| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 |
Primary
Part 1 – Dose Finding:
• To characterize the safety and tolerability of EOS884448 (EOS-448) in combination with standard of care and/or investigational therapies and of dostarlimab combined with inupadenant HCl in participants with advanced solid tumors.
• To determine the recommended phase 2 dose (RP2D) of EOS-448 in combination with standard of care and/or investigational therapies and of inupadenant in combination with dostarlimab in participants with advanced solid tumors.
Part 2 – Expansion:
• To assess the antitumor activity (i) of the combination of EOS-448 with pembrolizumab in participants with first-line metastatic non-small-cell lung cancer (1L mNSCLC, Parts 2A and 2B); (ii) of the combination of EOS-448 with dostarlimab in first-line metastatic head and neck squamous cell carcinoma (1L mHNSCC, Parts 2C and 2D); (iii) of the combination of EOS-448 with inupadenant HCl in anti-PD-(L)1 resistant metastatic cutaneous melanoma (Part 2E). |
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| E.2.2 | Secondary objectives of the trial |
Secondary
Part 1 – Dose Finding:
• To assess the antitumor activity of EOS-448 in combination with standard of care and/or investigational therapies and of inupadenant in combination with dostarlimab in participants with advanced solid tumors.
• Overall Response Rate (ORR) will be defined according to RECIST v1.1.
Part 1 and Part 2:
• To assess the antitumor activity according to time-to-event in participants treated with EOS-448 in combination with standard of care and/or investigational therapies and of inupadenant in combination with dostarlimab in participants with advanced solid tumors.
• To assess the pharmacokinetics (PK) and immunogenicity of EOS-448 in combination with standard of care and/or investigational therapies in participants with advanced solid tumors.
• To assess the PK of inupadenant when the drug (free base or HCl salt) is administered in combination with (i) EOS-448, (ii) dostarlimab, or (iii) EOS-448 and dostarlimab |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provide a signed written informed consent for the trial and consent for biopsies before and during administration of study treatment at Cycle 2 with an optional consent for biopsy at Cycle 5 and at disease progression, if applicable.
Note: For Part 1G, Part 2C & 2D only: biopsies are optional, therefore consent for biopsies is optional
2. Be ≥18 years of age on day of signing informed consent.
3. Have measurable disease, per RECIST v1.1 for solid tumor (Appendix 8.1) based on local assessment.
4. Have a predicted life expectancy of ≥ 16 weeks.
5. Have an Eastern Cooperative Oncology Group (ECOG) performance status of Grade 0 or 1 (Appendix 8.2).
6. Have adequate organ function as defined by the following criteria collected within 10 days prior to start of study treatment. A participant not qualifying for any of these parameters on the initial screening assessment can be considered eligible providing that recovery is expected during the screening period and the criteria above are met prior to the start of therapy (Note: please refer to inclusion criterion #13 specific to Part 1G):
a. Serum albumin ≥ 30 g/L (3.0 g/dL)
b. Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L
c. Platelet count ≥ 100 × 109/L
d. Absolute neutrophil count ≥ 1.2 × 109/L
e. Measured or calculated creatinine clearance ≥ 30 mL/min for Parts 1A, 1D, 2A, 2B, 2C, 2D and ≥ 60 mL/min for Part 1B, 1C, 1E, 1F and 2E, using the formula of Cockroft and Gault (1976).
f. Adequate hepatic function within 28 days prior to C1D1: Total bilirubin < 1.5 X ULN (except participants with Gilbert's syndrome [hereditary indirect hyperbilirubinemia] who must have a total bilirubin of ≤ 2.5 X ULN (upper limit of normal)) and both AST (aspartate transaminase) and ALT (alanine transaminase) < 3.0 X ULN.
g. International normalized ratio (INR) ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy provided that prothrombin time (PT) or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants.
7. Female participants of childbearing potential (defined as women with < 12 continuous months of amenorrhea with no identified cause other than menopause, or not surgically sterile), must have a negative pregnancy test within 7 days before the first administration of study treatment and agree to use highly efficient contraception, as defined in Appendix 8.5, during the treatment and until 60 days after the last administration of EOS-448 or inupadenant, 120 days after the last administration of pembrolizumab or dostarlimab whichever applicable date is the latest. Prolonged period may be required in case of chemotherapy according to summary of product characteristics (SmPC), package insert or equivalent document for the specific country/region and should follow local standard of care (SOC) beyond 120 days.
8. Male participants with female partner(s) of childbearing potential must agree to remain sexually abstinent or use condoms during the treatment and 120 days after the last dose of the study medication whichever applicable date is the latest. Prolonged period may be required in case of chemotherapy according to SmPC and should follow local SOC beyond 120 days. In addition, male participants must forego sperm donation during this time.
Additional inclusion criteria for Parts 1A, 1B, 1C, 1D, 1E and 1F (advanced solid tumors):
9. Have histologically or cytologically confirmed advanced or metastatic solid tumor for whom no standard treatment with survival benefit is available.
Additional inclusion criteria for Part 1G (1L mNSCLC):
10. Have a histologically confirmed or cytologically confirmed previously untreated stage IV OR stage III not amenable to curative chemoradiotherapy or surgery (AJCC 8th edition) nonsquamous NSCLC OR squamous NSCLC.
11. Are eligible to receive anti-PD(L)1 therapy combined with chemotherapy in first line metastatic setting.
12. Have a documented PD-L1 status as determined by immunohistochemistry with anti-PD-L1 antibody (IHC 22C3 pharmDx or other method used as standard per local practices) from a core or excisional biopsy (fine needle aspirate is not sufficient).
13. Have adequate organ function as defined by the following criteria collected within 10 days prior to start of study treatment. A participant not qualifying for any of these parameters on the initial screening assessment can be considered eligible providing that recovery is expected during the screening period and the criteria above are met prior to the start of therapy:
a. Serum albumin ≥ 30 g/L (3.0 g/dL)
b. Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L
c. Platelet count ≥ 100 × 109/L
d. Absolute neutrophil count ≥ 1.5 × 109/L
e. Measured or calculated creatinine clearance ≥ 50 mL/min using the formula of Cockcroft and Gault (1976). |
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| E.4 | Principal exclusion criteria |
2. Have received a live vaccine within 30 days prior to the first dose of study treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. All approved COVID-19 vaccines are authorized unless otherwise indicated by the sponsor.
3. Have known primary Central Nervous System (CNS) cancer.
4. Have known CNS metastases (including leptomeningeal disease) except for the following:
a. Participants with previously treated CNS metastases that are well controlled for at least one month (defined as clinically stable, no edema, no steroid dose increases for 4 weeks and stable on 2 scans at least 4 weeks apart), are allowed.
b. Participants with known CNS metastases for whom the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy are allowed.
c. In case of known CNS metastases, baseline CNS imaging must be obtained up to 4 weeks before the start of the study treatment to document CNS metastases measurements.
6. Have received lung radiation therapy of >30 Gy within 6 months of the first dose of study treatment.
7. Have a history of Grade ≥ 2 pneumonitis, active autoimmune disease, or persistent immune-mediated toxicity caused by immune checkpoint inhibitor therapy of Grade ≥ 2 with the exception of residual endocrinopathy adequately substituted, vitiligo, Type 1 diabetes mellitus, or psoriasis not requiring systemic therapy.
8. Have toxicity (except for alopecia) related to prior anti-cancer therapy and/or surgery, unless the toxicity is either resolved, returned to baseline or Grade 1, or deemed irreversible.
9. Have any active neuropathy > Grade 2 (CTCAE v5.0).
10. Have history of grade 3 or higher liver toxicity or life-threatening toxicity related to prior immune therapy or any toxicity that resulted in permanent discontinuation of prior immune therapy.
11. Have any condition requiring concurrent use of systemic immunosuppressants or corticosteroids > 10 mg daily prednisone equivalents or other immunosuppressive medications within 14 days of study treatment administration (permitted: premedication/prophylaxis if indicated, e.g. for IV contrast, treatment with a short course of steroids [< 5 days] up to 7 days before initiating study treatment, topical glucocorticoids, or steroid replacement doses for adrenal insufficiency).
12. Have evidence of active infection that requires systemic antibacterial, antiviral, or antifungal therapy ≤ 7 days before the first dose of study treatment (except for viral infections that are presumed to be associated with the underlying tumor type required for study entry).
