IVONESCIMAB for Metastatic non-small cell lung cancer

Inclusion criteria

• {"criterion_text":"- Voluntarily sign a written informed consent form (ICF)\n- Age ≥ 18 years old at the time of enrollment\n- Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1\n- Expected life expectancy ≥ 3 months\n- Metastatic (Stage IV) NSCLC, according to American Joint Committee on Cancer (AJCC) 8th edition\n- Histologically or cytologically confirmed squamous or non-squamous NSCLC.\n- Patients must have a TPS or TC for PD-L1 expression prior to randomization. The TPS/TC score can be obtained from an existing report or be performed any time before study entry using archival tissue utilizing on a clinical assay approved/cleared by local health authorities. If site is unable to perform a TPS/TC score locally, then the site should provide tumor tissue (fresh or achival) for central TPS/TC determination.\n- At least one measurable noncerebral lesion according to RECIST 1.1. Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions since radiotherapy.\n- No prior systemic treatment for metastatic NSCLC. Patients receiving adjuvant or neoadjuvant therapy or curative-intent chemoradiotherapy with or without PD- 1/L1 inhibitors are eligible if the adjuvant/neoadjuvant therapy was completed at least 6 months prior to the development of metastatic disease.\n- Adequate Organ Function: • a. Hematology (no blood transfusions or growth factor therapy used within 7 days of the screening CBC): • i. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L •\tii. Platelet count ≥ 100 × 109/L • iii. Hemoglobin ≥ 9.0 g/dL • b. Kidneys: • i. Creatinine clearance (CrCl) ≥ 50 mL/min using the Cockcroft-Gault formula or estimated glomerular filtration rate (eGFR) value ≥50 mL/min using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation • ii. Urine protein < 2+ or 24 hour urine protein quantification < 1.0 g • c. Liver: • i. Serum total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); For patients with liver metastases or confirmed/suspected Gilbert syndrome, TBIL ≤3 × ULN • ii. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN; For patients with liver metastases, AST and ALT ≤ 5 × ULN • d. Coagulation: prothrombin time (PT) or international normalized ratio (INR) ≤ 1.5 x ULN, and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN (unless abnormalities are unrelated to coagulopathy). This applies only to patients who are not on therapeutic anti- coagulation. Patients receiving therapeutic anti-coagulation should be on a stable dose.\n- Female patients of childbearing age must have negative serum pregnancy test results before randomization or per region-specific guidance documented in the informed consent and a negative urine pregnancy test on the day of first dose prior to dosing.\n- Female patient of childbearing potential having sex with an unsterilized male partner must agree to use a highly effective method of contraception from the beginning of screening until 120 days after the last dose of ivonescimab/pembrolizumab or until 6 months after last dose of chemotherapy (whichever is longer).\n- Male patient having sex with a female partner of childbearing potential, or a pregnant or breastfeeding partner, must agree to use barrier contraception (male condom) for the duration of the treatment period until 120 days after the last dose of ivonescimab/pembrolizumab and/or until 6 months after last dose of chemotherapy (whichever is longer). Male patients with female partners of childbearing potential must have the female partner agree to use at least 1 form of highly effective contraception for the duration of the treatment period until 120 days after the last dose of ivonescimab/pembrolizumab or until 6 months after last dose of chemotherapy (whichever is longer)."}

