Phase Ib Study of the Safety of T-DXd and Immunotherapy Agents With and Without Chemotherapy in Advanced or Metastatic HER2+, Non-squamous NSCLC

Locally Advanced or Metastatic Non-Small Cell Lung Cancer Clinical Trial

— DL03  

Official title:

A Phase Ib Multicenter, Open-label Study to Evaluate the Safety and Tolerability of Trastuzumab Deruxtecan (T-DXd) and Immunotherapy Agents With and Without Chemotherapy Agents in First-line Treatment of Patients With Advanced or Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC) and Human Epidermal Growth Factor Receptor 2 (HER2) Overexpression (OE) (DESTINY-Lung03)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04686305
• Other study ID #: D967YC00001
• Secondary ID: 2020-003260-31
• Status: Recruiting
• Phase: Phase 1
• Start date: March 9, 2021
• Est. completion date: December 23, 2025

Study information

• Verified date: April 2024
• Source: AstraZeneca
• Contact: AstraZeneca Clinical Study Information Center
• Phone: 1-877-240-9479
• Email: information.center[@]astrazeneca.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

DESTINY-Lung03 will investigate the safety and tolerability of trastuzumab deruxtecan in combination with Immunotherapy Agents with and without chemotherapy in patients with HER2 over-expressing non-small cell lung cancer. The efficacy will be also analyzed as a secondary endpoint.

Description:

Part 1 is a dose escalation study by design, allowing the assessment of safety, tolerability and recommended dose levels of the combination of T-DXd and durvalumab plus cisplatin, carboplatin or pemetrexed. No more patients will be enrolled in this part of the study. Part 2, expansions in the treatment naïve setting on any recommended dose level will not be initiated. The evaluation of T-DXd combination treatment with immunotherapy continues in Part 3, assessing T-DXd and MEDI5752 with or without carboplatin (Arms 3A and 3B, respectively), using a dose confirmation and expansion design. For Part 3, patients will be randomized 1:1 to Arms 3A and 3B, beginning with the cohorts receiving the MEDI5752 starting dose (SD). A total of 6 DLT-evaluable patients will be enrolled to the SD cohorts in each arm. If the combination of T-DXd with MEDI5752 at the starting dose is deemed safe, a dose escalation (E1) cohort will be opened for 6 DLT-evaluable patients. Once all open dose confirmation cohorts have 6 DLT-evaluable patients, the SRC will convene to select the MEDI5752 RP2D to be used in the dose-expansion (DE) cohorts of each arm (n=34). The target population of interest (for Part 3) are patients with advanced or metastatic non-small cell lung cancer measurable disease by RECIST criteria, HER2 overexpression, ECOG PS of 0 to 1, patients who are treatment naïve for recurrent, unresectable or metastatic disease. Patients with tumors that harbor a known genomic alteration or driver for which approved therapies are available are excluded.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 168
• Est. completion date: December 23, 2025
• Est. primary completion date: December 23, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

• Histologically documented unresectable locally advanced/metastatic non-squamous NSCLC
• Part 1: Progression after 1 or 2 lines of systemic therapy for recurrent or metastatic setting.
• Part 3: Treatment-naïve for non curative treatment for locally advanced or metastatic NSCLC.
• Part 3: Patients must have tumors without known genomic alterations or actionable driver kinases, as determined by existing local test results, for which approved therapies are available are allowed. Patients who received prior adjuvant, neoadjuvant chemotherapy, or definitive chemoradiation for advanced disease are eligible, provided that progression has occurred > 6 months from end of last therapy
• HER2overexpression status as determined by central review of tumor tissue
• WHO / ECOG performance status of 0 or 1
• Measurable target disease assessed by the investigator using RECIST 1.1
• Has protocol defined adequate organ and bone marrow function
• Part 3: Minimum body weight of 35 kg.

Exclusion criteria:

• HER2 mutation if previously known
• Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
• Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder and prior pneumonectomy
• Active primary immunodeficiency known HIV infection, or active hepatitis B (positive hepatitis B virus surface antigen or hepatitis B virus core antibody) or hepatitis C infection
• Active infection including tuberculosis and uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
• Spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms
• Medical history of myocardial infarction within 6 months before treatment assignment, symptomatic CHF (New York Heart Association Class II to IV), clinically important cardiac arrhythmias, or a recent (< 6 months) cardiovascular event including stroke
• Cardiomyopathy of any etiology, symptomatic CHF (as defined by New York Heart Association Class > II), unstable angina pectoris, history of MI within the past 12 months, or cardiac arrhythmia (Part 3).
• A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or CART (Concentrated Ascites Reinfusion Therapy)
• Unresolved toxicities not yet resolved to Grade = 1 or baseline from previous anticancer therapy OR prior discontinuation of any planned study therapy due to toxicity.
• must not have any medical contraindication to platinum-based chemotherapy.
• Part 3 patients must not have had prior exposure to anti-PD-1, anti-PD-L1, anti-CTLA-4, anti-TIGIT or any other experimental immunotherapy in any setting.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Locally Advanced or Metastatic Non-Small Cell Lung Cancer
• Lung Neoplasms

Intervention

Drug:
• T-DXd
T-DXd: administered as an IV infusion

Biological:
• Durvalumab
Durvalumab: administered as an IV infusion

Drug:
• Cisplatin
Cisplatin: administered as an IV infusion
• Carboplatin
Carboplatin: administered as an IV infusion
• Pemetrexed
Pemetrexed: administered as an IV infusion (drug not used)
• MEDI5752
MEDI5752: administered as an IV infusion

