Evaluation of Pharmacokinetics, Efficacy, and Safety of BAT3306 with Chemotherapy Versus Pembrolizumab with Chemotherapy in Stage IV Non-squamous NSCLC
- Trial ID
- 2024-510640-32-00
- Protocol
- BAT-3306-002-CR
- Sponsor
- Bio-Thera Solutions Ltd.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the pairwise **pharmacokinetic** (PK) similarities between BAT3306 and EU-Keytruda®, BAT3306 and US-Keytruda®, and between EU-Keytruda® and US-Keytruda® in participants with Stage IV non-squamous non-small cell lung cancer (nsNSCLC). Additionally, the study aims to compare the efficacy of BAT3306 and EU-Keytruda® and US-Keytruda® when administered with chemotherapy as a first-line treatment, using the objective response rate (ORR) assessed by blinded independent review committee (BIRC) to demonstrate clinical equivalence in participants with nsNSCLC. These objectives are clinically relevant as they seek to establish the therapeutic equivalence and potential interchangeability of these treatments, which could impact treatment decisions and accessibility for patients with advanced nsNSCLC.
Secondary objectives include: - Evaluating the PK characteristics of BAT3306, EU-Keytruda®, and US-Keytruda® in participants with nsNSCLC. - Assessing the safety and tolerability of BAT3306, EU-Keytruda®, and US-Keytruda®. - Evaluating the immunogenicity of BAT3306, EU-Keytruda®, and US-Keytruda®. - Further evaluating the efficacy of BAT3306, EU-Keytruda®, and US-Keytruda® given with chemotherapy using ORR at different time points, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). - Evaluating the immunogenicity of BAT3306, EU-Keytruda®, and US-Keytruda® and its impact on PK, efficacy, and safety in participants with nsNSCLC.
Participants
The clinical trial involves a total of **653 participants** diagnosed with **Stage IV non-squamous non-small cell lung cancer**. The study population includes both male and female subjects, aged **18 years and older**, who have not received prior systemic treatment for their advanced or metastatic condition. Participants were selected based on their ability to provide informed consent and their willingness to adhere to study procedures. They must have a life expectancy of at least three months and an **ECOG performance status** of 0 or 1. The trial excludes individuals with tumors harboring EGFR mutations, ROS1 rearrangements, or ALK rearrangements. Participants are required to have adequate organ function and measurable disease per RECIST v1.1 criteria. Lifestyle considerations include adherence to state and national COVID-19 exposure minimization guidelines. The trial does not involve a vulnerable population, and both genders are equally represented.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the pharmacokinetics, efficacy, and safety of BAT3306 in combination with chemotherapy compared to Keytruda® plus chemotherapy in participants with Stage IV non-squamous non-small cell lung cancer. The trial is structured in two phases, Phase I and Phase III, and is expected to span from October 2024 to December 2028. Participants will be randomly assigned to receive either BAT3306 or Keytruda® alongside chemotherapy, with the primary objective of comparing pharmacokinetic parameters and tumor response as assessed by blinded independent review committee (BIRC) according to RECIST Version 1.1.
The study involves a series of visits, beginning with a screening visit to assess eligibility based on inclusion criteria such as age, organ function, and disease status. Following successful screening, participants will undergo baseline assessments before the initiation of treatment. Regular follow-up visits will be scheduled to monitor safety, efficacy, and pharmacokinetic parameters, including vital signs, physical examinations, and laboratory tests. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to evaluate the overall response and any adverse events.
Participant involvement is anticipated to last up to 24 months, depending on the treatment arm and individual response to therapy. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial aims to ensure rigorous monitoring and adherence to protocol to maintain the integrity and reliability of the data collected.
Treatment
The clinical trial involves the administration of **KEYTRUDA** (pembrolizumab), a **concentrate for solution for infusion**. This experimental medication is provided at a concentration of 25 mg/mL and is administered via **intravenous infusion**. The maximum daily dose is 200 mg, with a total maximum dose of 3600 mg over a treatment period of up to 12 months. The product is manufactured by Merck Sharp & Dohme B.V. and is classified as a biological medicinal product. The administration schedule and participant compliance are monitored throughout the trial to ensure adherence to the dosing regimen.
Another treatment used in the study is **Pemetrexed Fresenius Kabi**, also a concentrate for solution for infusion, with a concentration of 25 mg/mL. This medication is administered via **intravenous infusion** with a maximum daily dose of 500 mg/m² and a total maximum dose of 17500 mg/m² over a treatment period of up to 24 months. The product is manufactured by Fresenius Kabi Deutschland GmbH and is classified as a chemical medicinal product. Compliance with the dosing schedule is closely monitored to ensure accurate administration.
The trial also includes the use of a **Recombinant Humanized Anti-PD-1 Monoclonal Antibody Solution for injection**, known as BAT3306, which contains the active substance **pembrolizumab**. This solution is administered via **intravenous injection** with a maximum daily dose of 200 mg and a total maximum dose of 7000 mg over a treatment period of up to 24 months. The product is developed by Bio-Thera Solutions Ltd. and is classified as a biological medicinal product. Participant adherence to the dosing schedule is monitored to ensure proper administration.
Additionally, **Carboplatin Kabi**, a concentrate for solution for infusion, is used as a comparator treatment. It is administered via **intravenous infusion** with a maximum daily dose of 750 mg and a total maximum dose of 3000 mg over a treatment period of up to 3 months. This product is manufactured by Fresenius Kabi Deutschland GmbH and is classified as a chemical medicinal product. The administration schedule is strictly followed, and participant compliance is monitored throughout the trial.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **PK parameters** and the confirmed best overall tumor response as assessed by BIRC according to RECIST Version 1.1. Tumor assessments conducted after the initiation of a new anti-cancer treatment will be excluded from this evaluation. Secondary endpoints encompass a range of parameters, including PK parameters such as Ctrough, vital signs, physical examination, electrocardiogram parameters, clinical laboratory tests, and adverse events. Additionally, immunogenicity evaluation will be conducted, focusing on ADA positive rate, ADA titer, and NAb. The secondary endpoints also include ORR based on tumor response as assessed by BIRC, confirmed best overall response by the end of the study according to RECIST Version 1.1, duration of response (DoR), progression-free survival (PFS), and overall survival (OS) as determined by local radiologists or investigators. The relationship between ADA or NAb results and drug concentrations, tumor responses, and adverse events will also be analyzed.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female, age ≥18 years on the day of signing informed consent.
- Participants are able to give voluntary informed consent and understand the study and are willing to follow and complete all the test procedures.
- Life expectancy ≥3 months per the investigator’s evaluation.
- ECOG performance status ≤1.
- Histologically/cytologically confirmed diagnosis of Stage IV (AJCC 8th edition) nsNSCLC.
- Tumors without EGFR mutation/ROS1 rearrangement /ALK rearrangement
- Have not received prior systemic treatment for their advanced/metastatic nsNSCLC. Participants who received adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 12 months prior to the development of metastatic disease.
- Have provided tumor tissue from locations not radiated prior to biopsy; formalin-fixed specimens after the participants have been diagnosed with metastatic disease will be preferred for determination of PD-L1 status prior to randomization. Biopsies obtained prior to receipt of adjuvant/neoadjuvant chemotherapy will be permitted if recent biopsy is not feasible.
- Have measurable disease per RECIST v1.1. that was not in a prior radiation or other locally treated area as determined by BIRC assessment. Target lesions situated in a previously irradiated area will be considered measurable if progression has been demonstrated in such lesions.
- Have adequate organ function as indicated by the following laboratory values: Bone marrow reserve: • Absolute neutrophil count ≥1.5 × 109/L without growth factor support in the 2 weeks prior to study drug administration • Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without growth factor support and transfusion in 2 weeks prior to study drug administration • Platelet count ≥100 × 109/L without growth factor support and transfusion in 2 weeks prior to study drug administration Hepatic function: • Total bilirubin ≤1.5 × the ULN or direct bilirubin ≤1.0×ULN for participants with total bilirubin levels>1.5×ULN. • AST and ALT ≤2.5 × ULN (or ≤5 × ULN for participants with liver metastases). Renal function: • Calculated creatinine clearance (CrCL) ≥50 mL/min (Cockroft-Gault Equation: CGGFR={[140-age (yrs.)] × weight (kg)/[72×serum creatinine (mg/dL)]} × (0.85 if female). Coagulation function: • Coagulation tests International normalized ratio (INR) or Prothrombin Time (PT) ≤1.5 × ULN, Activated Partial Thromboplastin Time (aPTT) or Partial Thromboplastin Time (PTT) ≤1.5 × ULN (INR in the range of 2-3 is acceptable on oral anticoagulants).
- Female of childbearing potential should have a negative urine or serum pregnancy test within 7 days prior to receiving the first dose of study intervention. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
- Female of childbearing potential must be willing to use an adequate method of contraception, for the course of the study through 120 days after the last dose of study intervention (BAT3306, EU-Keytruda®, or US-Keytruda®) and through 180 days after last dose of chemotherapeutic agents as specified in the protocol. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the participant.
- Male participant with a female partner(s) of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study intervention through 120 days after the last dose of study intervention (BAT3306, EU-Keytruda®, or US-Keytruda®) and through 180 days after last dose of chemotherapeutic agents as specified in the protocol. Male participant with a pregnant partner must agree to use a condom; no additional method of contraception is required for the pregnant partner. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the participant.
- Must agree to adhere to the current state and national advice regarding minimizing exposure to COVID-19 from the first Screening Visit until the EOS Visit.
Exclusion Criteria
- Is pregnant or a nursing female.
- Has predominantly squamous cell histology NSCLC. If small cell element is present the participant is ineligible.
- Is currently participating and receiving an investigational agent or has participated in a study of an investigational agent and received an investigational agent or used an investigational device within 4 weeks prior to administration of the first dose of study intervention.
- Before the first dose of study intervention: • Had received prior systemic antineoplastic chemotherapy and targeted, biological therapy and other types of anti-tumor therapies (e.g., osimertinib, bevacizumab, cetuximab), for metastatic disease. • Had prior treatment with any other anti-PD-1, PD-L1 or PD-L2 agent or an antibody targeting other immuno-regulatory receptors or mechanisms. Examples of such antibodies include (but are not limited to) antibodies against TIGIT, IDO, PD-L1, CTLA-4, and LAG3. • Has participated in any other BAT3306 study and has been treated with BAT3306. • Had major surgery <3 weeks prior to first dose. • Received radiation therapy to the lung that is > 30 Gy within 6 months of the first dose of study intervention. • Completed palliative radiotherapy within 14 days of the first dose of study intervention.
- Is expected to require any other form of antineoplastic therapy while participating in the study.
- Vaccinated with any live virus vaccine within 4 weeks prior to first dose of study intervention. Seasonal flu vaccines that are categorized as inactivated or killed virus are permitted. COVID-19 vaccination: An approved COVID-19 vaccine within 2 weeks prior to the first dose of study intervention is not permitted. There can be exceptions on a case-by-case as approved by Medical Monitor.
- Has clinically active diverticulitis, intra-abdominal abscess, gastro-intestinal obstruction, or peritoneal carcinomatosis.
- Has known active central nervous system metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are clinically stable for at least 2 weeks prior to first dose of study intervention and have no imaging evidence of new or enlarging brain metastases in 2 weeks prior to first dose of study intervention and are off steroids at least 3 days prior to first dose of study intervention. Stable brain metastases by this definition should be established prior to the first dose of study intervention. Participants with known untreated, asymptomatic brain metastases (i.e., no neurological symptoms, no requirements for corticosteroids, no or minimal surrounding edema, and no lesion >1.5 cm) may participate but will require regular imaging of the brain as a site of disease.
- History of a Grade 3 - 4 allergic reaction to treatment with another antibody.
- Has active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
- Known allergies, hypersensitivity, or intolerance to any of the study intervention or their excipients.
- Is on chronic systemic steroids. Participants with asthma that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study.
- Is unable or unwilling to take folic acid or vitamin B12 supplementation
- Has an active infection requiring therapy or the participants need to receive intravenous antibiotics within two weeks prior to first dose, or they need any type of antibiotics within one week prior to first dose.
- Human immunodeficiency virus infection, syphilis, or active tuberculosis infection at Screening. Screening for HIV, syphilis, and tuberculosis will be performed according to local practice and local regulatory guidance.
- Active Hepatitis B or C. Only when HBV carriers without active disease (HBV DNA titer < 1000 cps/mL or 200 IU/mL) or cured Hepatitis C (negative HCV RNA test) may be enrolled.
- Has known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study.
- Is, at the time of signing informed consent, a known regular user of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol).
- Has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.
- Has a history of interstitial lung disease/ (non-infectious) pneumonitis that required steroids or current interstitial lung disease/(non-infectious) pneumonitis.
- Participants with a history of tissue or organ transplantation.
- Severe or uncontrolled cardiac disease requiring treatment, congestive heart failure (New York Heart Association) NYHA III or IV, unstable angina pectoris even if medically controlled, history of myocardial infarction during the last 6 months (at Screening), serious arrhythmias requiring medication (with exception of atrial fibrillation or paroxysmal supraventricular tachycardia).
- Poorly controlled hypertension or resting blood pressure > 150/100 mmHg in the presence of a stable regimen of antihypertensive therapy during screening..
- Previous malignancy other than NSCLC in the last 5 years except for basal cell cancer of the skin or pre-invasive cancer of the cervix.
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the Investigator.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Slovakia | Not Recruiting | 01 Oct 2024 | 23 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 200 | 12 | PRD4323105 |
Pemetrexed Fresenius Kabi 25 mg/ml concentrate for solution for infusion | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 500 | 24 | PRD7936183 |
Recombinant Humanized Anti-PD-1 Monoclonal Antibody Solution for injection | Test | SOLUTION FOR INJECTION | INTRAVENOUS | 200 | 24 | PRD10992365 |
PEMBROLIZUMAB | Comparator | — | INTRAVENOUS INFUSION | 200 | 24 | SUB167136 |
Carboplatin Kabi 10 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Other | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS INFUSION | 750 | 3 | PRD669106 |