Datopotamab Deruxtecan + Immunotherapy for Non-Small Cell Lung Cancer

(TROPION-Lung04 Trial)

Recruiting in Palo Alto (17 mi)

+59 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: AstraZeneca

Disqualifiers: Autoimmune disorders, Cardiac disease, Hepatitis, HIV, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This study will assess safety, tolerability, and treatment activity of datopotamab deruxtecan (Dato-DXd) in combination with immunotherapy with or without carboplatin in participants with advanced or metastatic non-small cell lung cancer (NSCLC).

Do I need to stop my current medications to join the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is the combination of Datopotamab Deruxtecan and Durvalumab safe for humans?

Durvalumab, one of the drugs in the combination, has shown acceptable tolerability in patients with non-small cell lung cancer and other solid tumors, although treatment-related toxicity is an important consideration. Ongoing studies are expected to provide more detailed safety data.

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What makes the drug Datopotamab Deruxtecan + Durvalumab unique for non-small cell lung cancer?

This drug combination is unique because it combines Datopotamab Deruxtecan, a TROP2-directed antibody-drug conjugate, with Durvalumab, an immunotherapy that blocks PD-L1, potentially enhancing the immune system's ability to fight cancer cells in non-small cell lung cancer.

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Eligibility Criteria

Adults with advanced or metastatic non-small cell lung cancer (NSCLC) who are either treatment-naïve or have had one prior chemotherapy without immune checkpoint inhibitors. Participants must have good organ function, measurable disease, no severe illnesses, and an ECOG performance status of 0 or 1. Those with certain genetic alterations in NSCLC or a history of other cancers are excluded.

Inclusion Criteria

You have a disease that can be measured according to specific guidelines within the 28 days before starting treatment.

I am 18 years or older and have signed the consent form.

My advanced lung cancer does not have EGFR or ALK mutations.

Exclusion Criteria

I have severe lung problems due to a recent illness.

I do not have active brain metastases or spinal cord compression.

I do not have an infection needing IV drugs.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Dato-DXd in combination with immunotherapy with or without carboplatin. Part 1 involves dose escalation or confirmation, and Part 2 involves dose expansion.

4 cycles of carboplatin (approximately 12 weeks)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of disease control rate and pharmacokinetic parameters.

9 months

Long-term follow-up

Participants are monitored for overall survival and other secondary outcomes.

Approximately 60 months

Participant Groups

The trial is testing the combination of Datopotamab deruxtecan (Dato-DXd), a new drug, with immunotherapy agents MEDI5752/AZD2936 and Durvalumab, plus Carboplatin for some groups. It aims to evaluate safety and how well these treatments work together in patients.

Group I: Cohort 9 Experimental Treatment 3 Interventions

Datopotamab deruxtecan (Dato-DXd) + MEDI5752 + Carboplatin in participants with treatment-naïve NSCLC

Group II: Cohort 8 Experimental Treatment 3 Interventions

Datopotamab deruxtecan (Dato-DXd) + AZD2936 + Carboplatin in participants with treatment-naïve NSCLC

Group III: Cohort 7 Experimental Treatment 3 Interventions

Datopotamab deruxtecan (Dato-DXd) + AZD2936 + Carboplatin in participants with treatment-naïve NSCLC

Group IV: Cohort 6 Experimental Treatment 2 Interventions

Datopotamab deruxtecan (Dato-DXd) + AZD2936 in participants with treatment-naïve NSCLC

Group V: Cohort 5 Experimental Treatment 2 Interventions

Datopotamab deruxtecan (Dato-DXd) + AZD2936 in participants with treatment-naïve NSCLC

Group VI: Cohort 4A Experimental Treatment 3 Interventions

Datopotamab deruxtecan (Dato-DXd) + Durvalumab + carboplatin in participants with treatment-naïve NSCLC

Group VII: Cohort 4 Experimental Treatment 3 Interventions

Datopotamab deruxtecan (Dato-DXd) + Durvalumab + Carboplatin in NSCLC participants who are either treatment-naïve or have received only 1 prior line of systemic chemotherapy without concomitant ICI therapy

Group VIII: Cohort 3 Experimental Treatment 3 Interventions

Datopotamab deruxtecan (Dato-DXd) + Durvalumab + Carboplatin in NSCLC participants who are either treatment-naïve or have received only 1 prior line of systemic chemotherapy without concomitant ICI therapy

Group IX: Cohort 2 Experimental Treatment 2 Interventions

Datopotamab deruxtecan (Dato-DXd) + Durvalumab in NSCLC participants who are either treatment-naïve or have received only 1 prior line of systemic chemotherapy without concomitant ICI therapy

