A First-in-Human Study of CAN04 in Patients 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.

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.