tosedostat (CHR-2797) / SOBI - LARVOL DELTA

Outcome of Intensively Treated Elderly AML Patients Reported to the Harmony Alliance Compares Well to Outcome of Control Patients of the Prospective Randomized HOVON 103 Study in Elderly AML (ASH 2023) - " The H103 trial consecutively randomized newly diagnosed AML patients aged >65 years between standard induction chemotherapy with or without lenalidomide, tosedostat, or selinexor. External control patients concerned newly diagnosed (HARMONY: 2010-2018; NCR: 2014-2018) and intensively treated (intensified cytarabine/anthracycline) elderly AML patients aged >60 years... Characteristics of H103-controls and HARMONY patients appeared largely comparable, while NCR patients were more frequently ELN 2022 non-favorable risk. Following matching, OS was similar between H103-controls and HARMONY patients, while NCR patients showed inferior OS. The inclusion of a large proportion of trial patients in the HARMONY cohort, adhering to strict inclusion and exclusion criteria and fewer comorbidities compared to RWD patients, might explain these observations."

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

The expression signature, prognostic significance and immune cell infiltration of the OAS gene family in gastric cancer. (PubMed, Sci Rep) - "Drug prediction and molecular docking identified chlorendic acid, idarubicin, PHA-848,125, and tosedostat as potential activators of the OAS family due to their strong binding affinity. Conversely, GW842166, NSC 23,766, and metolazone showed high binding affinity for OASL and may inhibit its expression. In summary, The OAS gene family, associated with poor prognosis in gastric cancer, promotes tumour progression and represents a promising therapeutic target."

Journal • Gastric Cancer • Oncology • Solid Tumor • ACTA2 • IL17A • OASL • SFRP4

Aminopeptidase N: a multifunctional and promising target in medicinal chemistry. (PubMed, RSC Adv) - "Some of them, such as bestatin or tosedostat, have already been tested as therapeutics with partial success. This article aims to bring an overview of multiple APN functions and implications for various diseases and their inhibitors which have already been prepared, and to suggest areas where the development of inhibitors may be promising in the future."

Journal • Review • Dermatitis • Infectious Disease • Inflammation • Novel Coronavirus Disease • Oncology

8265134: Crossover Trial of the Effect of a High-Fat Meal on the PK of Oral CHR 2797 in Healthy Male Subjects (clinicaltrials.gov) - P1 | N=18 | Completed | Sponsor: CTI BioPharma | Unknown status ➔ Completed

Trial completion

REAL-WORLD DATA AS SUPPLEMENTARY CONTROLS FOR THE PROSPECTIVE RANDOMIZED HOVON-103 TRIAL IN INTENSIVELY TREATED ELDERLY ACUTE MYELOID LEUKEMIA PATIENTS (EHA 2023) - " The H103 randomized 679 patients between standard first-line intensive chemotherapy with or without selinexor, tosedostat, or lenalidomide, in 3 consecutive randomizations. Selected NCR-patients were comparable with H103-controls for most patient characteristics present in both databases. However, a significantly lower OS was observed for NCR-patients. The lack of recorded performance status and absence of comorbidity and toxicity scores in NCR-patients might explain these differences."

Clinical • Real-world • Real-world evidence • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Targeting NPEPPS overcomes cisplatin resistance in patient-derived bladder cancer tumoroids (AACR 2023) - "We confirm that NPEPPS is associated with cisplatin-resistance in an ex vivo MIBC tumoroid model. These findings have potential for rapid translation into the clinic and invite trials investigating tosedostat to overcome chemoresistance."

Clinical • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • CASP3 • CASP7

Prediction of Early Mortality with Non-Intensive Acute Myeloid Leukemia (AML) Therapies: Analysis of 1336 Patients from MRC/NCRI and SWOG (ASH 2021) - "Treatments included: Low dose Ara-C (LDAC) alone, sapacitabine alone and LDAC in combination with vosaroxin, tosedostat or ganetespib (MRC/NCRI); Azacytidine (AZA) alone, tipifarnib alone, and AZA in combination with mylotarg, midostaurin, and nivolumab (SWOG). Our ability to predict early death in older patients treated with lower intensity AML therapies is limited with routinely available clinical variables. Inclusion of cytogenetic risk, FLT3-ITD, and NPM1 mutation status minimally improved the prognostic accuracy as did some of the QLQ-C30 subscales. Our data highlight the difficulties in predicting outcomes with non-intensive AML therapy with routinely available baseline clinical information."

Clinical • Acute Myelogenous Leukemia • Anorexia • Fatigue • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • FLT3 • NPM1

A phase I/II study combining tosedostat with capecitabine in patients with metastatic pancreatic ductal adenocarcinoma (PDAC). (ASCO-GI 2017) - P1/2; "A fluorouracil-based regimen is recommended for patients who progress on a gemcitabine-based therapy. The combination of tosedostat and capecitabine is a well-tolerated regimen with impressive clinical activity in the subset of patients studied thus far."

Clinical • P1/2 data • Biliary Cancer • Biosimilar • Gastrointestinal Cancer • Oncology • Pancreatic Cancer

Review: Aminopeptidases in Cancer, Biology and Prospects for Pharmacological Intervention. (PubMed, Curr Cancer Drug Targets) - "While there are agents that directly target aminopeptidases which demonstrate potential as cancer therapies, such as bestatin and tosedostat, more selective and more targeted therapeutic approaches are needed. This article specifically looks at the biological role of aminopeptidases in both normal and cancer processes, and their potential as a biological target for future therapeutic strategies."