Group X: Cohort 14 Experimental Treatment 2 Interventions

Datopotamab deruxtecan (Dato-DXd) + AZD7789 in participants with treatment-naïve NSCLC

Group XI: Cohort 13 Experimental Treatment 2 Interventions

Datopotamab deruxtecan (Dato-DXd) + AZD7789 in participants with CPI acquired resistant NSCLC

Group XII: Cohort 12 Experimental Treatment 2 Interventions

Datopotamab deruxtecan (Dato-DXd) + AZD7789 in participants with CPI acquired resistant NSCLC

Group XIII: Cohort 11 Experimental Treatment 2 Interventions

Datopotamab deruxtecan (Dato-DXd) + MEDI5752 in participants with treatment-naïve NSCLC

Group XIV: Cohort 10 Experimental Treatment 3 Interventions

Datopotamab deruxtecan (Dato-DXd) + MEDI5752 + Carboplatin in participants with treatment-naïve NSCLC

Group XV: Cohort 1 Experimental Treatment 2 Interventions

Datopotamab deruxtecan (Dato-DXd) + Durvalumab in NSCLC participants who are either treatment-naïve or have received only 1 prior line of systemic chemotherapy without concomitant ICI therapy

Datopotamab deruxtecan is already approved in Japan for the following indications:

🇯🇵 Approved in Japan as Dato-DXd for:

• HER2-negative breast cancer

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Mary Crowley Cancer Research Dallas, TX

Fox Chase Cancer Center Philadelphia, PA

John Theurer Cancer Center at Hackensack University Medical Center Hackensack, NJ

Washington University Saint Louis, MO

More Trial Locations

Who Is Running the Clinical Trial?

AstraZeneca Lead Sponsor

Daiichi Sankyo Industry Sponsor

Daiichi Sankyo, Inc. Industry Sponsor

References

1. England pubmed.ncbi.nlm.nih.gov

Durvalumab for the treatment of non-small cell lung cancer. [2019] In non-small cell lung cancer (NSCLC), immunotherapy is one of today's most important and ground-breaking systemic treatments, mainly represented by antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death protein 1 or ligand 1 (PD-1/PD-L1). Durvalumab (MEDI4736) is a high-affinity human IgG1 monoclonal antibody that binds to PD-1 and CD80, blocking PD-L1, but not PD-L2. Areas covered: In advanced NSCLC patients, durvalumab has demonstrated activity and acceptable tolerability, particularly with ≥25% PD-L1 tumor expression in the EGFR and ALK wild-type population. However, preliminary data have shown lower efficacy in EGFR mutant and ALK-positive patients. The results from the recent PACIFIC study in locally advanced patients have placed durvalumab as standard of care in consolidation after chemoradiation, leading to Food and Drug Administration (FDA) approval. Expert commentary: Early data suggest promising activity for durvalumab with the CTLA-4 inhibitor tremelimumab, regardless of PD-L1 expression, and potentially in combination with other drugs such as platinum-doublet chemotherapy. However, treatment-related toxicity associated with the combinations is an important aspect of the benefit-risk evaluation in the decision-making process. Results of ongoing phase III trials will provide illuminating data to confirm the place of durvalumab in the management of NSCLC patients.

2. New Zealand pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. [2022] The prominent immune checkpoint molecule, programmed cell death ligand-1 (PD-L1), is the object of increasing attention. Here, we report a meta-analysis investigating the safety and efficacy of durvalumab (MEDI4736), an inhibitor of PD-L1, in various solid tumors.

3. United States pubmed.ncbi.nlm.nih.gov

A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma. [2023] MEDI0680 is a humanized anti-programmed cell death-1 (PD-1) antibody, and durvalumab is an anti-PD-L1 antibody. Combining treatment using these antibodies may improve efficacy versus blockade of PD-1 alone. This phase II study evaluated antitumor activity and safety of MEDI0680 plus durvalumab versus nivolumab monotherapy in immunotherapy-naïve patients with advanced clear-cell renal cell carcinoma who received at least one prior line of antiangiogenic therapy.

4. England pubmed.ncbi.nlm.nih.gov

Efficacy, safety and biomarker analysis of durvalumab in patients with mismatch-repair deficient or microsatellite instability-high solid tumours. [2023] In this study we aimed to evaluate the efficacy and safety of the PD-L1 inhibitor durvalumab across various mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumours in the Drug Rediscovery Protocol (DRUP). This is a clinical study in which patients are treated with drugs outside their labeled indication, based on their tumour molecular profile.

5. United States pubmed.ncbi.nlm.nih.gov

Meta-Analysis of the Risk of Immune-Related Adverse Events With Anticytotoxic T-Lymphocyte-Associated Antigen 4 and Antiprogrammed Death 1 Therapies. [2022] We assessed the risks of immune-related adverse events with anticytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and antiprogrammed death 1 (PD1) therapies by meta-analysis. Twenty-one studies including 11,144 patients were found. Anti-CTLA4 therapy was associated with a significantly higher risk of overall immune-related adverse events: diarrhea, immune-related colitis, pruritus, and rash compared to control therapies (relative risk (RR) = 2.43, 2.10, 11.39, 3.88, 3.87, 95% confidence interval (CI) = 1.77-3.34, 1.52-2.45, 6.30-20.59, 2.37-6.37, 2.39-6.27, P

6. New Zealand pubmed.ncbi.nlm.nih.gov

Daratumumab: First Global Approval. [2018] Daratumumab (Darzalex™) is a first-in-class, humanized IgG1κ monoclonal antibody that targets the CD38 epitope and was developed by Janssen Biotech and Genmab. Intravenous daratumumab was recently approved via an accelerated approval programme in the USA for patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent. The drug is in preregistration for this indication in the EU and Canada. In a phase II trial in patients with previously treated (as described above) relapsed or refractory multiple myeloma, monotherapy with daratumumab 16 mg/kg achieved an overall response rate of approximately 30 %. This article summarizes the milestones in the development of daratumumab leading to this first approval for multiple myeloma.

7. United States pubmed.ncbi.nlm.nih.gov

Clinical Implications of Complex Pharmacokinetics for Daratumumab Dose Regimen in Patients With Relapsed/Refractory Multiple Myeloma. [2023] New therapeutic strategies are urgently needed to improve clinical outcomes in patients with multiple myeloma (MM). Daratumumab is a first-in-class, CD38 human immunoglobulin G1κ monoclonal antibody approved for treatment of relapsed or refractory MM. Identification of an appropriate dose regimen for daratumumab is challenging due to its target-mediated drug disposition, leading to time- and concentration-dependent pharmacokinetics. We describe a thorough evaluation of the recommended dose regimen for daratumumab in patients with relapsed or refractory MM.

8. Ireland pubmed.ncbi.nlm.nih.gov

A randomized, double-blind, placebo-controlled phase 2 study of tigatuzumab (CS-1008) in combination with carboplatin/paclitaxel in patients with chemotherapy-naïve metastatic/unresectable non-small cell lung cancer. [2022] Tigatuzumab, a humanized monoclonal DR5 agonist antibody induces apoptosis in human cancer cell lines. The objective of this study was to investigate the antitumor effects of tigatuzumab combined with carboplatin/paclitaxel in chemotherapy-naïve patients with metastatic/unresectable non-small cell lung cancer (NSCLC).

9. United States pubmed.ncbi.nlm.nih.gov

Phase I/II Trial of Immunotherapy With Durvalumab and Tremelimumab With Continuous or Intermittent MEK Inhibitor Selumetinib in NSCLC: Early Trial Report. [2021] Current strategies to improve clinical outcomes in v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog-mutant non-small-cell lung cancer (NSCLC) patients include mitogen-activated protein kinase kinase 1 inhibitor and programmed death (PD) 1 (PD-1)/PD ligand 1 (PD-L1) immune checkpoint blockade combinations. Experience from treatment of melanoma suggests that anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-PD-1/PD-L1 combinations improve outcomes, but similar benefits remain to be seen for treatment of NSCLC. This report describes a single center, investigator-initiated phase I/II clinical trial to compare 2 combination schedules of intermittent or continuous selumetinib (AZD6244, ARRY-142886), tremelimumab (anti-CTLA-4), and durvalumab (anti-PD-L1) treatment with historical controls in patients with previously treated, unresectable NSCLC. Forty patients will be accrued at the University of Texas M.D. Anderson Cancer Center. Primary objectives include maximum tolerated dose (dose escalation phase) and progression-free survival (dose expansion phase). Secondary objectives include response rate according to Response Evaluation Criteria In Solid Tumors version 1.1, disease control rate, overall survival, safety, and duration of response. Exploratory objectives are to assess biomarkers of response and resistance on the basis of biopsies and peripheral blood taken before and after treatment using immune profiling, transcriptome, and protein readouts.