Locations

Country	Name	City	State
Australia	Research Site	Adelaide
Australia	Research Site	Heidelberg
Australia	Research Site	Nedlands
Belgium	Research Site	Edegem
Canada	Research Site	London	Ontario
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Winnipeg	Manitoba
France	Research Site	Bordeaux Cedex
France	Research Site	Dijon
France	Research Site	Pierre Benite Cedex
France	Research Site	Saint Herblain
France	Research Site	Villejuif Cedex
Israel	Research Site	Kfar-Saba
Israel	Research Site	Tel Hashomer
Italy	Research Site	Milano
Italy	Research Site	Milano
Italy	Research Site	Monza
Italy	Research Site	Napoli
Italy	Research Site	Padova
Korea, Republic of	Research Site	Cheongju-si
Korea, Republic of	Research Site	Goyang-si
Korea, Republic of	Research Site	Jinju-si
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Malaysia	Research Site	George Town
Malaysia	Research Site	Kuala Lumpur
Malaysia	Research Site	Kuching
Malaysia	Research Site	Selangor
Netherlands	Research Site	Amsterdam
Philippines	Research Site	Bacolod
Philippines	Research Site	Cebu City
Philippines	Research Site	Davao City
Philippines	Research Site	Manila
Philippines	Research Site	Manila
Philippines	Research Site	Quezon City
Philippines	Research Site	Quezon City
Philippines	Research Site	San Juan
Philippines	Research Site	Taguig City
Poland	Research Site	Gdansk
Poland	Research Site	Kraków
Poland	Research Site	Olsztyn
Poland	Research Site	Tomaszów Mazowiecki
Poland	Research Site	Warszawa
Singapore	Research Site	Singapore
Singapore	Research Site	Singapore
Singapore	Research Site	Singapore
Spain	Research Site	Badalona
Spain	Research Site	Madrid
Spain	Research Site	Sevilla
Spain	Research Site	Valencia
Taiwan	Research Site	Kaohsiung city
Taiwan	Research Site	Taichung
Taiwan	Research Site	Taichung City
Taiwan	Research Site	Tainan
Taiwan	Research Site	Taipei
Taiwan	Research Site	Taipei
Taiwan	Research Site	Taipei
Taiwan	Research Site	Taoyuan
Thailand	Research Site	Bangkok
Thailand	Research Site	Bangkok
Thailand	Research Site	Hat Yai
Thailand	Research Site	Khon Kaen
Thailand	Research Site	Muang
Turkey	Research Site	Ankara
Turkey	Research Site	Ankara
Turkey	Research Site	Bornova-Izmir
United States	Research Site	Baltimore	Maryland
United States	Research Site	Bronx	New York
United States	Research Site	Buffalo	New York
United States	Research Site	Detroit	Michigan
United States	Research Site	Duarte	California
United States	Research Site	Fairfax	Virginia
United States	Research Site	Houston	Texas
United States	Research Site	New York	New York
United States	Research Site	Newport Beach	California
United States	Research Site	Orange	California
United States	Research Site	Santa Rosa	California
United States	Research Site	Tacoma	Washington
United States	Research Site	Westwood	Kansas

Sponsors (2)

Lead Sponsor	Collaborator
AstraZeneca	Daiichi Sankyo

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  France,  Israel,  Italy,  Korea, Republic of,  Malaysia,  Netherlands,  Philippines,  Poland,  Singapore,  Spain,  Taiwan,  Thailand,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Frequency of AEs and SAEs	Occurrence of AEs and SAEs graded according to NCI CTCAE v5.0	Safety will be assessed for approximately 20 months from informed consent
Secondary	Confirmed Objective Response Rate (ORR)	Confirmed ORR per RECIST 1.1 is the percentage of patients with Complete Response or Partial Response that is subsequently confirmed, based on investigator assessment	An average of approximately 12 months
Secondary	Duration of Response (DoR)	DOR is defined as the time from the date of first documented response until the date of documented progression or death, based on RECIST assessment	An average of approximately 20 months
Secondary	Disease Control Rate (DCR)	DCR is the percentage of patients who have a best overall response of complete response (CR) or partial response (PR) or stable disease (SD), based on RECIST assessment	An average of approximately 12 months
Secondary	Progression-free survival (PFS)	PFS is the time from first dose of study treatment until the date of objective disease progression or death, based on RECIST assessment	An average of approximately 20 months
Secondary	Overall survival (OS)	OS is the time form the date of first dose of study treatment until death due to any cause	An average of approximately 20 months
Secondary	Frequency of AEs and SAEs	Occurrence of AEs and SAEs graded according to NCI CTCAE v5.0	Safety will be assessed for approximately 20 months from informed consent
Secondary	Pharmacokinetics (PK) assessed by the serum concentration of T-DXd, total anti-HER2 antibody, and MAAA-1181 in all arms	Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for T-DXd, total anti-HER2 antibody and MAAA-1181a	An average of approximately 20 months
Secondary	Pharmacokinetics (PK) assessed by the serum concentration of durvalumab in study arms including T-DXd in combination with durvalumab	Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for durvalumab, including T-DXd in combination with durvalumab	An average of approximately 20 months
Secondary	Pharmacokinetics (PK) assessed by the serum concentration of MEDI5752 in study arms including T-DXd in combination with MEDI5752	Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for MEDI5752, including T-DXd in combination with MEDI5752	An average of approximately 20 months
Secondary	The immunogenicity of T-DXd, durvalumab and MEDI5752 assessed by the presence of ADAs for T-DXd,durvalumab and MEDI5752	Individual participant data and descriptive statistics will be provided for data at each time point for each dose level for T-DXd, durvalumab and MEDI5752	An average of approximately 20 months