Clinical trial NCT03267316: A First-in-Human Study of CAN04 in Patients With Solid Malignant Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Non Small Cell Lung Cancer
Pancreatic Ductal Adenocarcinoma
Triple Negative Breast Cancer
Colorectal Cancer
Keywords: First-in-Human
Phase 1
Phase 2
Antibody, Monoclonal
IL1RAP
Safety
Tolerability
Cancer
Solid tumor
Malignant
Dose escalation
Dose expansion
CAN04
Immunoglobulin
Clinical Trial
Infusion
Antineoplastic
Anticancer
Lead sponsor: Cantargia AB
Sponsor class: INDUSTRY
First posted: 2017-08-30
Enrollment: 167
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Part I of the study is designed to define the Maximum Tolerated Dose/ Recommended Phase 2 Dose (MTD/RP2D) of CAN04 in subjects with relapsed or refractory Non-Small Cell Lung Cancer (NSCLC), Pancreatic Ductal Adenocarcinoma (PDAC), Triple Negative Breast Cancer (TNBC) or Colorectal Cancer (CRC). \[Completed December 2018\]

Part II consists of seven treatment arms and aims to establish the safety and tolerability of CAN04 as monotherapy and in combination with the standard of care in subjects with NSCLC or PDAC, as well as to investigate early signs of efficacy \[Enrollment to all arms completed\].
Primary purpose: TREATMENT

Brief summary: 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.

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. \[Enrollment to all arms completed\]

Eligibility criteria: 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.

Primary outcomes:
measure: Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)
timeFrame: 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 outcomes:
measure: Maximum concentration (Cmax)
timeFrame: 5 weeks
measure: Terminal half-life (t1/2)
timeFrame: 5 weeks
measure: Clearance (CL)
timeFrame: 5 weeks
measure: Apparent volume of distribution during the terminal phase (VZ)
timeFrame: 5 weeks
measure: Area under the curve from time 0 to infinity (AUC0-∞)
timeFrame: 5 weeks
measure: Anti-drug antibodies (ADA) against CAN04
timeFrame: Through study completion, an average of 6 months
measure: Preliminary signs of efficacy as assessed by tumor response
timeFrame: One year
Other outcomes:
Locations:
city: Salzburg
country: Austria
facility: Landeskrankenhaus Salzburg
city: Vienna
country: Austria
facility: Medizinische Universität Wien
city: Brussels
country: Belgium
facility: Institut Jules Bordet
city: Leuven
country: Belgium
facility: University Hospital Gasthuisberg
city: Liège
country: Belgium
facility: CHU de Liège
city: Aalborg
country: Denmark
facility: Aalborg University Hospital
city: Copenhagen
country: Denmark
facility: Rigshospitalet, Department of Oncology
city: Herlev
country: Denmark
facility: Herlev og Gentofte Hospital
city: Odense
country: Denmark
facility: Odense University Hospital
city: Tallinn
country: Estonia
facility: East Tallinn Central Hospital
city: Tartu
country: Estonia
facility: Tartu University Hospital
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin
city: Hamburg
country: Germany
facility: Asklepios Klinik Altona
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Riga
country: Latvia
facility: Pauls Stradiņš Clinical University Hospital
city: Riga
country: Latvia
facility: Riga East Clinical University Hospital
city: Kaunas
country: Lithuania
facility: The Hospital of Lithuanian University of Health Sciences
city: Vilnius
country: Lithuania
facility: National Cancer Institute
city: Amsterdam
country: Netherlands
facility: Netherlands Cancer Institute
city: Rotterdam
country: Netherlands
facility: Erasmus University Medical Center, Department of Medical Oncology
city: Oslo
country: Norway
facility: Oslo University Hospital, Radiumhospitalet
city: Madrid
country: Spain
facility: Hospital 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario Quirónsalud Madrid
city: Oviedo
country: Spain
facility: Hospital Universitario Central de Asturias
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
Study officials:
affiliation: Jules Bordet Institute, Brussels, Belgium
name: Ahmad Awada, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.