A Randomized, Controlled, Multiregional Phase 3 Study of Ivonescimab Combined With Chemotherapy Versus Pembrolizumab Combined With Chemotherapy for the First-line Treatment of Metastatic Squamous Non-small Cell Lung Cancer (HARMONi-3)

JRCT ID: jRCT2031230688

Registered date:11/03/2024

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Squamous Non-small Cell Lung Cancer
• Date of first enrollment: 18/03/2024
• Target sample size: 36
• Countries of recruitment: US,Japan,Canada,Japan,Germany,Japan,Greece,Japan,Ireland,Japan,Italy,Japan,Poland,Japan,Spain,Japan,China,Japan
• Study type: Interventional

Intervention(s)

Drug : ivonescimab, Pembrolizumab
[Monotherapy Part] The subjects will receive 20 mg / kg Q3W ivonescimab. A fixed dose of 3200 mg for ivonescimab should be used for patients >= 160 kg.
[Phase III Part] The subjects will receive up to 4 cycles of ivonescimab or pembrolizumab with chemotherapy (carboplatin-paclitaxel/nab-paclitaxel) once every 3 weeks (Q3W) followed by single-agent ivonescimab or pembrolizumab maintenance therapy Q3W.

Outcome(s)

Primary Outcome

[Monotherapy Part]
- Safety assessment: dose limiting toxicities (DLTs), incidence and severity of adverse events (AEs) and clinically significant abnormal laboratory test results
- PK characteristics: ivonescimab serum drug concentrations profiles
[Phase III Part]
- OS

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

Monotherapy Part :
1. Voluntarily sign a written informed consent form (ICF)
2. Age >= 18 years old at the time of enrollment
3. ECOG performance status score of 0 or 1
4. Expected life expectancy >= 3 months
5. Advanced or metastatic NSCLC, according to American Joint Committee on Cancer (AJCC) 8th edition with no standard of care treatment options available
6. Adequate Organ Function:
Phase 3 Part :
1. Voluntarily sign a written informed consent form (ICF)
2. Age >= 18 years old at the time of enrollment
3. ECOG performance status score of 0 or 1
4. Expected life expectancy >= 3 months
5. Metastatic (Stage IV) NSCLC, according to American Joint Committee on Cancer
(AJCC) 8th edition
6. Histologically or cytologically confirmed squamous NSCLC. Patients with mixed histology (eg, adenosquamous) are allowed if there is squamous component.
7. Patients must have Tumor Proportion Score (TPS) with PD-L1 expression percent or provide tissue for measurement of PD-L1 expression.
8. At least one measurable noncerebral lesion according to RECIST 1.1.
9. No prior systemic treatment for metastatic NSCLC. Patients receiving adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 12 months prior to the development of metastatic disease.
10. Adequate Organ Function:
11. 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.

Exclude criteria

Monotherapy Part :
1. Concurrent enrollment in another clinical study
2. Received systemic therapy within 4 weeks prior to enrollment; received nonspecific immunomodulatory therapy (eg, interleukin, interferon, thymus peptide, tumor necrosis factor) within 2 weeks prior to enrollment, excluding IL-11 for the treatment of thrombocytopenia.
3. Imaging during the screening period shows that the patient has:
a. Radiologically documented evidence of major blood vessel invasion or encasement by cancer
b. Radiographic evidence of intratumor cavitation
4. Symptomatic CNS metastases, CNS metastasis >=1.5 cm, CNS radiation within 2 weeks prior to enrollment, potential need for CNS radiation within the first cycle, or leptomeningeal disease
5. Other prior malignancy
6. Active autoimmune or lung disease requiring systemic therapy (eg, with disease- modifying drugs, prednisone >=10 mg daily or equivalent, immunosuppressant therapy) within 2 years prior to enrollment
7. History of major diseases before enrollment
8. Live vaccine or live attenuated vaccine within 4 weeks prior to planned enrollment, or if scheduled to receive a live vaccine or live attenuated vaccine during the study period. Inactivated vaccines are permitted.
9. Severe infection within 4 weeks prior to enrollment, including but not limited to comorbidities requiring hospitalization, sepsis, or severe pneumonia; active infection requiring systemic anti-infective therapy within 2 weeks prior to enrollment.
10. Major surgical procedures or serious trauma within 4 weeks prior to enrollment, 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 enrollment.
11. History of bleeding tendencies or coagulopathy and/or clinically significant bleeding symptoms or risk within 4 weeks prior to enrollment
12. Current hypertension after oral antihypertensive therapy
13. Presence of pleural effusions, pericardial effusions, or ascites that is clinically symptomatic or requires repeated drainage
14. History of noninfectious pneumonia requiring systemic corticosteroids, or current interstitial lung disease
15. Active or prior history of inflammatory bowel disease
16. Known history of HIV
17. Current use of systemic corticosteroids (>=10 mg daily prednisone or equivalent)
18. Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation
19. History of hepatitis B or active hepatitis B, patients with active hepatitis C
20. Known allergy to any component of any study drug; known history of severe hypersensitivity to other monoclonal antibodies interest of the subject to participate, in the opinion of the treating investigator
21. Patient is breastfeeding or plans to breastfeed during the study
22. Other conditions where the investigator considers the patient inappropriate for enrollment
Phase 3 Part :
1. Histologic or cytopathologic evidence of the presence of small cell lung carcinoma, or non-squamous NSCLC histology.
2. Known actionable genomic alterations in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or ROS1 or genes for which first-line approved therapies are available
3. Has received any prior therapy for NSCLC in the metastatic setting
Note: Local therapy (plus/minus corticosteroids) for CNS or bone metastases is allowed.
4. Concurrent enrollment in another clinical study, unless patient is enrolled in a non- interventional clinical study
5. Imaging during the screening period shows that the patient has:
a. Radiologically documented evidence of major blood vessel invasion or encasement by cancer
b. Radiographic evidence of intratumor cavitation
6. Symptomatic CNS metastases, CNS metastasis >=1.5 cm, CNS radiation within 2 weeks prior to randomization, potential need for CNS radiation within the first cycle, or leptomeningeal disease
7. Other prior malignancy
8. Active autoimmune or lung disease requiring systemic therapy (eg, with disease- modifying drugs, prednisone >=10 mg daily or equivalent, immunosuppressant therapy) within 2 years prior to randomization
9. History of major diseases before randomization
10. 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 2 weeks prior to randomization
11. Has pre-existing peripheral neuropathy
12. 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.
13. Severe infection within 4 weeks prior to randomization, including but not limited to comorbidities requiring hospitalization, sepsis, or severe pneumonia; active infection requiring systemic anti-infective therapy within 2 weeks prior to randomization (excluding antiviral therapy for hepatitis B or C)
14. 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.
15. History of bleeding tendencies or coagulopathy and/or clinically significant bleeding symptoms or risk within 4 weeks prior to randomization
16. Current hypertension after oral antihypertensive therapy
17. Presence of pleural effusions, pericardial effusions, or ascites that is clinically symptomatic or requires repeated drainage
18. History of noninfectious pneumonia requiring systemic corticosteroids, or current interstitial lung disease
19. Active or prior history of inflammatory bowel disease
20. Known history of HIV
21. Current use of systemic corticosteroids (>=10 mg daily prednisone or equivalent)
22. Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation
23. Patients with active hepatitis B or active hepatitis C
24. Known allergy to any component of any study drug; known history of severe hypersensitivity to other monoclonal antibodies
26. Patient is breastfeeding or plans to breastfeed during the study
27. Other conditions where the investigator considers the patient inappropriate for enrollment

Related Information

• Primary Sponsor: Noam Frey
• Secondary ID(s): NCT05899608