Advanced or Metastatic NSCLC
Conditions
Keywords
Advanced or Metastatic NSCLC, Datopotamab deruxtecan (Dato-DXd), DS-1062a, Durvalumab, AZD2936, MEDI5752, AZD7789
Brief summary
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).
Detailed description
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 15 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.
Interventions
DRUGDatopotamab deruxtecan
Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle
DRUGDurvalumab
Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle
DRUGCarboplatin
Intravenous infusion Q3W on Day 1 or Day 2 of each 21-day cycle
DRUGAZD2936
Intravenous infusion prior to Dato-DXd every 3 weeks (Q3W) on Day 1 prior to Dato-Dxd of each 21-day cycle
DRUGMEDI5752
Intravenous infusion prior to Dato-DXd every 3 weeks (Q3W) on Day 1 prior to Dato-Dxd of each 21-day cycle
DRUGAZD7789
Intravenous infusion prior to Dato-DXd every 3 weeks (Q3W) on Day 1 prior to Dato-Dxd of each 21-day cycle
Sponsors
Daiichi Sankyo
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Dose escalation and dose expansion model
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 4a, 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. Cohort 4a will enroll participants whose tumors have squamous histology only; Cohorts 5 Part 2A and Part 2B as well as Cohorts 12 and 13 will enroll participants whose tumors have non-squamous histology only. * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with DLTs; TEAEs and other safety parameters during the study. | 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 60 months) | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response as assessed by investigator per RECIST version 1.1 | 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 60 months). | 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. |
| Disease Control Rate as assessed by the investigator per RECIST version 1.1 | 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 60 months). | 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. |
| Progression-free Survival as assessed by the investigator per RECIST v1.1 | 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 60 months). | 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 |
| Time to Response as assessed by investigator per RECIST Version 1.1 | 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 60 months). | 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) |
| Best percentage change in the Sum of Diameters of measurable tumors | 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 60 months). | 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. |
| ORR as assessed by investigator per RECIST Version 1.1 | 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 60 months). | ORR is defined as the proportion of participants with measurable disease at baseline who achieved a BOR of confirmed CR or confirmed PR. |
| 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. | 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 60 months). | Cmax = Maximum concentration |
| Pharmacokinetic Parameter Time to Maximum Plasma/Serum Concentration (Tmax) of Dato-DXd, Total anti-TROP2 antibody, and MAAA-1181a. | 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 60 months). | Tmax = time to reach maximum concentration. |
| Pharmacokinetic Parameter Area Under the Plasma Concentration-Time Curve (AUC) of Dato-DXd, Total anti-TROP2 antibody, and MAAA-1181a. | 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 60 months). | 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. |
| Prevalence of Dato-Dxd, durvalumab, AZD2936, MEDI5752 and AZD7789 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 60 months). | 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) |
| Incidence of Dato-DXd, durvalumab, AZD2936, MEDI5752 and AZD7789 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 60 months). | ADA incidence is defined as the proportion of participants having treatment-emergent ADA during the study period |
| Overall Survival | 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 60 months). | 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 |
Countries
Belgium, Italy, Japan, Poland, Spain, Taiwan, Turkey (Türkiye), United States
Outcome results
None listed