Clinical trial NCT04612751: Phase 1b Study of Dato-DXd in Combination With Immunotherapy With or Without Carboplatin in Advanced or Metastatic Non-Small Cell Lung Cancer
Official title: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Advanced or Metastatic NSCLC
Keywords: Advanced or Metastatic NSCLC
Datopotamab deruxtecan (Dato-DXd)
DS-1062a
Durvalumab
AZD2936
MEDI5752
AZD7789
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Daiichi Sankyo
First posted: 2020-11-03
Enrollment: 371
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Dose escalation and dose expansion model
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of participants with DLTs; TEAEs and other safety parameters during the study.
timeFrame: 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)
Secondary outcomes:
measure: ORR as assessed by investigator per RECIST Version 1.1
timeFrame: 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).
measure: Duration of Response as assessed by investigator per RECIST version 1.1
timeFrame: 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).
measure: Disease Control Rate as assessed by the investigator per RECIST version 1.1
timeFrame: 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).
measure: Progression-free Survival as assessed by the investigator per RECIST v1.1
timeFrame: 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).
measure: Time to Response as assessed by investigator per RECIST Version 1.1
timeFrame: 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).
measure: Best percentage change in the Sum of Diameters of measurable tumors
timeFrame: 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).
measure: Overall Survival
timeFrame: 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).
measure: 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.
timeFrame: 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).
measure: Pharmacokinetic Parameter Time to Maximum Plasma/Serum Concentration (Tmax) of Dato-DXd, Total anti-TROP2 antibody, and MAAA-1181a.
timeFrame: 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).
measure: Pharmacokinetic Parameter Area Under the Plasma Concentration-Time Curve (AUC) of Dato-DXd, Total anti-TROP2 antibody, and MAAA-1181a.
timeFrame: 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).
measure: Prevalence of Dato-Dxd, durvalumab, AZD2936, MEDI5752 and AZD7789 ADA
timeFrame: 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).
measure: Incidence of Dato-DXd, durvalumab, AZD2936, MEDI5752 and AZD7789 ADA
timeFrame: 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).
Other outcomes:
Locations:
city: Duarte
country: United States
facility: Research Site
state: California
city: La Jolla
country: United States
facility: Research Site
state: California
city: Santa Ana
country: United States
facility: Research Site
state: California
city: Chicago
country: United States
facility: Research Site
state: Illinois
city: Detroit
country: United States
facility: Research Site
state: Michigan
city: Saint Louis
country: United States
facility: Research Site
state: Missouri
city: Lebanon
country: United States
facility: Research Site
state: New Hampshire
city: Hackensack
country: United States
facility: Research Site
state: New Jersey
city: New York
country: United States
facility: Research Site
state: New York
city: Cleveland
country: United States
facility: Research Site
state: Ohio
city: Hershey
country: United States
facility: Research Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: Research Site
state: Pennsylvania
city: Nashville
country: United States
facility: Research Site
state: Tennessee
city: Dallas
country: United States
facility: Research Site
state: Texas
city: Houston
country: United States
facility: Research Site
state: Texas
city: San Antonio
country: United States
facility: Research Site
state: Texas
city: Fairfax
country: United States
facility: Research Site
state: Virginia
city: Falls Church
country: United States
facility: Research Site
state: Virginia
city: Hasselt
country: Belgium
facility: Research Site
city: Mechelen
country: Belgium
facility: Research Site
city: Roeselare
country: Belgium
facility: Research Site
city: Paris Cedex 05
country: France
facility: Research Site
city: Aviano
country: Italy
facility: Research Site
city: Meldola
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Orbassano
country: Italy
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: Koto-ku
country: Japan
facility: Research Site
city: Sunto-gun
country: Japan
facility: Research Site
city: Yokohama-shi
country: Japan
facility: Research Site
city: Busan
country: Korea, Republic of
facility: Research Site
city: Cheongiu
country: Korea, Republic of
facility: Research Site
city: Hwasun-gun
country: Korea, Republic of
facility: Research Site
city: JinJoo
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Suwon-si
country: Korea, Republic of
facility: Research Site
city: Suwon
country: Korea, Republic of
facility: Research Site
city: Gdańsk
country: Poland
facility: Research Site
city: Lublin
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Łódź
country: Poland
facility: Research Site
city: Łódź
country: Poland
facility: Research Site
city: A Coruña
country: Spain
facility: Research Site
city: Badalona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Pozuelo de Alarcon
country: Spain
facility: Research Site
city: Sevilla
country: Spain
facility: Research Site
city: Changhua
country: Taiwan
facility: Research Site
city: Hsinchu
country: Taiwan
facility: Research Site
city: Kaohsiung City
country: Taiwan
facility: Research Site
city: Taichung
country: Taiwan
facility: Research Site
city: Tainan
country: Taiwan
facility: Research Site
city: Taipei City
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Taoyuan
country: Taiwan
facility: Research Site
city: Adana
country: Turkey
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Istanbul
country: Turkey
facility: Research Site
city: Izmir
country: Turkey
facility: Research Site
city: Konya
country: Turkey
facility: Research Site
city: Malatya
country: Turkey
facility: Research Site
Study officials:
References: