iniparib (BSI 201) / Sanofi - LARVOL DELTA

Restricted mean survival time based on Wu-Kolassa estimator compared to Kaplan-Meier estimator. (PubMed, Contemp Clin Trials) - "The Wu-Kolassa estimator is superior to the Kaplan-Meier estimator as it reduces the estimation bias and increases the power in the RMST analysis when the censoring rate is high or when the reference group has more censoring data than the test group."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Affinity Chromatographic Method for Determining Drug-Protein Interaction with Enhanced Speed Than Typical Frontal Analysis. (PubMed, Langmuir) - "The method involved synthesis of a stationary phase by immobilizing poly(ADP-ribose) polymerase-1 (PARP) onto macroporous silica gel through a one-step bioorthogonal reaction, characterization of mutual displacement interaction of two canonical drugs to the immobilized PARP, determination of the interaction between three (iniparib, rucaparib, and olaparib) drugs and the protein, and validation of these parameters by typical frontal analysis. The method was high speed since it allowed simultaneous determination of binding parameters between two drugs and a protein with a smaller number of experiments to be performed. Such a feature made the method an attractive alternative for high-speed analysis of drug-protein interaction or the other bindings in a binary system."

Journal • Breast Cancer • Oncology • Solid Tumor • PARP1

"The zany history of Parps. Lynparza: ex Kudos, bought by $AZN ($210m) in 2006. Rubraca: Agouron -> WL -> $PFE -> $CLVS -> ? Talzenna: Lead -> $BMRN ($18m) -> $MDVN ($410m) -> $PFE Zejula: $TSRO -> $GSK iniparib: Bipar -> $SNY, then found not to be a Parp" (@JacobPlieth)

PARP1

"Yes I think iniparib really shook up the whole PARP therapy space." (@gvansant1)

Spatial mapping of the immune microenvironment in primary triple-negative breast cancer (TNBC) and association with neoadjuvant therapy response (SABCS 2018) - P2; "We previously assessed both stromal TILs (sTILs) and intraepithelial TILs (iTILs) from pre-treatment tumor samples from patients enrolled on a phase II study of neoadjuvant gemcitabine, carboplatin and iniparib (PrECOG 0105; NCT00813956). Spatial mapping of the immune microenvironment in primary TNBC reveals distinct immune cell populations associated with response to neoadjuvant platinum-based therapy. "

BRCA Biomarker • Clinical • IO biomarker • PARP Biomarker • PD(L)-1 Biomarker • Tumor mutational burden • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Phase II Trials of Iniparib (BSI-201) in Combination with Gemcitabine and Carboplatin in Patients with Recurrent Ovarian Cancer. (PubMed, Oncologist) - P2 | "Given the subsequent lack of efficacy demonstrated for iniparib in breast cancer, these are studies of GC and demonstrate a higher than traditionally appreciated activity in patients with platinum-sensitive and -resistant recurrent ovarian cancer, especially in patients that harbor a BRCA mutation, resetting the benchmark for efficacy in phase II trials. (ClinicalTrials.gov Identifiers: NCT01033292 & NCT01033123)."

Combination therapy • Journal • P2 data • Breast Cancer • Fallopian Tube Cancer • Hematological Disorders • Neutropenia • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • Thrombocytopenia • BRCA • MUC16

Differential effects of poly(ADP ribose) polymerase inhibitor-based metronomic therapy on programmed death-ligand 1 and matrix-associated factors in human myeloid cells. (PubMed, Am J Transl Res) - "We recently showed that while partial poly(ADP-ribose) polymerase (PARP)-1 inhibition with a low metronomic sub-half-maximal inhibitory concentration/dose (IC50) of olaparib provides superior protection against colon cancer in mice compared to complete inhibition by blocking the suppressive function of myeloid-derived suppressor cells (MDSCs) and synergizing with anti-program cell death (PD)-1-based immunotherapy...A sub-IC50 concentration of other clinically used PARPi (rucaparib, niraparib, and talazoparib) as well as the failed PARPi, iniparib, exerted similar effects...Thus, PARPi-based metronomic therapy may promote functional changes in myeloid cells that provide an additional rationale for combining it with immunotherapy. Our results also provide new opportunities for iniparib in cancer therapy."

IO biomarker • Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • MMP2 • MMP9 • PD-L1 • TIMP2

Crystal structures of the catalytic domain of human PARP15 in complex with small molecule inhibitors. (PubMed, Biochem Biophys Res Commun) - "Here, we solved high-resolution crystal structures of the human PARP15 catalytic domain in complex with three marketed drugs of PARP inhibitors, which includes compounds 3-AB, iniparib and niraparib. The structures reported here contribute to our understanding of the ligand binding modes and structural features in the PARP15 catalytic domain, which can be employed to guide the rational design of selective inhibitors of PARPs."

