BNC105 / Bionomics - LARVOL DELTA

Effect of the ex situ physical and in situ chemical modification of bacterial nanocellulose on mechanical properties in the context of its potential applications in heart valve design. (PubMed, Int J Biol Macromol) - "The study presents the results of various analyses, including tensile tests, nanoindentation tests, X-ray diffraction (XRD) tests, scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR) and Raman spectroscopy, conducted on BNC chemically modified in situ with hyaluronic acid (BNC/HA) and physically modified ex situ through a dehydration/rehydration process (BNC 25DR, BNC105DR, BNC FDR and BNC/HA 25DR, BNC/HA 105DR, BNC/HA FDR)...Results show the effect of the crystalline structure of BNC on its mechanical properties. There is correlation between hardness and Young's modulus and Iα/Iβ index for BNC/HA and between creep rate of BNC/HA, and Young's modulus for BNC vs Iα/Iβ index."

Journal • Cardiovascular

Discovery, synthesis, activities, structure-activity relationships, and clinical development of combretastatins and analogs as anticancer drugs. A comprehensive review. (PubMed, Nat Prod Rep) - "These antimitotic agents inhibited tubulin polymerization by reversibly binding to the colchicine binding sites...Medicinal chemistry efforts led to the identification of three new leads (AVE8062, BNC105P, SCB01A) with improved in vitro and in vivo potency and an often-improved cellular spectrum...Clinical trials with tumor genetic mapping, particularly from previous responders, may help boost the success of these compounds in future studies. A comprehensive review of combretastatin series A-D, including bioassay guided discovery, total syntheses, and structure-activity relationship (SAR) studies, biological and mechanistic studies, and preclinical and clinical evaluations of the isolated combretastatins and analogs, along with the personal perspective of the author who originated this project, is presented."

Journal • Review • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma

A Study of BNC105P Combined With Ibrutinib (clinicaltrials.gov) - P1 | N=6 | Completed | Sponsor: Dartmouth-Hitchcock Medical Center | Active, not recruiting ➔ Completed

Trial completion • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • CCND1 • CD19 • CD5 • FCER2

A phase I trial of BNC105P and ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia. (PubMed, EJHaem) - No abstract available

Journal • P1 data • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

[VIRTUAL] The AGITG Modulate study: Randomised phase II study testing manipulation of the tumour micro environment (TME) to enable synergy with PD1 inhibitors in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) (ESMO 2021) - "The Modulate study tested 2 strategies designed to alter the TME in MSS mCRC, thereby enabling synergy with PD1 inhibitors. Eligibility included MSS mCRC, measurable disease, failure of standard prior therapies including oxaliplatin, fluoropyrimidine, irinotecan, bevacizumab and an EGFR inhibitor (if ras/raf wild type), adequate organ function, PS0-1 and informed consent. Eligible patients were randomised to arm A (nivolumab 240mg q2w plus the vascular disrupting agent BNC105 16mg/m2 d1,8 q3w) or arm B (nivolumab 240mg q2w plus the STAT3 inhibitor napabucasin 240mg bd po)... Although neither treatment achieved the anticipated RR, it was well tolerated and anti-tumour activity was demonstrated in both arms with encouraging OS for arm A. Ongoing translational evaluation will examine the impact of the interventions on the TME."

Clinical • P2 data • Tumor microenvironment • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

A Study of BNC105P Combined With Ibrutinib (clinicaltrials.gov) - P1 | N=6 | Active, not recruiting | Sponsor: Dartmouth-Hitchcock Medical Center | Trial completion date: Jun 2022 ➔ Jan 2023

Trial completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • CCND1 • CD19 • CD5 • FCER2

BNC105P in Combination With Everolimus/Following Everolimus For Progressive Metastatic Clear Cell Renal Cell Carcinoma (clinicaltrials.gov) - P1/2 | N=154 | Completed | Sponsor: Hoosier Cancer Research Network | Active, not recruiting ➔ Completed | Phase classification: P2 ➔ P1/2

Phase classification • Trial completion • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

A Study of BNC105P Combined With Ibrutinib (clinicaltrials.gov) - P1 | N=6 | Active, not recruiting | Sponsor: Dartmouth-Hitchcock Medical Center | Trial completion date: Dec 2021 ➔ Jun 2022 | Trial primary completion date: Dec 2021 ➔ Jun 2022

