A First-in-Human Study of CAN04 in Patients With Solid Malignant Tumors (CANFOUR)

An Open Label, Dose Escalation Followed by Dose Expansion, Safety and Tolerability Trial of CAN04, a Fully Humanized Monoclonal Antibody Against IL1RAP, in Subjects With Solid Malignant Tumors

This study will evaluate the safety, tolerability, and preliminary antitumor activity of CAN04 both as a monotherapy and in combination with standard of care treatment in subjects with solid cancer tumors.

Following completion of the first part, the dose escalation cohorts, and determination of maximum tolerated dose or recommended phase 2 dose (MTD/RP2D), safety and tolerability will be further evaluated in an expanded cohort of subjects with pancreatic or lung cancer, as monotherapy or in combination with the standard of care treatment and to identify the RP2D of CAN04 in combination with standard of care. In addition, early signs of efficacy during treatment with CAN04 will be investigated.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer; Non Small Cell Lung Cancer; Triple Negative Breast Cancer; Pancreatic Ductal Adenocarcinoma
• Intervention / Treatment: Biological: CAN04; Drug: Cisplatin; Drug: Gemcitabine; Drug: Nab-paclitaxel; Drug: Carboplatin; Drug: Pemetrexed

Detailed Description

CAN04 is a first-in-class fully humanized and ADCC enhanced monoclonal antibody, targeting the Interleukin 1 Receptor Accessory Protein (IL1RAP).

The CAN04 strategy is to attack the IL1RAP target molecule using an effective antibody-based cancer treatment. In preclinical (in vitro and in vivo) studies, CAN04 has shown two distinct mechanisms of action:

1. By blocking the intracellular signals from the IL1RAP target molecule, thereby impairing the cancer cells' ability to secrete tumor stimulating cytokines, in turn reducing tumor inflammation and tumor progression.
2. Through antibody dependent cellular cytotoxicity (ADCC) against IL1RAP expressing tumor cells where CAN04 stimulates natural killer (NK) cells to attack the tumor cells.

The study is a combined phase 1/2a, open-label, dose-escalation followed by dose expansion, safety and tolerability clinical trial, in patients with relapsed or refractory solid tumors. It consists of two parts.

In Part I (Dose Escalation - DE), the intention is to include patients with any of the four solid tumor types: Non-Small Cell Lung Cancer (NSCLC), Pancreatic Ductal Adenocarcinoma (PDAC), Triple Negative Breast Cancer (TNBC) or Colorectal Cancer (CRC). In this part of the study safety and tolerability will be documented and the MTD/ RP2D will be determined. Patients will stay on CAN04 treatment until disease progression, unacceptable toxicity, or discontinuation for any other reason. [Completed December 2018]

In Part II (Expansion Cohort - EC), safety and tolerability will be further evaluated in an expanded cohort of subjects with PDAC or NSCLC to identify RP2D of CAN04 in combination with standard of care. In addition, early signs of efficacy during treatment with CAN04 will be investigated, as monotherapy or in combination with the standard of care.

Patients will stay on treatment until disease progression, unacceptable toxicity, or discontinuation for any other reason. [Enrollment to all arms completed]

• Study Type: Interventional
• Enrollment (Actual): 167
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Austria
  • Salzburg, Austria, 5020
    • Landeskrankenhaus Salzburg
  • Vienna, Austria, A-1090
    • Medizinische Universität Wien
• Belgium
  • Brussels, Belgium, 1000
    • Institut Jules Bordet
  • Leuven, Belgium, 3000
    • University Hospital Gasthuisberg
  • Liège, Belgium, B-4000
    • CHU de Liège
• Denmark
  • Aalborg, Denmark, 9000
    • Aalborg University Hospital
  • Copenhagen, Denmark, 2100
    • Rigshospitalet, Department of Oncology
  • Herlev, Denmark, 2730
    • Herlev og Gentofte Hospital
  • Odense, Denmark, 5000
    • Odense University Hospital
• Estonia
  • Tallinn, Estonia, 11312
    • East Tallinn Central Hospital
  • Tartu, Estonia, 50406
    • Tartu University Hospital
• Germany
  • Berlin, Germany, 10117
    • Charité Universitätsmedizin Berlin
  • Hamburg, Germany, 227 63
    • Asklepios Klinik Altona
  • Ulm, Germany, 89081
    • Universitatsklinikum Ulm
• Latvia
  • Riga, Latvia, 1002
    • Pauls Stradinš Clinical University Hospital
  • Riga, Latvia, 1079
    • Riga East Clinical University Hospital
• Lithuania
  • Kaunas, Lithuania, 50161
    • The Hospital of Lithuanian University of Health Sciences
  • Vilnius, Lithuania, 08660
    • National Cancer Institute
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Netherlands Cancer Institute
  • Rotterdam, Netherlands, 3015 CE
    • Erasmus University Medical Center, Department of Medical Oncology
• Norway
  • Oslo, Norway, 0379
    • Oslo University Hospital, Radiumhospitalet
• Spain
  • Madrid, Spain, 28041
    • Hospital 12 de Octubre
  • Madrid, Spain, 28223
    • Hospital Universitario Quironsalud Madrid
  • Oviedo, Spain, 33011
    • Hospital Universitario Central de Asturias
• Sweden
  • Stockholm, Sweden, 171 64
    • Karolinska University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥ 18 year.
2. Measurable disease in accordance to iRECIST by computed tomography (CT) or magnetic resonance imaging (MRI) scan, no more than 6 weeks prior to screening.
3. At least 4 weeks since the last dose of radiation therapy, immunotherapy, or surgery; at least 6 weeks for therapy which is known to have delayed toxicity; at least 4 weeks since treatment with biologic/targeted therapies.
4. Eastern Cooperative Oncology Group (ECOG) performance status ≤1.