Exclusion criteria

• {"criterion_text":"- Histologic or cytopathologic evidence of the presence of small cell lung carcinoma.\n- Patients with > 30 Gy of chest radiation therapy within 6 months prior to randomization; non-thoracic radiation therapy > 30 Gy within 4 weeks prior to randomization, or palliative radiation therapy of ≤ 30 Gy within 7 days prior to randomization\n- Has pre-existing peripheral neuropathy that is ≥ Grade 2 by Common Terminology Criteria for Adverse Events (CTCAE) version 5\n- Live vaccine or live attenuated vaccine within 4 weeks prior to planned randomization, or if scheduled to receive a live vaccine or live attenuated vaccine during the study period. Inactivated vaccines are permitted.\n- Severe infection within 4 weeks prior to randomization, including but not limited to comorbidities requiring hospitalization, sepsis, or severe pneumonia; active infection (as determined by the investigator) requiring systemic anti-infective therapy within 2 weeks prior to randomization (excluding antiviral therapy for hepatitis B or C)\n- Major surgical procedures or serious trauma within 4 weeks prior to randomization, or plans for major surgical procedures within 4 weeks after the first dose (as determined by the investigator). Minor local procedures (excluding central venous catheterization and port implantation) within 3 days prior to randomization.\n- History of bleeding tendencies or coagulopathy and/or clinically significant bleeding symptoms or risk within 4 weeks prior to randomization, including but not limited to: a. Hemoptysis (defined as coughing up ≥ 0.5 teaspoon of fresh blood or small blood clots) Note: transient hemoptysis associated with diagnostic bronchoscopy is allowed. b. Nasal bleeding /epistaxis (bloody nasal discharge is allowed). c. Current use of prophylactic or full-dose anticoagulants or anti-platelet agents for therapeutic purposes that is not stable prior to randomization is not allowed. The use of full-dose anticoagulants is permitted as long as the INR or activated partial thromboplastin time (aPTT) is within therapeutic limits according to the medical standard of the enrolling institution.\n- Poorly controlled hypertension with repeated systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg after oral antihypertensive therapy\n- Uncontrolled pleural effusions, pericardial effusions, or ascites that is clinically symptomatic. Note: Patients managed with indwelling catheters (eg, PleurX) are allowed.\n- History of non-infectious pneumonia requiring systemic corticosteroids, or current interstitial lung disease\n- Active or prior history of inflammatory bowel disease (eg, Crohn’s disease, ulcerative colitis, or chronic diarrhea)\n- Known actionable genomic alterations (epidermal growth factor receptors [EGFR], anaplastic lymphoma kinase [ALK], ROS1, and BRAF V600E) for which first-line approved therapies are available. For non-squamous histology patients, actionable driver mutation testing results are required before randomization.\n- Known history of human immunodeficiency virus (HIV) whose viral load is not controlled\n- Current use of systemic corticosteroids (≥10 mg daily prednisone or equivalent)\n- Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation\n- Patients with active hepatitis B are required to have stable or declining levels of hepatitis B DNA by PCR on appropriate anti-viral therapy with acceptable tolerability for one month prior to randomization. All active hepatitis C patients (hepatitis C virus [HCV] antibody positive with HCV RNA levels above the lower limit of detection) are excluded.\n- Known allergy to any component of any study drug; known history of severe hypersensitivity to other monoclonal antibodies\n- History or current evidence of any condition (medical [including adverse events from prior anti-cancer therapy, disorders secondary to tumor], surgical or psychiatric [including substance abuse]), or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, might lead to higher medical risk and/or is not in the best interest of the subject to participate, in the opinion of the treating investigator\n- Patient is breastfeeding or plans to breastfeed during the study\n- Other conditions where the investigator considers the patient inappropriate for enrollment\n- Has received any prior therapy for NSCLC in the metastatic setting. Note: Local radiation therapy (plus/minus corticosteroids) for CNS or bone metastases is allowed.\n- Concurrent enrollment in another clinical study, unless patient is enrolled in a non-interventional clinical study or is completing survival follow-up.\n- Imaging during the screening period shows that the patient has: a. Radiologically documented evidence of major blood vessel invasion (central pulmonary artery, central pulmonary veins, aorta, brachiocephalic artery, common carotid artery, subclavian artery, superior vena cava) or tumor invading organs (heart, pericardium, trachea, esophagus, central bronchi [not including segmental bronchi]) or if there is a risk of esophagotracheal or esophagopleural fistula in the opinion of the investigator. b. Radiographic evidence of major blood vessel encasement with narrowing of the vessel or intratumor lung cavitation or necrosis that the investigator determines will pose a significantly increased risk of bleeding.\n- Symptomatic CNS metastases, CNS metastasis with hemorrhagic features, CNS metastasis ≥ 1.5 cm, CNS radiation within 7 days prior to randomization, potential need for CNS radiation within the first cycle, or leptomeningeal disease Note: Patients must have stopped corticosteroids or be on stable corticosteroid therapy (prednisone ≤ 10 mg daily or equivalent)."}

Primary endpoints

• {"endpoint_text":"- Overall Survival (OS)","definition_or_measurement_approach":"To compare overall survival (OS) between ivonescimab combined with platinum-doublet chemotherapy and pembrolizumab combined with platinum-doublet chemotherapy."}
• {"endpoint_text":"- PFS assessed by IRRC based on RECIST v1.1","definition_or_measurement_approach":"To compare independent radiology review committee (IRRC) assessed progression-free survival (PFS) based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 between ivonescimab combined with platinum-doublet chemotherapy and pembrolizumab combined with platinum-doublet chemotherapy."}

Secondary endpoints

• {"endpoint_text":"- ORR and DoR assessed by IRRC based on RECIST v1.1","definition_or_measurement_approach":"Objective response rate (ORR) and duration of response (DoR) as assessed by the Independent Radiology Review Committee (IRRC) using RECIST v1.1."}
• {"endpoint_text":"- Safety assessment: incidence and severity of adverse events (AEs) and clinically significant abnormal laboratory test results","definition_or_measurement_approach":"Incidence and severity grading of adverse events and clinically significant abnormal laboratory test results (per study safety reporting procedures)."}
• {"endpoint_text":"- PK characteristics: ivonescimab serum drug concentrations profiles","definition_or_measurement_approach":"Pharmacokinetic assessment of ivonescimab serum concentration-time profiles."}
• {"endpoint_text":"- Immunogenicity: number and percentage of patients with detectable anti-ivonescimab antibody (ADA) at baseline and post treatment","definition_or_measurement_approach":"Detection and reporting of anti-ivonescimab antibodies (ADA) at baseline and post-treatment; number and percentage of patients with detectable ADA."}

Primary sponsor

Full Name

Summit Therapeutics Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Next CRO SYMVOULOI FARMAKEUTIKON EPICHEIRISEON M.E.P.E.

Responsibilities

Duties codes: 1, 12

Name

Fortrea Inc.

Responsibilities

Safety Database hosting, SAE Management, Submission of SAEs/SUSARs to RAs (except FDA), ECs, and Sites; submissions of annual reports/DSUR to all RAs (except FDA) & ECs.

Name

Medidata Solutions Inc.

Responsibilities

Medidata RAVE and RSTM

Name

Veeva Systems Inc.

Responsibilities

Electronic Trial Master File

Name

Ice Global Consulting Inc.

Responsibilities

Site CDA, Budgets, Contracts

Name

Precision for Medicine (HU) Kft.

Responsibilities

Start-up, clinical operations management, feasibility, site services, vendor management, TMF and CTMS maintenance

Name

Almac Clinical Services Limited

Responsibilities

QP GMP Certification and as manufacturer and importer

Third parties

• {"country":"Greece","full_name":"Next CRO SYMVOULOI FARMAKEUTIKON EPICHEIRISEON M.E.P.E.","duties_or_roles":"Sponsor duties codes: 1, 12","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"Medidata RAVE and RSTM","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Veeva Systems Inc.","duties_or_roles":"Electronic Trial Master File","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Fortrea Inc.","duties_or_roles":"Safety Database hosting, SAE Management, Submission of SAEs/SUSARs to the RAs (except FDA), ECs, and Sites; Submissions of annual reports/DSUR to all RAs (except FDA) & ECs.","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Ice Global Consulting Inc.","duties_or_roles":"Site CDA, Budgets, Contracts","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Hungary","full_name":"Precision for Medicine (HU) Kft.","duties_or_roles":"Start-up, Clinical operations management, Feasibility, Site services, Vendor management, TMF Maintenance, CTMS Maintenance; duties codes include 1,12,15,2,5,9","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom (Northern Ireland)","full_name":"Almac Clinical Services Limited","duties_or_roles":"QP GMP Certification and as manufacturer and importer","organisation_type":"Pharmaceutical company"}