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 tumorsKurztitel
Bestimmung der Sicherheit und Tolerierbarkeit von CAN04 (Antikörper gegen Interleukin-1 Receptor Accessory Protein (IL1RAP)) bei Patienten mit NSCLC oder PDAC-Tumoren bei Verabreichung als Monotherapie oder in Kombination mit einer Standard-Chemotherapie
Untersuchte Krankheit, GesundheitsproblemICD-Code
- C34.9 - Bronchus oder Lunge, nicht näher bezeichnet
- C25.9 - Pankreas, nicht näher bezeichnet
18 - 120Geschlecht
1. Ability to understand and willingness to provide written informed consent before any trial-related activities. (Trial-related activities are any procedures that would not have been performed during normal management of the subject).
2. Age ≥ 18 year.
3. Measurable disease in accordance to irRC by computed tomography (CT) or magnetic resonance imaging (MRI) scan, no more than 6 weeks prior to screening.
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 biologic/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
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 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. Subjects with histologically or cytologically confirmed, locally advanced, metastatic NSCLC, PDAC, CRC or TNBC tumor, relapsed or refractory to standard therapy or for which there is no standard therapy.
1. Known or suspected allergy to trial product or related product.
2. Subjects receiving any 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 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. Subjects with history of HIV, hepatitis B or C exposure currently controlled by antiviral therapy.
12. Known bleeding disorder or coagulopathy.
13. Subjects with microbial or viral infection, which is not controlled by appropriate medication.
14. Women who are pregnant or breastfeeding.
15. Women of childbearing potential (WOCBP) 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 months after the last dose of study medication.
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 compliance with the protocol.
17. Other medical conditions that in the opinion of the investigator disqualify the subject for inclusion.
The incidence of Grade 3 or 4 adverse events (AEs) related to CAN04 administration and according to the National Cancer Institute - Common Terminology Criteria for Adverse Events (CTCAE, version 4.03).Sekundärer Endpunkt
Concentration at the end of infusion (Cinf end).
Maximum concentration (Cmax).
Time taken to reach maximum concentration (tmax).
Terminal half-life (t½).
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)
Mean residence time (MRT).
Serum concentration of soluble IL1RAP (sIL1RAP).
Anti-drug antibodies (ADA) against CAN04
Anti-Drug Antibodies (ADA) against CAN04.
Preliminary signs of efficacy
Overall Response Rate (ORR) using irRC and RECIST 1.1; with irRC to be the decision-making criteria.
Duration of Response (DoR).
Progression Free Survival (PFS) at 12 months and for the duration of the trial
Overall Survival (OS) at 12, 24 and 36 months
Additional endpoints for Part II
Health-related QoL as assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (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 LC13 (EORTC QLQ - LC13).