imaradenant (AZD4635) / AstraZeneca, Nxera Pharma - LARVOL DELTA

Chirality-Guided Optimization of A2A Adenosine Receptor Antagonists for Enhanced Metabolic Stability and Antitumor Efficacy. (PubMed, J Med Chem) - "This approach led to the discovery of (S)-E8, a chiral compound with markedly improved binding affinity, cellular activity, and in vivo potency compared with AZD4635, a Phase II clinical candidate...Mechanistic studies identified CYP1A2 as the primary enzyme driving the metabolic differences among the enantiomers. These findings underscore the value of chirality-guided design in optimizing drug-like properties and reveal CYP1A2's pivotal role in enantioselective metabolism, offering a promising direction for the development of next-generation A2AAR antagonists."

Journal • Oncology • CYP1A2

Oleclumab (MEDI9447) Epidermal Growth Factor Receptor Mutant (EGFRm) Non-small Cell Lung Cancer (NSCLC) Novel Combination Study (clinicaltrials.gov) - P1/2 | N=43 | Active, not recruiting | Sponsor: MedImmune LLC | Trial completion date: Jul 2025 ➔ Mar 2026

Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Interaction of Purine and its Derivatives with A1, A2-Adenosine Receptors and Vascular Endothelial Growth Factor Receptor-1 (Vegf-R1) as a Therapeutic Alternative to Treat Cancer. (PubMed, Drug Res (Stuttg)) - "Besides, adenosine, cgs-15943, rolofylline, cvt-124, wrc-0571, luf-5834, cvt-6883, AZD-4635, cabozantinib, pazopanib, regorafenib, and sorafenib drugs were used as controls...Besides, the inhibition constants (Ki) values for purine and their derivatives 5: , 9: , 10: , 14: , 15: , 16: , and 20: were lower compared with the controls Theoretical data suggest that purine and their derivatives 5: , 9: , 10: , 14: , 15: , 16: , and 20: could produce changes in cancer cell growth through inhibition of A1, A2-adenosine receptors and VEGFR-1 inhibition. These data indicate that these purine derivatives could be a therapeutic alternative to treat some types of cancer."

Journal • Oncology • FLT1 • VEGFA

A phase II study (AARDVARC) of AZD4635 in combination with durvalumab and cabazitaxel in patients with progressive, metastatic, castration-resistant prostate cancer. (PubMed, ESMO Open) - "Although the safety profile of both combinations was consistent with known safety data of the individual agents, the results of this trial do not support further development of the combinations."

Combination therapy • Journal • Metastases • P2 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Hematological Disorders • Metastatic Castration-Resistant Prostate Cancer • Neutropenia • Oncology • Prostate Cancer • Solid Tumor

Oleclumab (MEDI9447) Epidermal Growth Factor Receptor Mutant (EGFRm) Non-small Cell Lung Cancer (NSCLC) Novel Combination Study (clinicaltrials.gov) - P1/2 | N=43 | Active, not recruiting | Sponsor: MedImmune LLC | Trial completion date: Jan 2025 ➔ Jul 2025

Combination therapy • Metastases • Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

A phase 2 study of AZD4635 in combination with durvalumab or oleclumab in patients with metastatic castration-resistant prostate cancer. (PubMed, Cancer Immunol Immunother) - P2 | "In this heavily pretreated population, AZD4635 with durvalumab or oleclumab demonstrated minimal antitumor activity with a manageable safety profile."

Combination therapy • Journal • Metastases • P2 data • Fatigue • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

Oleclumab (MEDI9447) Epidermal Growth Factor Receptor Mutant (EGFRm) Non-small Cell Lung Cancer (NSCLC) Novel Combination Study (clinicaltrials.gov) - P1/2 | N=43 | Active, not recruiting | Sponsor: MedImmune LLC | Phase classification: P1b/2 ➔ P1/2 | Trial completion date: Sep 2024 ➔ Jan 2025

Combination therapy • Metastases • Phase classification • Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Safety and pharmacokinetics of imaradenant (AZD4635) in Japanese patients with advanced solid malignancies: a phase I, open-label study. (PubMed, Cancer Chemother Pharmacol) - P1 | "No new or unexpected safety concerns were identified, and imaradenant had an acceptable safety profile at both 50- and 75-mg QD."

