Asparec (PEGylated recombinant Erwinia chrysantemi-derived L-asparaginase) / Jazz - LARVOL DELTA

Calaspargase-Pegol-Mknl Combined with BCL-2 and MCL-1 Inhibition for Acute Myeloid Leukemia. (PubMed, Int J Mol Sci) - "Our previous studies have demonstrated that pegcrisantaspase (PegC), a long-acting Erwinia asparaginase, synergizes with the BCL-2 inhibitor Venetoclax (Ven) in vitro and in vivo; however, the anti-leukemic activity of E. coli-derived asparaginases in combination with BCL-2 inhibition, and potential synergy with inhibitors of MCL-1, a key resistance factor of BCL-2 inhibition, has yet to be determined. Using a combination of human AML cells lines, primary samples, and in vivo xenograft mouse models, we established the anti-leukemic activity of the BCL-2 inhibitor S55746 and the MCL-1 inhibitor S63845, alone and in combination with the long-acting E. coli asparaginase calaspargase pegol-mknl (CalPegA)...The S55746-CalPegA combination inhibited protein synthesis and increased eIF4E/4EBP1 interaction, suggesting an inhibition of translational complex formation. These results support the clinical evaluation of CalPegA in combination with BCL-2 inhibition for AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • EIF4E • EIF4EBP1

Fludarabine, Cytarabine, and Pegcrisantaspase for the Treament of Relapsed or Refractory Leukemia (clinicaltrials.gov) - P1 | N=19 | Terminated | Sponsor: M.D. Anderson Cancer Center | Active, not recruiting ➔ Terminated; Administratively Complete

Trial termination • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • Prolymphocytic Leukemia • T Acute Lymphoblastic Leukemia

AALL1821: A Study to Compare Blinatumomab Alone to Blinatumomab With Nivolumab in Patients Diagnosed With First Relapse B-Cell Acute Lymphoblastic Leukemia (B-ALL) (clinicaltrials.gov) - P2 | N=300 | Suspended | Sponsor: National Cancer Institute (NCI) | N=550 ➔ 300

Checkpoint inhibition • Combination therapy • Enrollment change • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Developmental Disorders • Genetic Disorders • Hematological Malignancies • Leukemia • Oncology • CD19

A phase 1 study of the amino acid modulator pegcrisantaspase and venetoclax for relapsed/refractory acute myeloid leukemia. (PubMed, Blood) - P1 | "Response correlated with alterations in proteins involved in mRNA translation. In patients with RUNX1 mutations, the composite complete rate was 100%."

IO biomarker • Journal • P1 data • Acute Myelogenous Leukemia • Cardiovascular • Fatigue • Hematological Disorders • Hematological Malignancies • Hepatology • Leukemia • Oncology • Pancreatitis • RUNX1

Pegcrisantaspase (PegC) Induces an Increase in Plasma Threonine in Patients With Acute Myeloid Leukemia (AML) (SOHO 2024) - "We recently conducted a phase 1 clinical trial with a novel regimen combining venetoclax and a long-acting Erwinia-derived asparaginase/glutaminase PegC in relapsed/refractory AML. A significant increase in threonine after PegC treatment was observed. The increase in threonine may represent a compensatory change due to glutamine depletion through glutamine transporter SLC1A5 that also exports threonine from the intracellular compartment into the plasma. Keywords: AML (acute myeloid leukemia), PegC, glutamine depletion, amino acid metabolism, metabolic targeting, phase 1"

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • SLC1A5

Long-acting Erwinia chrysanthemi, Pegcrisantaspase, induces alternate amino acid biosynthetic pathways in a preclinical model of pancreatic ductal adenocarcinoma. (PubMed, Cancer Metab) - "Taken together, our results demonstrate the potential therapeutic use of PegC in PDAC and highlight the importance of identifying candidates for combination regimens that could improve cytotoxicity and/or reduce the induction of resistance pathways."

