Results from the?CANFOUR clinical trial presented in a poster presentation during the annual meeting of the European Society for medical Oncology (ESMO 2018), held October 19 – 24, 2018 in Munich, Germany, shows that 6 mg/kg of nidanilimab (CAN04; Cantargia AB) was well tolerated and can be considered a safe dose.[1]

Nidanilimab is a first-in-class fully humanized and antibody-dependent cell-mediated cytotoxicity (ADCC) enhanced monoclonal antibody, targeting the Interleukin 1 Receptor Accessory Protein (IL1RAP), which is an indispensible molecule in the IL-1 receptor signal transduction complex necessary to link events on the plasma membrane level to downstream signaling pathways, allowing IL-1-dependent activation of transcription factors and gene expression. [2]

ADCC against tumors
The process of antibody-dependent cell-mediated cytotoxicity against tumor cells is triggered by the interaction of the fragment crystallizable (Fc) portion of a monoclonal antibody with the Fc receptors on effector cells like natural killer (NK) cells, macrophages, ?? T cells, and dendritic cells. By augmenting this process, the antitumor activity of monoclonal antibodies can be significantly increased. [3]

Nidanilimab is one of the investigational agents being developed that enhance ADCC. Researchers believe that by combining existing tumor-targeting antibodies and ADCC-promoting agents deigned to stimulate effector cells, it is possible to have a greater clinical response.

Poster presentation
The poster presentation, given by the coordinating investigator Professor Ahmad Awada, MD, Ph.D, from the Institut Jules Bordet, Universit? Libre de Bruxelles, Brussels, Belgium, included data from 16 heavily pretreated patients with advanced colorectal cancer (9), non-small cell lung cancer (3) or pancreatic cancer (4), who were being treated at escalating dose levels from 1 mg/kg and 6 mg/kg nidanilimab.[1]

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Prior to being treated with nidanilimab, these patients had received an average of 4 different cancer therapies.

The presentation included data up to the cutoff date of October 5, 2018.

Adverse effects
The most common side effects of nidanilimab were infusion related reactions and related events, such as nausea, fatigue and fever. These side effects were generally associated with the first dose and were reversible. Based on the results, the researchers concluded that 6 mg/kg is a safe dose. The maximum tolerated dose of nidanilimab is expected to be higher. The investigational agent is now being studied at dose levels of 10 mg/kg before moving into Phase IIa study.

?I am very pleased with the results obtained so far. Nidanilimab has generally been well tolerated using repeated dosing. The good safety profile and initial effects are encouraging and supportive for the next step in the trial, which is combination with chemotherapy,? Awada said.

Biomarker analysis
The initial biomarker analysis showed that the serum levels of IL-6 were reduced in 11 out of 14 patients after two weeks and serum levels of CRP were reduced in 9 out of 11 patients with available samples. Levels of IL-6 and CRP are often increased in cancer patients and are associated with disease progression. In this trial, preliminary efficacy results showed that five patients achieved stable disease, eight progressed and three could not be evaluated. One patient with NSCLC had stable disease for six months.

?Presenting the first clinical dataset from nidanilimab treatment of patients with advanced cancer at a major cancer conference is an important milestone for Cantargia. The results have strengthened our view that nidanilimab can become an important future cancer therapy. We look forward to the last step in the Phase I part and the initiation of Phase IIa in NSCLC and pancreatic cancer using an expanded number of clinical sites,? said G?ran Forsberg, Chief Executive Office of Cantargia.

Trial objective
The primary objective of the Phase I part of the CANFOUR trial is to assess safety and tolerability of weekly nidanilimab in order to define the Maximum Tolerated Dose (MTD)/Recommended Phase II Dose. Patients with relapsed or refractory non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), breast or colorectal cancer are eligible in the initial part of the trial using a 3+3 dose escalation design.

The Phase I part of the trial is currently in the final stage and is planned to be finalized during Q4 2018 with phase IIa also starting Q4 2018. Besides monotherapy, combination with cisplatin/gemcitabine in NSCLC or gemcitabine/nab-paclitaxel in pancreatic cancer at an earlier stage of the disease will be studied in phase IIa.

[1]A First-in-Human Study of CAN04 in Patients With Solid Malignant Tumors (CANFOUR) – NCT03267316
[2] Wesche H, Korherr C, Kracht M, Falk W, Resch K, Martin MU. The interleukin-1 receptor accessory protein (IL-1RAcP) is essential for IL-1-induced activation of interleukin-1 receptor-associated kinase (IRAK) and stress-activated protein kinases (SAP kinases). J Biol Chem. 1997 Mar 21;272(12):7727-31.
[3] Rajasekaran N, Chester C, Yonezawa A, Zhao X, Kohrt HE. Enhancement of antibody-dependent cell mediated cytotoxicity: a new era in cancer treatment. Immunotargets Ther. 2015 May 15;4:91-100. doi: 10.2147/ITT.S61292.

Last Editorial Review: October 20, 2018

Featured Image: Attendees of ESMO 2018. Courtesy: ? 2018 European Society for Medical Oncology. Used with permission.

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