A Multicenter, Open-Label, Phase I/II Study of EOS884448 in combination with standard of care and/or investigational therapies in participants with advanced solid tumors

Overview

Sponsor-declared trial summary

Key facts

Sponsor

iTeos Belgium

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

28 Jul 2021 → 16 May 2025

Decision date (initial)

2024-11-20

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

iTeos Belgium SA

External identifiers

EU CT number

2024-512227-36-00

EudraCT number

2021-001329-29

ClinicalTrials.gov

NCT05060432

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Pharmacodynamic, Therapy, Dose response, Safety

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).
To further characterize the safety and tolerability of EOS-448 in combination with pembrolizumab in participants with 1L mNSCLC, (Part 2A and 2B)
To further characterize the safety and tolerability of EOS-448 in combination with dostarlimab in participants with 1L mHNSCC (Part 2C and 2D).
To further characterize the safety and tolerability of EOS-448 in combination with inupadenant HCl in participants with anti-PD-(L)1 resistant metastatic cutaneous melanoma (Part 2E).

Secondary objectives 5

1. 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.
2. 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.
3. Part 1 and Part 2: 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.
4. Part 1 and Part 2: 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
5. Part 1 and Part 2: To assess the PK and immunogenicity of dostarlimab in combination with standard of care and/or investigational therapies.

Conditions and MedDRA coding

Advanced solid tumors

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 23

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 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 Parts 1B, 1C, 1E, 1F and 2E, using the formula of Cockcroft 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) and both AST and ALT < 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 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.
9. Additional inclusion criteria for Parts 1A, 1B, 1C, 1D, 1E and 1F (advanced solid tumors): Have histologically or cytologically confirmed advanced or metastatic solid tumor for whom no standard treatment with survival benefit is available.
10. Additional inclusion criteria for Part 1G (1L mNSCLC): Have a histologically confirmed or cytologically confirmed previously untreated stage IV OR stage III not amenable to curative chemotherapy or surgery (AJCC 8th edition) nonsquamous NSCLC OR squamous NSCLC.
11. Additional inclusion criteria for Part 1G (1L mNSCLC): Are eligible to receive anti-PD(L)1 therapy combined with chemotherapy in first line metastatic setting
12. Additional inclusion criteria for Part 1G (1L mNSCLC): 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. Additional inclusion criteria for Part 1G (1L mNSCLC): 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). 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) and both AST and ALT < 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.
14. Additional inclusion criteria applicable for Part 2: For Parts 2A and 2B: Are eligible to receive pembrolizumab monotherapy in first line (1L) metastatic setting, as approved and according to local treatment guidelines.
15. Additional inclusion criteria applicable for Part 2: For Parts 2A and 2B: Have histologically or cytologically documented diagnosis of NSCLC in stage IIIB/IV.
16. Additional inclusion criteria applicable for Part 2: For Parts 2A and 2B: Have a PD-L1 status as determined by immunohistochemistry with anti-PD-L1 antibody (IHC 22C3 pharmDx) from a core or excisional biopsy (fine needle aspirate is not sufficient). If TPS status is unknown, it must be determined during the screening period.  1L metastatic NSCLC with TPS ≥ 50% will be included in Part 2A.  1L metastatic NSCLC 1% ≤ TPS < 50% will be included in Part 2B.
17. Additional inclusion criteria applicable for Part 2: For Parts 2C and 2D: Have histologically or cytologically confirmed recurrent advanced or metastatic head and neck squamous cell carcinoma considered incurable by local therapies  Participants should not have had prior systemic therapy administered in the recurrent or metastatic setting. Systemic therapy which was completed more than 6 months prior to signing consent if given as part of multimodal treatment for locally advanced disease is allowed. No prior anti-PD-(L)1 therapy allowed.
18. Additional inclusion criteria applicable for Part 2: For Parts 2C and 2D: Primary tumor locations of oropharynx, oral cavity, hypopharynx, or larynx. Participants may not have a primary tumor site of nasopharynx (any histology).
19. Additional inclusion criteria applicable for Part 2: For Parts 2C and 2D: Have a 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). If CPS status is unknown, it must be determined during the screening period.  1L metastatic HNSCC with CPS ≥ 20 will be included in Study Part 2C.  1L metastatic HNSCC 1 ≤ CPS < 20 will be included in Study Part 2D.
20. Additional inclusion criteria applicable for Part 2: For Parts 2C and 2D: Have documented results from testing of human papillomavirus (HPV) status for oropharyngeal, hypopharyngeal, laryngeal and oral cavity cancer. If HPV status is unknown at screening, participant can be enrolled providing HPV status can be determined during the study.
21. Additional inclusion criteria applicable for Part 2: For Part 2E: Have histologically or cytologically documented advanced unresectable or metastatic melanoma of the skin
22. Additional inclusion criteria applicable for Part 2: For Part 2E: Must have progressed on treatment with an anti-PD-(L)1 monoclonal antibody (mAb) administered either as monotherapy, or in combination with other therapies. PD-(L)1 treatment progression is defined by meeting all of the following criteria: a. Have received at least 2 doses of an approved anti-PD-(L)1 mAb b. Have demonstrated disease progression on or after PD-(L)1 as defined by RECIST v1.1 (Appendix 8.1). The initial evidence of disease progression is to be confirmed by a second assessment no less than four weeks from the date of the first documented disease progression, in the absence of rapid clinical progression c. Progressive disease has been documented within 12 weeks of the last dose of anti-PD-(L)1 mAb. No systemic cancer therapy should have been received between the progression under anti-PD-(L)1 mAb and the entry into the study.
23. Additional inclusion criteria applicable for Part 2: For Part 2E: Must have known BRAF status and participants with mutated BRAF must have received prior BRAF-MEK targeted therapy if indicated (either in the (neo)adjuvant or 1L/2L metastatic setting).