Journal • Preclinical • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Fludarabine, Cytarabine, and Pegcrisantaspase for the Treament of Relapsed or Refractory Leukemia (clinicaltrials.gov) - P1 | N=19 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Recruiting ➔ Active, not recruiting | N=62 ➔ 19

Enrollment change • Enrollment closed • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • Prolymphocytic Leukemia • T Acute Lymphoblastic Leukemia

Long-Acting E. coli-Derived Asparaginase Potentiates the Anti-Leukemic Effect of BCL2 Inhibition, but Not MCL1 Inhibition, in Preclinical Models of Acute Myeloid Leukemia (ASH 2023) - "Our previous studies have shown that pegcrisantaspase (PegC), a long-acting pegylated crisantaspase, synergizes with the BCL2 inhibitor, Venetoclax (Ven), to kill several AML cell lines and patient-derived primary AML cells with complex karyotype in vitro and in vivo in a xenograft mouse model... Using a panel of 4 human AML cell lines (MOLM14, MV411, MonoMac6, HL60) as well as primary AML patient samples, weestablished the anti-leukemic activity of the BCL2 inhibitor S55746 and the MCL1 inhibitor S63845 alone and in combination with the long-acting E. coli asparaginase, calaspargase pegol-mknl (CalPegA)... We report that the E. coli asparaginase, CalPegA, enhances the anti-leukemic effect of the BCL2 inhibitor, S55746, but does not impact the activity of the MCL1 inhibitor, S63845, in AML cell lines, patient derived primary AML samples, and in an AML xenograft mouse model. Ongoing studies are further investigating the anti-leukemic mechanism of S55476/S63845 + CalPegA..."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • EIF4E • EIF4EBP1

Overcoming Venetoclax (Ven) Resistance through Glutamine (Gln) Depletion: Final Analysis of the Phase 1 Trial of Ven and Pegcrisantaspase (PegC) Combination in Relapsed and Refractory (R/R) Acute Myeloid Leukemia (AML) (ASH 2023) - P1 | "We reported in vitro and in vivo depletion of Gln induced by long-acting Erwinia asparaginase, PegC, inhibited proliferation of complex karyotype (CK) AML and synergistically enhanced the antiapoptotic activity of Ven-mediated antagonism of Bcl-2 by decreasing the expression of proteins such as Mcl-1, whose translation is cap-dependent...Pt 31 (post-alloHSCT relapsed AML with FLT3-ITD) who had persistent disease after gilteritinib achieved an MRD-negative CRi, pending 2nd alloHSCT... VenPegC is a novel regimen that can induce complete remission in some heavily pretreated R/R AML patients, even with previous exposure to Ven. Pts with RUNX1 mutation, whose translation depends on pheIF4E, may benefit further from this regimen."

IO biomarker • P1 data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Dyslipidemia • Hematological Disorders • Hematological Malignancies • Hepatology • Hypertriglyceridemia • Leukemia • Oncology • Pancreatitis • Transplantation • BCL2 • CSF3R • EIF4E • EIF4EBP1 • FLT3 • MCL1 • NRAS • PTPN11 • RUNX1 • TP53

Jazz Pharmaceuticals to Present New Data Highlighting Advancements in Solid Tumors and Rare Blood Cancers at Upcoming Oncology Meetings (PRNewswire) - "Jazz Pharmaceuticals plc...today announced that the Company and its partners will present two abstracts at the 2023 San Antonio Breast Cancer Symposium (SABCS) from December 5-9; 11 abstracts at the 65th Annual American Society of Hematology (ASH) Annual Meeting from December 9-12; and two abstracts at the International Association for the Study of Lung Cancer (IASLC) 2023 North America Conference on Lung Cancer (NACLC) from December 1-3. New data include updated findings from a Phase 2a trial of the investigational HER2-targeted bispecific antibody zanidatamab in combination with palbociclib and fulvestrant as a chemotherapy-free option for HER2+/ HR+ metastatic breast cancer (mBC)....'Additionally, we look forward to sharing new data through numerous presentations at ASH 2023 that underscore our commitment to improving standards of care in blood cancer and other hematologic diseases, as well as real-world findings at NACLC that provide evidence of Zepzelca's..."