Trial completion date • Trial primary completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • CCND1 • CD19 • CD5 • FCER2

MODULATE: Modulation Of The Tumour Microenvironment Using Either Vascular Disrupting Agents or STAT3 Inhibition in Order to Synergise With PD1 Inhibition in Microsatellite Stable, Refractory Colorectal Cancer (clinicaltrials.gov) - P2; N=90; Completed; Sponsor: Australasian Gastro-Intestinal Trials Group; Active, not recruiting ➔ Completed; Trial completion date: Aug 2022 ➔ Apr 2021; Trial primary completion date: Aug 2022 ➔ Jan 2021

Trial completion • Trial completion date • Trial primary completion date • Tumor microenvironment • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Gene expression signature correlates with outcomes in metastatic renal cell carcinoma patients treated with everolimus alone or with a vascular disrupting agent. (PubMed, Mol Cancer Ther) - "Among 43 patients (52.4%) with low expression of an 18-gene signature, everolimus+BNC105P was associated with significantly longer mPFS compared to everolimus alone (10.4 vs 6.9 months, HR 0.49, 95%CI=0.24-1.002, p=0.047). These signatures warrant further validation to select patients who may benefit from everolimus alone or with a VDA."

Biomarker • Clinical • Journal • Genito-urinary Cancer • Immune Modulation • Inflammation • Oncology • Renal Cell Carcinoma • Solid Tumor • ASXL1 • DUSP6 • ERCC2

A Study of BNC105P Combined With Ibrutinib (clinicaltrials.gov) - P1; N=6; Active, not recruiting; Sponsor: Dartmouth-Hitchcock Medical Center; Recruiting ➔ Active, not recruiting; N=15 ➔ 6; Trial primary completion date: Mar 2021 ➔ Dec 2021

Clinical • Enrollment change • Enrollment closed • Trial primary completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • CCND1 • CD19 • CD5

BNC105P Combination Study in Partially Platinum Sensitive Ovarian Cancer Patients (clinicaltrials.gov) - P1/2; N=134; Recruiting; Sponsor: Hoosier Oncology Group; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Oncology • Ovarian Cancer • Solid Tumor

BNC105P Combination Study in Partially Platinum Sensitive Ovarian Cancer Patients (clinicaltrials.gov) - P1/2; N=134; Recruiting; Sponsor: Hoosier Oncology Group

Clinical • New P1/2 trial • Oncology • Ovarian Cancer • Solid Tumor

BNC105P Combination Study in Partially Platinum Sensitive Ovarian Cancer Patients (clinicaltrials.gov) - P1/2; N=134; Recruiting; Sponsor: Hoosier Oncology Group; Initiation date: Jul 2012 ➔ Oct 2012

Clinical • Trial initiation date • Oncology • Ovarian Cancer • Solid Tumor

BNC105P Combination Study in Partially Platinum Sensitive Ovarian Cancer Patients (clinicaltrials.gov) - P1/2; N=134; Completed; Sponsor: Hoosier Cancer Research Network; Recruiting ➔ Completed

Clinical • Trial completion • Oncology • Ovarian Cancer • Solid Tumor

BNC105P Combination Study in Partially Platinum Sensitive Ovarian Cancer Patients (clinicaltrials.gov) - P1/2; N=0; Withdrawn; Sponsor: Hoosier Cancer Research Network; N=134 ➔ 0; Completed ➔ Withdrawn

Clinical • Enrollment change • Trial withdrawal • Oncology • Ovarian Cancer • Solid Tumor

MODULATE: Modulation Of The Tumour Microenvironment Using Either Vascular Disrupting Agents or STAT3 Inhibition in Order to Synergise With PD1 Inhibition in Microsatellite Stable, Refractory Colorectal Cancer (clinicaltrials.gov) - P2; N=90; Active, not recruiting; Sponsor: Australasian Gastro-Intestinal Trials Group; Recruiting ➔ Active, not recruiting

Enrollment closed • Tumor microenvironment • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Bionomics completes Phase 2 of MODULATE combination clinical trial for colorectal cancer (Proactiveinvestors) - “Bionomics Ltd…has completed the MODULATE clinical trial, an experimental phase 2 trial of its drug candidate BNC105 in combination with Bristol Myers Squibb’s (NYSE:BMY) nivolumab, in patients with metastatic colorectal cancer. The trial sponsor, the Australasian Gastro-Intestinal Trials Group (AGITG), is expecting that results will be ready in the second quarter of 2021, which is ahead of the previously announced timeline for topline data of early 2023.”

P2 data • Trial completion • Colorectal Cancer • Gastrointestinal Cancer • Oncology

The microtubule-disrupting drug BNC105 is a potent inducer of apoptosis in AML patient samples (AACR 2018) - "BNC105 targets the colchicine-binding site on tubulin, causing chronic disruption of adhesion molecules, and was developed to be best-in-class with high specificity to actively dividing cells. The LSC-containing population, measured by CD34/CD38 and GPR56 or CD93 staining, was targeted by BNC105 in all AML patient samples tested. These results suggest that AML cells can be directly targeted by BNC105 at clinically relevant concentrations and hence further clinical investigation of BNC105 is warranted for AML treatment in a patient population with high unmet need."

Clinical • IO Biomarker • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Indolent Lymphoma

A Study of BNC105P Combined With Ibrutinib (clinicaltrials.gov) - P1; N=15; Recruiting; Sponsor: Dartmouth-Hitchcock Medical Center; Trial completion date: Dec 2020 ➔ Dec 2021; Trial primary completion date: Sep 2020 ➔ Mar 2021

Clinical • Trial completion date • Trial primary completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • CD19

A Study of BNC105P Combined With Ibrutinib (clinicaltrials.gov) - P1; N=15; Recruiting; Sponsor: Dartmouth-Hitchcock Medical Center; Trial primary completion date: Feb 2020 ➔ Sep 2020

Clinical • Trial primary completion date • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2

Bionomics completes enrolment for BNC105 Phase II renal cancer trial (Bionomics) - P2, N=135; "Bionomics Limited has completed enrolment into a randomized Phase II clinical trial testing the combination of BNC105 plus everolimus (Afinitor) to treat patients with advanced renal cell carcinoma. ...This Phase II trial was conducted at sites across the US, Australia and Singapore and enrolled 135 patients with advanced metastatic renal cell carcinoma."

Enrollment closed • Oncology • Renal Cell Carcinoma

Phase I results of a phase I/II trial of BNC105P with everolimus in metastatic renal cell carcinoma (mRCC) patients previously treated with VEGFR tyrosine kinase inhibitors (ASCO 2012) - Presentation time: Sunday June 3, 8:00 AM to 12:00 PM; P1/2, N=12; Study ID HOG GU09-145; The MTD of BNC105P (16 mg/m2) can be combined with full dose everolimus; No DLTs (drug-related, during cycle 1) were observed in any of the P1 subjects; Toxicities on study deemed to be drug-related included single grade 3 events of anemia & pericardial effusion; 7/12 P1 subjects achieved at least disease stabilization with a minimum time on therapy of 18 weeks (6 cycles)

P1 data • Renal Cell Carcinoma

Association of baseline IL-8 and ferritin with clinical outcome with everolimus and BNC105P in the DisrupTOR-1 trial (ASCO-GU 2015) - Abstract #475; P2, N=139; DisrupTOR-1(NCT01034631); "Increases in matrix metalloproteinase-9 (MMP-9) and stem cell factor (SCF) were associated with improved PFS (p=0.0421 and p=0.0291, respectively). Decreases in sex hormone binding globulin (SHBG) and serum amyloid protein (SAP) were associated with improved PFS (p=0.0184 and p=0.0063). With respect to static biomarkers, elevated baseline ferritin and lower baseline IL-8 were associated with improved PFS (p=0.0291 and p=0.0149, respectively)."

Biomarker • P2 data • Oncology • Renal Cell Carcinoma

Phase I/II study of a BNC105P/everolimus regimen for progressive metastatic renal cell carcinoma (mRCC) following prior tyrosine kinase inhibitors (Hoosier Oncology Group) (2012 Genitourinary Cancers Symposium) - P1/2, N=12; BNC105P / everolimus combination was well tolerated & no DLTs were observed in any of the P1 pts; Drug-related toxicities included single events of Grade 2 anemia, thrombocytopenia & mucositis; Medium number of cycles is 3 (range: 1-14) & 3 pts have been administered >6 cycles of treatment; MTD of BNC105P (16 mg/m2) can be combined with full dose everolimus & is being evaluated in the randomized P2 study

P1 data • Oncology • Renal Cell Carcinoma