Exclusion criteria 39

1. Have received any anti-cancer therapy, unless at least 4 weeks (or 5 half-lives, whichever is shorter) since the last dose of prior cytotoxic, biologic or any investigational agents (6 weeks for mitomycin C or nitrosoureas), have elapsed before the first administration of study treatment. Chronic treatment with non-investigational gonadotropin-releasing hormone analogs or other hormonal or supportive care is permitted.
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 metastasis, baseline CNS imaging must be obtained up to 4 weeks before the start of the study treatment to document CNS metastases measurements.
5. Have concomitant second malignancies unless a complete remission was achieved at least 2 years before study entry with no additional therapy required or anticipated to be required during the study period.
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.
14. Have known active or chronic hepatitis B or C (unless treated with no detectable virus) (participants are NOT required to be tested for the presence of such viruses before therapy on this protocol).
15. Have known history of human immunodeficiency virus (HIV) (participants are NOT required to be tested for the presence of HIV before therapy on this protocol).
16. Have been tested for COVID-19 and had a positive result within 2 weeks prior to first study dosing. Participants may be re-screened 2 weeks after the last positive test for COVID-19, if COVID-19 related symptoms have resolved to Grade ≤ 1. Participants are NOT required to be tested for the presence of COVID-19 prior to therapy on this protocol.
17. Have any known or underlying medical, psychiatric condition, and/or social situations that, in the opinion of the investigator, would limit compliance with study requirements.
18. Have history of allergy to the study treatment(s) or any components.
19. Are pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study medication.
20. Are unable to comply with the requirements of the study or who in the opinion of the investigator should not participate in the study, are not eligible.
21. Have had an allogenic tissue/solid organ transplant.
22. Have undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years. Participants who have had a transplant greater than 5 years ago are eligible provided that there are no symptoms of graft versus host disease (GVHD).
23. Have received packed red blood cells or platelet transfusion within 2 weeks of the first dose of study treatment.
24. Additional exclusion criteria For Parts 1A, 1B, 1C, 1D, 1E and 1F: Have undergone major surgery (defined as any surgical procedure that requires more than 24 hours admission in a hospital) within 5 weeks before initiating treatment or minor surgical procedure within 7 days before initiating treatment (except for minor surgical procedure needed for tumor biopsy).
25. Additional exclusion criteria For Parts 1A, 1B, 1C, 1D, 1E and 1F: Have received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease.
26. Additional exclusion criteria For Part 1G: Do not meet requirements as per local prescribing guidelines for receiving treatment with the selected chemotherapy regimens (carboplatin and paclitaxel OR pemetrexed and cisplatin or carboplatin).
27. Additional exclusion criteria For Part 1G: Have a known sensitivity to any component of cisplatin, carboplatin, paclitaxel or pemetrexed.
28. Additional exclusion criteria For Part 1G: For those receiving pemetrexed, unable or unwilling to take folic acid or vitamin B12 supplementation.
29. Additional exclusion criteria For Part 1G: Have symptomatic ascites or pleural effusion. A participant clinically stable after appropriate treatments is eligible.
