| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| RAS wild-type colorectal cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| A specific subtype of colon and/or rectum cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
| To estimate the antitumor efficacy of nanrilkefusp alfa in combination with cetuximab |
|
| E.2.2 | Secondary objectives of the trial |
- To further evaluate the antitumor efficacy of nanrilkefusp alfa in combination with cetuximab
- To assess the safety and tolerability of nanrilkefusp alfa in combination with cetuximab
- To determine the RP2D of nanrilkefusp alfa in combination with cetuximab
- To characterize the pharmacokinetics (PK) of nanrilkefusp alfa and cetuximab in a subset of patients
- To determine the immunogenicity of nanrilkefusp alfa in combination with cetuximab
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. > or =18 years of age on the day of signing informed consent
2. Ability to understand and sign written informed consent to participate in the study
3. Provides written informed consent for the study
4. Life expectancy >6 months
5. Histologically or cytologically confirmed advanced and/or metastatic RAS wild-type colorectal cancer as confirmed by the investigational site within 3 months prior to the first administration of study treatment. For the assessment of the RAS mutational status, a US Food and Drug Administration (FDA)-approved test or an experienced local laboratory using validated test methods for the detection of K-RAS and N-RAS (exons 2, 3, and 4) mutations must be used.
6.RAS wild type as confirmed by:
• locally performed US Food and Drug Administration (FDA)-approved test or an experienced local laboratory using validated test methods for the detection, based on tumor biopsy or
• locally performed ctDNA assessment including at least mutations in exon 2 (G12D, G12V, G12C, G12S, G12A, G12R, G13D) and determined by a laboratory using validated test methods
• samples must be taken within 3 months prior to first study administration.
7. Patients who are relapsed/refractory or intolerant to prior treatment with irinotecan- and oxaliplatin-containing chemotherapy
8. Have at least one measurable lesion according to RECIST 1.1
9. Eastern Cooperative Oncology Group (ECOG) performance score 0-2
10. Must have recovered from all AEs due to previous therapies to grade ≤1 toxicity (excluding alopecia)
11. Hematology:
- Absolute neutrophil count ≥1,500/μL
- Platelets ≥100,000/μL
- Hemoglobin ≥9.0 g/dL (criteria must be met without packed red blood cell transfusion within the prior 2 weeks; patients can be on stable dose of erythropoietin [≥3 months])
12. Renal function: Creatinine clearance rate ≥50 mL/min as calculated using Cockcroft-Gault equation
13. Hepatic function: ALT/AST ≤2.5× upper limit of normal (ULN) and total bilirubin ≤2×ULN in patients without liver metastasis (benign hereditary hyperbilirubinemias,e.g., Gilbert’s syndrome, are permitted if total bilirubin <3 mg/dL). In patients with liver metastasis, ALT/AST ≤5×ULN is allowed but total bilirubin must be ≤2×ULN.
14. Prothrombin time and activated partial thromboplastin time ≤1.5×ULN
15. A locally performed hepatitis B (HBV) test is required during
screening.
16. A locally performed hepatitis C (HCV) test is required during
screening
17. A female patient is eligible to participate if she is not pregnant, not breastfeeding, and one of the following conditions applies:
- Not a woman of childbearing potential (WOCBP).
- A WOCBP who agrees to use a highly effective contraceptive method during the treatment period and for at least 60 days after the last dose of cetuximab or at least 30 days after last dose of nanrilkefusp alfa, whichever is later.
18. Male patients must agree to use a condom during the treatment period and for at least 60 days after the last dose of cetuximab or at least 30 days after last dose of nanrilkefusp alfa, whichever is later. |
|
| E.4 | Principal exclusion criteria |
1. Prior exposure to drugs that are agonists of IL-2 or IL-15
2. Therapy with cetuximab within 3 months prior to ICF signature or patients who had progressive disease as best response to prior cetuximab-containing regimen
3. Prior systemic anti-cancer therapies, including investigational agents before study entry (ICF signature).
4. Has received more than 4 prior lines of systemic anticancer treatment
5. Has received prior radiotherapy within 2 weeks of the start of study treatments. A 1-week radiation-free period is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system disease. Patients must have recovered from all radiation-related toxicities and not require corticosteroids.
6. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study treatments
7. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 3 weeks or 5 half-lives (whichever longer) before study entry (ICF signature).
8. Patients with known BRAF mutations
9. Clinically significant cardiac abnormalities including prior history of any of the following:
-Cardiomyopathy, with left ventricular ejection fraction lower than the lower limit of the institutional normal range at screening
- Congestive heart failure of New York Heart Association grade ≥2
- History of clinically significant (i.e., active) atherosclerotic cardiovascular disease, specifically myocardial infarction, unstable angina, cerebrovascular accident within 6 months prior to the first dose of study treatments, and any history of coronary heart disease and clinically significant peripheral and/or carotid artery disease
-Prolongation of QTcF >450 msec; history or family history of congenital long QT - Uncontrolled cardiac arrhythmia requiring medication
10. Uncontrolled hypertension defined as systolic blood pressure >160 mmHg, diastolic blood pressure >110 mmHg.
11. Has a clinical diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatments.
12. History of or serology positive for HIV. A locally performed HIV test is required during screening.
13. Has a known additional malignancy that is progressing or has required active treatment within the past 5 years.
14. Has known active central nervous system metastases and/or carcinomatous meningitis.
15. Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
16. Has an active infection requiring systemic therapy
17. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient’s participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating investigator
18. Has a known psychiatric or substance abuse disorder that would interfere with the patient’s ability to cooperate with the requirements of the study
19. History of hypersensitivity to any component of cetuximab or to compounds of similar biological or chemical composition of nanrilkefusp
alfa and/or the excipients contained in the study drug formulations |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| - Objective response rate (ORR) according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of disease progression, and as a basis for all protocol guidelines related to disease status (e.g., discontinuation of study interventions). according to schedule of activities this is at the follow up phase |
|
| E.5.2 | Secondary end point(s) |
ORR according to RECIST for immune-based therapeutics (iRECIST)20 (iORR)
• Best overall response according to RECIST 1.1 (BOR) and iRECIST (iBOR)
• Duration of response according to RECIST 1.1 (DoR) and iRECIST (iDoR)
• Clinical benefit rate according to RECIST 1.1 (CBR) and iRECIST (iCBR)
• Progression-free survival (PFS) according to RECIST 1.1 and iRECIST (iPFS)
• Time to response according to RECIST 1.1 (TtR) and iRECIST (iTtR)
• Time to progression according to RECIST 1.1 (TtP) and iRECIST (iTtP)
Type, frequency, and severity of treatment-emergent AEs (TEAEs) according to Common Terminology Criteria for Adverse Events (CTCAE), version 5.0; safety laboratory findings; vital signs; electrocardiography findings
• Dose-limiting toxicities (DLTs)
• Serum concentrations and calculated PK parameters of SOT101 and cetuximab
• Incidence, titer, and time course of anti-drug antibodies (ADAs) against SOT101
• Incidence, titer, and time course of ADAs against cetuximab
• |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| according to RECIST 1.1 and iRECIST |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability, Immunogenicity |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| 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 | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 | Yes |
| 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
|
The study will end one year after the last patient’s last dose of study treatment (nanrilkefusp alfa and/or cetuximab [whichever occurs later]) or 3 years after the last patient has received the first dose of nanrilkefusp
alfa (whichever occurs earlier). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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