Journal • Oncology

Targeting Acetyl-CoA carboxylase in pre-clinical breast cancer models (SABCS 2021) - " We performed in vitro cytotoxicity assays in 15 breast cancer cell lines and in normal mammary epithelial HMEC cells, examined effect on apoptosis and cell cycle progression, and tested for synergy with alpelisib, docetaxel, doxorubicin, everolimus, iniparib, neratinib and TEPP46 (PKM2 and PKLR activator). The small molecule ACC inhibitor, PF05175157, has significant single agent in vitro and in vivo growth inhibitory effect on a range of breast cancer cell lines at concentrations that can be achieved in human serum. It showed synergy with iniparib and another metabolic inhibitor (TEPP46). Targeting de novo fatty acid synthesis by inhibiting ACC is a promising therapeutic strategy."

Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Fooled by randomness. The misleading effect of treatment crossover in randomized trials of therapies with marginal treatment benefit. (PubMed, Cancer Invest) - "Crossover can bias clinical outcomes of randomized clinical trials by increasing the risk of both type I (false positive) and type II (false negative) error.To show how crossover can increase type I error, we provide computer simulation and review herein illustrative examples (iniparib, olaratumab) of recently reported RCTs that demonstrated false positive treatment efficacy signals due to crossover.The ethic issues associated to crossover are also discussed."

Clinical • Journal

Biodegradable Oxygen-producing Manganese-chelated Metal Organic Frameworks for Tumor-targeted Synergistic Chemo/photothermal/ photodynamic Therapy. (PubMed, Acta Biomater) - "Herein, to overcome tumor-associated hypoxia, and further achieve tumor-targeted synergistic chemotherapy/PDT/photothermal therapy (PTT), we have constructed a biodegradable oxygen-producing nanoplatform (named Ini@PM-HP), which was composed of the porous metal-organic framework (PCN-224(Mn)), the poly (ADP-ribose) polymerase (PARP) inhibitor (Iniparib), and the polydopamine-modified hyaluronic acid (HA-PDA)...STATEMENT OF SIGNIFICANCE: A delicately designed biodegradable oxygen-producing nanoplatform Ini@PM-HP is constructed to achieve combination therapy of solid tumors. Taking advantage of the active-targeting, PTT, enhanced PDT and PARPi, this nanotherapeutic approach successfully enables the combined chemo/photothermal/photodynamic therapy with great inhibition of solid tumors."

Journal • Oncology • Solid Tumor • CD44

TriAct Therapeutics Announces Iniparib Granted Orphan Drug Designation by the FDA for Treatment of Malignant Glioma (PRNewswire) - "TriAct Therapeutics, a private, late clinical stage oncology therapeutics company, today announced that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation (ODD) to its lead drug, iniparib, for the treatment of patients with malignant gliomas. The FDA noted that the designation granted is broader than the glioblastoma indication proposed in the Company's request and that treatment of glioblastoma is within the scope of this orphan drug designation."

Orphan drug • Brain Cancer • CNS Tumor • Glioma • Oncology

"#TriActTherapeutics Announces #Iniparib Granted #OrphanDrugDesignation by the #FDA for Treatment of #MalignantGlioma https://t.co/h5Lq37RRdU" (@1stOncology)

Orphan drug • Brain Cancer • Glioma • Oncology • Solid Tumor

The Impact of Platinum-Containing Chemotherapies in Advanced Triple-Negative Breast Cancer: Meta-Analytical Approach to Evaluating Its Efficacy and Safety. (PubMed, Oncol Res Treat) - "Platinum-containing chemotherapy remains a highly recommended therapeutic regimen due to greater effectiveness and tolerance for patients with advanced TNBC."

Clinical • Breast Cancer • Gastrointestinal Disorder • Oncology • Solid Tumor • Triple Negative Breast Cancer

SOLTI NEOPARP: Two Regimens of SAR240550/Weekly Paclitaxel and Paclitaxel Alone as Neoadjuvant Therapy in Triple Negative Breast Cancer Patients (clinicaltrials.gov) - P2; N=141; Active, not recruiting; Sponsor: Sanofi; Recruiting ➔ Active, not recruiting

Clinical • Combination therapy • Enrollment closed • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PGR

SOLTI NEOPARP: Two Regimens of SAR240550/Weekly Paclitaxel and Paclitaxel Alone as Neoadjuvant Therapy in Triple Negative Breast Cancer Patients (clinicaltrials.gov) - P2; N=141; Completed; Sponsor: Sanofi; Active, not recruiting ➔ Completed

Clinical • Combination therapy • Trial completion • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PGR

CRISPR/Cas9-mediated mutagenesis at microhomologous regions of human mitochondrial genome. (PubMed, Sci China Life Sci) - "InDel mutagenesis was significantly improved by sgRNA multiplexing and a DSB repair inhibitor, iniparib, demonstrating the evidence of rewiring DSB repair status to manipulate mtDNA using CRISPR/Cas9. These findings would provide novel insights into mtDNA mutagenesis and mitochondrial gene therapy for diseases involving pathogenic mtDNA."

