Clinical trial NCT06449209: Safety, Preliminary Effectiveness of BNT327, an Investigational Therapy for Patients With Small-cell Lung Cancer in Combination With Chemotherapy
Official title: A Phase II, Multi-site, Open-label, Parallel Group Trial of BNT327 in Combination With Chemotherapy for Participants With Untreated Extensive-stage Small-cell Lung Cancer and Participants With Previously Treated Small-cell Lung Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Extensive-stage Small-cell Lung Cancer
Small-cell Lung Cancer
Keywords: Programmed Death-1 (PD-1)
Programmed Death Ligand-1 (PD-L1)
Programmed Death-1 monoclonal antibodies
Combination chemotherapy
Anti vascular endothelial growth factor (VEGF)
Previously treated small-cell lung cancer
Untreated extensive-stage small-cell lung cancer
Dose optimization
Time to progression
Lead sponsor: BioNTech SE
Sponsor class: INDUSTRY
First posted: 2024-06-07
Enrollment: 110
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase II, multi-site, open-label, parallel group study in participants with untreated extended-stage small-cell lung cancer (ES-SCLC) (Cohort 1) or small-cell lung cancer (SCLC) which has progressed on first- or second-line treatment (Cohort 2 and Cohort 3). This study will assess the safety, efficacy, and pharmacokinetics (PK) of BNT327.

Detailed description: In Cohort 1 of this study, two dose levels of BNT327 will be studied in combination with etoposide and carboplatin to identify an optimized dose for future clinical investigation.

Cohort 2 and Cohort 3 will explore the combination of two dose levels of BNT327 with paclitaxel, or topotecan in the second- or third-line setting.

Patients will be treated until disease progression, intolerable toxicity, patient withdrawal, study termination or up to 2 years (whichever occurs first).

Participants will be assigned to either Cohort 1 or Cohort 2/Cohort 3 based on their disease type (i.e., untreated ES-SCLC for Cohort 1 and SCLC which has progressed on first- or second-line treatment for Cohort 2 and Cohort 3). Assignment to either Cohort 2 or Cohort 3 will be the investigator's choice.

Participants will be randomized to each arm within each cohort:

* Participants enrolled to Cohort 1 and Cohort 3 will be randomized in a 1:1 ratio to Arm 1 or Arm 2.
* Participants enrolled to Cohort 2 will be randomized in a 2:1 ratio to Arm 1 or Arm 2.

Eligibility criteria: Inclusion Criteria (applicable to all participants unless otherwise specified):

* Cohort 1 only: Have histologically or cytologically confirmed ES-SCLC (using the American Joint Committee on Cancer \[AJCC\]) tumor node metastasis \[TNM\] staging system combined with Veterans Administration Lung Study Group two-stage classification scheme). For AJCC TNM staging system: AJCC 8th edition stage IV (T any, N any, M1a/b/c), or T3\~4 for multiple lung nodules or tumor/nodule volume that cannot be encompassed in a tolerable radiotherapy plan.
* Cohort 1 only: Participants who have not received systemic therapy for ES-SCLC for various reasons including potential intolerance of the standard-of-care per the patient's treating physician's judgment. However, participants with prior chemoradiotherapy for Limited-Stage Small-Cell Lung Cancer (LS-SCLC) must have been treated with curative intent and had a treatment-free interval of at least 6 months since the last systemic anticancer treatment including chemotherapy, radiotherapy, or chemoradiotherapy before the diagnosis of ES-SCLC to be eligible.
* Cohort 2 and Cohort 3 only: Participants with SCLC who have disease progression/relapse after first-line platinum-based chemotherapy with or without immunotherapy, or after first-line platinum-based chemotherapy and one second-line of chemotherapy (not the same chemotherapy agent in the specific arm to be enrolled to) with time to progression ≥3 months during second-line treatment.
* Have given informed consent by signing and dating an informed consent form before initiation of any study-specific procedures.
* Male or female, aged ≥18 years at the time of giving informed consent.
* Are willing and able to comply with scheduled visits, treatment schedule, the planned study assessments, laboratory tests, lifestyle restrictions, and other requirements of the study. This includes that they are able to understand and follow study-related instructions.
* Have at least one measurable lesion as the targeted lesion based on RECIST 1.1. Lesions treated after prior local treatment (radiotherapy, ablation, interventional procedures, etc.) are generally not considered as target lesions. If the lesion with prior local treatment is the only targeted lesion, evidence-based radiology must be provided to demonstrate disease progression (the single bone metastasis or the single central nervous system metastasis should not be considered as a measurable lesion).
* Eastern Cooperative Oncology Group performance status of 0 or 1.
* Have a minimum life expectancy of \>3 months.
* Have adequate organ function, as defined below:

  * Hematology:

    * Absolute neutrophil count ≥1.5 × 10\^9/L.
    * Platelet count ≥100 × 10\^9/L.
    * Hemoglobin ≥90 g/L or 5.6 mmol/L.
  * Liver function:

    * Total bilirubin ≤1.5 × upper limit of normal (ULN).
    * With Gilbert's syndrome total bilirubin \<3 mg/dL and direct bilirubin ≤ULN. Note, Gilbert's syndrome must be documented appropriately as past medical history.
    * Participants without liver metastasis alanine aminotransferase and aspartate aminotransferase ≤2 × ULN.
    * Participants with liver metastasis alanine aminotransferase and aspartate aminotransferase ≤5 × ULN.
    * Albumin ≥3.0 g/dL.
  * Renal function: Serum creatinine ≤1.5 × ULN or creatinine clearance ≥50 mL/min. Cockcroft-Gault formula.
  * Qualitative urine protein ≤1+. If qualitative urine protein ≥2+, a 24-hour urine protein quantitative test is required. If the 24-hour urine protein result is \<1 g, the participant can be enrolled.
  * Coagulation function: International normalized ratio or prothrombin time and activated partial thromboplastin time ≤1.5 × ULN unless the participant is receiving anticoagulation therapy as long as prothrombin or activated partial thromboplastin is within therapeutic range of intended use of anticoagulant.
* Are women of childbearing potential (WOCBP) who have a negative serum beta-human chorionic gonadotropin test at screening and before each IMP dose. Women born female that are postmenopausal (defined as 12 months with no menses without an alternative medical cause) or permanently sterilized (verified by medical records) will not be considered WOCBP and therefore will not be required to undergo pregnancy testing.
* Are WOCBP who agree to practice a highly effective form of contraception and to require their male sexual partners to use barrier contraception methods (preferably condoms), starting at Screening and continuously until 6 months after receiving the last study treatment.
* Are men who are sexually active with a partner born female and have not had a vasectomy who agree to use condoms and to ask their sexual partners to practice a highly effective form of contraception during the study, starting at the Screening Period and continuously until 6 months after receiving the last dose of IMP.
* Are WOCBP who agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study, starting at the Screening Period and continuously 6 months after receiving the last dose of IMP.
* Are men who are willing to refrain from sperm donation, starting at the Screening Period and continuously until 6 months after the last dose of IMP.

Exclusion Criteria (applicable to all participants):

* Are pregnant or breastfeeding or are planning pregnancy or planning to father children during the study or within 6 months after the last dose of IMP.
* Have a medical, psychological, or social condition which, in the opinion of the investigator, could compromise their wellbeing if they participate in the study, or that could prevent, limit, or confound the protocol-specified assessments or procedures, or that could impact adherence to protocol-described requirements.
* Have histologically or cytologically confirmed SCLC with combined histologies.
* Have received any of the following therapies or drugs within the noted time intervals prior to the initiation of study treatment:

  * Within 2 weeks: small molecule targeted agents with half-life of \<7 days; or radiation not involving the thoracic cavity; local radiation for brain lesion is allowed; local radiation for bone lesions is allowed.
  * Within 4 weeks: radiation involving the thoracic cavity; small molecule targeted agents with half-life of ≥7 days; monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, or T-cell or other cell-based therapies.
  * Participants who received prior treatment with a PDL-1/VEGF bispecific antibody.
  * Have received systemic corticosteroids (at a dosage greater than 10 mg/day of prednisone or an equivalent dose of other corticosteroids) within 10 days prior to the initiation of study treatment. Note: The following are allowed: local, intranasal, intraocular, intra-articular or inhaled corticosteroids, short-term use (≤7 days) of corticosteroids for prophylaxis (e.g., prevention of contrast agent allergy) or treatment of non-autoimmune conditions (e.g., delayed hypersensitivity reactions caused by exposure to allergens).
  * Have been vaccinated with live attenuated vaccine(s) within 4 weeks prior to initiation of the study treatment.
  * Received broad-spectrum intravenous antibiotics therapy within 2 weeks prior to initiation of study treatment.
  * Use of any non-study IMP within 3 weeks before initiation of study treatment in this study or ongoing participation in the active treatment phase of another interventional clinical study.
* Have undergone major organ surgery (core needle biopsies are allowed \>7 days prior study start), significant trauma, or invasive dental procedures (such as dental implants) within 28 days prior to the initiation of study treatment or plan to undergo elective surgery during the study. Placement of vascular infusion devices is allowed.
* Have received allogeneic hematopoietic stem cell transplantation or organ transplantation.
* Have the following central nervous system metastases:

  * Participants with untreated brain metastases that are symptomatic or large (e.g., \>2 cm).
  * Participants who received treatment for central nervous system metastases are not neurologically stable or still on steroids 10 days before initiating IMP of this study.
  * Participants with known leptomeningeal metastases.
* Have active autoimmune disease or history of autoimmune diseases with anticipated relapse (such as systemic lupus erythematosus, rheumatoid arthritis, vasculitis, etc.), except for those with clinically stable autoimmune thyroid disease or type 1 diabetes.
* Have had other malignant tumors within 2 years prior to the study treatment are not allowed. Except for those: who have been cured with local treatment (such as basal cell or squamous cell carcinoma of the skin, superficial or non-invasive bladder cancer, carcinoma in situ of the cervix, ductal carcinoma in situ of the breast, papillary carcinoma of thyroid and early stage prostate cancer).
* Have any of the following heart conditions within 6 months prior to the study treatment:

  * Acute coronary syndrome, coronary artery bypass grafting, congestive heart failure, aortic dissection, stroke, or other Grade 3 and above cardiovascular and cerebrovascular events.
  * New York Heart Association functional classification ≥II heart failure or left ventricular ejection fraction \<50%.
  * Those who have ventricular arrhythmias requiring clinical intervention, second- to third-degree atrioventricular block, or congenital long QT syndrome. Participants with treated cardiac arrythmia/atrial fibrillation are allowed.
  * Mean QT interval corrected by Fridericia's method \>480 ms (the electrocardiogram can be repeated at the discretion of the investigator).
  * Use of cardiac pacemaker.
  * Cardiac troponin I or T \>2 x ULN.
* Have any of the following hypertension or diabetic conditions prior to initiation of study treatment:

  * Uncontrolled hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg) while on antihypertensive medicine.
  * Those with a history of hypertensive crisis or hypertensive encephalopathy.
  * Poorly controlled diabetes (fasting blood glucose ≥13.3 mmol/L \[240 mg/dL\]).
* Have serious non-healing wounds, ulcers, or bone fractures. This includes history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess for which an interval of 6 months must pass before enrollment into this study. In addition, the participant must have undergone correction (or spontaneous healing) of the perforation/fistula and/or the underlying process causing the fistula/perforation.
* Participants with evidence of major coagulation disorders or other significant risks of hemorrhage such as:

  * History of intracranial or intraspinal hemorrhage.
  * Tumor lesions invading large vessels and with significant risk of bleeding
  * Had clinically significant hemoptysis or tumor hemorrhage within 1 month prior to the initiation of study treatment.
* Have uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Participants with indwelling catheters (e.g., PleurX) are allowed. However, participants who are clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis or with indwelling catheters, e.g., PleurX) are allowed.
* Participants with a history of serious Grade 3 or higher immune-related adverse events (irAEs) that led to treatment discontinuation of a prior immunotherapy. Participants with a history of Grade ≥3 irAEs that did not lead to discontinuation of a prior immunotherapy but fully recovered may be enrolled per investigator's discretion. The investigator may request sponsor guidance in such cases.
* Have a known or suspected hypersensitivity to the study treatments including any active ingredient or excipients thereof.
* Have known human immunodeficiency virus infection or known acquired immunodeficiency syndrome, with the following exceptions:

  * Participants with cluster of differentiation 4 (CD4)+ T-cell (CD4+) counts ≥350 cells/µL per local laboratory should generally be eligible for the study.
  * Participants who have not had an opportunistic infection within the past 12 months.
* Have a known history/positive serology for hepatitis B requiring active antiviral therapy (unless immune due to vaccination or resolved natural infection or unless passive immunization due to immunoglobulin therapy). Individuals with positive serology must have hepatitis B virus viral load below the limit of quantification.
* Have an active hepatitis C virus infection; individuals who have completed curative antiviral treatment with hepatitis C virus viral load below the limit of quantification are allowed.
* Participants with AEs from prior antitumor therapy whose AE(s) have not returned to Grade 1 (graded by NCI CTCAE v5.0 criteria) or below (unless the investigator determines that certain AEs pose no safety risk to participants, such as hair loss, Grade 2 peripheral neuropathy or stable hypothyroidism under hormone replacement therapy) are not eligible for the study.
* Have superior vena cava syndrome or symptoms of spinal cord compression.
* Those with active, or a history of, pneumonitis requiring treatment with steroids, or has active, or a history of, interstitial lung disease. Those with a history of pulmonary fibrosis, or currently diagnosed with severe lung diseases such as interstitial pneumonia, pneumoconiosis, chemical pneumonitis, or any other condition resulting in significant impairment in lung function. Exception: Asymptomatic interstitial changes caused by previous radiation therapy, chemotherapy, or other factors such as smoking are acceptable.
* Have active tuberculosis.
* Have underlying condition(s) that may increase the risk of the combination treatment or complicate the interpretation of AEs, as judged by the investigator, or other scenarios in which the investigator consider the participant as not eligible for the study.
* Are vulnerable individuals, i.e., are individuals whose willingness to volunteer in a clinical study may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. This includes all sponsor, study site, or third party (e.g., contract research organization, vendor) personnel directly involved in the conduct of the sudy and their family members or dependents, as well as all study site personnel otherwise supervised by the investigator.

Primary outcomes:
measure: Occurrence of treatment emergent adverse events (TEAEs), adverse events of special interest (AESIs), treatment-related TEAEs, treatment-related serious adverse events (SAEs) and treatment-related treatment emergent SAEs
timeFrame: up to 100 days after the last dose of treatment
measure: Occurrence of dose interruption, reduction, and discontinuation of study treatment due to TEAEs
timeFrame: up to 100 days after the last dose of treatment
measure: Objective Response Rate
timeFrame: up to 24 months after completion of study treatment of the last participant
measure: Best percentage change from baseline in the tumor size
timeFrame: up to 24 months after completion of study treatment of the last participant
measure: Proportion of participants who have achieved early tumor shrinkage
timeFrame: up to 2 months after first dose of treatment
Secondary outcomes:
measure: PK assessment: Maximum concentration (Cmax) derived from serum concentration of investigational medicinal product (IMP)
timeFrame: from pre-dose to 21 days after study treatment
measure: PK assessment: Area under the curve during the dosing interval (AUCtau) values derived from serum concentration of IMP
timeFrame: from pre-dose to 21 days after study treatment
measure: Incidence of detectable BNT327 antidrug antibodies in serum
timeFrame: from pre-dose to 100 days after last dose of study treatment
measure: Duration of Response
timeFrame: up to 24 months after completion of study treatment of the last participant
measure: Disease Control Rate
timeFrame: up to 24 months after completion of study treatment of the last participant
measure: Time to Response
timeFrame: up to 24 months after completion of study treatment of the last participant
measure: Progression-Free Survival (PFS)
timeFrame: up to 24 months after completion of study treatment of the last participant
measure: PFS rate
timeFrame: up to 24 months after completion of study treatment of the last participant
measure: Overall Survival (OS)
timeFrame: up to 24 months after completion of study treatment of the last participant
measure: OS rate
timeFrame: up to 24 months after completion of study treatment of the last participant
Other outcomes:
Locations:
city: Anchorage
country: United States
facility: Alaska Oncology and Hematology, LLC
state: Alaska
city: Los Angeles
country: United States
facility: Valkyrie Clinical Trials
state: California
city: Clermont
country: United States
facility: Clermont Oncology Center
state: Florida
city: Port Saint Lucie
country: United States
facility: Hematology Oncology Associates of Treasure Coast
state: Florida
city: Tallahassee
country: United States
facility: Tallahassee Memorial Physician Partners - Cancer & Hematology Specialists
state: Florida
city: Urbana
country: United States
facility: Carle Foundation Hospital d/b/a Carle Cancer Center
state: Illinois
city: Fort Wayne
country: United States
facility: Fort Wayne Medical Oncology and Hematology, Inc
state: Indiana
city: Lexington
country: United States
facility: University of Kentucky Chandler Medical Center (UKCMC) - Markey Cancer Center (Lucille P. Markey Cancer Center)
state: Kentucky
city: Minneapolis
country: United States
facility: Allina Health
state: Minnesota
city: Hattiesburg
country: United States
facility: Hattiesburg Clinic - Hattiesburg
state: Mississippi
city: Fenton
country: United States
facility: SSM Health Cancer Care - St. Clare
state: Missouri
city: Lincoln
country: United States
facility: Nebraska Hematology-Oncology (NHO) - Lincoln
state: Nebraska
city: Westbury
country: United States
facility: Clinical Research Alliance Inc
state: New York
city: Clyde
country: United States
facility: Haywood Infusion Center
state: North Carolina
city: Pinehurst
country: United States
facility: FirstHealth Outpatient Cancer Center
state: North Carolina
city: Cincinnati
country: United States
facility: The Christ Hospital Cancer Center
state: Ohio
city: Knoxville
country: United States
facility: University of Tennessee Medical Center
state: Tennessee
city: Houston
country: United States
facility: Millenium Research & Clinical Development
state: Texas
city: Madison
country: United States
facility: SSM Health Cancer Care
state: Wisconsin
city: Adelaide
country: Australia
facility: Lyell McEwin Hospital
city: Fitzroy
country: Australia
facility: St. Vincent's Hospital
city: Frankston
country: Australia
facility: Peninsula Oncology Centre
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
city: Westmead
country: Australia
facility: Westmead Hospital
city: Cheongju-si
country: Korea, Republic of
facility: Chungbuk National University Hospital
city: Daegu
country: Korea, Republic of
facility: Yeungnam University Medical Center
city: Goyang-si
country: Korea, Republic of
facility: National Cancer Center
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center
city: Jinju-si
country: Korea, Republic of
facility: Gyeongsang National University Hospital (GNUH)
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea Seoul St. Mary's Hospital
city: Suwon-si
country: Korea, Republic of
facility: Ajou University Hospital
city: Adana
country: Turkey
facility: Baskent University Hospital Adana Dr Turgut Noyan Research Center
city: Adana
country: Turkey
facility: Medical Park Seyhan Hospital
city: Adana
country: Turkey
facility: Adana City Training and Research Hospital
city: Ankara
country: Turkey
facility: Gulhane Egitim ve Arastirma Hastanesi
city: Ankara
country: Turkey
facility: Ankara Etlik Sehir Hastanesi
city: Ankara
country: Turkey
facility: Dr. Abdurrahman Yurtaslan Oncology Training and Research Hospital
city: Ankara
country: Turkey
facility: Hacettepe University Medical Faculty Oncology Hospital
city: Ankara
country: Turkey
facility: Memorial Ankara Hospital
city: Ankara
country: Turkey
facility: Liv Hospital
city: Ankara
country: Turkey
facility: Ankara City Hospital
city: Gaziantep
country: Turkey
facility: Gaziantep Sanko University Medical Faculty
city: Istanbul
country: Turkey
facility: Koc Universitesi Hastanesi (Koc University Hospital)
city: Istanbul
country: Turkey
facility: Bezmialem Vakif Universitesi Tip Fakultesi Hastanesi
city: Istanbul
country: Turkey
facility: Acibadem Adana Hastanesi
city: Istanbul
country: Turkey
facility: Yeditepe University Kosuyolu Hospital
city: Istanbul
country: Turkey
facility: Goztepe Prof. Dr. Suleyman Yalcin Sehir Hastanesi
city: İzmir
country: Turkey
facility: Medical Point Izmir Hospital
city: Kocaeli
country: Turkey
facility: Kocaeli Universitesi Tip Fakultesi
city: Sakarya
country: Turkey
facility: Sakarya University - Faculty of Medicine
city: Tekirdağ
country: Turkey
facility: Namik Kemal University Hospital
city: Yenimahalle
country: Turkey
facility: Gazi University Medical Faculty
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital Birmingham - University Hospitals Birmingham NHS Foundation Trust
city: Cardiff
country: United Kingdom
facility: Velindre Hospital - Velindre NHS Trust
city: Dundee
country: United Kingdom
facility: Ninewells Hospital and Medical School - Tayside Health Board
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital, Wonford - Royal Devon And Exeter NHS Foundation Trust
city: Huddersfield
country: United Kingdom
facility: Huddersfield Royal Infirmary - Calderdale and Huddersfield NHS Foundation Trust
city: Leeds
country: United Kingdom
facility: St James's University Hospital - Leeds Teaching Hospitals NHS Trust
city: London
country: United Kingdom
facility: Sarah Cannon Research Institute
city: Newcastle Upon Tyne
country: United Kingdom
facility: Northern Centre for Cancer Care,The Newcastle Upon Tyne Hospitals NHS Foundation Trust
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
city: Preston
country: United Kingdom
facility: Royal Preston Hospital - Lancashire Teaching Hospitals NHS Foundation Trust
city: Stoke-on-Trent
country: United Kingdom
facility: Royal Stoke University Hospital - University Hospitals of North Midlands NHS Trust
Study officials:
affiliation: BioNTech SE
name: BioNTech Responsible Person
role: STUDY_DIRECTOR
References: