Clinical trial NCT06396065: Phase III Study of AK112 for NSCLC Patients
Official title: A Randomized, Double-blind, Multi-center, Phase III Study of AK112 or Placebo Combined with Pemetrexed and Carboplatin in Patients with EGFR-mutant Locally Advanced or Metastatic Non-squamous NSCLC Who Have Failed to EGFR-TKI Treatment
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Non-Squamous Non-small Cell Lung Cancer
Keywords: NSCLC
EGFR Positive
ivonescimab
Lead sponsor: Summit Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: Akeso
First posted: 2024-05-02
Enrollment: 420
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: A Randomized, Double-blind, Multi-center, Phase III Clinical Study of AK112 or Placebo Combined With Pemetrexed and Carboplatin in Patients With EGFR-mutant Locally Advanced or Metastatic Non-squamous Non-small Cell Lung Cancer Who Have Progressed on or Following Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) Treatment (HARMONi)

Detailed description: The trial will be performed as a randomized, Double-Blind, Multicenter trial to compare Ivonescimab (SMT112 /AK112) Plus Pemetrexed and Carboplatin to Placebo Plus Pemetrexed and Carboplatin in Patients with Locally Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Harboring. Approximately 420 subjects will be randomized to two treatment arms at the ratio of 1:1. Each enrolled subject will receive an intravenous infusion of the Ivonescimab (SMT112 /AK112)/Placebo Plus Pemetrexed and Carboplatin (Q3W,up to 4 cycles) in treatment periods per the randomization schedule. Afterward, Ivonescimab (SMT112 /AK112)/ Placebo Plus Pemetrexed will be used for maintenance treatment (administered on Day 1 of each cycle, Q3W) up to 2 years.

Eligibility criteria: Inclusion Criteria:

1. Ability to understand and voluntarily sign a written informed consent form (ICF), which must be signed before the specified study procedures required for the study are performed.
2. Males or females aged ≥ 18 to ≤ 75 years at the time of signing informed consent. (For patients from North America and Europe, there will be no upper age cutoff)
3. ECOG performance status score of 0 or 1.
4. Expected survival ≥3 months.
5. Histologically or cytology-confirmed, locally advanced (Stage IIIB/IIIC) or metastatic (Stage IV) non-squamous NSCLC (according to TNM staging of lung cancer, 8th edition) that cannot be completely resected by surgery and cannot receive radical concurrent/sequential chemoradiation.
6. EGFR activation mutations that are confirmed by tumor histology or cytology or blood test before enrollment (eg, exon 18 point mutations, exon 19 deletions, exon 20 point mutations, and exon 21 point mutations). Patients must provide a previous EGFR mutation test report, otherwise tumor tissue samples, peripheral blood samples, or pleural fluid samples will need to be collected for EGFR status testing prior to enrollment.
7. Prior treatment with EGFR TKI and treatment failure, meeting any of the following requirements: Progression after treatment with first- or second-generation EGFR TKI, and confirmation of absence of T790M mutation after progression (only for patients enrolled in China). Progression after treatment with a third-generation EGFR TKI (eg, osimertinib, ametinib, vometinib). Note, for North America and Europe patients only.
8. According to RECIST v1.1, there is at least 1 measurable noncerebral lesion.
9. Adequate organ function determined by the following requirements
10. Female patients of childbearing age have a negative serum pregnancy test result within 3 days before the first dose
11. If a female patient of childbearing potential has sex with an unsterilized male partner, the patient must use a highly effective method of contraception from the beginning of screening and must agree to continue using these precautions until 120 days after the last dose of the study drug or until 6 months after the last carboplatin and pemetrexed dose (whichever is longer).
12. If an unsterilized male patient has sex with a female partner of childbearing potential, the patient must use an effective method of contraception from the beginning of screening to day 120 after the last dose or until 6 months after the last carboplatin and pemetrexed dose (whichever is longer). The decision to stop contraception after this time point should be discussed with investigator.

