AVID100, an anti-EGFR-DM1 conjugate, showed potent activity in preclinical models
Patients with advanced or metastatic epithelial malignancies without available therapy and likely to express EGFR are being enrolled into sequential dose escalation cohorts (Phase 1a) to assess safety, tolerability, and PK parameters to identify the recommended Phase 2 dose (R2PD) of 1-hour infusions on an every 3 week schedule. In the Phase 2a segment preliminary antitumor activity will be assessed in expansion cohorts of patients with breast cancer (BC) and squamous cell carcinoma of the head and neck (SCCHN) with EGFR overexpression (3+ in ≥ 50% of tumor cells).
No cycle 1 dose limiting toxicities (DLTs) have been observed in Cohorts 1-6 (dose (N); 20 (1), 40 (1), 80 (3), 120 (3), 180 (3), and 220 (3) mg/m2 every 3 weeks). Currently, patients are being evaluated in Cohort 7 (270 mg/m2; approximately 6.9 mg/kg). Preliminary clinical PK results show exposure levels of AVID100 have been achieved that exceed therapeutic levels predicted from preclinical studies. Safety and tolerability have been acceptable with G2-3 lipase elevations without clinical sequelae, infusion-related reactions ameliorated by premedication and infusion prolongation, reversible thrombocytopenia, and reversible transaminase elevations without other evidence of hepatic toxicity. Other G1-2 treatment-related adverse events reported include: rash, nausea, vomiting, fatigue, headache, anorexia, mucositis, diarrhea, elevated amylase, elevated alkaline phosphatase, hypomagnesemia, and hypokalemia. Patients entered to the Phase 1a segment were not screened for EGFR overexpression and included patients with: colorectal cancer (9); breast cancer (2); and single cases of ovarian, pancreatic, urothelial, and cervical cancer. Prolonged disease stabilization has been observed in 3 of these unselected patients (colorectal, ovarian, cervical).
AVID100 is a well-tolerated anti-EGFR-DM1 conjugate with evidence for exposure levels at or above those observed for cetuximab and ado-trastuzumab emtansine. Antitumor activity will be evaluated in EGFR-overexpressing patients with BC and SCCHN.
NCT03094169
Formation Biologics
CPRIT
A. Tolcher: Former investigator for Formation Biologics and am currently a member of the Board of Directors of Formation Biologics. K. Papadopoulos: Investigator on a clinical study for Formation Biologics. Y. Cole, K. Rivas: Research nurse working on a clinical study for Formation Biologics. S. Chandana, N. Lakhani: Investigator on a study for Formation Biologics. S. Sinclair: Employee of Formation Biologics. D. Wood, P.I. Nadler: Medical consultant for Formation Biologics.
The number of cytotoxic payload classes with different modes-of-action which have been successfully employed in antibody-drug conjugates (ADC) is still rather limited. So far, ADCs with microtubule inhibitors, DNA binding payloads, or topoisomerase I inhibitors have been advanced into clinical testing. To this end, the identification of ADC payload classes with a novel mode of action will increase therapeutic options. The kinesin spindle protein (KSP/Eg5/KIF11) is an ATP-dependent motor protein involved in the separation of centrosomes in G2/M phase which is an essential event in mitosis. KSP inhibitors (KSPi) have generated interest due to their high antitumor activity in preclinical models. However, transferring the preclinical potency of small molecule KSP inhibitors (SMOL KSPis) into highly efficient clinical regimens with a sufficient therapeutic window has remained challenging. Targeted delivery of payloads selectively to tumor cells while sparing normal cells may enlarge the therapeutic window of KSPis.
We have investigated a new pyrrole subclass of KSPis. The KSP inhibitor was profiled on a large panel of 370 cancer cell lines and showed sub-nM potency against cell lines originating from different cancer indications. ADCs were generated through the conjugation of the KSPi to antibodies targeting different cancer antigens and characterized
KSPi-ADCs showed strong and specific internalization and displayed specific and potent anti-proliferative activity
Bayer AG
A. Sommer: Stock shareholder of Bayer AG. My husband is employed by Boehringer Ingelheim.
Has not received any funding
Targeted alpha therapy (TAT) involves selective delivery of isotopes that emit highly energetic alpha particles to cancer cells leading to their ultimate destruction, while minimizing collateral damage to healthy surrounding cells. The high linear energy transfer of alpha particles makes it possible to consider targets with relatively low cellular expression levels (or concentration) and to treat hypoxic and chemotherapy resistant tumors. The limited emission of beta and gamma radiation from the appropriate alpha emitting isotopes significantly reduces the complexities of administration and decreases the chance of exposure to caregivers and family members. Despite the potential, clinical development of targeted alpha therapeutics has been slow due to a variety factors that will be discussed.
Radium-223 dichloride, the only approved alpha therapy in clinical medicine, provides the proof of concept for internal alpha emitting radioisotope therapy in cancer treatment. 223RaCl2 is “targeted” via its fundamental physicochemical properties as it incorporates into the bone matrix at sites of bone formation. The interest in TAT is based partly on the clinical usefulness of 223RaCl2 in castration resistant prostate cancer. However, 223RaCl2 is only suitable for treating bone metastases, so new targeted therapies that aim to treat liquid and solid soft tissue tumors are now under clinical development. The clinical experience to date with TAT will be reviewed focusing on the status, advantages and disadvantages of different radioisotope payloads (213Bi, 225Ac, 211At, 212Pb and 227Th), targets (CD33, CD20, CD22, PSMA, HER2, somatostatin receptor and others), and targeting agents (small molecules, peptide and antibodies) that have been employed to date.
The momentum in the TAT field is illustrated by a growing number of promising TAT compounds that are in or near starting clinical trials. The current status of these TAT molecules (225Ac-PSMA-617, 212Pb-AR-RMX, 225Ac-lintuzumab, FPX-01, 211At-BC8-B10, BAY1862864) will be discussed with particular attention to those agents that use 225Ac (t½ 10 days) and 227Th (t½ 18.7 days) as the therapeutic payload. The half-life of these two alpha emitting isotopes permits manufacturing and delivery of ready-to-use doses to patients. Biodistribution and dosimetry may require the use of a separate imaging radioimmunoconjugate when alpha isotopes with limited gamma emission are used.
The potential role of TAT in hematological malignancies and in solid tumor treatment will also be discussed along with systemic and local administrations strategies, both of which may prove to have clinical utility in coming years.
Fusion Pharmaceuticals
Fusion Pharmaceuticals
I. Molnar, E. Burak, J. Valliant: Employee and stockholder of Fusion Pharmaceuticals Inc. E. Burak, J. Valliant: Employee and stockholder of Fusion Pharmaceuticals. J. Forbes, R. Simms: Employee of Fusion Pharmaceuticals.
Antibody drug conjugates (ADCs) can offer significant benefit to patients suffering from a variety of solid and liquid tumors by combining the specificity of monoclonal antibodies and the cellular cytotoxicity of antineoplastic small molecules. While ADCs have tremendous potential, dose-limiting toxicity remains the largest barrier to robust patient responses. Through the utilization of proprietary protease cleavable N-acyl sulfonamide (NAcS) linked hemiasterlin and auristatin payloads, we have generated highly efficacious ADCs with improved therapeutic indices. Antibody drug conjugates (ADCs) can offer significant benefit to patients suffering from a variety of solid and liquid tumors by combining the specificity of monoclonal antibodies and the cellular cytotoxicity of antineoplastic small molecules. While ADCs have tremendous potential, dose-limiting toxicity remains the largest barrier to robust patient responses. Through the utilization of proprietary protease cleavable N-acyl sulfonamide (NAcS) linked hemiasterlin and auristatin payloads, we have generated highly efficacious ADCs with improved therapeutic indices.
Antibodies against HER2 and three additional known clinical targets were conjugated with our
NAcS-ADCs demonstrated similar
The increase in tolerability and comparable efficacy of the NAcS-ADCs
Zymeworks Inc.
Zymeworks Inc.
J. Babcook, R. Davies, S. Barnscher, J. Rich, K. Yin, V. Fung, G. Winters, G. Garnett, P. Kaminker, K. Hamblett: Employee of Zymeworks Inc. and have a financial interest in the company in the form of stock or stock-options.