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

Sponsor

Cantargia AB (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03267316

Collaborator

(none)

140

Enrollment

Locations

Arms

60.4

Anticipated Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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, 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.

Condition or Disease	Intervention/Treatment	Phase
Non Small Cell Lung Cancer Pancreatic Ductal Adenocarcinoma Triple Negative Breast Cancer Colorectal Cancer	Biological: CAN04 Drug: Cisplatin Drug: Gemcitabine Drug: Nab-paclitaxel	Phase 1/Phase 2

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:

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.
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 at the RP2D level. 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 monotherapy arms completed]

Study Design

Study Type:

Interventional

Anticipated Enrollment :

140 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

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 six 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 monotherapy arms completed].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 six 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 monotherapy arms completed].

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Sep 19, 2017

Anticipated Primary Completion Date :

Mar 1, 2022

Anticipated Study Completion Date :

Oct 1, 2022

Arms and Interventions

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 - NSCLC 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 - 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

Outcome Measures

Primary Outcome Measures

Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) [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]
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).

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age ≥ 18 year.
Measurable disease in accordance to iRECIST by computed tomography (CT) or magnetic resonance imaging (MRI) scan, no more than 6 weeks prior to screening.
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.
Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
Histologically or cytologically confirmed diagnosis of unresectable stage III or stage IV squamous or non-squamous NSCLC (applicable Part II, Combination - NSCLC 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.

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

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

Exclusion Criteria:

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.
Clinical evidence of an active metastatic second malignancy.
Subjects with a life expectancy <12 weeks.
Uncontrolled or significant cardiovascular disease defined as New York Heart Association Classification III, or IV.
Immunocompromised subject currently receiving systemic therapy.
Other medical conditions that in the opinion of the investigator disqualify the subject for inclusion.
Applicable Part II, Combination - NSCLC arm 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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Landeskrankenhaus Salzburg	Salzburg	Austria	5020
2	Medizinische Universität Wien	Vienna	Austria	A-1090
3	Institut Jules Bordet	Brussels	Belgium	1000
4	University Hospital Gasthuisberg	Leuven	Belgium	3000
5	CHU de Liège	Liège	Belgium	B-4000
6	Aalborg University Hospital	Aalborg	Denmark	9000
7	Rigshospitalet, Department of Oncology	Copenhagen	Denmark	2100
8	Herlev og Gentofte Hospital	Herlev	Denmark	2730
9	Odense University Hospital	Odense	Denmark	5000
10	East Tallinn Central Hospital	Tallinn	Estonia	11312
11	Tartu University Hospital	Tartu	Estonia	50406
12	Charité Universitätsmedizin Berlin	Berlin	Germany	10117
13	Universitätsklinikums Frankfurt am Main	Frankfurt	Germany	60590
14	Asklepios Klinik Altona	Hamburg	Germany	227 63
15	Universitätsklinikum Ulm	Ulm	Germany	89081
16	Pauls Stradiņš Clinical University Hospital	Riga	Latvia	1002
17	Riga East Clinical University Hospital	Riga	Latvia	1079
18	The Hospital of Lithuanian University of Health Sciences	Kaunas	Lithuania	50161
19	The Hospital of Lithuanian University of Health Sciences	Kaunas	Lithuania	50161
20	National Cancer Institute	Vilnius	Lithuania	08660
21	National Cancer Institute	Vilnius	Lithuania	08660
22	Netherlands Cancer Institute	Amsterdam	Netherlands	1066 CX
23	Erasmus University Medical Center, Department of Medical Oncology	Rotterdam	Netherlands	3015 CE
24	Oslo University Hospital, Radiumhospitalet	Oslo	Norway	0379
25	Hospital 12 de Octubre	Madrid	Spain	28041
26	Hospital Universitario Quirónsalud Madrid	Madrid	Spain	28223
27	Hospital Universitario Central de Asturias	Oviedo	Spain	33011
28	Karolinska University Hospital	Stockholm	Sweden	171 64