Phase 1b Study of Dato-DXd in Combination With Immunotherapy With or Without Carboplatin in Advanced or Metastatic Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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This study will assess safety, tolerability, and treatment activity of datopotamab deruxtecan (Dato-DXd) in combination with immunotherapy in participants with advanced or metastatic non-small cell lung cancer (NSCLC).

Detailed Description
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The primary objective is to assess the safety and tolerability of Dato-DXd in combination with immunotherapy with or without 4 cycles of carboplatin in participants with advanced or metastatic NSCLC. Two dose levels of Dato-DXd will be studied in combination with immunotherapy (durvalumab, AZD2936, MEDI5752, or AZD7789) with or without 4 cycles of carboplatin in 14 study cohorts Each cohort will start with Part 1 (dose escalation or confirmation), where 3 to 9 participants will be assessed for dose-limiting toxicities (DLT) in the first cycle of treatment. if the DLT incidence rate meets the criteria based on the modified toxicity probability interval-2 (mTPI-2), then Part 2 (dose expansion) may be opened.

Official Title
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A Phase 1b, Multicenter, 2-Part, Open-Label Study of Datopotamab Deruxtecan (Dato-DXd) in Combination With Immunotherapy With or Without Carboplatin in Participants With Advanced or Metastatic Non-Small Cell Lung Cancer (Tropion-Lung04)

Conditions
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Advanced or Metastatic NSCLC

Intervention / Treatment
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* Drug: Datopotamab deruxtecan
* Drug: Durvalumab
* Drug: Carboplatin
* Drug: AZD2936
* Drug: MEDI5752
* Drug: AZD7789


