HARMONi-3

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Summit Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

10 Sep 2024 → ongoing

Decision date (initial)

2025-05-28

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Summit Therapeutics Sub, Inc.

External identifiers

EU CT number

2024-513087-26-00

ClinicalTrials.gov

NCT05899608

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacokinetic, Safety

• To compare overall survival (OS) between ivonescimab combined with platinum-doublet chemotherapy and pembrolizumab combined with platinum-doublet chemotherapy.
• 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 objectives 4

1. To compare the objective response rate (ORR) and duration of response (DoR) between ivonescimab combined with platinum-doublet chemotherapy versus pembrolizumab combined with platinum-doublet chemotherapy, as assessed by IRRC, based on RECIST v1.1
2. To evaluate the safety and tolerability of ivonescimab in combination with platinum-doublet chemotherapy and compare to pembrolizumab combined with platinum-doublet chemotherapy
3. To evaluate the pharmacokinetic (PK) profile of ivonescimab in combination with platinum-doublet chemotherapy
4. To evaluate the immunogenicity of ivonescimab

Conditions and MedDRA coding

Metastatic Non-small Cell Lung Cancer

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-003378-PIP01-23

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Voluntarily sign a written informed consent form (ICF)
2. Age ≥ 18 years old at the time of enrollment
3. Eastern Cooperative Oncology Group (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 or non-squamous NSCLC.
7. 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.
8. 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.
9. 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.
10. 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 • ii. 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.
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.
12. 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).
13. 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 27

1. Histologic or cytopathologic evidence of the presence of small cell lung carcinoma.
2. 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.
3. 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.
4. Concurrent enrollment in another clinical study, unless patient is enrolled in a non-interventional clinical study or is completing survival follow-up.
5. 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.
6. 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).
7. Other prior malignancy unless the patient has undergone curative therapy with no evidence of disease recurrence within 3 years prior to randomization. The following malignancies will be allowed without the 3-year interval after adequate treatment: basal cell or squamous cell carcinoma of skin, superficial bladder cancer, in situ cervical cancer, other in situ cancers, or other local tumors (e.g. prostate cancer) that are considered cured.
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, however the following will be allowed: a. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is permitted. b. Use of bronchodilators, inhaled corticosteroids, or local corticosteroid injections is permitted.
9. History of major diseases before randomization, specifically: a. Unstable angina, myocardial infarction, congestive heart failure (New York Heart Association [NYHA] classification ≥ grade 2) or unstable vascular disease (eg, aortic aneurysm at risk of rupture, Moyamoya disease) that required hospitalization within 12 months prior to randomization, or other cardiac impairment that may affect the safety evaluation of the study drug (eg, poorly controlled arrhythmias, myocardial ischemia) b. History of esophageal gastric varices, severe ulcers, wounds that do not heal, abdominal fistula, intra-abdominal abscesses, or acute gastrointestinal bleeding within 6 months before randomization c. History of any grade arterial thromboembolic event, Grade 3 and above venous thromboembolic event as specified in National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 5.0, transient ischemic attack, cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathy within 12 months prior to randomization d. Acute exacerbation of chronic obstructive pulmonary disease within 4 weeks before randomization e. 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) within 6 months prior to 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 7 days prior to randomization
11. Has pre-existing peripheral neuropathy that is ≥ Grade 2 by Common Terminology Criteria for Adverse Events (CTCAE) version 5
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 (as determined by the investigator) 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, 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.
16. Poorly controlled hypertension with repeated systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg after oral antihypertensive therapy
17. Uncontrolled pleural effusions, pericardial effusions, or ascites that is clinically symptomatic. Note: Patients managed with indwelling catheters (eg, PleurX) are allowed.
18. History of non-infectious pneumonia requiring systemic corticosteroids, or current interstitial lung disease
19. Active or prior history of inflammatory bowel disease (eg, Crohn’s disease, ulcerative colitis, or chronic diarrhea)
20. Known history of human immunodeficiency virus (HIV) whose viral load is not controlled
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 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.
24. Known allergy to any component of any study drug; known history of severe hypersensitivity to other monoclonal antibodies
25. 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
26. Patient is breastfeeding or plans to breastfeed during the study
27. Other conditions where the investigator considers the patient inappropriate for enrollment

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Overall Survival (OS)
2. PFS assessed by IRRC based on RECIST v1.1

Secondary endpoints 4

1. ORR and DoR assessed by IRRC based on RECIST v1.1
2. Safety assessment: incidence and severity of adverse events (AEs) and clinically significant abnormal laboratory test results
3. PK characteristics: ivonescimab serum drug concentrations profiles
4. Immunogenicity: number and percentage of patients with detectable anti-ivonescimab antibody (ADA) at baseline and post treatment

Investigational products

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

Test 6

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Summit Therapeutics Inc.

Sponsor organisation

Summit Therapeutics Inc.

Address

2882 Sand Hill Road Suite 106

City

Menlo Park

Postcode

94025-7057

Country

United States

Scientific contact point

Organisation

Summit Therapeutics Inc.

Contact name

Medical Information

Public contact point

Organisation

Summit Therapeutics Inc.

Contact name

Medical Information

Third parties 7

Locations

9 EU/EEA countries · 86 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Corrective measures 1 · Art. 77 CTR

Results and documents

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

Documents 77 files

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

Application history

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