irofulven-1 (LP-100) / Lantern Pharma, Eisai, Allarity Therap - LARVOL DELTA

Targeting DNA repair vulnerabilities to eradicate TP53 mutated AML. (ASH 2025) - "Current treatment strategies, includingconventional chemotherapy, hypomethylating agents, and venetoclax-based therapies, have shown limitedefficacy in TP53mut AML, with low response rates and poor overall survival...XPC and DDB2 are the key proteins in the global genome NER (GG-NER).GG-NER removes bulky melphalan (a nitrogen mustard used in the management of multiple myeloma) DNAmonoadducts, but not irofulven-mediated DNA damage which is recognized by transcription-coupled NER (TC-NER)...We are currently testing the combination of melphalan and RAD51i in mice carrying TP53mut AML.We pinpointed the "Achilles heels" of DDR in TP53mut AMLs: stimulation of HRR and downregulation of GG-NER. These weaknesses were successfully targeted by the combination of RAD51i which attacks HRR andmelphalan which explores GG-NER deficiency."

Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Multiple Myeloma • BRCA2 • DDB2 • HRD • RAD51 • TP53 • XPC

Click-code-seq reveals strand biases of DNA oxidation and depurination in human genome. (PubMed, Nat Chem Biol) - "Notably, oxidized guanines and apurinic sites, both irofulven induced and endogenous, are depleted in gene transcribed strands, with the strand bias increasing with gene expression. This work substantially advances click-code-seq for deciphering the impacts of key modifications in human DNA on cellular physiology and toxicological responses."

Journal • CNS Disorders • Oncology

Glucose Deprivation-Induced Disulfidptosis via the SLC7A11-INF2 Axis: Pan-Cancer Prognostic Exploration and Therapeutic Validation. (PubMed, Adv Sci (Weinh)) - "Moreover, the DRG scores predict prognosis and therapeutic responses. The SLC7A11-INF2 axis regulates disulfidptosis, migration, and drug sensitivity, highlighting its potential as a marker of metabolic vulnerability in ovarian cancer."

IO biomarker • Journal • Pan tumor • Oncology • Ovarian Cancer • Solid Tumor • SLC7A11

Mapping the immune-genetic architecture of aging: A single-cell causal framework for biomarker discovery and therapeutic targeting. (PubMed, Ageing Res Rev) - "Our findings provide new insights into the immune-genetic architecture of aging and establish a scalable framework for identifying cell-type-specific causal genes and repurposable drug targets. This approach enhances precision medicine strategies aimed at promoting healthy aging and delaying age-related decline."

Biomarker • Journal • Review • FUBP1

Irofulven in AR-targeted and Docetaxel-Pretreated mCRPC Patients With Drug Response Predictor (DRP®) (clinicaltrials.gov) - P2 | N=15 | Completed | Sponsor: Allarity Therapeutics | Active, not recruiting ➔ Completed | N=27 ➔ 15

Enrollment change • Trial completion • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

A new TGF-β risk score predicts clinical and immune landscape in colorectal cancer patients. (PubMed, Ann Gastroenterol Surg) - "The feature gene TGFB2 could inhibit the efficacy of drugs such as XAV-939, Staurosporine, and Dasatinib, but promote the efficacy of drugs such as CUDC-305 and by-product of CUDC-305. Similarly, RBL1 could inhibit the drug action of Fluphenazine and Imiquimod but promote that of Irofulven. A CRC risk prognostic signature was developed on basis of TGF-β-related genes, which provides a reference for risk and further therapeutic selection of CRC patients."

IO biomarker • Journal • Tumor mutational burden • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • RBL1 • TGFB1 • TGFB2 • TMB

Irofulven in AR-targeted and Docetaxel-Pretreated mCRPC Patients With Drug Response Predictor (DRP®) (clinicaltrials.gov) - P2 | N=27 | Active, not recruiting | Sponsor: Allarity Therapeutics | Trial completion date: May 2024 ➔ Aug 2024

Metastases • Trial completion date • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

Safety, efficacy, pharmacokinetics, and pharmacodynamics of the illudofulvene drug CAP-0121. (ASCO 2024) - "Further investigation in clinical trials is warranted to confirm these preclinical observations."

Clinical • PK/PD data • Hematological Disorders • Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Thrombocytopenia

Nucleotide excision repair deficiency is a targetable therapeutic vulnerability in clear cell renal cell carcinoma. (PubMed, Sci Rep) - "Approximately 10% of ccRCC patients in the TCGA cohort showed mutational signatures consistent with ERCC2 inactivation associated NER deficiency and also substantial levels of PTGR1 expression. These patients may be responsive to irofulven, a previously abandoned anticancer agent that has minimal activity in NER-proficient cells."