Clinical data • Late-breaking abstract • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Breast Cancer • Chronic Myelomonocytic Leukemia • Hematological Disorders • Hematological Malignancies • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Leukemia • Lung Cancer • Lymphoma • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology • Small Cell Lung Cancer • Solid Tumor

Fludarabine, Cytarabine (ARA-C) and Pegylated Erwinase (PEGCRISANTASPASE) in Patients with Relapsed or Refractory Leukemia (ASH 2023) - "In this high-risk, heavily treated population, the combination of fludarabine, cytarabine, and PegC is feasible. Responding patients included 2 AML and 1 ALL. Further exploratory analysis about the relation between response and asparagine depletion as well as specific sensitive subsets could clarify which patients might benefit the most from this combination."

Clinical • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Febrile Neutropenia • Hematological Malignancies • Infectious Disease • Leukemia • Oncology • Sarcoma • Septic Shock • Solid Tumor • ASNS

PEGylation versus glycosylation: effect on the thermodynamics and thermostability of crisantaspase. (PubMed, Prep Biochem Biotechnol) - "The activation energy of denaturation of PEG-crisantaspase (307.1 kJ mol) was higher than for crisantaspase (218.1 kJ mol) and Glyco-crisantaspase (120.0 kJ mol), which means that more energy is required to overcome the energy barrier of the unfolding process. According to our results, PEG-crisantaspase is more thermostable than its native form, while Glyco-crisantaspase is more thermosensitive."

Journal

Pegcrisantaspase in Combination With Venetoclax for Treatment of Relapsed or Refractory Acute Myeloid Leukemia (R/R AML) (clinicaltrials.gov) - P1 | N=27 | Active, not recruiting | Sponsor: University of Maryland, Baltimore | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • IDH1 • TP53

Fludarabine, Cytarabine, and Pegcrisantaspase for the Treament of Relapsed or Refractory Leukemia (clinicaltrials.gov) - P1 | N=62 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Dec 2022 ➔ Dec 2024 | Trial primary completion date: Dec 2022 ➔ Dec 2024

Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • Prolymphocytic Leukemia • T Acute Lymphoblastic Leukemia

Phase 1 Dose Escalation Trial of Pegcrisantaspase in Combination with Venetoclax in Adults with Relapsed or Refractory Acute Myeloid Leukemia (ASH 2022) - P1 | "Ven-PegC is a well-tolerated regimen with a novel metabolically-targeted mechanism of action. Early efficacy results in patients with poor prognosis R/R AML, a population with very limited treatment options, has been very promising. A clear correlation between the dose of PegC administered and the reduction in plasma Gln was observed."

Clinical • Combination therapy • IO biomarker • P1 data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Dyslipidemia • Hematological Disorders • Hematological Malignancies • Hypertriglyceridemia • Leukemia • Oncology • EIF4EBP1 • TP53

Comprehensive Plasma Amino Acid Analysis Following Administration of Short- and Long-Acting Erwinia Asparaginase (Crisantaspase) Demonstrated Significant Increase in Plasma Serine and Glycine Levels (ASH 2022) - P1 | "Mouse plasma samples were from studies that included treatment with pegcrisantaspase (PegC), a long-acting Erwinia-derived asparaginase, in both immunodeficient and immunocompetent mice. We report a comprehensive evaluation of plasma AA alterations in both mice and humans treated with crisantaspase. We observed a reproducible crisantaspase-induced increase in plasma Ser and Gly, which we are currently exploiting for synergism with other AML treatment modalities."

Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Erwinia asparaginase (crisantaspase) increases plasma levels of serine and glycine. (PubMed, Front Oncol) - P1 | "To the best of our knowledge, we are the first to report comprehensive plasma amino acid changes in mice and humans treated with asparaginase. As dysregulated serine metabolism has been implicated in tumor development, our findings offer insights into how leukemia/cancer cells may potentially overcome glutamine/asparagine restriction, which can be used to design future synergistic therapeutic approaches."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

Pegcrisantaspase in Combination with Venetoclax for Treatment of Relapsed or Refractory Acute Myeloid Leukemia: A Phase 1 Study (ASH 2021) - P1 | "The study is currently open at the University of Maryland Greenebaum Comprehensive Cancer Center. ClinicalTrials.gov Identifier is NCT04666649."

Combination therapy • IO biomarker • P1 data • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Pancreatitis • EIF4E • FLT3 • IDH1 • TP53

PHASE 1 TRIAL OF PEGCRISANTASPASE IN COMBINATION WITH VENETOCLAX IN ADULTS WITH RELAPSED OR REFRACTORY ACUTE MYELOID LEUKEMIA (R/R AML) - SAFETY, EFFICACY AND PK/PD IN THE FIRST TWO COHORTS (EHA 2022) - P1 | "The Ven-PegC combination at the lowest dose of PegC administered, produced an MRD negative CRh in one patient and a transient substantial reduction in bone marrow blast count in another, both associated with decreases in plasma Gln levels. The study is ongoing."

Clinical • Combination therapy • P1 data • PK/PD data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Septic Shock • Transplantation • EIF4E • EIF4EBP1

Pegcrisantaspase in Combination With Venetoclax for Treatment of Relapsed or Refractory Acute Myeloid Leukemia (R/R AML) (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: University of Maryland, Baltimore | Trial completion date: Jul 2023 ➔ Sep 2025 | Trial primary completion date: Apr 2023 ➔ Sep 2024

Combination therapy • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • IDH1 • TP53

Translatome changes in acute myeloid leukemia cells post-exposure to pegcrisantaspase and venetoclax. (PubMed, Exp Hematol) - "We validated the observed changes in gene/protein expression in vitro and confirmed our cell line-based studies in the bone marrow of an AML PDX model after Ven-PegC treatment. These results support examining alterations in the translatome post-chemotherapy to offer insight into drug mechanism of action and to inform future therapeutic decisions."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • TRIB3

Fludarabine, Cytarabine, and Pegcrisantaspase for the Treament of Relapsed or Refractory Leukemia (clinicaltrials.gov) - P1; N=62; Recruiting; Sponsor: M.D. Anderson Cancer Center; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • Prolymphocytic Leukemia • T Acute Lymphoblastic Leukemia

Pegcrisantaspase in Combination With Venetoclax for Treatment of Relapsed or Refractory Acute Myeloid Leukemia (R/R AML) (clinicaltrials.gov) - P1; N=30; Recruiting; Sponsor: University of Maryland, Baltimore; Not yet recruiting ➔ Recruiting; Trial completion date: Jul 2022 ➔ Jul 2023; Trial primary completion date: Apr 2022 ➔ Apr 2023

Combination therapy • Enrollment open • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • IDH1 • TP53

A Dose Confirmation and Pharmacokinetic Study of Pegcrisantaspase Administered as Intravenous (IV) Infusion in Children and Young Adults With Acute Lymphoblastic Leukemia (ALL) /Lymphoblastic Lymphoma (LBL). Following Hypersensitivity to Pegaspargase... (clinicaltrials.gov) - P2; N=4; Terminated; Sponsor: Jazz Pharmaceuticals; N=81 ➔ 4; Suspended ➔ Terminated

Enrollment change • Trial termination • Acute Lymphocytic Leukemia • Biosimilar • Hematological Malignancies • Leukemia • Oncology

Phase I Study of mPEG-R-Crisantaspase Given IV (clinicaltrials.gov) - P1; N=36; Completed; Sponsor: Jazz Pharmaceuticals; Recruiting -> Completed ; Trial primary completion date: Dec 2015 ->Feb 2015

Trial completion • Trial primary completion date • Biosimilar • Hematological Malignancies • Leukemia • Non-Hodgkin’s Lymphoma • Oncology