Phase III Study of AK112 for NSCLC Patients

Non-Squamous Non-small Cell Lung Cancer Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06396065
• Other study ID #: AK112-301 (HARMONi)
• Status: Recruiting
• Phase: Phase 3
• Start date: May 4, 2023
• Est. completion date: December 31, 2025

Study information

• Verified date: June 2024
• Source: Summit Therapeutics
• Contact: Lori Styles, MD
• Phone: 1-833-256-0522
• Email: medicalinformation[@]smmttx.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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)

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 420
• Est. completion date: December 31, 2025
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Non-Squamous Non-small Cell Lung Cancer

Intervention

Drug:
• AK112 Injection
Subjects will receive AK112 Plus Pemetrexed and Carboplatin via intravenous infusion (IV) Q3W, up to 4 cycles. Afterward, AK112 Plus Pemetrexed will be used for maintenance treatment (administered on Day 1 of each cycle, Q3W) up to 2 years.
• Placebo Injection
Subjects will receive Placebo Plus Pemetrexed and Carboplatin via intravenous infusion (IV) Q3W, up to 4 cycles in treatment periods per the randomization schedule. Afterward, Placebo Plus Pemetrexed will be used for maintenance treatment (administered on Day 1 of each cycle, Q3W) up to 2 years.

Locations

Country	Name	City	State
Canada	Cross cancer Institute	Edmonton	Alberta
Canada	Lung Cancer Canada	Ottawa	Ontario
Canada	Universite Hospital Laval	Québec
Canada	Allan Blaire Cancer Centre	Regina	Saskatchewan
Canada	Princess Margaret Cancer Centre	Toronto	Ontario
Canada	BC Cancer	Vancouver	British Columbia
France	CHI Creteil	Creteil
France	Léon Bérard Cancer Center, Lyon	Lyon
France	Hospital Bichat-Claude Bernard	Paris
France	Institut Curie	Paris
France	Gustave Roussy Cancer	Villejuif
Italy	Istituto Nazionale dei Tumori	Milan
Italy	Instituto Europeo di Oncologia	Milano
Italy	University Hospital of Parma	Parma
Italy	Campus Bio-Medico University	Roma
Italy	Istituto Nazionale Tumori Regina Elena	Roma
Italy	Istituto Nazionale Tumori, Regina Elena	Rome
Spain	Badalona-Hospital Germans Trias i Pujol	Barcelona
Spain	Vall d'Hebron Institute of Oncology	Barcelona
Spain	Hospital Teresa Herrera	Coruña
Spain	omplejo Hospitalario Universitario Insular-Materno Infantil de Gran Canaria	Las Palmas
Spain	Lucus Augusti University Hospital	Lugo
Spain	Hospital General Universitario Gregorio Maranon	Madrid
Spain	Hospital Universitario Clinico San Carlos	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz	Madrid
Spain	Puerta de Hierro University Hospital	Majadahonda
Spain	Hospital Regional Universitario de Malaga	Malaga
Spain	Hospital Universitario Nuestro Senora de Valme	Sevilla
United Kingdom	The Royal Marsden	London
United Kingdom	The Christie NHS Foundation Trust	Manchester
United States	New York Oncology/Hematology	Albany	New York
United States	Texas Oncology South Austin	Austin	Texas
United States	CBCC Global Research	Bakersfield	California
United States	Hematology/Oncology Clinic - SCRI	Baton Rouge	Louisiana
United States	American Oncology Partners	Bethesda	Maryland
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Medical University South Carolina	Charleston	South Carolina
United States	Zangmeister Cancer Center	Columbus	Ohio
United States	Texas Oncology Baylor Charles A. Sammons Cancer Center	Dallas	Texas
United States	Williamette Valley Cancer Institute and Research	Eugene	Oregon
United States	Virginia Cancer specialisits	Fairfax	Virginia
United States	Oncology Hematology Care	Fairfield	Ohio
United States	Sanford Roger Maris Cancer Center	Fargo	North Dakota
United States	The Oncology Institute of Hope & Innovation	Fort Lauderdale	Florida
United States	MD Anderson University of Texas	Houston	Texas
United States	UC San Diego	La Jolla	California
United States	Rocky Mountain Cancer Center	Lone Tree	Colorado
United States	UCLA Department of Medicine - Hematology/Oncology	Los Angeles	California
United States	University of Southern California	Los Angeles	California
United States	Valkyrie Clinical Trials	Los Angeles	California
United States	University of Miami	Miami	Florida
United States	Palo Alto Medical Foundation Research Institute	Mountain View	California
United States	NYU Langone Laura and Isaac Perlmutter Cancer Center	New York	New York
United States	Florida Cancer Associates - Ocala Oncology	Ocala	Florida
United States	Providence St. Joseph	Orange	California
United States	UC Irvine	Orange	California
United States	BRCR Global	Plantation	Florida
United States	Kaiser Permanente Northwest	Portland	Oregon
United States	Sutter Cancer center	Sacramento	California
United States	UC DAVIS Comprehensive Cancer Center	Sacramento	California
United States	HealthPartners Cancer Research Center	Saint Paul	Minnesota
United States	Florida Cancer Specialists - North	Saint Petersburg	Florida
United States	Sharp Memorial Hospital	San Diego	California
United States	California Pacific Medical Center	San Francisco	California
United States	Providence Medical Foundation	Santa Rosa	California
United States	New England Cancer Specialists	Scarborough	Maine
United States	BRCR Global	Tamarac	Florida
United States	Compass Oncology	Vancouver	Washington
United States	Texas Oncology Webster	Webster	Texas
United States	Florida Cancer Specialists -East	West Palm Beach	Florida
United States	Presbyterian Intercommunity Hospital	Whittier	California

Sponsors (2)

Lead Sponsor	Collaborator
Summit Therapeutics	Akeso

Countries where clinical trial is conducted

United States,  Canada,  France,  Italy,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free survival (PFS)	Progression-free survival (PFS) assessed by IRC per RECIST v1.1 in the ITT population.	Up to 2 years
Primary	Overall Survival (OS) in the ITT population	Overall Survival (OS) in the ITT population	Up to 2 years
Secondary	ORR	Efficacy measures such as overall response rate (ORR) and duration of response (DoR), which is the proportion of subjects with CR or PR by IRRC based on RECIST v1.1	Up to 2 years
Secondary	AE	Incidence and severity of adverse events (AEs) and serious adverse events (SAEs), and clinically significant abnormal laboratory results.	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
Secondary	Observed concentrations of AK112	The endpoints for assessment of PK of AK112 include serum concentrations of AK112 at different timepoints after AK112 administration	through study completion, an average of 2 years
Secondary	Number of subjects who develop detectable anti-drug antibodies (ADAs)	The immunogenicity of AK112 will be assessed by summarizing the number of subjects who develop detectable antidrug antibodies (ADAs)	From first dose of AK112 through 90 days after last dose of AK112, up to 2 years
Secondary	DoR	Duration of response (DoR) which is the proportion of subjects with CR or PR by IRRC based on RECIST v1.1	Up to 2 years