Phase 1b Study of Dato-DXd in Combination With Immunotherapy With or Without Carboplatin in Advanced or Metastatic Non-Small Cell Lung Cancer (TROPION-Lung04)

AstraZeneca

Status and phase: Active, not recruiting; Phase 1

Conditions: Advanced or Metastatic NSCLC

Treatments: Drug: MEDI5752; Drug: AZD2936; Drug: Datopotamab deruxtecan; Drug: Carboplatin; Drug: AZD7789; Drug: Durvalumab

Study type: Interventional

Funder types: Industry

Identifiers

NCT04612751

2023-505992-54-00 (Registry Identifier)

2021-000274-28 (EudraCT Number)

D926FC00001

Details and patient eligibility

About

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).

Full 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.

Enrollment: 155 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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155 participants in 15 patient groups

Cohort 1

Experimental group

Description:

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

Treatment:

Drug: Durvalumab

Drug: Datopotamab deruxtecan

Cohort 2

Experimental group

Description:

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

Treatment:

Drug: Durvalumab

Drug: Datopotamab deruxtecan

Cohort 3

Experimental group

Description:

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

Treatment:

Drug: Durvalumab

Drug: Carboplatin

Drug: Datopotamab deruxtecan

Cohort 4

Experimental group

Description:

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

Treatment:

Drug: Durvalumab

Drug: Carboplatin

Drug: Datopotamab deruxtecan

Cohort 5

Experimental group

Description:

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

Treatment:

Drug: Datopotamab deruxtecan

Drug: AZD2936

Cohort 6

Experimental group

Description:

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

Treatment:

Drug: Datopotamab deruxtecan

Drug: AZD2936

Cohort 7

Experimental group

Description:

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

Treatment:

Drug: Carboplatin

Drug: Datopotamab deruxtecan

Drug: AZD2936

Cohort 8

Experimental group

Description:

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

Treatment:

Drug: Carboplatin

Drug: Datopotamab deruxtecan

Drug: AZD2936

Cohort 9

Experimental group

Description:

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

Treatment:

Drug: Carboplatin

Drug: Datopotamab deruxtecan

Drug: MEDI5752

Cohort 10

Experimental group

Description:

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

Treatment:

Drug: Carboplatin

Drug: Datopotamab deruxtecan

Drug: MEDI5752

Cohort 11

Experimental group

Description:

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

Treatment:

Drug: Datopotamab deruxtecan

Drug: MEDI5752

Cohort 12

Experimental group

Description:

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

Treatment:

Drug: AZD7789

Drug: Datopotamab deruxtecan

Cohort 13

Experimental group

Description:

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

Treatment:

Drug: AZD7789

Drug: Datopotamab deruxtecan

Cohort 14

Experimental group

Description:

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

Treatment:

Drug: AZD7789

Drug: Datopotamab deruxtecan

Cohort 4A

Experimental group

Description:

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

Treatment:

Drug: Durvalumab

Drug: Carboplatin

Drug: Datopotamab deruxtecan