Clinical and preclinical data for CX-2009, a Probody-drug Conjugate or PDC designed to target the cell surface protein CD166 and deliver the tubulin-destabilizing maytansine payload, DM4, to cancer cells, were presented at the annual meeting of the American Association for Cancer Research (AACR), held March 29 – April 3, 2019, in Atlanta, Georga.
CD166, the drugs target, is highly and homogeneously expressed on multiple tumor types. In preclinical studies, CD166 has been shown to effectively internalize antibody-drug conjugates or ADCs resulting in potent cell killing in vitro.
CX-2009, which is being developed by CytomX Therapeutics, has shown anti-cancer activity in multiple preclinical models.
?Collectively, these data presented during the annual meeting highlights the potential opportunity for CX-2009, a novel first-in-class CD166-targeting anti-cancer agent,? noted Sean McCarthy, D. Phil., president, chief executive officer and chairman of CytomX Therapeutics.
?In our first clinical dose escalation with CX-2009, we have seen clear evidence of tumor shrinkage in multiple cancers in heavily pretreated patients and an encouraging safety profile. The safety profile of CX-2009 is of particular note given the widespread expression of CD166 on normal tissues and suggests that CytomX masking technology can allow targeting of novel, broadly distributed antigens,” McCarthy explained.
“Moreover, our preclinical and clinical research is revealing a relationship between target levels and anti-cancer activity, further validating CD166 as a potential new point of intervention in cancer treatment. In addition, our preclinical research into the combination of CX-2009 with a PD-1 Probody provides preliminary evidence for the potential of these two mechanisms to synergize with each other.
Proclaim studies
CX-2009 is being studied within Proclaim clinical trial program (PRObody CLinical Assessment In Man), an international modular umbrella clinical trial program that includes Phase I/II development of multiple Probody therapeutics.
Among the trials in the program is the PROCLAIM-CX-2009 study, is a dose-finding Phase I/II study evaluating CX-2009 as monotherapy in patients with select cancer types, including non-small cell lung cancer, breast cancer, ovarian cancer, endometrial cancer, cholangiocarcinoma (bile duct cancer), head and neck cancer and castration-resistant prostate cancer.
The objectives of the study are to establish the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity of CX-2009.
Preliminary results
Preliminary results of PROCLAIM-CX-2009, a First-in-Human, Dose-Finding trial of Study CytomX Probody-drug Conjugate CX-2009 in patients with advanced solid tumors were presented by Funda Meric-Bernstam. MD., Chair of the Department of Investigational Cancer Therapeutics, Medical Director of the Institute for Personalized Cancer Therapy, and Professor, Divisions of Cancer Medicine and Surgery, MD Anderson Cancer Center [1]
Meric-Bernstam reported data from the dose-escalation phase (Part A and A2) of the ongoing PROCLAIM-CX-2009 study in seven selected tumor types. As of a February 26, 2019 data snapshot, 78 patients were enrolled. Of 71 patients evaluable for efficacy, for patients who received ?4 mg/kg of CX-2009 and had at least one post-baseline on-study tumor assessment, 15/39 (38%) achieved tumor shrinkage, including seven unconfirmed partial responses (4 patients with breast cancer, 2 with ovarian cancer and one with head and neck cancer). 29/39 (74%) achieved stable disease or better at the time of the first on-treatment scan.
CX-2009 was generally well tolerated. The maximum tolerated dose (MTD) was not reached at the highest dose level tested of 10 mg/kg. The most common treatment-related adverse events (TRAE) were grade 1 and 2 and included nausea (32%), fatigue (24%) and decreased appetite (23%). The most common grade 3/4 TRAE was keratitis (8%).
CX-2009 targeting PD-1
Anti-tumor activity of CX-2009 studied in a syngeneic mouse model showed that the combination treatment of CX-2009 with a surrogate mouse anti-PD-1 Probody significantly inhibited tumor growth in mouse CT-26 tumors engineered to express human CD166, as compared to either agent as a monotherapy.
In addition, CX-2009 was shown to induce immunogenic cell death of cancer cells in vitro while sparing T cells, an action that may enhance T-cell priming. These results, presented by Erwan Le Scolan, Ph.D., Senior Scientist at CytomX highlight the potential to combine the PDC CX-2009 with a Probody therapeutic targeting the PD pathway, such as the CytomX anti-PD-L1 Probody, CX-072, as well as potentially combining other antibody drug conjugates or PDCs with immune checkpoint inhibitors.
Treatment of Patient-derived Xenograft Models in a Mouse Clinical Trial Format
In a separate study researchers at CytomX evaluated the anti-tumor activity of CX-2009 in 198 PDX tumor models in a mouse clinical trial format dosed with 5 mg/kg of CX-2009 every 2 weeks for 3 doses.
As part of the study, 129 models (65%) had been dosed at the time of data cutoff. Results from the ongoing study, presented by Bob Liu, Ph.D., Senior Scientist at CytomX, showed anti-tumor activity in 82% of the models compared to control. Tumor shrinkage relative to pre-dosing was observed in 22% of models relative to untreated controls, and 48% of CX-2009-treated tumors yielded tumor growth inhibition of greater than 50%. CD166 mRNA level was associated with anti-tumor activity, which may provide a strategy for prospectively identifying patients most likely to respond to CX-2009.
“Based on these integrated observations presented at AACR 2019, we are excited to advance CX-2009 to the next phase of development,? CytomX McCarthy concluded.
References
[1] PROCLAIM-CX-2009: A Trial to Find Safe and Active Doses of an Investigational Drug CX-2009 for Patients With Selected Solid Tumors – NCT03149549 [Clinical Trial]
Last Editorial Review: April 3, 2019
Featured Image: Poster Session at the American Association for Cancer Research Annual Meeting, Sunday March 31, 2019. Courtesy:? 2010 ? 2019 AACR/Todd Buchanan. Used with permission.
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