Journal • Gene Therapies

Construction and optimization of gene expression signatures for prediction of survival in two-arm clinical trials. (PubMed, BMC Bioinformatics) - "The tools presented here should be of general use for building and using predictive multivariate signatures in oncology and in other therapeutic areas."

Clinical • Journal • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Mutations of BRCA2 in canine mammary tumors and their targeting potential in clinical therapy. (PubMed, BMC Vet Res) - "Early investigations show tolerability of iniparib in dogs...Mutations in the canine BRCA2 gene have the potential to be exploited in clinical therapy through the usage of PARP inhibitors. However, further investigations are needed before introducing PARP inhibitors in veterinary clinical practice."

Clinical • Journal • Review • Breast Cancer • Oncology • Solid Tumor

[Poster coverage] Combined neoadjuvant iniparib and carboplatin in locally advanced or metastatic canine mammary tumors (MT) to support human clinical studies (SABCS-2013) - Abstract #P2-05-08; “Treated and control groups shared similar features concerning animal breeds, age, neutering status and tumor location. 75% of the treated MT were malignant. Necrosis and apoptosis were significantly increased in respectively 63 and 56% of iniparib treated tumors.”

Preclinical • Breast Cancer • Oncology

ADP ribose polymerase inhibitors for treating non-small cell lung cancer: new additions to the pharmacotherapeutic armamentarium. (PubMed, Expert Opin Pharmacother) - "In fact, the activity of these drugs would not be based only on direct cytotoxic action, but also on the modification of the intra-tumor microenvironment, in particular by increasing the expression of PD-L1 on tumor cells. This action might potentially enhance available treatments with a modest increase in toxicity."

IO Biomarker • Journal • Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Thoracic Cancer

Tumor immune microenvironment and genomic evolution in a patient with metastatic triple negative breast cancer and a complete response to atezolizumab. (PubMed, J Immunother Cancer) - P1 | "This case report describes the evolution of TiME and TNBC molecular subtypes/genomics over time with sequential therapies in a TNBC patient with a CR to atezolizumab monotherapy. These data suggest the TiME is pliable and may be manipulated to maximize response to immunotherapy (NCT01375842, https://clinicaltrials.gov/ct2/show/NCT01375842?term=NCT01375842&rank=1 )."

Biomarker • Clinical • IO Biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Triple-negative breast cancer: New perspectives for novel therapies (Med Oncol) - PMID: 23824643; "In recent years, a greater understanding of the biology of this disease has led to the development of numerous and varied therapeutic approaches, especially the trials on poly (ADP-ribose) polymerase inhibitors BSI-201 and olaparib, and antiangiogenic agents such as bevacizumab and sunitinib, which have raised hopes in the treatment for TNBC and BRCA1/2-positive disease."

Review • Biosimilar • Breast Cancer • Oncology

Multi-omic profiling to predict response to gemcitabine/ carboplatin (GC) plus iniparib (BSI-201) as neoadjuvant therapy for triple-negative (TN) and BRCA1/2 mutation-associated breast cancer using a pathway-based approach (AACR 2014) - Presentation time: Monday, Apr 07, 2014, 1:00 PM - 5:00 PM; Abstract #2826; P2, N=75; "Overall, a low RCB (0,1) was observed in 43 (58%) patients and a high RCB (2,3) in 31 (42%) patients. Pathway-based analysis of these breast tumors revealed significant alterations in 459 of 1466 (31%) of the cancer-related pathways. Gene set enrichment analysis on the PARADIGM results identified differentially expressed pathways in tumors with RCB 0 (65 pathways at p<0.05) versus RCB 3 (37 pathways at p<0.05)."

P2 data • Breast Cancer

Randomized phase III trial of gemcitabine (G)/carboplatin (C) with or without iniparib (I) in patients (Pts) with previously untreated stage IV squamous lung cancer (WCLC 2013) - Presentation time: Tuesday, October 29, 10:30 AM - 12:00 PM; Abstract #: O15.06; P3, N=780; NCT01082549; "The median OS for GC/GCI was 8.9 v. 8.9 months, HR 1.08 (0.92-1.28), p=.348. 1-year OS was 41 v. 40%. The median progression-free survival (PFS) for GC vs GCI was 4.9 v. 4.8 months, HR 0.99 (0.83-1.19), p=.92. The objective response rate (ORR) for GC v GCI was 34 v. 32%, p=.648. The safety profile was similar in both arms...."

P3 data: top line • Non Small Cell Lung Cancer