HARMONi-3

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Summit Therapeutics Sub Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2024-01-05

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Summit Therapeutics Sub, Inc.

External identifiers

EU CT number

2023-504989-37-00

ClinicalTrials.gov

NCT05899608

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy

To compare overall survival (OS) between ivonescimab combined with carboplatin and paclitaxel or nab-paclitaxel versus pembrolizumab combined with carboplatin and paclitaxel or nab-paclitaxel

Secondary objectives 5

1. To compare investigator assessed PFS based on RECIST v1.1 between ivonescimab combined with carboplatin and paclitaxel or nab-paclitaxel and pembrolizumab combined with carboplatin and paclitaxel or nab-paclitaxel
2. To compare the ORR and DoR between ivonescimab combined with carboplatin and paclitaxel or nab-paclitaxel versus pembrolizumab combined with carboplatin and paclitaxel or nab-paclitaxel, as assessed by investigator, based on RECIST v1.1
3. To evaluate the safety and tolerability of ivonescimab in combination with carboplatin and paclitaxel or nab-paclitaxel and compare to pembrolizumab combined with carboplatin and paclitaxel or nab-paclitaxel
4. To evaluate the pharmacokinetic profile of ivonescimab in combination with carboplatin and paclitaxel or nab-paclitaxel
5. To evaluate the immunogenicity of ivonescimab

Conditions and MedDRA coding

Metastatic Squamous Non-small Cell Lung Cancer

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-003378-PIP01-23

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. 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 (from available reports or archival tumor tissue based on a clinical assay) or provide tissue for measurement of PD-L1 expression
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. Sites of biopsy cannot be included as target lesions unless no other measurable lesions are present
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. Note: Patients previously treated with PD-1/L1 inhibitors in the adjuvant / neoadjuvant setting are excluded.
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 (adjustment by BSA is not required for eGFR) CrCL or eGFR can be determined using the calculator from the National Kidney Foundation website (www.kidney.org). 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 × ULN, and partial prothrombin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN (unless abnormalities are unrelated to coagulopathy or prophylactic coagulation)
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 the study treatment.
13. Unsterilized male patient having sex with a female partner of childbearing potential must agree to use an effective method of contraception from the beginning of screening until Day 120 after the last dose of study treatment and until 6 months after last carboplatin dose (whichever is longer).

Exclusion criteria 27

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 noninterventional 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 Note: Patients with asymptomatic and untreated metastasis are eligible if the lesion is ≤ 0.5 cm and does not have hemorrhagic features. Patients with asymptomatic treated brain metastasis are eligible if the lesion is < 1.5 cm. Patients must have stopped corticosteroids for more than 3 days before randomization.
7. Other prior malignancy, with the following exceptions: a. If the patient has undergone curative therapy with no evidence of recurrence of the disease for 3 years prior to randomization, the following malignancies will be allowed: basal cell or squamous cell carcinoma of skin; superficial bladder cancer; and in situ cervical cancer, other in situ cancers, or other local tumors that are considered cured (eg, prostate cancer). b. If the patient was treated with systemic chemotherapy and has no evidence of recurrence of the prior malignancy for at least 5 years prior to randomization, the patient will be allowed to enroll into the study.
8. Active autoimmune or lung disease requiring systemic therapy (eg, with diseasemodifying 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. Intermittent 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 vascular disease (eg, aortic aneurysm at risk of rupture) 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 arterial thromboembolic event, venous thromboembolic event of Grade 3 and above 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 6 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 2 weeks 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 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. Gastrointestinal bleeding b. Hemoptysis (defined as coughing up ≥ 0.5 teaspoon of fresh blood or small blood clots) Note: transient hemoptysis associated with diagnostic bronchoscopy is allowed. c. Nasal bleeding /epistaxis (bloody nasal discharge is allowed) d. Need for therapeutic anticoagulant therapy within 14 days prior to randomization Note: Prophylactic anticoagulation for DVT/PE or to maintain venous patency is allowed.
16. Current hypertension with systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg 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 (eg, Crohn’s disease, ulcerative colitis, or chronic diarrhea)
20. Known history of human immunodeficiency virus (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 untreated active hepatitis B are required to receive anti-hepatitis B virus (HBV) therapy for the duration of study treatment; all active hepatitis C patients (hepatitis C virus [HCV] antibody positive and 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 1

1. Overall Survival (OS)

Secondary endpoints 5

1. PFS assessed by investigator based on RECIST v1.1
2. ORR (including DoR) assessed by investigator based on RECIST v1.1
3. Safety assessment: incidence and severity of adverse events (AEs) and clinically significant abnormal laboratory test results
4. PK characteristics: ivonescimab serum drug concentrations profiles
5. 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 1

Comparator 1

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Summit Therapeutics Sub Inc.

Sponsor organisation

Summit Therapeutics Sub Inc.

Address

2882 Sand Hill Road Suite 106

City

Menlo Park

Postcode

94025-7057

Country

United States

Scientific contact point

Organisation

Summit Therapeutics Sub Inc.

Contact name

Medical Information

Public contact point

Organisation

Summit Therapeutics Sub Inc.

Contact name

Medical Information

Third parties 1

Locations

7 EU/EEA countries · 47 investigational sites

By country

Investigational sites

Application history

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