Journal • Bladder Cancer • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • DRD • ERCC2 • PTGR1

Predicting Survival Signature of Bladder Cancer Related to Cancer-Associated Fibroblast (CAF) Constructed by Intersecting Genes in TCGA and GEO. (PubMed, Mol Biotechnol) - "Potential drugs targeted different CAF-related genes like vemurafenib, irofulven, ghiotepa, and idarubicin were found as well. We constructed a novel 9 CAF-related mRNAs prognostic model and explored the gene expression and potential functional information of related genes, which might be worthy of clinical application. In addition, potential chemotherapy drugs could provide useful insights into the potential clinical treatment of bladder cancer."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • GADD45B • KLF6 • STMN3

Tumor sensitization to PARP inhibitors by DNA damaging synthetically lethal acylfulvenes. (ASCO 2023) - "Similarly in a BRCA2 mutant prostate cancer cell line 22Rv1, LP-100 combination with rucaparib was synergistic (Bliss score 18)...Moreover, LP-184 treatment resulted in early onset and complete tumor regression in 7 PDX models of PARPi resistant triple negative breast cancers (TNBC) harboring BRCA1/2 loss whereas olaparib/ niraparib remained entirely ineffective in these... AF response is influenced by tumor DNA repair competence. LP-100 and LP-184 are synthetically lethal resulting from their abilities to cause unresolvable DNA damage where tumor cells express high PTGR1 and are deficient in the HR pathway. LP-184 single agent was superior to PARPi in TNBC and LP-100 combination made an olaparib resistant tumor highly sensitive, thereby facilitating a path to extend the opportunities for both AFs and PARPis and enhance the clinical utilization of PARPi."

Synthetic lethality • Breast Cancer • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Solid Tumor • Triple Negative Breast Cancer • BRCA1 • BRCA2 • HRD • PTGR1

Irofulven in AR-targeted and Docetaxel-Pretreated mCRPC Patients With Drug Response Predictor (DRP®) (clinicaltrials.gov) - P2 | N=27 | Active, not recruiting | Sponsor: Allarity Therapeutics | Trial completion date: May 2023 ➔ May 2024

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

Lantern Pharma to Host Virtual KOL Webinar on Synthetic Lethality, the Powerful Mechanism of Action Behind Several of Lantern’s Drug Candidates, Featuring Zoltan Szallasi, M.D. (Businesswire) - "Lantern Pharma Inc...today announced that it will host a virtual key opinion leader (KOL) webinar on March 21, 2023 at 12:00 p.m. ET focusing on synthetic lethality, the unique and powerful mechanism of action behind Lantern’s drug candidates LP-184, LP-284, and LP-100. The webinar will feature a leading expert on synthetic lethality in DNA damage repair (DDR) deficient tumors, Zoltan Szallasi, M.D., who serves joint appointments as group leader of the Translational Cancer Genomics Department at the Danish Cancer Society Research Center and as faculty of the Computational Health Informatics Program (CHIP) and Assistant Professor of Pediatrics at Boston Children's Hospital, which are affiliated with Harvard Medical School."

Preclinical • Bladder Cancer • Brain Cancer • Breast Cancer • CNS Tumor • Gastrointestinal Cancer • Genito-urinary Cancer • Glioblastoma • Glioma • Gynecologic Cancers • Hematological Malignancies • Lung Cancer • Lymphoma • Mantle Cell Lymphoma • Melanoma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Rhabdoid Tumor • Sarcoma • Skin Cancer • Soft Tissue Sarcoma • Solid Tumor • Thoracic Cancer • Triple Negative Breast Cancer

Lantern Pharma Announces New Data and Development Focus for LP-100 with PARP Inhibitors (Businesswire) - P2 | N=27 | NCT03643107 | Sponsor: Allarity Therapeutics | "LP-100 has previously been in a genomic signature guided Phase 2 clinical trial in Denmark where the drug candidate was used without PARP inhibitors for patients with metastatic castration-resistant prostate cancer (mCRPC). In this trial 9 patients (out of a targeted enrollment of 27) were treated and had a median overall survival (OS) of approximately 12.5 months, which is an improvement over other similar fourth-line treatment regimens for mCRPC."

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

Lantern Pharma Announces New Data and Development Focus for LP-100 with PARP Inhibitors (Businesswire) - "Lantern Pharma Inc...announced new data for its product candidate LP-100 supporting the development of LP-100 in combination with the class of anticancer agents known as PARP inhibitors (PARPi)....In prostate cancer mouse xenograft studies, LP-100 demonstrated synergistic potency when used in combination with the FDA-approved PARP inhibitor Olaparib. LP-100 also demonstrated synergy with the FDA-approved PARP inhibitors Olaparib, Rucaparib, and Niraparib in ovarian cancer cell line studies. The observations from these studies are further supported by in-silico evaluation of LP-100 in combination with PARP inhibitors using Lantern’s AI platform, RADR^®."

Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer

Irofulven in AR-targeted and Docetaxel-Pretreated mCRPC Patients With Drug Response Predictor (DRP®) (clinicaltrials.gov) - P2 | N=27 | Active, not recruiting | Sponsor: Allarity Therapeutics | Trial completion date: Sep 2022 ➔ May 2023

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

The mutational impact of Illudin S on human cells. (PubMed, DNA Repair (Amst)) - "Accordingly, ILS treatment led to the rapid recruitment of the Y-family DNA polymerase kappa onto chromatin, supporting its preferential use for ILS lesion bypass. Altogether, our work provides the first global assessment of the genomic impact of ILS, demonstrating the contribution of multiple DNA repair pathways to ILS resistance and mutagenicity."

Journal • ERCC2 • POLK

Irofulven in AR-targeted and Docetaxel-Pretreated mCRPC Patients With Drug Response Predictor (DRP®) (clinicaltrials.gov) - P2 | N=27 | Active, not recruiting | Sponsor: Allarity Therapeutics | Trial completion date: Mar 2022 ➔ Sep 2022

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

Optimization of the production process for the anticancer lead compound illudin M: process development in stirred tank bioreactors. (PubMed, Microb Cell Fact) - "By identifying and controlling key process parameters, the production process for illudin M was transferred from shake flasks into 2 L stirred tank bioreactors reaching a comparable titer (> 900 mg L), which is significantly higher than any previously reported. The insights obtained from 10 L scale pave the way towards further scale-up studies that will enable a sustainable supply of illudin M to support preclinical and clinical development programs."

Journal • Oncology

Optimization of the production process for the anticancer lead compound illudin M: improving titers in shake-flasks. (PubMed, Microb Cell Fact) - "After strict standardization of seed-preparation and cultivation parameters, a combination of experimental design, empirical trials and additional supply of limiting biosynthetic precursors, led to a highly reproducible process in shake flasks with high titers of illudin M. These findings are the base for further work towards a scalable biotechnological process for a stable illudin M supply."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Preclinical evaluation of CAP-0121 for multidrug resistant cancers (AACR 2022) - "This response of CAP-0121 in drug resistant xenografts is observed at nontoxic doses. Synergistic action is observed when CAP-0121 is administered in combination with traditional drugs used for treating ovarian cancer, including taxanes, platinum agents, and PARP inhibitors."

Preclinical • Hepatocellular Cancer • Oncology • Ovarian Cancer • Solid Tumor • ABCB1

Irofulven in AR-targeted and Docetaxel-Pretreated mCRPC Patients With Drug Response Predictor (DRP®) (clinicaltrials.gov) - P2 | N=27 | Active, not recruiting | Sponsor: Allarity Therapeutics | Trial completion date: Oct 2021 ➔ Mar 2022

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

Lantern Pharma Announces Collaboration & Research Agreement with The Danish Cancer Society Research Center to Support Clinical Development of Drug Candidates, LP-100 and LP-184, in Solid Tumors (PRNewswire) - "Lantern Pharma...announced a collaboration and research agreement with The Danish Cancer Society Research Center (DCRC) to support clinical development of Lantern's acylfulvene class drug candidates, LP-100 and LP-184, as well as the development of improved diagnostic methods to identify nucleotide excision repair (NER) deficient tumors....The research study conducted as part of the collaboration will use expanded mutational signature-based analyses to achieve this objective. The study will include a comprehensive analysis of breast, ovarian, prostate, lung, kidney, bladder, stomach, pancreatic and esophageal cancer."

Licensing / partnership • Bladder Cancer • Breast Cancer • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Gynecologic Cancers • Kidney Cancer • Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Solid Tumor • Urothelial Cancer

The Positive Enantiomer of a Novel Chiral DNA Alkylating Agent Exhibits Nanomolar Potency in Hematologic Cancers (ASH 2021) - "Here, we show that LP-284, the synthetic positive enantiomer of LP-184, exhibited the greatest and broadest hematologic cancer antiproliferative activities among the 6 acylfulvenes, including illudin S, illudin M, Irofulven (LP-100), the semisynthetic racemic LP-184, the synthetic negative enantiomer LP-184, and LP-284...We also investigated the therapeutic potential of LP-284 in combination with spironolactone in treating MM...We hypothesize that LP-284 induces DNA lesions, which may be lethal to TC-NER deficient cells and may block transcription of short-lived fusion genes that are essential for cancer cell survival until repaired. Therefore, our discovery of the novel enantiomer LP-284 may provide a targeted therapy option for hematologic cancers with compromised DNA repair."

Acute Lymphocytic Leukemia • Chronic Myeloid Leukemia • Hematological Disorders • Hematological Malignancies • Hypertension • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • ERCC3 (ERCC Excision Repair 3, TFIIH Core Complex Helicase Subunit) • PTGR1

Study of Irofulven in Combination With Oxaliplatin in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1/2; N=63; Completed; Sponsor: Eisai Inc.; Active, not recruiting ➔ Completed

Trial completion • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor