| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Solid malignant tumors, in the following four indications;
Non-Small Cell Lung Cancer (NSCLC),
Pancreatic Ductal Adenocarcinoma (PDAC),
Triple negative Breast Cancer (TNBC) or
Colorectal Cancer (CRC) |
|
| E.1.1.1 | Medical condition in easily understood language |
Solid malignant tumors, in the following four indications;
Non-Small Cell Lung Cancer (NSCLC)
Pancreatic Ductal Adenocarcinoma (PDAC)
Triple negative Breast Cancer (TNBC) or
Colorectal Cancer(CRC) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part I
• To define the Maximum Tolerated Dose (MTD) or Recommended Phase 2 dose (RP2D) of CAN04 given weekly (Q1W) in subjects with relapsed or refractory NSCLC, PDAC, TNBC or CRC.
Part II
• To determine the safety and tolerability of CAN04 in subjects with
NSCLC or PDAC tumors, when given as monotherapy or in combination with standard chemotherapy regimen and to identify the RP2D of CAN04 in combination with standard of care (SoC) chemotherapy.
|
|
| E.2.2 | Secondary objectives of the trial |
• To assess pharmacokinetic (PK) parameters of CAN04.
• To assess anti-drug antibody (ADA) formation against CAN04.
• To determine preliminary signs of clinical efficacy of CAN04 as a single agent.
Additional secondary objectives for Part II
• To assess health-related quality of life (QoL)
• To determine preliminary signs of clinical efficacy of CAN04 when given in combination with standard chemotherapy regimen.
Exploratory Objectives:
• To assess disease-related, inflammatory, immune or
microenvironment-related parameters related to the trial drug, in the
circulation and in tumor tissue.
• To assess levels of C-Reactive Protein (CRP).
• To assess volumetric size of tumor.
• To evaluate mechanisms behind infusion related reactions (IRRs) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Ability to understand and willingness to provide written informed consent before any trial-related activities. (Trial-related activities are any proce-dures that would not have been performed during normal management of the subject).
2. Age ≥ 18 years.
3. Measurable disease in accordance with irRC (subjects enrolled prior to protocol version 7.0) or iRECIST (subjects enrolled after protocol version 7.0) by computed tomography (CT) or magnetic resonance imaging (MRI) scan. Imaging tests performed up to 2 weeks before ICF signature are valid for trial entry if they are performed with the same technique/equipment as the future follow-up tests.
4. At least 4 weeks since the last dose of chemotherapy, 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 biolog-ic/targeted therapies.
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
6. Adequate bone marrow, hepatic, renal and coagulation function.
7. Clinical laboratory values at screening:
- Serum creatinine <1.5xULN
- Hemoglobin >9.0 g/dL
- Absolute neutrophil count >1000/µL in Part I and >1500/µL in Part II
No G-CSF is allowed 2 weeks prior to C1D1.
- Platelets >75x109/L for CAN04 monotherapy, and 100x109/L for the combination with chemotherapy (Arms C, D, PDEX2,5, PDEX1 and NCP).
Transfusions are not allowed 2 weeks prior to C1D1.).
- Total bilirubin <1.5x ULN
- Aspartate Transaminase (AST) and Alanine Transaminase (ALT) ≤3x ULN (for subjects with hepatic metastases < 5x ULN)
- Prothrombin Time (PT) & Partial Thromboplastin Time (PTT) within 1.5x institutional ULN.
- In case there are no normal ranges available for the prothrombin time (PT) test, the international normalized ratio (INR) test may be used instead of PT. At screening, subjects should have an INR <1.5x ULN.
Additional inclusion criterion for Part I:
8. Subject with histologically or cytologically confirmed, unresectable, locally advanced or metastatic NSCLC, PDAC, CRC or TNBC tumor, relapsed or refractory to standard therapy or for which there is no standard therapy.
Additional inclusion criterion for Part II:
9. Arm A, arm B and arm E: Subjects with histologically or cytologically confirmed, unresectable, locally advanced or metastatic squamous or non-squamous NSCLC or PDAC, relapsed or refractory to standard of care therapy or for whom there is no standard therapy.
10. Arm A, Arm B, Arm C, Arm D and Arm E and NCP: Presence of tumor lesions amenable to biopsy and willingness to undergo repeat biopsies of these tumor lesions. It is not necessary to repeat the baseline biopsy procedure if: (i) there is enough archival material available, (ii) it has been preserved adequately, (iii) the subject did not receive any systemic anticancer treatment from the day of biopsy sampling and until the first dose of study drug, and (iv) if the sample is less than 60 days old from the treatment start.
11. Arm C only:
11a: Subjects with histologically or cytologically confirmed diagnosis of stage III or stage IV squamous or non-squamous NSCLC
11b: Subjects must be eligible to receive a 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 for them is a platinum doublet.
11c: Subjects who underwent (neo)adjuvant treatments are eligible if the (neo)adjuvant treatment ended at least 6 months prior to inclusion.
12. Arms D, PDEX2.5 and PDEX1 only:
12a: Subjects with newly diagnosed, treatment naive, histologically or cytologically
confirmed, unresectable, locally advanced or metastatic (stage III or
stage IV) PDAC.
12b: Subjects must be eligible to receive treatment with nab-paclitaxel
and gemcitabine.
12c: Subjects who underwent (neo)adjuvant treatments are eligible if the (neo)adjuvant treatment ended at least 6 months prior to inclusion.
13. Arm NCP only:
13a: Unresectable stage III or stage IV non-squamous NSCLC
13b: Subjects must be eligible to receive a standard of care treatment
with carboplatin/pemetrexed as first-line or as second-line
chemotherapy after relapsing from first line with pembrolizumab
monotherapy (or when for other reason subject is not able to receive
pembrolizumab). 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
for them is a platinum doublet.
13c: Subjects who underwent previous systemic treatment ((neo-)
adjuvant), are eligible if such treatment ended at least 6 months prior to
inclusion.
13d: Creatinine clearance >45 mL/min |
|
| E.4 | Principal exclusion criteria |
1. Known or suspected allergy to trial product or related product.
2. Subjects receiving live vaccination, etanercept or other TNF-α inhibitors or other investigational agents during or just prior to (within 28 days of first study drug administration) participation in this study.
3. Previous participation in this trial (enrolled).
4. Clinical evidence of an active metastatic second malignancy.
5. Subjects with a life expectancy <12 weeks.
6. Uncontrolled or significant cardiovascular disease defined as New York Heart Association Classification III, or IV.
7. Dementia or altered mental status that would prohibit the understanding or rendering of informed consent.
8. Not recovered from the adverse effects of prior therapy at the time of enrollment to ≤ grade 1, with the exception of alopecia grade 2.
9. Symptomatic brain metastases which are either untreated or uncontrolled by surgery and/or radiotherapy.
10. Immunocompromised subject currently receiving systemic therapy.
11. Known history of human immunodeficiency virus (HIV) infection, or any other relevant congenital or acquired immunodeficiency. Known hepatitis B (HBV) surface antigen seropositive or detectable hepatitis C (HCV) infection viral load. Note: Subjects who have positive hepatitis B core antibody or hepatitis B surface antibody can be enrolled but must have an undetectable hepatitis B viral load. Subjects who have positive hepatitis C antibody must have an undetectable hepatitis C viral load.
12. Known bleeding disorder or coagulopathy.
13. Subjects with microbial or viral infection which is not controlled by appro-priate medication. Subjects with any type of chronic infection.
14. Women who are pregnant or breastfeeding.
15. Women of childbearing potential (WOCBP, defined as < 2 years after last menstruation and not surgically sterile) or men whose sexual partners are WOCBP who are unwilling or unable to use a highly effective method of contraception for at least 1 month prior to study entry, for the duration of the study, and for at least 3-6 months after the last dose of study medication, depending on the treatment arm. Also see section 7.1.10.1 – Contraception Methods.
16. Evidence of serious uncontrolled medical disorder or active infection that, in the opinion of the Investigator or Medical Monitor, makes it undesirable for the subject to participate in the study or that would jeopardize compli-ance with the protocol.
17. History of biliary stent placement or cholangitis less than 30 days
before the calculated first administration of CAN04. In the case of
cholangitis, antibiotic treatment (IV and/or oral) must be completed at
least 2 weeks before the first CAN04 dose and there should not be signs
or symptoms of infection.
18. Other medical conditions that in the opinion of the investigator disqualify the subject for inclusion.
19. Only for Arm C:
19a Prior lines of treatment with anti-cancer medication other than pembrolizumab monotherapy administered as 1st line.
19b Known tumor EGFR mutation, unless contraindication to EGFR-directed
therapy or if the subject has already progressed to all approved anti-EGFR therapies.
19c Known tumor ALK rearrangements, unless contraindication to ALK-directed therapy, ALK-directed therapy not available or has progressed
to all approved anti-ALK therapies.
20. Only for Arm NCP:
20a: Subject is unable to interrupt aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs), other than an aspirin dose ≤ 1.3 g per
day, for a 5-day period (8-day period for long-acting agents, such as
piroxicam).
20b: Subject is unable or unwilling to take folic acid or vitamin B12
supplementation. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part I and II
• The incidence of Grade 3 and 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). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Ongoing during the complete trial. |
|
| E.5.2 | Secondary end point(s) |
Pharmacokinetics
• Concentration at the end of an injection/infusion (Cinf end).
• Maximum concentration (Cmax).
• Time taken to reach maximum concentration (Tmax).
• Terminal half-life (t½).
• Clearance (CL).
• Apparent volume of distribution during the terminal phase (Vz).
• Area under the curve from time 0 to infinity (AUC0-∞).
• Area under the curve from time 0 to time t (AUC0-t).
• Area under the curve from time 0 to time 24h (AUC0-24)
• Area under the curve from time 0 to time 168 h (AUC0-168)
• Mean residence time (MRT).
• Serum concentration of soluble IL1RAP.
Additional pharmacokinetic endpoint for Part II:
• Area under the curve from time 0 to tau (AUC0-τ)
Immunogenicity:
• Anti-Drug Antibodies (ADA) against CAN04.
Preliminary signs of efficacy
• Overall Response Rate (ORR) using irRC (Part I and Part II Arms A, B, and E), iRECIST (Part II, Arms C and D) and RECIST 1.1 (both Part I and II); with irRC (before protocol version 7.0) or iRECIST (from protocol version 7.0 onwards) to be the decision-making criteria.
• Duration of Response (DoR).
• Median PFS by RECIST 1.1 and iRECIST
• Median Progression Free Survival (PFS) at 6 and 12 months and for the duration of the trial
• Median Overall Survival (OS) at 12, 24 and 36 months
Additional endpoints for Part II
• Health-related Quality of Life (HRQL) assessed by using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ C30; version 3.0).
• In addition and ONLY for subjects with NSCLC: Health-related QoL as
assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ - LC13).
Exploratory End Points:
• IL1RAP expression and other disease-related, inflammatory, immune
or microenvironment-related emerging biomarkers (protein, RNA,
genomic or other) in tumor tissue
Part I: in archival (historic) tumor tissue
Part II: in paired pre- and during -treatment biopsies, and if available,
archival (historic) tumor tissue. (Paired pre- and during treatment
biopsies not applicable for Arms PDEX2.5 and PDEX1)
• Other disease-related, inflammatory, immune or microenvironmentrelated
emerging biomarkers in circulation, including but not be limited
to: IL-1α, IL-1β, IL-1RA, IL-6, IL-8 IL-33, TNF-α
• Serum levels of CRP (for efficacy purposes)
• Volumetric assessment of tumor size |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Depending on the end point. Ongoing during the complete trial. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Pt II: IMP Q1W /IMP Q2W /IMP Q1W/Q2W + SOC/ IMP 2-3x per 28d cycle + SOC/ IMP 2x per 15d cycle+SOC |
|
| E.8.2.4 | Number of treatment arms in the trial | 8 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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