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant ≥18 years old on the day of signing the ICF (local regulatory requirement to consent should be followed). Histologically or cytologically confirmed diagnosis of advanced or metastatic NSCLC, without EGFR or ALK genomic alterations (testing not required for participants with documented squamous histology) and no known genomic alterations in other actionable driver kinases with approved therapies. Participants whose tumors harbor KRAS mutations are eligible for this study. For Cohorts 1 to 4, participants must be treatment-naïve or have received and radiologically progressed after only 1 prior line of systemic chemotherapy, without concomitant immune checkpoint inhibitors for advanced or metastatic NSCLC. For Cohorts 5 to 11 and 14, participants must be treatment-naïve for advanced or metastatic NSCLC. For Cohorts 12 to 13, participants must be CPI acquired resistant after 1 or 2 prior lines of systemic therapy for advanced or metastatic NSCLC, of which 1 should have contained an approved anti-PD-1/PD L1 Willing and able to undergo a mandatory tumor biopsy. A tumor biopsy that was recently collected (within 3 months of screening) after completion of the most recent anticancer treatment regimen may be substituted for the biopsy collected during screening. For Cohorts 12 and 13, a tumor sample taken ≤24 months prior to screening is acceptable. Has measurable disease per RECIST1.1 within 28 days prior to Cycle 1 Day 1 Eastern Co-operative Oncology Group (ECOG) performance status of 0 or 1 at screening Has adequate bone marrow reserve and organ function at baseline within 7 days prior to Cycle 1 day 1 For Cohorts 5 to 14 only: Documented IHC PD-L1 expression per analytically validated Ventana PD-L1 (SP263) IHC assay, 22C3 PharmDx assay, or 28-8 PharmDx assay Exclusion Criteria: Active or prior documented autoimmune or inflammatory disorders Uncontrolled or significant cardiac disease History of another primary malignancy with exceptions active or uncontrolled hepatitis B or C virus or uncontrolled HIV infection spinal cord compression or clinically active CNS metastases History of (non-infectious) ILD/pneumonitis that required steroids Clinically severe pulmonary compromise resulting from intercurrent pulmonary illness Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals Clinically significant corneal disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Dose escalation and dose expansion model
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>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 | Drug: Datopotamab deruxtecan<br>* Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle<br>* Other names: Dato-DXd;Drug: Durvalumab<br>* Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle<br>* Other names: Imfinzi;|
| Experimental: Cohort 2<br>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 | Drug: Datopotamab deruxtecan<br>* Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle<br>* Other names: Dato-DXd;Drug: Durvalumab<br>* Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle<br>* Other names: Imfinzi;|
| Experimental: Cohort 3<br>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 | Drug: Datopotamab deruxtecan<br>* Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle<br>* Other names: Dato-DXd;Drug: Durvalumab<br>* Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle<br>* Other names: Imfinzi;Drug: Carboplatin<br>* Intravenous infusion Q3W on Day 1 or Day 2 of each 21-day cycle<br>|
| Experimental: Cohort 4<br>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 | Drug: Datopotamab deruxtecan<br>* Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle<br>* Other names: Dato-DXd;Drug: Durvalumab<br>* Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle<br>* Other names: Imfinzi;Drug: Carboplatin<br>* Intravenous infusion Q3W on Day 1 or Day 2 of each 21-day cycle<br>|
| Experimental: Cohort 5<br>Datopotamab deruxtecan (Dato-DXd) + AZD2936 in participants with treatment-naïve NSCLC | Drug: Datopotamab deruxtecan<br>* Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle<br>* Other names: Dato-DXd;Drug: AZD2936<br>* Intravenous infusion prior to Dato-DXd<br>* Other names: rilvegostomig;|
| Experimental: Cohort 6<br>Datopotamab deruxtecan (Dato-DXd) + AZD2936 in participants with treatment-naïve NSCLC | Drug: Datopotamab deruxtecan<br>* Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle<br>* Other names: Dato-DXd;Drug: AZD2936<br>* Intravenous infusion prior to Dato-DXd<br>* Other names: rilvegostomig;|
| Experimental: Cohort 7<br>Datopotamab deruxtecan (Dato-DXd) + AZD2936 + Carboplatin in participants with treatment-naïve NSCLC | Drug: Datopotamab deruxtecan<br>* Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle<br>* Other names: Dato-DXd;Drug: Carboplatin<br>* Intravenous infusion Q3W on Day 1 or Day 2 of each 21-day cycle<br>Drug: AZD2936<br>* Intravenous infusion prior to Dato-DXd<br>* Other names: rilvegostomig;|
| Experimental: Cohort 8<br>Datopotamab deruxtecan (Dato-DXd) + AZD2936 + Carboplatin in participants with treatment-naïve NSCLC | Drug: Datopotamab deruxtecan<br>* Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle<br>* Other names: Dato-DXd;Drug: Carboplatin<br>* Intravenous infusion Q3W on Day 1 or Day 2 of each 21-day cycle<br>Drug: AZD2936<br>* Intravenous infusion prior to Dato-DXd<br>* Other names: rilvegostomig;|
| Experimental: Cohort 9<br>Datopotamab deruxtecan (Dato-DXd) + MEDI5752 + Carboplatin in participants with treatment-naïve NSCLC | Drug: Datopotamab deruxtecan<br>* Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle<br>* Other names: Dato-DXd;Drug: Carboplatin<br>* Intravenous infusion Q3W on Day 1 or Day 2 of each 21-day cycle<br>Drug: MEDI5752<br>* Intravenous infusion prior to Dato-DXd<br>* Other names: volrustomig;|
| Experimental: Cohort 10<br>Datopotamab deruxtecan (Dato-DXd) + MEDI5752 + Carboplatin in participants with treatment-naïve NSCLC | Drug: Datopotamab deruxtecan<br>* Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle<br>* Other names: Dato-DXd;Drug: Carboplatin<br>* Intravenous infusion Q3W on Day 1 or Day 2 of each 21-day cycle<br>Drug: MEDI5752<br>* Intravenous infusion prior to Dato-DXd<br>* Other names: volrustomig;|
| Experimental: Cohort 11<br>Datopotamab deruxtecan (Dato-DXd) + MEDI5752 in participants with treatment-naïve NSCLC | Drug: Datopotamab deruxtecan<br>* Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle<br>* Other names: Dato-DXd;Drug: MEDI5752<br>* Intravenous infusion prior to Dato-DXd<br>* Other names: volrustomig;|
| Experimental: Cohort 12<br>Datopotamab deruxtecan (Dato-DXd) + AZD7789 in participants with CPI acquired resistant NSCLC | Drug: AZD7789<br>* Intravenous infusion prior to Dato-DXd<br>* Other names: sabestomig;|
| Experimental: Cohort 13<br>Datopotamab deruxtecan (Dato-DXd) + AZD7789 in participants with CPI acquired resistant NSCLC | Drug: AZD7789<br>* Intravenous infusion prior to Dato-DXd<br>* Other names: sabestomig;|
| Experimental: Cohort 14<br>Datopotamab deruxtecan (Dato-DXd) + AZD7789 in participants with treatment-naïve NSCLC | Drug: AZD7789<br>* Intravenous infusion prior to Dato-DXd<br>* Other names: sabestomig;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with DLTs; TEAEs and other safety parameters during the study. | DLTs, TEAEs, SAEs, AESIs, ECOG PS, vital sign measurements, standard clinical laboratory parameters (hematology, clinical chemistry, and urinalysis), ECG parameters, ECHO/MUGA scan findings, and ophthalmologic findings | DLTs: within first cycle (21 days); TEAEs and other safety parameters: when all participants have either discontinued the study or the last participant enrolled in the study has completed at least 9 months of follow-up (approximately 55 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR as assessed by investigator per RECIST Version 1.1 | ORR is defined as the proportion of participants with measurable disease at baseline who achieved a BOR of confirmed CR or confirmed PR. | At the time of the final analysis (when all participants have either discontinued the study or the last participant enrolled in the study has completed at least 9 months of follow-up, approximately 55 months). | 
| Duration of Response as assessed by investigator per RECIST version 1.1 | Duration of Response is defined as the time from the date of the first documentation of objective response (confirmed CR or confirmed PR) to the date of the first documentation of objective PD, or death due to any cause, whichever occurs first. | At the time of the final analysis (when all participants have either discontinued the study or the last participant enrolled in the study has completed at least 9 months of follow-up, approximately 55 months). | 
| Disease Control Rate as assessed by the investigator per RECIST version 1.1 | Disease Control Rate is defined as the proportion of participants who achieved a Best Overall Response of confirmed complete response, confirmed partial response, or stable disease. | At the time of the final analysis (when all participants have either discontinued the study or the last participant enrolled in the study has completed at least 9 months of follow-up, approximately 55 months). | 
| Progression-free Survival as assessed by the investigator per RECIST v1.1 | Progression-free Survival is defined as the time interval from the date of the start of study treatment to the earlier of the dates of the first documentation of objective PD or death due to any cause, whichever occurs first | At the time of the final analysis (when all participants have either discontinued the study or the last participant enrolled in the study has completed at least 9 months of follow-up, approximately 55 months). | 
| Time to Response as assessed by investigator per RECIST Version 1.1 | Time to Response is defined as the time from the date of the start of study treatment to the date of the first documentation of objective response (confirmed complete response or confirmed partial response) | At the time of the final analysis (when all participants have either discontinued the study or the last participant enrolled in the study has completed at least 9 months of follow-up, approximately 55 months). | 
| Best percentage change in the Sum of Diameters of measurable tumors | The best percentage change in the Sum of Diameters of measurable tumors is defined as the percentage change in the smallest Sum of Diameters from all postbaseline tumor assessments, taking as reference the baseline Sum of Diameters. | At the time of the final analysis (when all participants have either discontinued the study or the last participant enrolled in the study has completed at least 9 months of follow-up, approximately 55 months). | 
| Overall Survival | Overall Survival is defined as the time from the date of the start of study treatment to the date of death due to any cause | At the time of the final analysis (when all participants have either discontinued the study or the last participant enrolled in the study has completed at least 9 months of follow-up, approximately 55 months). | 
| Pharmacokinetic Parameter Maximum Plasma/Serum Concentration (Cmax) of Dato-DXd, Total anti-TROP2 antibody, and MAAA-1181a. Serum concentrations of durvalumab and MEDI5752, AZD2936, MEDI5752 and AZD7789. | Cmax = Maximum concentration | At the time of the final analysis (when all participants have either discontinued the study or the last participant enrolled in the study has completed at least 9 months of follow-up, approximately 55 months). | 
| Pharmacokinetic Parameter Time to Maximum Plasma/Serum Concentration (Tmax) of Dato-DXd, Total anti-TROP2 antibody, and MAAA-1181a. | Tmax = time to reach maximum concentration. | At the time of the final analysis (when all participants have either discontinued the study or the last participant enrolled in the study has completed at least 9 months of follow-up, approximately 55 months). | 
| Pharmacokinetic Parameter Area Under the Plasma Concentration-Time Curve (AUC) of Dato-DXd, Total anti-TROP2 antibody, and MAAA-1181a. | Area under the plasma concentration-time curve up to last quantifiable time (AUClast) and area under the plasma concentration-time curve during dosing interval (AUCtau) will be assessed. | At the time of the final analysis (when all participants have either discontinued the study or the last participant enrolled in the study has completed at least 9 months of follow-up, approximately 55 months). | 
| Prevalence of Dato-Dxd, durvalumab, AZD2936, MEDI5752 and AZD7789 ADA | ADA prevalence is defined as the proportion of all participants having ADA at any point in time (including pre-existing ADA at baseline and treatment-emergent ADA) | At the time of the final analysis (when all participants have either discontinued the study or the last participant enrolled in the study has completed at least 9 months of follow-up, approximately 55 months). | 
| Incidence of Dato-DXd, durvalumab, AZD2936, MEDI5752 and AZD7789 ADA | ADA incidence is defined as the proportion of participants having treatment-emergent ADA during the study period | At the time of the final analysis (when all participants have either discontinued the study or the last participant enrolled in the study has completed at least 9 months of follow-up, approximately 55 months). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced or Metastatic NSCLC, Datopotamab deruxtecan (Dato-DXd), DS-1062a, Durvalumab, AZD2936, MEDI5752, AZD7789