Save

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

PHASE1RECRUITING

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.

Simpliy with AI

Study details:

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.

Simplify with AI

Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

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).

Simplify with AI

Eligibility

Age eligible for study : 18 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2021-03-09

Primary completion: 2025-12-23

Study completion finish: 2025-12-23

Study type

TREATMENT

Phase

PHASE1

Trial ID

NCT04686305

Intervention or treatment

DRUG: T-DXd

BIOLOGICAL: Durvalumab

DRUG: Cisplatin

DRUG: Carboplatin

DRUG: Pemetrexed

DRUG: Volrustomig

DRUG: Rilvegostomig

Conditions

• Locally Advanced or Metastatic Non-Small Cell Lung Cancer

Image related to Locally Advanced or Metastatic Non-Small Cell Lung Cancer

Condition: Locally Advanced or Metastatic Non-Small Cell Lung Cancer
DRUG: T-DXd and other drugs
Heidelberg, Not Specified, Australia and more
Sponsor: AstraZeneca

You may be eligible to participate in this trial based on your search. Check eligibility by answering some questions.

Are you running this trial? If you're a clinic or sponsor, you can claim this study. Claim or learn more.

Find a site

Closest Location:

Research Site

Research sites nearby

Select from list below to view details:

Research Site
Heidelberg, Not Specified, Australia
Research Site
Nedlands, Not Specified, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Arm 1A: T-DXd, Durvalumab and Cisplatin T-DXd, Durvalumab and Cisplatin	DRUG: T-DXd T-DXd: administered as an IV infusion
EXPERIMENTAL: Arm 1B: T-DXd, Durvalumab and Carboplatin T-DXd, Durvalumab and Carboplatin	DRUG: T-DXd T-DXd: administered as an IV infusion
EXPERIMENTAL: Arm 1C: T-DXd, Durvalumab and Pemetrexed T-DXd, Durvalumab and Pemetrexed (Arm not initiated)	DRUG: T-DXd T-DXd: administered as an IV infusion
EXPERIMENTAL: Arm 1D: T-DXd T-DXd	DRUG: T-DXd T-DXd: administered as an IV infusion
EXPERIMENTAL: Arm 3A: T-DXd and Volrustomig Drug: T-DXd and Volrustomig T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion Other Name: Volrustomig	DRUG: T-DXd T-DXd: administered as an IV infusion
EXPERIMENTAL: Arm 3B: T-DXd, Volrustomig and Carboplatin Drug: T-DXd, Volrustomig and Carboplatin T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion Other Name: Volrustomig Drug: Carboplatin Carboplatin: administered as an IV infusion	DRUG: T-DXd T-DXd: administered as an IV infusion
EXPERIMENTAL: Arm 4A: T-DXd and Rilvegostomig T-DXd and Rilvegostomig Drug: T-DXd, Rilvegostomig T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Rilvegostomig Rilvegostomig: administered as an IV infusion Other Name: Rilvegostomig, AZD2936	DRUG: T-DXd T-DXd: administered as an IV infusion
EXPERIMENTAL: Arm 4B T-DXd and Rilvegostomig with Carboplatin Drug: T-DXd, Rilvegostomig and Carboplatin T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Rilvegostomig Rilvegostomig: administered as an IV infusion Other Name: Rilvegostomig, AZD2936 Drug: Carboplatin Carboplatin: administered as an IV infusion	DRUG: T-DXd T-DXd: administered as an IV infusion

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
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 outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
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
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
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
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
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
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
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
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
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
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

Frequently Asked Questions

Please note: some questions and answers are submitted by anonymous patients or using AI, and have not been verified by Clinrol

No questions submitted. Be the first to ask a question!

You may be eligible to participate in this trial based on your search.Apply for study

Are you running this trial? If you're a clinic or sponsor, you can claim this study.Claim this trial

References

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