5. Histologically or cytologically confirmed diagnosis of unresectable stage III or stage IV squamous or non-squamous NSCLC (applicable Part II, Combination - NSCLC (NCG) arm only).

   • Subjects must be eligible to receive first line standard chemotherapy regimen with cisplatin/gemcitabine or a second line standard chemotherapy regimen with cisplatin/gemcitabine after relapsing from first line with pembrolizumab monotherapy.
   • Subjects with actionable mutations (EGFR, ALK, ROS) can be enrolled if they have previously progressed to all approved standard of care targeted therapies and the next line of standard therapy is a platinum doublet.

6. Histologically or cytologically confirmed diagnosis of unresectable stage III or stage IV non-squamous NSCLC (applicable Part II, Combination - non-squamous NSCLC NCP arm only).

   • Subjects must be eligible to receive first line standard chemotherapy regimen with carboplatin/pemetrexed or a second line standard chemotherapy regimen with carboplatin/pemetrexed after relapsing from first line with pembrolizumab monotherapy.
   • Subjects with actionable mutations (EGFR, ALK, ROS) can be enrolled if they have previously progressed to all approved standard of care targeted therapies and the next line of standard therapy is a platinum doublet.

7. Newly diagnosed, treatment naїve, histologically confirmed, unresectable, locally advanced or metastatic (stage III or stage IV) PDAC (applicable Part II, Combination - PDAC arms only).

   • Subjects must be eligible to receive treatment with nab-paclitaxel and gemcitabine.

Exclusion Criteria:

1. Subjects receiving live vaccination, etanercept or other TNF-α inhibitors or any other investigational agents during or just prior to (within 28 days of first study drug administration) participation in this study.
2. Clinical evidence of an active metastatic second malignancy.
3. Subjects with a life expectancy <12 weeks.
4. Uncontrolled or significant cardiovascular disease defined as New York Heart Association Classification III, or IV.
5. Immunocompromised subject currently receiving systemic therapy.
6. Other medical conditions that in the opinion of the investigator disqualify the subject for inclusion.

7. Applicable Part II, Combination - NSCLC (NCG and NCP) arms only

   • Prior lines of treatment with anti-cancer medication other than pembrolizumab administered as 1st line.
   • Known tumor EGFR mutation, unless contraindication to EGFR-directed therapy or if the subject has progressed to all approved anti-EGFR therapies.
   • Known tumor ALK rearrangements, unless contraindication to ALK-directed therapy or ALK-directed therapy not available or if the subject has progressed to all approved anti-EGFR therapies.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose escalation; Cohorts of 3 subjects will receive once weekly (Q1W) treatment with CAN04. The Dose Limiting Toxicity (DLT) observation period for each dose level will be the first 21 days of treatment with CAN04. [Completed December 2018]	Biological: CAN04; A fully humanized monoclonal immunoglobulin G1 (IgG1) antibody (hmAb) in aqueous solution administered by i.v. infusion.
Experimental: Monotherapy (Q1W); Subjects with either PDAC or NSCLC, will receive treatment with CAN04 monotherapy once weekly (Q1W).	Biological: CAN04; A fully humanized monoclonal immunoglobulin G1 (IgG1) antibody (hmAb) in aqueous solution administered by i.v. infusion.
Experimental: Monotherapy (Q1W/Q2W); Subjects with either PDAC or NSCLC, will receive treatment with CAN04 monotherapy once weekly (Q1W) for the first 6 weeks followed by treatment every second week (Q2W).	Biological: CAN04; A fully humanized monoclonal immunoglobulin G1 (IgG1) antibody (hmAb) in aqueous solution administered by i.v. infusion.
Experimental: Combination - PDAC; Subjects with PDAC will receive treatment with CAN04 once weekly (Q1W) for the first 6 weeks followed by treatment every second week (Q2W) in combination with standard-of-care therapy (nab-paclitaxel/gemcitabine).	Biological: CAN04; A fully humanized monoclonal immunoglobulin G1 (IgG1) antibody (hmAb) in aqueous solution administered by i.v. infusion.; Drug: Gemcitabine; Standard of care treatment; Drug: Nab-paclitaxel; Standard of care treatment
Experimental: Combination - PDAC (1 mg/kg); Subjects with PDAC will receive CAN04 on Day 1 and 15 in cycles of 28 days in combination with standard-of-care therapy (nab-paclitaxel/gemcitabine). During first cycle CAN04 also to be administered on Day 8.	Biological: CAN04; A fully humanized monoclonal immunoglobulin G1 (IgG1) antibody (hmAb) in aqueous solution administered by i.v. infusion.; Drug: Gemcitabine; Standard of care treatment; Drug: Nab-paclitaxel; Standard of care treatment
Experimental: Combination - PDAC (2,5 mg/kg); Subjects with PDAC will receive CAN04 on Day 1 and 15 in cycles of 28 days in combination with standard-of-care therapy (nab-paclitaxel/gemcitabine). During first cycle CAN04 also to be administered on Day 8.	Biological: CAN04; A fully humanized monoclonal immunoglobulin G1 (IgG1) antibody (hmAb) in aqueous solution administered by i.v. infusion.; Drug: Gemcitabine; Standard of care treatment; Drug: Nab-paclitaxel; Standard of care treatment
Experimental: Combination - NSCLC (NCG); Subjects with NSCLC will receive treatment with CAN04 once weekly (Q1W) for the first 6 weeks followed by treatment every second week (Q2W) in combination with standard-of-care therapy (cisplatin/gemcitabine).	Biological: CAN04; A fully humanized monoclonal immunoglobulin G1 (IgG1) antibody (hmAb) in aqueous solution administered by i.v. infusion.; Drug: Cisplatin; Standard of care treatment; Drug: Gemcitabine; Standard of care treatment
Experimental: Combination - non-squamous NSCLC (NCP); Subjects with non-squamous NSCLC will receive CAN04 on Day 1 and 8 in cycles of 21 days in combination with standard-of-care therapy (carboplatin/pemetrexed).	Biological: CAN04; A fully humanized monoclonal immunoglobulin G1 (IgG1) antibody (hmAb) in aqueous solution administered by i.v. infusion.; Drug: Carboplatin; Standard of care treatment; Drug: Pemetrexed; Standard of care treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)	The incidence of Grade 3 or higher adverse events (AEs) related to CAN04 administration and according to the National Cancer Institute - Common Terminology Criteria for Adverse Events (CTCAE, version 4.03).	From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever occurs first