Exclusion Criteria:

1. Histologic or cytopathologic evidence of the presence of a small cell carcinoma component, or a predominantly squamous cell carcinoma.
2. Patients who have received immune checkpoint inhibitors (eg, anti-PD-1/L1 antibodies, anti-CTLA-4 antibodies, anti-LAG-3 antibodies, etc.)
3. Received prior systemic chemotherapy, anti-angiogenic therapy, or more than one prior line of antitumor therapy (other than EGFR inhibitors) for advanced stage (IIIB to IV) NSCLC.
4. Concurrent enrollment in another clinical study, unless it is a noninterventional clinical study or the follow-up period of the interventional study is more than 4 weeks from the last dose of the prior clinical study or more than 5 half-lives of the prior study drug, whichever is shorter.
5. Received EGFR inhibitor therapy within 2 weeks (with the exception of osimertinib to be within 7 days) prior to the first dose; received nonspecific immunomodulatory therapy (eg, interleukin, interferon, thymus peptide, tumor necrosis factor) within 2 weeks prior to the first dose, excluding IL-11 for the treatment of thrombocytopenia; have received Chinese herbal medicines or proprietary Chinese medicines with antitumor indications within 1 week before the first dose.
6. Imaging during the screening period shows that the tumor surrounds important blood vessels or has obvious necrosis and/or cavitation of tumor lesions within the lung parenchyma.
7. Imaging during the screening period shows that the tumor invades the surrounding vital organs and blood vessels, such as the heart and pericardium, trachea, esophagus, aorta, superior vena cava, or patient is at risk of esophageal tracheal fistula or esophageal pleural fistula.
8. Symptomatic metastases of the central nervous system.
9. Malignant tumors other than NSCLC within 3 years before the first dose.
10. Active autoimmune disease requiring systemic therapy (eg, with disease-modifying drugs, corticosteroids, immunosuppressant therapy) within 2 years prior to the first dose (excluding ir AEs due to PD-1/L1 inhibitors). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy (prednisone ≤ 10 mg daily or equivalent) for adrenal or pituitary insufficiency) is permitted.
11. There is a history of major diseases before the first dose
12. History of perforation of the gastrointestinal tract and/or fistula, history of gastrointestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition), extensive bowel resection (partial colectomy or extensive small bowel resection, complicated by chronic diarrhea) within 6 months before the first study drug administration.
13. Patients with \>30 Gy of chest radiation therapy within 6 months prior to the first dose, nonthoracic radiation therapy \>30 Gy within 4 weeks prior to the first dose, and palliative radiation therapy of ≤30 Gy within 2 weeks prior to the first dose and failed to recover from the toxicity and/or complications of these interventions to NCI CTCAE Grade ≤1 (except hair loss and fatigue). Palliative radiotherapy for symptom control is permitted if it has been completed at least 2 weeks before the first dose, and no additional radiotherapy for the same lesion is planned.
14. Inactivated vaccines are allowed. Patients are excluded if they have received a live vaccine or live attenuated vaccine within 4 weeks prior to the first dose, or if they are scheduled to receive a live vaccine or live attenuated vaccine during the study period.
15. Severe infection within 4 weeks prior to the first dose, including but not limited to comorbidities requiring hospitalization, sepsis, or severe pneumonia; active infection that has received systemic anti-infective therapy within 2 weeks prior to the first dose (excluding antiviral therapy for hepatitis B or C)

Primary outcomes:
measure: Progression-free survival (PFS)
timeFrame: Up to 2 years
measure: Overall Survival (OS) in the ITT population
timeFrame: Up to 2 years
Secondary outcomes:
measure: ORR
timeFrame: Up to 2 years
measure: AE
timeFrame: From the subject signs the ICF to 30 days (AE) and 90 days (SAE) after the last dose of study treatment or initiation of other anti-tumor therapy, whichever occurs first,up to 2 years
measure: Observed concentrations of AK112
timeFrame: through study completion, an average of 2 years
measure: Number of subjects who develop detectable anti-drug antibodies (ADAs)
timeFrame: From first dose of AK112 through 90 days after last dose of AK112, up to 2 years
measure: DoR
timeFrame: Up to 2 years
Other outcomes:
Locations:
city: Bakersfield
country: United States
facility: CBCC Global Research
state: California
city: La Jolla
country: United States
facility: UC San Diego
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Los Angeles
country: United States
facility: Valkyrie Clinical Trials
state: California
city: Los Angeles
country: United States
facility: UCLA Department of Medicine - Hematology/Oncology
state: California
city: Mountain View
country: United States
facility: Palo Alto Medical Foundation Research Institute
state: California
city: Orange
country: United States
facility: Providence St. Joseph
state: California
city: Orange
country: United States
facility: UC Irvine
state: California
city: Sacramento
country: United States
facility: Sutter Cancer center
state: California
city: Sacramento
country: United States
facility: UC DAVIS Comprehensive Cancer Center
state: California
city: San Diego
country: United States
facility: Sharp Memorial Hospital
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: Santa Rosa
country: United States
facility: Providence Medical Foundation
state: California
city: Whittier
country: United States
facility: Presbyterian Intercommunity Hospital
state: California
city: Lone Tree
country: United States
facility: Rocky Mountain Cancer Center
state: Colorado
city: Fort Lauderdale
country: United States
facility: The Oncology Institute of Hope & Innovation
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Ocala
country: United States
facility: Florida Cancer Associates - Ocala Oncology
state: Florida
city: Plantation
country: United States
facility: BRCR Global
state: Florida
city: Saint Petersburg
country: United States
facility: Florida Cancer Specialists - North
state: Florida
city: Tamarac
country: United States
facility: BRCR Global
state: Florida
city: West Palm Beach
country: United States
facility: Florida Cancer Specialists -East
state: Florida
city: Baton Rouge
country: United States
facility: Hematology/Oncology Clinic - SCRI
state: Louisiana
city: Scarborough
country: United States
facility: New England Cancer Specialists
state: Maine
city: Bethesda
country: United States
facility: American Oncology Partners
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Saint Paul
country: United States
facility: HealthPartners Cancer Research Center
state: Minnesota
city: Clifton Park
country: United States
facility: New York Oncology/Hematology
state: New York
city: New York
country: United States
facility: NYU Langone Laura and Isaac Perlmutter Cancer Center
state: New York
city: New York
country: United States
facility: Mount Sinai
state: New York
city: Fargo
country: United States
facility: Sanford Roger Maris Cancer Center
state: North Dakota
city: Columbus
country: United States
facility: Zangmeister Cancer Center
state: Ohio
city: Fairfield
country: United States
facility: Oncology Hematology Care
state: Ohio
city: Eugene
country: United States
facility: Williamette Valley Cancer Institute and Research
state: Oregon
city: Portland
country: United States
facility: Kaiser Permanente Northwest
state: Oregon
city: Charleston
country: United States
facility: Medical University South Carolina
state: South Carolina
city: Memphis
country: United States
facility: Baptist Hospital
state: Tennessee
city: Austin
country: United States
facility: Texas Oncology South Austin
state: Texas
city: Dallas
country: United States
facility: Texas Oncology Baylor Charles A. Sammons Cancer Center
state: Texas
city: Houston
country: United States
facility: MD Anderson University of Texas
state: Texas
city: Webster
country: United States
facility: Texas Oncology Webster
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer specialisits
state: Virginia
city: Vancouver
country: United States
facility: Compass Oncology
state: Washington
city: Edmonton
country: Canada
facility: Cross cancer Institute
state: Alberta
city: Vancouver
country: Canada
facility: BC Cancer
state: British Columbia
city: Ottawa
country: Canada
facility: Lung Cancer Canada
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Regina
country: Canada
facility: Allan Blaire Cancer Centre
state: Saskatchewan
city: Québec
country: Canada
facility: Universite Hospital Laval
city: Creteil
country: France
facility: CHI Creteil
city: Lyon
country: France
facility: Léon Bérard Cancer Center, Lyon
city: Paris
country: France
facility: Hospital Bichat-Claude Bernard
city: Paris
country: France
facility: Institut Curie
city: Villejuif
country: France
facility: Gustave Roussy Cancer
city: Milan
country: Italy
facility: Istituto Nazionale dei Tumori
city: Milan
country: Italy
facility: Instituto Europeo di Oncologia
city: Parma
country: Italy
facility: University Hospital of Parma
city: Roma
country: Italy
facility: Campus Bio-Medico University
city: Rome
country: Italy
facility: Istituto Nazionale Tumori, Regina Elena
city: Barcelona
country: Spain
facility: Vall d'Hebron Institute of Oncology
city: Barcelona
country: Spain
facility: Badalona-Hospital Germans Trias i Pujol
city: Coruña
country: Spain
facility: Hospital Teresa Herrera
city: Las Palmas
country: Spain
facility: omplejo Hospitalario Universitario Insular-Materno Infantil de Gran Canaria
city: Lugo
country: Spain
facility: Lucus Augusti University Hospital
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario Clinico San Carlos
city: Madrid
country: Spain
facility: Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Majadahonda
country: Spain
facility: Puerta de Hierro University Hospital
city: Malaga
country: Spain
facility: Hospital Regional Universitario de Malaga
city: Sevilla
country: Spain
facility: Hospital Universitario Nuestro Senora de Valme
city: London
country: United Kingdom
facility: The Royal Marsden
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
Study officials:
References: