Phase II Multicenter, Open-Label Study of Datopotamab Deruxtecan in Non-Squamous NSCLC Patients with Active Brain Metastases (TUXEDO-5)
- Trial ID
- 2024-512369-14-00
- Protocol
- MEDOPP750
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **intracranial response rate** (ORR-IC) of Datopotamab Deruxtecan (Dato-DXd) at any timepoint in patients with non-small cell lung cancer (NSCLC) with active brain metastases. This is evaluated by the best central nervous system (CNS) response according to the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. The clinical relevance of this objective lies in its potential to provide insights into the efficacy of Dato-DXd in managing brain metastases, a significant complication in NSCLC that affects patient prognosis and quality of life.
Secondary objectives include:
- Evaluating the efficacy of Dato-DXd in terms of overall response rate in extracranial lesions (ORR-EC) and overall lesions using RECIST v.1.1 criteria.
- Assessing progression-free survival (PFS), clinical benefit rate (CBR), disease control rate (DCR), time to response (TTR), and duration of response (DoR) for intracranial lesions using RANO-BM criteria, and for extracranial and overall lesions using RECIST v.1.1.
- Evaluating overall survival (OS) in NSCLC patients with active brain metastases.
- Analyzing the best percentage of change in tumor burden according to ESMO-EANO guidelines for intracranial lesions and RECIST v.1.1 for extracranial and overall lesions.
- Evaluating neurologic function using the Neurologic Assessment in Neuro-Oncology (NANO) scale.
- Determining the safety and toxicity profile of Dato-DXd according to NCI-CTCAE v.5.0 and Corneal Toxicity Severity Grading Scale.
- Evaluating quality of life (QoL) and neurocognitive function using EORTC QLQ-C30 and QLQ-BN20 questionnaires.
- Exploring predictive, prognostic, and pharmacodynamic biomarkers associated with disease activity, patient outcomes, or response to treatment.
- Exploring the association between treatment efficacy, safety outcomes, and radiological imaging biomarkers.
Participants
The clinical trial involves participants diagnosed with **non-small cell lung cancer (NSCLC)**. The study population includes both male and female adults aged 18 years and older. Participants are required to have a general health status that allows for an Eastern Cooperative Oncology Group performance status of 2 or less, and a minimum life expectancy of at least 6 weeks at screening. The trial does not include a vulnerable population. Participants were selected based on their ability to understand the study's purpose and provide informed consent, as well as their medical history and current health status, including adequate bone marrow and liver function. Lifestyle considerations such as diet and physical activity are not specified. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed as a **phase II**, open-label, non-comparative, single-arm study to evaluate the efficacy and safety of **datopotamab deruxtecan** in patients with non-squamous **non-small cell lung cancer** (NSCLC) with active brain metastases. The primary objective is to assess the intracranial response rate (ORR-IC) using the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. The trial is expected to commence recruitment on July 15, 2025, and conclude by February 15, 2027, with an estimated duration of 24 months for each participant's involvement.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as an Eastern Cooperative Oncology Group performance status of ≤ 2 and a minimum life expectancy of ≥ 6 weeks. Following the screening, eligible participants will receive **datopotamab deruxtecan** via **intravenous administration**. The treatment period will last up to 24 months, with regular follow-up visits to monitor safety, efficacy, and any adverse events. The end-of-study visit will occur after the treatment period or upon early termination.
Study visits will include assessments of tumor response, safety evaluations, and quality of life measurements. Participants will be monitored for hematological and hepatic function, and any acute toxic effects of prior anticancer therapy must resolve to grade ≤ 1 before study treatment initiation. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The trial will adhere to rigorous scientific standards to ensure the reliability and validity of the findings.
Treatment
The clinical trial involves the administration of **Datopotamab deruxtecan**, an experimental medication provided as a **solution for infusion**. This investigational drug is administered via **intravenous administration**. The dosage is calculated based on the participant's body weight, with a maximum daily dose of 6.0 mg/kg. The treatment period is set for a maximum of 24 weeks. The active substance, **datopotamab deruxtecan**, is a protein-based compound developed by Daiichi Sankyo, Inc. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.
In addition to the experimental treatment, the study includes the use of **Polaramine 5 mg/ml solución inyectable**, which contains the active substance **dexchlorpheniramine maleate**. This **solution for injection** is administered as an **antihistaminic** treatment. The maximum daily dose is 5 mg/ml, with a total treatment period of 24 weeks. The product is manufactured by Laboratorios Farmacéuticos Rovi, S.A.
**Paracetamol Sandoz 500 mg – Tabletten** is also utilized in the study as an **analgesic**. This medication is provided in **tablet** form and administered **orally**. The maximum daily dose is 500 mg, with a treatment duration of up to 24 weeks. The active substance, **paracetamol**, is chemically derived and produced by Sandoz GmbH.
Another non-experimental treatment used is **Dibondrin Ampullen**, containing **diphenhydramine hydrochloride**. This **solution for injection** serves as an **antihistaminic** and is administered with a maximum daily dose of 30 mg/l. The treatment period is consistent with the other medications, lasting up to 24 weeks. The product is manufactured by Pharmazeutische Fabrik Montavit Ges.m.b.H.
Additionally, **Dibondrin Dragees** are included in the trial, also containing **diphenhydramine hydrochloride**. These are **coated tablets** administered **orally**. The maximum daily dose is 50 mg, with a treatment period of 24 weeks. This product is also produced by Pharmazeutische Fabrik Montavit Ges.m.b.H.
**Polaramine 2 mg comprimidos**, another form of **dexchlorpheniramine maleate**, is used as an **antihistaminic** in **tablet** form. It is administered **orally** with a maximum daily dose of 2 mg, over a 24-week period. This product is provided by ROVI.
Lastly, **Paracetamol Kabi 10 mg/ml solución para perfusión** is used as an **analgesic** in the form of a **solution for infusion**. The maximum daily dose is 10 mg/l, with a treatment period of 24 weeks. The active substance, **paracetamol**, is chemically derived and manufactured by Fresenius Kabi España S.A.U.
Efficacy
The efficacy of the investigational product, **Datopotamab deruxtecan**, in the clinical trial will be assessed primarily through the **intracranial response rate (ORR-IC)**. This is defined as the rate of patients achieving a complete response (CR) or partial response (PR) for intracranial lesions, as determined by local investigators using the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. The primary endpoint will be evaluated at any timepoint during the study, based on the best central nervous system (CNS) response.
Secondary efficacy endpoints include the overall response rate (ORR) for extracranial lesions (ORR-EC) and overall lesions, progression-free survival (PFS), clinical benefit rate (CBR), disease control rate (DCR), time to response (TTR), duration of response (DoR), overall survival (OS), and the best percentage of change in tumor burden. These will be assessed using RANO-BM criteria for intracranial lesions and RECIST v.1.1 for extracranial and overall lesions. Additionally, neurologic function will be evaluated using the NANO scale, and quality of life and neurocognitive function will be assessed with the EORTC QLQ-C30 and the brain-specific tool EORTC QLQ-BN20.
Safety and tolerability will be monitored according to the NCI-CTCAE v.5.0 and the Corneal Toxicity Severity Grading Scale. Exploratory endpoints, which are yet to be fully defined, may include associations of clinical outcomes with mutation profiling, gene expression, and radiological imaging biomarkers, among others. The trial is designed to provide comprehensive data on the efficacy and safety of **Datopotamab deruxtecan** in patients with non-squamous non-small cell lung cancer and active brain metastases.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant must be capable to understand the purpose of the study and have signed a written informed consent form (ICF) prior to beginning specific protocol procedures.
- Female or male adults ≥ 18 years old at the time of signing ICF.
- Histologically documented non-squamous NSCLC.
- Patients may have symptoms attributed to BM.
- No indication for immediate local therapy (neurosurgery, brain radiotherapy) for BM as per local investigator. Note: in the case immediate local therapy is needed, the study’s medical monitor should be consulted.
- Type II leptomeningeal disease (LMD) per ESMO-EANO guidelines are allowed.
- Patients must have known AGA status prior to study entry as per local investigator practice, and meets following criteria for NSCLC: a.Participants without AGA: i.Must have documented negative test results for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). ii. Must have no known genomic alterations in ROS proto-oncogene 1 (ROS1), neurotrophic tyrosine receptor kinase (NTRK), proto-oncogene B-raf (BRAF) V600, human epidermal growth factor receptor 2 (HER2) mesenchymal-epithelial transition (MET) exon 14 skipping or rearranged during transfection (RET). b.Participants with AGA must have one or more documented actionable genomic alteration(s): EGFR, ALK, ROS1, NTRK, BRAF V600, HER2, MET exon 14 skipping, or RET.
- Measurable disease according to Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, with at least one measurable brain lesion of ≥ 10 mm on T1-weighted, gadolinium-enhanced MRI.
- Patients with no, stable or decreasing dose of corticosteroids for 7 days.
- Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2.
- Minimum life expectancy of ≥ 6 weeks at screening.
- Patients without AGA must meet 1 of the following prior therapy requirements for advanced or metastatic NSCLC: a. Received platinum-based chemotherapy in combination with α-PD-1/α-PD-L1 monoclonal antibody (mAb) as the only prior line of therapy. i. Includes participants who received prior platinum-based/chemotherapy with or without radiotherapy with maintenance α-PD-1/α-PD-L1 mAb for stage III disease and relapsed/progressed within 6 months from the last dose of platinum-based chemotherapy. ii. Includes participants who received prior platinum-based/chemotherapy with or without radiotherapy (with or without maintenance α-PD-1/α-PD-L1 mAb) for stage III disease and subsequently received α-PD-1/α-PD-L1 mAb therapy (with or without platinum-based chemotherapy) for recurrent disease. iii. Includes patients with stage II/III diseases who received prior platinum-based/chemotherapy with or without α-PD-1/α-PD-L1 mAb administered in the neoadjuvant/perioperative or adjuvant setting and relapsed/progressed within 6 months from the last dose of platinum-based chemotherapy. iv. Includes patients with stage II/III diseases who received prior platinum-based/chemotherapy with or without α-PD-1/α-PD-L1 mAb administered in the neoadjuvant/perioperative or adjuvant setting and subsequently received α-PD-1/α-PD-L1 mAb therapy (with or without platinum-based chemotherapy) for recurrent disease. b. Received platinum-based chemotherapy and α-PD-1/α-PD-L1 mAb (in either order) sequentially as the only 2 prior lines of therapy.
- Patients with AGA must meet the following for advanced or metastatic NSCLC: a. Participants who have been treated with 1 or 2 prior lines of applicable targeted therapy that is locally approved for the participant's genomic alteration at the time of screening; i. Participants who received a targeted agent as adjuvant therapy for early-stage disease must have relapsed or progressed while on the treatment or within 6 months of the last dose (which may or may not be same agent used in the adjuvant setting) for relapsed/progressive disease. b. Participants who have been treated with 1 prior line of platinum-based chemotherapy alone or in combination with one α-PD-1/α-PD-L1 antibody: i. One platinum-containing regimen alone or in combination with one α-PD-1/α-PD-L1 antibody for advanced disease. ii. Those who received a platinum-containing regimen as adjuvant therapy for early-stage disease must have relapsed or progressed while on the treatment or within 6 months of the last dose OR received at least one additional course of platinum-containing therapy (which may or may not be same as in the adjuvant setting) for relapsed/progressive disease. c. May have received up to one α-PD-1/α-PD-L1 mAb alone or in combination with a cytotoxic agent.
- Able to provide the most recently available formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks of primary tissue and/or any metastatic site at the time of inclusion. If archival tissue is not available, a newly obtained baseline biopsy of an accessible tumor lesion is required prior to start of study treatment.
- Left ventricular ejection fraction (LVEF) of ≥ 50% or ≥ institution lower limit of normal (LLN) as assessed by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan.
- Patient has adequate bone marrow and liver function within 7 days before first study treatment dose:
- Hematological (without platelet, red blood cell transfusion/plasma transfusion within 1 week prior to screening assessment, and/or granulocyte colony-stimulating factor support): White blood cell (WBC) count > 3.0 x 109/L, absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100.0 x109/L, and hemoglobin ≥ 9.0 g/dL (≥ 5.6 mmol/L).
- Hepatic: Serum albumin ≥ 2.5 g/dL; total bilirubin ≤ 1.5 times upper limit of normal (ULN) (≤ 3 in patients with liver metastases or know history of Gilbert’s disease); alkaline phosphatase (ALP) ≤ 2.5 times ULN (≤ 5 in patients with liver metastases); aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 times ULN (≤ 5 in patients with liver metastases); international normalized ratio (INR) < 1.5.
- Adequate treatment washout period before randomization.
- Resolution of all acute toxic effects of prior anticancer therapy to grade ≤ 1 as determined by the US National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (v.5.0). Note: except for alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion.
- Females of childbearing potential who are sexually active with a non-sterilized male partner must have a negative serum pregnancy test within 14 days before study treatment initiation. In addition, they must agree to use one highly effective method of birth control from the time of screening until 7 months after the last dose of study treatment. Female patients must refrain from egg cell donation and breastfeeding during this same period of time.
- Male participants who are sexually active with a female partner of childbearing potential must be surgically sterile or using an acceptable method of contraception from the time of screening until 4 months after the last administration of the study drug. Male participants must not donate or bank sperm during this same period of time.
- Patient must be accessible for treatment and follow-up.
Exclusion Criteria
- Current participation in another therapeutic clinical trial, except other translational studies.
- Treatment with approved or investigational cancer therapy within 14 days prior to initiation of study drug.
- Mixed small-cell lung cancer (SCLC) and NSCLC histology, or large cell neuroendocrine carcinoma (LCNEC) histology.
- Histologically documented squamous-cell carcinoma (SCC).
- Had prior therapy with: a. Tumor-associated calcium signal transducer 2 (TROP2)-targeted therapy. b. Any agent including an antibody drug conjugate (ADC) containing a chemotherapeutic agent targeting topoisomerase I.
- Type I LMD per ESMO-EANO guidelines.
- Patients with symptomatic brain metastasis requiring increasing dose of steroids.
- Known history of invasive malignancy within 5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer. For other cancers considered to have a low risk of recurrence, discussion with the Sponsor’s Medical Monitor is required.
- Has a history of severe hypersensitivity reactions to either the drug or inactive ingredients (included but not limited to polysorbate 80) of Dato-DXd or its analogs.
- Has a history of severe hypersensitivity reactions to other monoclonal antibodies.
- Patients who received prior radiotherapy to the brain within 4 weeks of start of study intervention or received radiotherapy to the chest within 4 weeks of start of study intervention or have ongoing radiation-related toxicities requiring corticosteroids. Note: Target lesions will be selected according to RANO-BM criteria. Lesions with prior local treatment (i.e. stereotactic radiosurgery or surgical resection) can be considered measurable if progression has occurred since the time of local treatment. However, careful consideration should be given to lesions previously treated with stereotactic radiosurgery, in view of the possibility of treatment effect.
- Major surgical procedure or significant traumatic injury within 14 days before the first dose of study treatment or anticipation of need for major surgery within the course of the study treatment.
- Has an active cardiac disease or a history of cardiac dysfunction or conduction abnormalities including, but not confined, to any of the following: a. Unstable angina pectoris, documented myocardial infarction, or symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] Class II-IV) within 6 months prior to study entry. b. Symptomatic pericarditis. c. History of CHF NYHA Class III or IV. d. History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, or ventricular tachycardia), which is symptomatic or requires treatment (NCI-CTCAE grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers will be permitted to enroll. e. QT Interval Corrected by Fridericia’s formula (QTcF) prolongation to > 470 ms (females) or > 450 ms (males) based on average of the screening triplicate 12-lead electrocardiogram (ECG). f. History of QT prolongation associated with other medications that required discontinuation of that medication, or any current concomitant medication known to prolong the QT interval and cause Torsades de Pointes. g. Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives.
- Has clinically significant corneal disease.
- Has a history of non-infectious interstitial lung disease (ILD)/pneumonitis including radiation pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
- Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (e.g., pulmonary emboli within 3 months of the study enrolment, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion, post COVID-19 pulmonary fibrosis, etc.), and any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (e.g., rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, etc.), or prior pneumonectomy.
- Significant third-space fluid retention (for example ascites or pleural effusion) and is not amenable for required repeated drainage.
- Pregnant or lactating females or patients not willing to apply highly effective contraception as defined in the protocol.
- Receipt of live or attenuated vaccine within 30 days prior to the first dose of study treatment.
- Has active or uncontrolled infection with hepatitis B virus (HBV), or hepatitis C virus (HCV). Patients with past HBV infection or resolved HBV infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive hepatitis B core antibody [HBcAb] test, accompanied by a negative HBV DNA test) are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
- Has known human immunodeficiency virus (HIV) infection that is not well controlled.
- Other active uncontrolled infection at the time of enrollment.
- Is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment.
- A history of uncontrolled seizures, central nervous system (CNS) disorders, or serious and/or unstable pre-existing psychiatric disability judged by the investigator to be clinically significant and adversely affecting compliance to study drugs or interfering with subject safety.
- Known substance abuse or any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment, contraindicate patient participation.
- Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study.
- Inability or unwillingness to comply with the requirements of the protocol in the opinion of the investigator.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Yet Recruiting | 15 Jul 2025 | 4 |
 Spain | Not Yet Recruiting | 15 Jul 2025 | 16 |
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 |
|---|---|---|---|---|---|---|
Datopotamab deruxtecan | Test | SOLUTION FOR INFUSION | INTRAVENOUS ADMINISTRATION | 6.0 | 24 | PRD9684738 |
Polaramine 5 mg/ml solución inyectable | Other | SOLUCIÓN INYECTABLE | SOLUTION FOR INJECTION | 5 | 24 | PRD7436581 |
Paracetamol Sandoz 500 mg – Tabletten | Other | TABLETTEN | ORAL | 500 | 24 | PRD11931837 |
Dibondrin Ampullen | Other | AMPULLEN | SOLUTION FOR INJECTION | 30 | 24 | PRD1959904 |
Dibondrin Dragees | Other | DRAGEES | ORAL | 50 | 24 | PRD12026864 |
Polaramine 2 mg comprimidos | Other | COMPRIMIDOS | ORAL | 2 | 24 | PRD7694020 |
Paracetamol Kabi 10 mg/ml solución para perfusión | Other | SOLUCIÓN PARA PERFUSIÓN | SOLUTION FOR INJECTION | 10 | 24 | PRD12080311 |