MEDI3726 / ADC Therapeutics, AstraZeneca - LARVOL DELTA

Recent advances in antibody-drug conjugates for metastatic castration-resistant prostate cancer. (PubMed, Zhejiang Da Xue Xue Bao Yi Xue Ban) - P3 | "Among prostate-specific membrane antigen (PSMA)-targeted ADCs, ARX517 demonstrates superior safety and more significant prostate-specific antigen (PSA) reductions compared to earlier agents such as MLN2704, PSMA-ADC, and MEDI3726. ADCs targeting B7-H3, such as MGC018 and DB-1311, have also shown antitumor activity. ADCs targeting other antigens, including six-transmembrane epithelial antigen of the prostate (STEAP)1 (DSTP3086S), trophoblast cell surface antigen (TROP)2 (sacituzumab govitecan), and solute carrier (SLC) 44A4 (ASG-5ME), have shown preliminary antitumor activity in early trials but face challenges with insufficient efficacy or toxicity. Tisotumab vedotin (targeting tissue factor) has shown no significant therapeutic response in mCRPC. Meanwhile, disitamab vedotin (HER2-targeted), ABBV-969 (dual PSMA/STEAP1-targeted), and DXC008 (dual PSMA/STEAP1-targeted) are currently under evaluation. Notably, the B7-H3-targeted ADC ifinatamab deruxtecan has initiated..."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • HER-2 • SLC44A4 • SLC4A4 • STEAP1

MEDI3726, a prostate-specific membrane antigen (PSMA)-targeted antibody-drug conjugate (ADC) in mCRPC after failure of abiraterone or enzalutamide. (ASCO-GU 2020) - P1; "An MTD was not identified, but drug-related AEs (skin toxicities and effusions) prevented raising the dose over 0.3 mg/kg and limited the number of cycles. Responses were seen at higher doses, but were not durable as pts discontinued due to drug-related AEs. Clinical trial information: NCT02991911."

Genito-urinary Cancer

MEDI3726, a prostate-specific membrane antigen (PSMA)-targeted antibody-drug conjugate (ADC) in mCRPC after failure of abiraterone or enzalutamide. (ASCO-GU 2020) - P1; "An MTD was not identified, but drug-related AEs (skin toxicities and effusions) prevented raising the dose over 0.3 mg/kg and limited the number of cycles. Responses were seen at higher doses, but were not durable as pts discontinued due to drug-related AEs. Clinical trial information: NCT02991911."

Genito-urinary Cancer

Advances in PSMA-targeted therapy for prostate cancer. (PubMed, Prostate Cancer Prostatic Dis) - "Currently, a great deal of evidence suggests that significant progresses have been made in the PSMA-targeted therapy of PCa. Herein, different PSMA-targeted therapies for PCa are reviewed, including radioligand therapy (Lu-PSMA-RLT, Ac-PSMA-RLT), antibody-drug conjugates (MLN2704, PSMA-MMAE, MEDI3726), cellular immunotherapy (CAR-T, CAR/NK-92, PSMA-targeted BiTE), photodynamic therapy, imaging-guided surgery (radionuclide-guided surgery, fluorescence-guided surgery, multimodal imaging-guided surgery), and ultrasound-mediated nanobubble destruction."

IO biomarker • Journal • Review • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Phase I trial of MEDI3726, a prostate-specific membrane antigen-targeted antibody-drug conjugate, in patients with mCRPC after failure of abiraterone or enzalutamide. (PubMed, Clin Cancer Res) - "Following dose escalation, no MTD was identified. Clinical responses occurred at higher doses, but were not durable as patients had to discontinue treatment due to TRAEs."

Clinical • Journal • P1 data • Genito-urinary Cancer • Hematological Disorders • Oncology • Prostate Cancer • Solid Tumor • Thrombocytopenia • CTCs

Multifaceted Bioanalytical Methods for the Comprehensive Pharmacokinetic and Catabolic Assessment of MEDI3726, an Anti-PSMA PBD Antibody-Drug Conjugate. (PubMed, Anal Chem) - P1 | "Therefore, both heavy-light chain dissociation and the deconjugation of the warhead will affect the activity of MEDI3726. The concentration-time profiles of subjects dosed with MEDI3726 revealed catabolism of the protein scaffold manifested by the more rapid clearance of the Active ADC, while exhibiting minimal deconjugation of the pyrrolobenzodiazepine (PBD) warhead (SG3199)."

Journal • PK/PD data

A Phase 1/1b Study of MEDI3726 in Adults Subjects With Metastatic Castration Resistant Prostate Cancer (clinicaltrials.gov) - P1; N=33; Completed; Sponsor: MedImmune LLC; Active, not recruiting ➔ Completed

Clinical • Trial completion

Antitumor Activity of MEDI3726 (ADCT-401), a Pyrrolobenzodiazepine Antibody-drug Conjugate Targeting PSMA, in Pre-clinical Models of Prostate Cancer. (PubMed, Mol Cancer Ther) - P1; "MEDI3726 (previously known as ADCT-401) is an ADC consisting of an engineered version of the anti-PSMA antibody J591 site specifically conjugated to the pyrrolobenzodiazepine (PBD) dimer tesirine. This activity correlated with increased phosphorylated Histone H2AX in tumor xenografts treated with MEDI3726. MEDI3726 is being evaluated in a Phase 1 clinical trial as a treatment for patients with metastatic castrate-resistant prostate cancer (NCT02991911)."

Journal • Preclinical

Product discontinued (AstraZeneca Press Release) - P1, Prostate Cancer

Discontinuation

"$AZN MEDI3726 (PSMA ADC licensed from ADC Therapeutics), previously suspended in phase I, now confirmed discontinued" (@JacobPlieth)

A Phase 1/1b Study of MEDI3726 in Adults Subjects With Metastatic Castration Resistant Prostate Cancer (clinicaltrials.gov) - P1; N=33; Active, not recruiting; Sponsor: MedImmune LLC; Recruiting ➔ Active, not recruiting; N=224 ➔ 33; Trial completion date: Jun 2021 ➔ Oct 2019; Trial primary completion date: Jun 2021 ➔ Oct 2019

Clinical • Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date

The role of drug transporters in the acquired resistance to PBD dimer-containing antibody drug conjugates (AACR 2019) - "These include ADCT-301, ADCT-402, MEDI3726 and rovalpituzumab tesirine (Rova-T) that contain the payload tesirine which releases the PBD dimer warhead SG3199. These data show that acquired resistance to both PBD-ADCs and SG3199 can involve specific drug transporters. This has clinical implications as potential biomarkers of resistance and for the rational design of drug combinations."

Preclinical