Journal • Metastases • PK/PD data • Oncology • Solid Tumor • ADORA2A

A adenosine receptor agonists, antagonists, inverse agonists and partial agonists. (PubMed, Int Rev Neurobiol) - "However, only one selective AAR agonist (regadenoson, Lexiscan) and one selective AAR antagonist (istradefylline, Nouriast) have been approved by the FDA, as a pharmacological agent for myocardial perfusion imaging (MPI) and as a cotherapy for Parkinson's disease (PD), respectively...For example, imaradenant (AZD4635), a compound that was designed computationally, based on AAR X-ray structures and biophysical mapping. Mixed AAR/AAR antagonists are also hopeful for cancer treatment. AAR antagonists may also have potential as neuroprotective agents for treatment of Alzheimer's disease."

Journal • Alzheimer's Disease • CNS Disorders • Movement Disorders • Oncology • Parkinson's Disease

Oleclumab (MEDI9447) Epidermal Growth Factor Receptor Mutant (EGFRm) Non-small Cell Lung Cancer (NSCLC) Novel Combination Study (clinicaltrials.gov) - P1b/2 | N=43 | Active, not recruiting | Sponsor: MedImmune LLC | Trial completion date: Jan 2024 ➔ Sep 2024

Combination therapy • Metastases • Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

An Open-label, Phase II Study of AZD4635 in Patients With Prostate Cancer (clinicaltrials.gov) - P2 | N=59 | Completed | Sponsor: AstraZeneca | Active, not recruiting ➔ Completed | Trial completion date: Dec 2023 ➔ Apr 2023

Trial completion • Trial completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Phase 2 study (AARDVARC) of AZD4635 in combination with durvalumab and cabazitaxel in patients (pts) with progressive metastatic castrate-resistant prostate cancer (mCRPC). (ASCO-GU 2023) - P2 | "Background: Pts with mCRPC who progress on docetaxel and new hormonal agents (NHAs) have few therapeutic options. Although efficacy data are immature, enrollment was stopped for futility. Safety of the combination was consistent with the known safety profiles of the individual agents. Clinical trial information: NCT04089553."

Clinical • Combination therapy • Metastases • P2 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

A Phase 1 Clinical Study of AZD4635 in Patients With Advanced Solid Malignancies (clinicaltrials.gov) - P1 | N=313 | Completed | Sponsor: AstraZeneca | Active, not recruiting ➔ Completed | Trial completion date: Dec 2022 ➔ Mar 2023

Metastases • Monotherapy • Trial completion • Trial completion date • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Prostate Cancer • Solid Tumor • ALK • EGFR

Targeting tumor infiltrating myeloid cells in prostate cancer (AACR 2023) - "Treatments with the A2aR inhibitor AZD4635 alone and in combination with CD73 antibody blockade reduced adenosinergic genes as well as genes associated with TAN/MDSC immunosuppressive functions. Additionally, tumors from treated mice exhibited improved T cell mediated cytotoxicity. Together, our findings indicate that tumor associated myeloid cells are an additional source of ecADO contributing to immune suppression which can be targeted with A2aR and CD73 inhibitors."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ITGAM • PTEN • TP53

Optimizing breast cancer therapy by inhibiting the adenosine receptor and oxygen consumption (AACR 2023) - "In addition, we propose that blocking tumor oxygen consumption using deferiprone (DFP), phenformin (Phen) and metformin (Met) will further enhance A2aR and PD-1/PD-L1 blockade efficacy. Both 4T1-HRE and E0771-HRE demonstrated increased luciferase activity that correlated with increasing doses of CoCl2 in vitro. Future experiments will focus on characterizing the adenosine pathway in vivo in 4T1-HRE and E0771-HRE tumors and examine how drugs that target the adenosine A2AaR receptor (AZD4635), and oxygen consumption (DFP, Phen and Met) influence tumor oxygen consumption in vivo as well as the activation states of immune cells in the tumor microenvironment."

IO biomarker • Breast Cancer • Melanoma • Oncology • Solid Tumor • CD4 • CD8 • GZMB • HIF1A • IL2RA

A synergistic antitumor effect of PLAG with aPD-1 by modulating the adenosine signaling pathway in ICI low-sensitivity CRC model (AACR 2023) - "Our findings show that PLAG inhibits tumor growth by suppressing massive adenosine production, which may increase the antitumor efficacy of aPD-1 through improved CTLs infiltration. We propose that PLAG could be a novel therapeutic strategy for patients with ICI-resistant tumors."

Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Comprehensive clinical pharmacology characterization of AZD4635 in healthy participants to support dosing considerations. (PubMed, Br J Clin Pharmacol) - "The high-fat meal reduced the rate but not the extent of AZD4635 absorption. Effect of gastric pH on AZD4635 was minimal. Smoking had no effect on the exposure (C and AUC ) of AZD4635, while fluvoxamine increased AZD4635 C and total exposure. No new safety concerns were identified."

Journal • Oncology • Pain • CYP1A2

Oleclumab (MEDI9447) Epidermal Growth Factor Receptor Mutant (EGFRm) Non-small Cell Lung Cancer (NSCLC) Novel Combination Study (clinicaltrials.gov) - P1b/2 | N=43 | Active, not recruiting | Sponsor: MedImmune LLC | Trial completion date: Dec 2022 ➔ Jan 2024

Combination therapy • Metastases • Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Phase 1b/2 Study to Evaluate Novel Combinations With Oleclumab (MEDI9447) in Previously Treated Advanced EGFRm NSCLC (IASLC-WCLC 2018) - P1b/2; "In Part 1, the safety and tolerability of oleclumab in combination with either osimertinib (Arm A) or AZD4635 (Arm B) will be evaluated, and a recommended phase 2 dose for each combination will be identified. The study is open for enrollment and recruitment is ongoing, with a planned enrollment of up to approximately 98 patients. Result Section not applicable Conclusion Section not applicable "

P1/2 data • Non Small Cell Lung Cancer

Evidence of immune activation in the first-in-human Phase Ia dose escalation study of the adenosine 2a receptor antagonist, AZD4635, in patients with advanced solid tumors (AACR 2019) - P1; "This multicenter Phase I clinical trial (NCT02740985) assessed the safety, PK, pharmacodynamic, and preliminary clinical activity of AZD4635 as monotherapy (125mg BID, 75mg QD, 100mg QD) and in combination (75 or 100mg QD) with durvalumab @ 1.5g IV q4 wk in subjects with refractory solid tumors. As in preclinical studies, evaluation of gene expression revealed post-treatment increases in antigen presentation as well as evidence of both innate and adaptive immune activity. Durable responses were seen in patients with mCRPC, Further evaluation is ongoing in both immune checkpoint naïve and refractory patients."

Clinical • P1 data • PD(L)-1 Biomarker

An Open-label, Phase II Study of AZD4635 in Patients With Prostate Cancer (clinicaltrials.gov) - P2 | N=59 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Dec 2022 ➔ Dec 2023

Trial completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Phase II study of AZD4635 in combination with durvalumab or oleclumab in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) (ESMO 2022) - P2 | "Safety profiles of the treatment combinations were manageable and consistent with the known profiles of the individual agents. Exploring alternative dosing in less heavily treated pts may be beneficial."

Clinical • Combination therapy • IO biomarker • P2 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Phase Ia/b, Open-Label, Multicenter Study of AZD4635 (an Adenosine A2A Receptor Antagonist) as Monotherapy or Combined with Durvalumab, in Patients with Solid Tumors (Clin Cancer Res) - P1a/b | N=313 | NCT02740985 | Sponsor: AstraZeneca | "As of September 8, 2020, 250 patients were treated (AZD4635, n = 161; AZD4635+durvalumab, n = 89). In phase Ia, DLTs were observed with monotherapy (125 mg twice daily; n = 2) and with combination treatment (75 mg; n = 1) in patients receiving nanosuspension. The most common treatment-related adverse events included nausea, fatigue, vomiting, decreased appetite, dizziness, and diarrhea....In patients with mCRPC receiving monotherapy or combination treatment, tumor responses (2/39 and 6/37, respectively) and prostate-specific antigen responses (3/60 and 10/45, respectively) were observed. High versus low blood-based adenosine signature was associated with median progression-free survival of 21 weeks versus 8.7 weeks."

P1 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

AZD4635 Plus Durvalumab or Oleclumab Has Minimal Clinical Activity in mCRPC (OncLive) - P2 | N=59 | NCT04089553 | Sponsor: AstraZeneca | "The phase 2 trial aimed to further investigate AZD4635 in combination with durvalumab or oleclumab in this population....Additional data showed the median rPFS was 2.3 months (95% CI, 1.6-3.8) in module 1 and 1.5 months (95% CI, 1.3-4.0) in module 2. The median OS was 10.7 months (95% CI, 7.2–not evaluable [NE]) in module 1 and not yet reached (95% CI, 10.6 months-NE) in module 2....Among all patients, those with low adenosine signaling signature achieved a median PFS of 13.9 weeks (95% CI, 6.7-17.6) compared with 9.9 weeks (95% CI, 5.6-13.6) in those with a high signature (HR, 1.5; 95% CI, 0.8-2.8)."

P2 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

AARDVARC: A Study of AZD4635 With Durvalumab and With Cabazitaxel and Durvalumab in Patients With mCRPC. (clinicaltrials.gov) - P2 | N=30 | Completed | Sponsor: AstraZeneca | Active, not recruiting ➔ Completed

Combination therapy • Trial completion • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor