Background

AVID100, an anti-EGFR-DM1 conjugate, showed potent activity in preclinical models in vitro and in vivo including in cell lines resistant to approved anti-EGFR mAbs.

Methods

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).

Results

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).

Conclusions

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.

Clinical trial identification

NCT03094169

Legal entity responsible for the study

Formation Biologics

Funding

CPRIT

Disclosure

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.

Background

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.

Methods

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 in vitro and in vivo.

Results

KSPi-ADCs showed strong and specific internalization and displayed specific and potent anti-proliferative activity in vitro. The ADCs exhibited sub-nanomolar potency in antigen-positive cancer cell lines and more than 100-fold selectivity versus control-ADCs in cytotoxicity assays. Furthermore, selective anti-tumor efficacy of KSPi-ADCs was demonstrated in vivo using both cancer cell line-derived (CDX) as well as patient-derived (PDX) xenograft models. Specific accumulation of KSPi-ADC payload metabolites in the tumor versus other murine tissues was demonstrated in biodistribution studies.

Legal entity responsible for the study

Bayer AG

Funding

Has not received any funding

Disclosure

A. Sommer: Stock shareholder of Bayer AG. My husband is employed by Boehringer Ingelheim.

Background

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.

Legal entity responsible for the study

Fusion Pharmaceuticals

Funding

Fusion Pharmaceuticals

Disclosure

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.

Background

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.

Methods

Antibodies against HER2 and three additional known clinical targets were conjugated with our N-acyl sulfonamide auristatin (NAcS-ADCs) or with MMAE or DM4 controls (control ADCs) via cleavable linkers and used to assess in vitro binding and cytotoxicity. The therapeutic window of NAcS-ADCs and control ADCs was compared by assessing efficacy in mouse xenograft models and tolerability/pharmacokinetics in non-human primates (NHPs).

Results

NAcS-ADCs demonstrated similar in vitro binding and cytotoxicity compared to control ADCs. This activity was recapitulated in vivo with similar tumor growth inhibition in mouse xenograft models. In an NHP tolerability/pharmacokinetic study, the trastuzumab NAcS-ADC was well tolerated with a highest non-severely toxic dose (HNSTD) of 18 mg/kg, as compared to an HNSTD of 3 mg/kg for the trastuzumab MMAE control ADC. NAcS-ADCs for all three additional targets were well tolerated at doses of 18 mg/kg (single dose IV infusion) compared to their corresponding control ADCs that showed severe to life-threatening neutropenia at markedly lower doses.

Conclusions

The increase in tolerability and comparable efficacy of the NAcS-ADCs vs. the control ADCs against HER2 as well as three additional known clinical targets highlight the broad applicability of our novel NAcS-linked auristatin payload and its ability to expand the therapeutic window of ADC therapy.

Legal entity responsible for the study

Zymeworks Inc.

Disclosure

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.

Funding

Zymeworks Inc.