase 1 compared and 3.54 (1.92-6.52; p=0.0001) in non-treated pts. We have then more specifically analyzed the pts enrolled in single-agent dose-escalating phase I. The OS was 894, 272 and 395 days in pts receiving the 2 first dose-levels, in those receiving intermediate dose-levels and those receiving the phase 2-recommended dose, respectively (p=0.001). The OS was 328 in pts receiving molecular targeted agent and 539 in those receiving cytotoxic agents (p=0.004). In a multivariate analysis, the nature of investigational agent and the dose-level were not associated with better outcome. The sole prognostic factor for OS in multivariate analysis was the RMS (0+1 vs 2+3: HR=3.80 [1.76-8.20], p=0.01). Conclusions: Inclusion in phase 1 trial was associated with better outcome in both crude analysis and after adjustment to RMS. Among enrolled pts, in multivariate analysis RMS reflecting the tumor burden was the sole prognostic factor, the nature of the drug and the dose-level were not associated with the outcome.

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NL-201, a De Novo Agonist of IL-2 and IL-15 Receptors, Demonstrates Synergistic Antitumor Activity with Anti-PD-1 Checkpoint Inhibitor Therapy in a Preclinical Non-Hodgkin Lymphoma Model

Blood ◽

10.1182/blood-2021-148885 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4560-4560

Author(s):

Justin Huard ◽

Laurie Tatalick ◽

Carl Walkey ◽

Ryan Swanson

Keyword(s):

T Cells ◽

Antitumor Activity ◽

Hodgkin Lymphoma ◽

Stock Options ◽

Checkpoint Inhibitor ◽

Publicly Traded ◽

Non Hodgkin Lymphoma ◽

Checkpoint Inhibitor Therapy ◽

Privately Held

Abstract NL-201 is a potent, selective, and long-acting computationally designed alpha-independent agonist of the IL-2 and IL-15 receptors that is being developed as an immunotherapy for cancer. NL-201 binds to the beta and gamma subunits, selectively stimulating dose-dependent expansion and tumor infiltration of cytotoxic CD8+ T cells and natural killer (NK) cells, thereby enhancing the immune response to the tumor. Absence of binding to the IL-2 alpha subunit reduces the undesirable effects of traditional IL-2 therapies, such as vascular leak syndrome and expansion of immunosuppressive regulatory T cells. In this abstract, we demonstrate that NL-201, alone or in combination, demonstrates robust antitumor activity in preclinical models of non-Hodgkin lymphoma (NHL). We have previously demonstrated that NL-201 has marked antitumor activity in multiple syngeneic tumor models, including the A20 lymphoma model. These observations in lymphoma have been extended to explore the effects of NL-201 in combination with anti-mPD-1 checkpoint inhibitor therapy in vivo. In this model, NL-201 and anti-mPD-1 demonstrated tumor growth inhibition and increased median survival (21 days each vs 17 days as observed in control) when given alone. In combination, NL-201 and anti-mPD-1 resulted in increased antitumor activity and significant prolongation of survival (>51 days). We have also demonstrated that NL-201 does not directly induce signaling or cell death in B cell−derived NHL, suggesting that the observed antitumor activity is due to activation of non-malignant host immune cells. Additional in vitro and in vivo NHL models are being tested to enhance understanding of the interaction between NL-201 and other approved therapies within the hematopoietic tumor microenvironment. These data will be used to design future clinical trials of NL-201 in novel regimens to treat hematological malignancies. Disclosures Huard: Neoleukin Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Patents & Royalties. Tatalick: Neoleukin Therapeutics, Inc.: Consultancy, Current equity holder in publicly-traded company, Other: Independent paid nonclinical consultant for Neoleukin. Walkey: Neoleukin Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Swanson: Neoleukin Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties.

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