Journal • Review • Immunology • Oncology

A randomised evaluation of low-dose cytosine arabinoside (ara-C) plus tosedostat versus low-dose ara-C in older patients with acute myeloid leukaemia: results of the LI-1 trial. (PubMed, Br J Haematol) - "Despite promising pre-clinical, early non-randomised clinical data with acceptable toxicity and an improvement in response, we did not find evidence that the addition of tosedostat to LDAC produced a survival benefit in this group of patients with AML. International Standard Randomised Controlled Trial Number: ISRCTN40571019."

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

Inferior Outcome of Addition of the Aminopeptidase Inhibitor Tosedostat to Standard Intensive Treatment for Elderly Patients with AML and High Risk MDS. (PubMed, Cancers (Basel)) - "In the second cycle, patients received cytarabine 1000 mg/m twice daily on days 1-6 with or without tosedostat. Atrial fibrillation was more common in the tosedostat arm as well. The results of the present study show that the addition of tosedostat to standard chemotherapy does negatively affect the therapeutic outcome of elderly AML patients."

Clinical • Journal • Acute Myelogenous Leukemia • Atrial Fibrillation • Cardiovascular • Myelodysplastic Syndrome

Gene expression profile predicts response to the combination of tosedostat and low-dose cytarabine in elderly AML. (PubMed, Blood Adv) - P1 | "Finally, a negative predictive value of 100% was validated in an independent series, thus representing the first molecular predictor for clinical response to a specific combination drug treatment for AML. This trial has been registered at the European Medicines Agency and on the European Clinical Trials Database (https://www.clinicaltrialsregister.eu) as #2012-000334-19."

Clinical • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • PCR

Phase II study of the clinical efficacy and safety of tosedostat in patients with myelodysplastic syndromes (MDS) after failure of hypomethylating agent-based therapy. (PubMed, Leuk Lymphoma) - No abstract available

Clinical • Journal • P2 data • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

Discovery of anticancer clinical candidate, tosedostat, as an analgesic agent. (PubMed, ACS Chem Neurosci) - "Additionally, when given in combination with morphine, tosedostat exerts a synergistic analgesic effect resulting in a reduction of effective dosages required to achieve the same analgesic effect. With broad implications in addressing the opioid addiction crisis, these revelations attest to tosedostat being a highly valuable drug candidate with diverse pharmacological functions."

Clinical • Journal • Addiction (Opioid and Alcohol) • CNS Disorders • Oncology • Pain

[VIRTUAL] AMINOPEPTIDASE EXPRESSION IN MULTIPLE MYELOMA ASSOCIATES WITH DISEASE PROGRESSION AND SENSITIVITY TO MELFLUFEN (EHA 2020) - "Melflufen ex vivo response was detected in 77% (10/13), melphalan in 58% (7/12), bortezomib in 55% (6/11), selinexor in 64% (7/11) and 4-hydroperoxycyclophosphamide in 0% (0/6) of tested samples...Both, tosedostat and bestatin, decreased the viability of cell lines in a dose dependent manner and reduced their sensitivity towards melflufen. Conclusion Multiple aminopeptidases were found to be differentially expressed in MM samples and associated with disease progression and reduced survival. Very good ex vivo sensitivity for melflufen was observed in samples from RRMM patients."

Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation

Tosedostat in Combination With Cytarabine or Decitabine in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome (clinicaltrials.gov) - P2; N=34; Completed; Sponsor: Fred Hutchinson Cancer Research Center; Suspended -> Completed

Trial completion • Acute Myelogenous Leukemia • Biosimilar • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Tosedostat: Anticipated expiry of US and various foreign directed patents from 2017 to 2018 (CTI BioPharma) - Annual Report 2016

Anticipated patent expiry • Hematological Malignancies

Tosedostat and Cytarabine or Azacitidine in Treating Older Participants With Acute Myeloid Leukemia or High Risk Myelodysplastic Syndrome (clinicaltrials.gov) - P1/2; N=18; Terminated; Sponsor: M.D. Anderson Cancer Center; N=96 ➔ 18; Completed ➔ Terminated; In 2013 the FDA put a temporary hold on the trial and the Phase II portion of this study was cancelled.

Clinical • Enrollment change • Trial termination • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Phase Ib/II study combining tosedostat with capecitabine in patients with advanced pancreatic adenocarcinoma. (PubMed, J Gastrointest Oncol) - "Tosedostat with capecitabine displayed tolerable toxicity, and prolonged disease control in a subset of patients. These data encourage further exploration of aminopeptidase inhibitors in pancreatic cancer."

Clinical • Journal • P1/2 data

Tosedostat and Cytarabine or Azacitidine in Treating Older Participants With Acute Myeloid Leukemia or High Risk Myelodysplastic Syndrome (clinicaltrials.gov) - P1/2; N=96; Completed; Sponsor: M.D. Anderson Cancer Center; Active, not recruiting ➔ Completed; Trial completion date: Nov 2019 ➔ Jul 2019; Trial primary completion date: Nov 2019 ➔ Jul 2019

Clinical • Trial completion • Trial completion date • Trial primary completion date