A phase 2 study to research the safety and efficacy of datopotamab deruxtecan for non-squamous non-small cell lung cancer patients with active brain metastasis (TUXEDO-5).

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Medica Scientia Innovation Research S.L.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2025-07-14

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Daiichi Sankyo

External identifiers

EU CT number

2024-512369-14-00

ClinicalTrials.gov

NCT06676917

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

To assess the intracranial response rate (ORR-IC) of Dato-DXd at any timepoint per local investigator as judged by best CNS response according to Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria.

Secondary objectives 9

1. To evaluate the efficacy of Dato-DXd, defined as ORR in extracranial lesions (ORR-EC) and overall lesions (bicompartmental ORR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1.
2. To assess the efficacy of Dato-DXd, defined as investigator-assessed progression-free survival (PFS), clinical benefit rate (CBR), disease control rate (DCR), time to response (TTR), and duration of response (DoR) for intracranial (IC) lesions using the RANO-BM criteria and for EC lesions and overall lesions as per RECIST v.1.1.
3. To assess the efficacy defined as overall survival (OS) of Dato-DXd in NSCLC patients with active BMs.
4. To analyze the best percentage of change in tumor burden as per European Association of Neuro-Oncology – European Society for Medical Oncology (ESMO-EANO) guidelines for IC lesions and the EC and overall lesions (bicompartmental) as per RECIST v.1.1.
5. To evaluate the neurologic function in NSCLC patients with active BMs with the Neurologic Assessment in Neuro-Oncology (NANO) scale.
6. Safety objectives: To determine the safety and toxicity profile of Dato-DXd in NSCLC patients with active BMs according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v.5.0) and Corneal Toxicity Severity Grading Scale.
7. Safety objectives: To evaluate the quality of life (QoL) and neurocognitive function after Dato-DXd in NSCLC patients with active BMs with the European Organization for Research And Treatment Of Cancer (EORTC) quality of life questionnaire (QLQ-C30) and the brain cancer specific questionnaire (QLQ-BN20).
8. Exploratory objectives: Exploratory objectives are still to be defined but can include (but are not limited to): To explore predictive and/or prognostic and/or pharmacodynamic biomarkers associated with disease activity status, patient outcome or response to study treatments on archival and/or liquid biopsy samples.
9. Exploratory objectives: Exploratory objectives are still to be defined but can include (but are not limited to): To explore the association between treatment efficacy and/or safety outcomes and radiological imaging biomarkers.

Conditions and MedDRA coding

Non-small cell lung cancer (NSCLC).

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 23

1. 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.
2. Female or male adults ≥ 18 years old at the time of signing ICF.
3. Histologically documented non-squamous NSCLC.
4. Patients may have symptoms attributed to BM.
5. 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.
6. Type II leptomeningeal disease (LMD) per ESMO-EANO guidelines are allowed.
7. 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.
8. 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.
9. Patients with no, stable or decreasing dose of corticosteroids for 7 days.
10. Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2.
11. Minimum life expectancy of ≥ 6 weeks at screening.
12. 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.
13. 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.
14. 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.
15. 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.
16. Patient has adequate bone marrow and liver function within 7 days before first study treatment dose:
17. 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).
18. 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.
19. Adequate treatment washout period before randomization.
20. 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.
21. 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.
22. 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.
23. Patient must be accessible for treatment and follow-up.

Exclusion criteria 27

1. Current participation in another therapeutic clinical trial, except other translational studies.
2. Treatment with approved or investigational cancer therapy within 14 days prior to initiation of study drug.
3. Mixed small-cell lung cancer (SCLC) and NSCLC histology, or large cell neuroendocrine carcinoma (LCNEC) histology.
4. Histologically documented squamous-cell carcinoma (SCC).
5. 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.
6. Type I LMD per ESMO-EANO guidelines.
7. Patients with symptomatic brain metastasis requiring increasing dose of steroids.
8. 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.
9. 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.
10. Has a history of severe hypersensitivity reactions to other monoclonal antibodies.
11. 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.
12. 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.
13. 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.
14. Has clinically significant corneal disease.
15. 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.
16. 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.
17. Significant third-space fluid retention (for example ascites or pleural effusion) and is not amenable for required repeated drainage.
18. Pregnant or lactating females or patients not willing to apply highly effective contraception as defined in the protocol.
19. Receipt of live or attenuated vaccine within 30 days prior to the first dose of study treatment.
20. 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.
21. Has known human immunodeficiency virus (HIV) infection that is not well controlled.
22. Other active uncontrolled infection at the time of enrollment.
23. Is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment.
24. 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.
25. Known substance abuse or any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment, contraindicate patient participation.
26. 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.
27. Inability or unwillingness to comply with the requirements of the protocol in the opinion of the investigator.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. ORR-IC, defined as the rate of patients with complete response (CR) or partial response (PR) for IC lesions determined locally by investigator, using RANO-BM criteria.

Secondary endpoints 13

1. ORR, defined as the rate of patients with CR or PR determined locally by investigator as per RECIST v.1.1 for EC lesions (ORR-EC) and overall lesions.
2. PFS, defined as the period from treatment initiation to the first occurrence of disease progression or death from any cause, whichever occurs first. It will be determined locally by investigator as per RANO-BM for IC lesions and RECIST v.1.1 for EC and overall lesions.
3. CBR, defined as the rate of patients with objective response (CR or PR), or stable disease for at least 24 weeks, as per RANO-BM for IC lesions and RECIST v.1.1 for EC and overall lesions.
4. DCR, defined as the rate of patients with objective response (CR or PR), or stable disease (SD), as per RANO-BM for IC and RECIST v.1.1 for EC and overall lesions.
5. TTR, defined as the period from the treatment initiation to time of the first objective tumor response (tumor shrinkage of ≥ 30%) observed for patients who achieved a CR or PR, as per RANO-BM for IC lesions and RECIST v.1.1 for EC and overall lesions.
6. DoR, defined as the period from the first occurrence of a documented objective response to disease progression or death from any cause, observed for patients who achieved a CR or PR, as per RANO-BM for IC and RECIST v.1.1 for EC and overall lesions.
7. OS, defined as the period from treatment initiation to death from any cause or last available follow-up.
8. Best percentage of change in tumor burden as per RANO-BM for IC lesions and RECIST v.1.1 for EC and overall measurable lesions.
9. Neurologic function as per NANO scale.
10. Safety endpoints: Safety and tolerability as per NCI-CTCAE v.5.0 and Corneal Toxicity Severity Grading Scale.
11. Safety endpoints: Assessment of QoL and neurocognitive function with EORTC QLQ-C30 and the brain specific tool (EORTC QLQ-BN20).
12. Exploratory endpoints: Exploratory endpoints are still to be defined but can include (but are not limited to): Association of clinical outcomes, safety and/or tolerability profile with mutation profiling, copy number variability, gene expression, multiplex assays, proteomic analyses, digital pathology, immunohistochemistry, taxonomic or functional analyses performed on tissue and/or liquid biopsy samples.
13. Exploratory endpoints: Exploratory endpoints are still to be defined but can include (but are not limited to): Association of treatment efficacy and/or safety outcomes with radiological imaging biomarkers in all patients.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Medica Scientia Innovation Research S.L.

Sponsor organisation

Medica Scientia Innovation Research S.L.

Address

Torre Glories 27th Floor, Avinguda Diagonal 211 Avinguda Diagonal 211

City

Barcelona

Postcode

08018

Country

Spain

Scientific contact point

Organisation

Medica Scientia Innovation Research S.L.

Contact name

Alicia García

Public contact point

Organisation

Medica Scientia Innovation Research S.L.

Contact name

Luis Aparicio Galan

Locations

2 EU/EEA countries · 10 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 19 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

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