IRB Study Number 23-1011
Status Recruiting
Institute Taussig Cancer Institute
Description
2.1.1 Primary Objective
• To compare OS between ivonescimab combined with carboplatin and paclitaxel or nabpaclitaxel versus pembrolizumab combined with carboplatin and paclitaxel or nabpaclitaxel
2.1.2 Secondary Objectives
• To compare investigator assessed PFS based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 between ivonescimab combined with carboplatin and paclitaxel or nab-paclitaxel and pembrolizumab combined with carboplatin and paclitaxel or nabpaclitaxel
• To compare the objective response rate (ORR) and duration of response (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
• 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
• To evaluate the pharmacokinetic profile of ivonescimab in combination with carboplatin and paclitaxel or nab-paclitaxel
• To evaluate the immunogenicity of ivonescimab
Inclusion Criteria
Voluntarily sign a written informed consent form (ICF)
Age ≥ 18 years old at the time of enrollment
ECOG performance status score of 0 or 1
Expected life expectancy ≥ 3 months
Metastatic (Stage IV) NSCLC, according to American Joint Committee on Cancer
(AJCC) 8th edition
Histologically or cytologically confirmed squamous or non-squamous NSCLC
Patients must have a TPS for PD-L1 expression prior to randomization. The TPS score can be obtained from an existing report or be performed any time before study entry using archival tissue utilizing a clinical assay approved/cleared by local health authorities. If site is unable to perform a TPS score locally, then the site should provide tumor tissue (fresh or archival) for central TPS determination.
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
No prior systemic treatment for metastatic NSCLC. Patients receiving adjuvant or neoadjuvant chemotherapy 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
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 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 anticoagulation. Patients receiving therapeutic anti-coagulation should be on a stable dose.
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.
Female patient of childbearing potential having sex with an unsterilized male partner must agree to use a highly effective method of contraception (see Section 4.3.4) 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).
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) (see Section 4.3.4) 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
Tumor-related features and treatment:
Histologic or cytopathologic evidence of the presence of small cell lung carcinoma
Known actionable genomic alterations (EGFR, 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.
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.
Concurrent enrollment in another clinical study, unless patient is enrolled in a non- interventional clinical study or is completing survival follow-up
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, 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.
- Symptomatic CNS metastases, 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 with asymptomatic and untreated brain 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 or be on stable corticosteroid therapy (prednisone ≤ 10 mg daily or equivalent).
Past medical history and comorbidities:
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 that are considered cured.
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:
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is permitted.
Intermittent use of bronchodilators, inhaled corticosteroids, or local corticosteroid injections is permitted.
- 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
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
Has pre-existing peripheral neuropathy that is ≥ Grade 2 by Common Terminology Criteria for Adverse Events (CTCAE) version 5.
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.
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)
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.
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 international normalized ratio (INR) or activated partial thromboplastin time (aPTT) is within therapeutic limits according to the medical standard of the enrolling institution.
Poorly controlled hypertension with repeated systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg after oral antihypertensive therapy
Uncontrolled pleural effusions, pericardial effusions, or ascites that is clinically symptomatic Note: Patients managed with indwelling catheters (eg, PleurX) are allowed.
History of non-infectious pneumonia requiring systemic corticosteroids, or current interstitial lung disease
Active or prior history of inflammatory bowel disease (eg, Crohn’s disease, ulcerative colitis, or chronic diarrhea)
Known history of human immunodeficiency virus (HIV) whose viral load is not controlled
Current use of systemic corticosteroids (>10mg daily prednisone or equivalent)
Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation
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.
Known allergy to any component of any study drug; known history of severe hypersensitivity to other monoclonal antibodies
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
Others:
Patient is breastfeeding or plans to breastfeed during the study
Other conditions where the investigator considers the patient inappropriate for enrollment