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum concentration (Cmax)	Maximum plasma concentration of CAN04	5 weeks
Terminal half-life (t1/2)	Terminal half-life of CAN04	5 weeks
Clearance (CL)	Plasma clearance of CAN04	5 weeks
Apparent volume of distribution during the terminal phase (VZ)	Apparent volume of distribution of CAN04 during the terminal phase	5 weeks
Area under the curve from time 0 to infinity (AUC0-∞)	Area under the plasma concentration curve from time 0 to infinity	5 weeks
Anti-drug antibodies (ADA) against CAN04	Immunogenicity of CAN04 after repeated administrations, assessed by ADA titers in serum.	Through study completion, an average of 6 months
Preliminary signs of efficacy as assessed by tumor response	Tumor response (irRC Part I Part II Monotherapy arms; iRECIST Part II Combination arms)	One year

Collaborators and Investigators

• Sponsor: Cantargia AB
• Investigators: Principal Investigator: Ahmad Awada, Professor, Jules Bordet Institute, Brussels, Belgium

Publications and helpful links

General Publications

• Robbrecht D, Jungels C, Sorensen MM, Spanggaard I, Eskens F, Fretland SO, Guren TK, Aftimos P, Liberg D, Svedman C, Thorsson L, Steeghs N, Awada A. First-in-human phase 1 dose-escalation study of CAN04, a first-in-class interleukin-1 receptor accessory protein (IL1RAP) antibody in patients with solid tumours. Br J Cancer. 2022 Apr;126(7):1010-1017. doi: 10.1038/s41416-021-01657-7. Epub 2021 Dec 13.

Helpful Links

• Poster presentation at ESMO 2018
• Oral presentation at ASCO annual meeting 2019
• Poster presentation at ESMO 2021
• Poster presentation at ASCO annual meeting 2022
• Poster presentation at ASCO annual meeting 2022
• Poster presentation at AACR annual meeting 2023
• Poster presentation at ASCO annual meeting 2023

Study record dates

Study Major Dates

• Study Start (Actual): September 19, 2017
• Primary Completion (Actual): March 14, 2024
• Study Completion (Actual): March 14, 2024

Study Registration Dates

• First Submitted: August 24, 2017
• First Submitted That Met QC Criteria: August 29, 2017
• First Posted (Actual): August 30, 2017

Study Record Updates

• Last Update Posted (Actual): August 22, 2024
• Last Update Submitted That Met QC Criteria: August 21, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Safety; Cancer; First-in-Human; Phase 1; Dose escalation; Tolerability; Clinical Trial; Solid tumor; Malignant; Antibody, Monoclonal; Phase 2; Antineoplastic; Infusion; Immunoglobulin; CAN04; Dose expansion; Anticancer; IL1RAP
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Triple Negative Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Folic Acid Antagonists; Carboplatin; Paclitaxel; Pemetrexed; Gemcitabine
• Other Study ID Numbers: CAN04CLIN001; 2017-001111-36 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No