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: May 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 and Part 4, assessing T-DXd and volrustomig with carboplatin (Arm 3B) or without carboplatin (Arm 3A) and T-Dxd and rilvegostomig with carboplatin (Arm 4B) or without carboplatin (Arm 4A).

For Part 3, patients will be randomized to Arms 3A and 3B, beginning with the cohorts receiving the volrustomig 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 volrustomig 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 volrustomig RP2D to be used in the dose-expansion (DE) cohorts of each arm (n=34).

In Part 4, once a total of 6 DLT-evaluable patients/arm have been enrolled into Arm 4A and Arm 4B safety-run in (SR) cohorts and deemed safe, an additional 34 patients per arm will be enrolled in Arms 4A and 4B in dose expansion cohorts.

The target population of interest (for Part 3 and Part 4) are patients with advanced or metastatic non-small cell lung cancer measurable disease by RECIST 1.1 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: 248
• 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 and 4: Patients must have tumors that do not harbor known genomic alterations or actionable driver kinases, for which approved therapies are available are allowed.

• Part 3 and 4: Patient must be treatment-naïve for advanced or metastatic NSCLC. Patients who have received prior adjuvant, or 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 and part 4: 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 chronic and resolved hepatitis B (positive hepatitis B virus surface antigen [HBsAg+ve] or hepatitis B virus core antibody (anti-HBc +ve) regardless of HBV DNA level)) or hepatitis C infection. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Patients should be tested for HIV prior to treatment assignment if required by local regulations or IRB/EC

• 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

• For Part 3 and Part 4: 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 are to be excluded. Patients with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial related symptoms, should have a cardiologic consultation before treatment assignment to rule out acute cardiopulmonary events.

• Ascites or pericardial effusion that requires drainage, peritoneal shunt, Pleuroperitoneal shunt or CART (Concentrated Ascites Reinfusion Therapy)

• For Part 3 and Part 4: Active non-infectious skin disease (including any grade rash, urticarial, dermatitis, ulceration, or psoriasis) requiring systemic treatment, active or prior documented autoimmune or inflammatory disorders requiring chronic treatment with steroids or other immunosuppressive treatment.

• 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 and 4 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.

• For Part 3 and Part 4: History of substance abuse or any other medical or psychological conditions that may, in the opinion of the Investigator, interfere with the subject's participation in the clinical study or evaluation of the clinical study results

• For Part 3 and Part 4: History of thromboembolic events within 3 months before the first dose of IP (limited to pulmonary embolism, deep vein thrombosis, or cerebral venous sinus thrombosis).

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)
• Volrustomig
Volrustomig: administered as an IV infusion
• Rilvegostomig
Rilvegostomig: 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 and tolerability (and to determine RP2D) 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 1.1 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 1.1 assessment. DCR is assessed at 6 and 12 weeks	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 1.1 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	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 volrustomig in study arms including T-DXd in combination with volrustomig	Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for volrustomig, including T-DXd in combination with volrustomig	An average of approximately 20 months
Secondary	Pharmacokinetics (PK) assessed by the serum concentration of rilvegostomig in study arms including T-DXd in combination with rilvegostomig	Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for rilvegostomig, including T- DXd in combination with rilvegostomig	An average of approximately 20 months
Secondary	The immunogenicity of T-DXd, durvalumab, volrustomig and rilvegostomig assessed by the presence of ADAs for T-DXd, durvalumab, volrustomig, or rilvegostomig	Individual participant data and descriptive statistics will be provided for data at each time point for each dose level for T-DXd, durvalumab or volrustomig, or rilvegostomig	An average of approximately 20 months