13. Have uncontrolled or significant cardiovascular disease including, but not limited to, any of the following:
a. Left ventricular ejection fraction ≤ 50% determined by echocardiogram or other approved method of evaluation
b. Myocardial infarction within the past 2 years
c. Uncontrolled angina within the past 6 months
d History of clinically significant arrhythmias (such as atrial fibrillation and conduction disorders, ventricular tachycardia, ventricular fibrillation). For part 1G and 2C/2D, participants with prior history of atrial fibrillation may be enrolled if well controlled, without symptomatic acute episode(s) in the past 6 months.
e. QT interval corrected prolongation > 470 msec
f. History of other clinically significant heart disease (e.g., cardiomyopathy, congestive heart failure with New York Heart Association functional classification III-IV see Appendix 8.3, pericarditis, significant pericardial effusion, or myocarditis, of any grade)
g. Cardiovascular disease-related requirement for daily supplemental oxygen therapy
h. Diagnosis of deep vein thrombosis or pulmonary embolism within the past 6 months.
i. History of stroke or arterial disease within the past 6 months.
j. NOTE: Participants with Troponin and/or N-terminal pro b-type natriuretic peptide NTProBNP/
brain natriuretic peptide (BNP) ≥2 x ULN will require a cardiologist or locally appropriate
specialist review to identify underlying conditions that may meet exclusion criteria or that may
require increased monitoring on study. In addition, consider cardiologist or locally appropriate
specialist review for potentially significant ECG abnormalities such as atrioventricular (AV)
block (except for first degree), new cardiac arrhythmias, or frequent premature ventricular
contractions (PVCs). Please inform the Sponsor regarding these participants.
Exclusion criteria 1, 5 and from 14 onward are not included due to word limit, please refer to protocol.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1 – Dose Finding:
• Incidence and frequency of adverse events (AEs), serious adverse events (SAEs), dose-limiting toxicities (DLTs), AEs leading to discontinuation, deaths, vital signs, electrocardiogram (ECG) abnormalities, LVEF, and clinically significant laboratory abnormalities.
Part 2 – Expansion:
• Overall Response Rate (ORR) will be defined according to RECIST v1.1.
• Incidence and frequency of AEs, SAEs, DLTs, AEs leading to discontinuation, deaths, vital signs, ECG abnormalities, LVEF, and clinically significant laboratory abnormalities. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Please refer to:
• Table 16 and Table 17 for Part 1A
• Table 18 and Table 19 for Part 1B
• Table 20 and Table 21 for Part 1C
•Table 22 and Table 23 Part 1D
• Table 24 and Table 25 for Part 1E
• Table 26 and Table 27 for Part 1F
• Table 28 and Table 29 for Part 1G
• Table 30 and Table 31 for Parts 2A and 2B
• Table 32 and Table 33 for Parts 2C and 2D
• Table 34 and Table 35 for Part 2E of study protocol |
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| E.5.2 | Secondary end point(s) |
Part 1 – Dose Finding:
• Overall Response Rate (ORR) will be defined according to RECIST v1.1.
Part 1 and Part 2:
• Duration of Response (DOR), Disease Control Rate (DCR defined as the proportion of participants with a best response of partial response [PR], complete response [CR] or prolonged stable disease [SD]), progression-free-survival (PFS, time from starting treatment until disease progression or death for any reason) will be defined according to RECIST v1.1.
• Summary measures of PK parameters of EOS-448 and incidence of anti-drug antibodies (ADA) to EOS-448.
• Summary measures of PK parameters of inupadenant.
• Summary measures of PK parameters of dostarlimab and incidence of anti-drug antibodies (ADA) to dostarlimab.
Part 1 and Part 2:
• Change from baseline of PD and exploratory biomarkers in the tumor and in peripheral blood.
• Explore the association between PK and PD biomarkers.
• Explore the relationships between PD and other exploratory biomarkers, before and/or after treatment, and clinical outcomes. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Please refer to:
• Table 16 and Table 17 for Part 1A
• Table 18 and Table 19 for Part 1B
• Table 20 and Table 21 for Part 1C
•Table 22 and Table 23 Part 1D
• Table 24 and Table 25 for Part 1E
• Table 26 and Table 27 for Part 1F
• Table 28 and Table 29 for Part 1G
• Table 30 and Table 31 for Parts 2A and 2B
• Table 32 and Table 33 for Parts 2C and 2D
• Table 34 and Table 35 for Part 2E of study protocol
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| 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 | 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 | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| First time of administration of two combinations |
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| 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 |
| Basket study, evaluating the safety, tolerability, RP2D, PK, PD, antitumor activity of EOS-448 |
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| 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.8.3 |
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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United Kingdom |
| United States |
| Belgium |
| France |
| Italy |
| Spain |
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| 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
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| End of study visit will be defined as the last safety follow-up visit/call or the last assessment/phone call during the long-term follow-up whichever occurs last. |
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| 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 | 9 |
| 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 | 9 |
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