30. Additional exclusion criteria For Parts 2A and 2B: Have documented confirmation of a sensitizing epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or reactive oxygen species (ROS1) mutation or any other genomic aberration for which an approved directed therapy is available as primary therapy.
31. Additional exclusion criteria For Parts 2C and 2D: Have a high risk of bleeding in the judgment of the investigator (examples include but are not limited to tumors encasing or infiltrating a major vessel [carotid, jugular, bronchial artery] and/or exhibits other high risk features such as arteriovenous fistula), or active tumor bleeding.
32. Additional exclusion criteria For Parts 2C and 2D: Have Grade 3 or Grade 4 hypercalcemia
33. Additional exclusion criteria For Parts 2A, 2B, 2C and 2D: Have received prior immunotherapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
34. Additional exclusion criteria For Parts 2A, 2B, 2C and 2D: Have received prior chemotherapy administered in the recurrent advanced or metastatic setting (except for systemic therapy completed > 6 months prior to screening if given as part of multimodal treatment for locally advanced disease)
35. Additional exclusion criteria For Parts 1G, 2A, 2B, 2C, 2D and 2E: Have undergone major surgery within 3 weeks of the first dose of study treatment.
36. Additional exclusion criteria For Parts 1B, 1C, 1E, 1F and 2E: Have any active gastrointestinal dysfunction that prevents the participants from swallowing tablets or interferes with absorption of study treatment.
37. Additional exclusion criteria For Parts 1B, 1C, 1E, 1F and 2E: Are taking any drug that is a strong or moderate inducer or inhibitor of CYP3A4, inhibitors of P glycoprotein, or substrates of breast cancer resistance protein (BCRP) (see Protocol Appendix 8.4).
38. Additional exclusion criteria For Parts 1B, 1C, 1E, 1F and 2E: Are currently taking any drug that is generally considered to have a high risk of causing Torsades de Pointes. It will be at the determination of the treating physician to discontinue or substitute as appropriate. If discontinued, the washout period needs to be at least 5 half-lives of the drug.
39. Additional exclusion criteria For Parts 1B, 1C, 1E, 1F and 2E: Are consuming grapefruit, pomelo, Seville orange, grapefruit juice, Seville orange juice, or pomelo juice within 7 days before the first dose of treatment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. 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.
2. Part 2 – Expansion: Overall Response Rate (ORR) will be defined according to RECIST v1.1.
3. Part 2 – Expansion: Incidence and frequency of AEs, SAEs, DLTs, AEs leading to discontinuation, deaths, vital signs, ECG abnormalities, LVEF, and clinically significant laboratory abnormalities.

Secondary endpoints 5

1. Part 1 – Dose Finding: Overall Response Rate (ORR) will be defined according to RECIST v1.1.
2. 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.
3. Part 1 and Part 2: Summary measures of PK parameters of EOS-448 and incidence of anti-drug antibodies (ADA) to EOS-448.
4. Part 1 and Part 2: Summary measures of PK parameters of inupadenant.
5. Part 1 and Part 2: Summary measures of PK parameters of dostarlimab and incidence of anti-drug antibodies (ADA) to dostarlimab.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 8

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

iTeos Belgium

Sponsor organisation

iTeos Belgium

Address

Rue Des Freres Wright 29/3

City

Charleroi

Postcode

6041

Country

Belgium

Scientific contact point

Organisation

iTeos Belgium

Contact name

iTeos Belgium SA

Public contact point

Organisation

iTeos Belgium

Contact name

Clinical Trials department

Third parties 16

Locations

4 EU/EEA countries · 39 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 139 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications