Clinical trial NCT04686305: Phase Ib Study of the Safety of T-DXd and Immunotherapy Agents With and Without Chemotherapy in Advanced or Metastatic HER2+, Non-squamous NSCLC
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Locally Advanced or Metastatic Non-Small Cell Lung Cancer
Keywords: HER2+
HER2 expression
DS-8201a
T-DXd
Trastuzumab Deruxtecan
Volrustomig (MEDI5752)
Antibody - drug conjugate
bispecific antibody
Volrustomig
Rilvegostomig
Carboplatin
First line
Locally advanced and unresectable non-squamous NSCLC
Metastatic non-squamous NSCLC
Non-small cell lung cancer
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Daiichi Sankyo
First posted: 2020-12-28
Enrollment: 244
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The overall objective of DL-03 is to identify the partner of choice to be used in combination with T-DXd for first-line (treatment naïve patients with metastatic disease) HER2-overexpressing NSCLC patients.

Part 4 will consist of 2 Arms (4A and 4B) utilizing T-DXd in combination with rilvegostomig without or with carboplatin (ﬁrst 4 cycles in Arm 4B only). In addition to safety \& tolerability, the study will also assess preliminary efficacy based upon ORR, DoR, DCR, OS, PFS among treatment groups.

Part 3 will consist of 2 Arms (3A and 3B) utilizing T-DXd in combination with volrustomig without or with carboplatin (ﬁrst 4 cycles in Arm 3B only). The initial portion of Part 3 will assess two different doses of volrustomig for safety and tolerability. In addition to safety \& tolerability, the study will also assess preliminary efficacy based upon ORR, DoR, DCR, OS, PFS among treatment groups.

Part 2 was not initiated.

Part 1 is completed.
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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).

Primary outcomes:
measure: Frequency of AEs and SAEs
timeFrame: Safety and tolerability (and to determine RP2D) will be assessed for approximately 20 months from informed consent
Secondary outcomes:
measure: Confirmed Objective Response Rate (ORR)
timeFrame: An average of approximately 12 months
measure: Duration of Response (DoR)
timeFrame: An average of approximately 20 months
measure: Disease Control Rate (DCR)
timeFrame: An average of approximately 12 months
measure: Progression-free survival (PFS)
timeFrame: An average of approximately 20 months
measure: Overall survival (OS)
timeFrame: An average of approximately 20 months
measure: Pharmacokinetics (PK) assessed by the serum concentration of T-DXd, total anti-HER2 antibody, and MAAA-1181 in all arms
timeFrame: An average of approximately 20 months
measure: Pharmacokinetics (PK) assessed by the serum concentration of durvalumab in study arms including T-DXd in combination with durvalumab
timeFrame: An average of approximately 20 months
measure: Pharmacokinetics (PK) assessed by the serum concentration of volrustomig in study arms including T-DXd in combination with volrustomig
timeFrame: An average of approximately 20 months
measure: Pharmacokinetics (PK) assessed by the serum concentration of rilvegostomig in study arms including T-DXd in combination with rilvegostomig
timeFrame: An average of approximately 20 months
measure: The immunogenicity of T-DXd, durvalumab, volrustomig and rilvegostomig assessed by the presence of ADAs for T-DXd, durvalumab, volrustomig, or rilvegostomig
timeFrame: An average of approximately 20 months
Other outcomes:
Locations:
city: Duarte
country: United States
facility: Research Site
state: California
city: Newport Beach
country: United States
facility: Research Site
state: California
city: Orange
country: United States
facility: Research Site
state: California
city: Santa Rosa
country: United States
facility: Research Site
state: California
city: Westwood
country: United States
facility: Research Site
state: Kansas
city: Baltimore
country: United States
facility: Research Site
state: Maryland
city: Detroit
country: United States
facility: Research Site
state: Michigan
city: Bronx
country: United States
facility: Research Site
state: New York
city: Buffalo
country: United States
facility: Research Site
state: New York
city: New York
country: United States
facility: Research Site
state: New York
city: Houston
country: United States
facility: Research Site
state: Texas
city: Fairfax
country: United States
facility: Research Site
state: Virginia
city: Tacoma
country: United States
facility: Research Site
state: Washington
city: Adelaide
country: Australia
facility: Research Site
city: Heidelberg
country: Australia
facility: Research Site
city: Nedlands
country: Australia
facility: Research Site
city: Edegem
country: Belgium
facility: Research Site
city: Winnipeg
country: Canada
facility: Research Site
state: Manitoba
city: London
country: Canada
facility: Research Site
state: Ontario
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Bordeaux Cedex
country: France
facility: Research Site
city: Dijon
country: France
facility: Research Site
city: Pierre-Benite
country: France
facility: Research Site
city: Saint Herblain
country: France
facility: Research Site
city: Villejuif Cedex
country: France
facility: Research Site
city: Kfar-Saba
country: Israel
facility: Research Site
city: Tel Hashomer
country: Israel
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Monza
country: Italy
facility: Research Site
city: Napoli
country: Italy
facility: Research Site
city: Padova
country: Italy
facility: Research Site
city: Cheongju-si
country: Korea, Republic of
facility: Research Site
city: Goyang-si
country: Korea, Republic of
facility: Research Site
city: Jinju-si
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: George Town
country: Malaysia
facility: Research Site
city: Kuala Lumpur
country: Malaysia
facility: Research Site
city: Kuching
country: Malaysia
facility: Research Site
city: Selangor
country: Malaysia
facility: Research Site
city: Amsterdam
country: Netherlands
facility: Research Site
city: Bacolod
country: Philippines
facility: Research Site
city: Cebu City
country: Philippines
facility: Research Site
city: Davao City
country: Philippines
facility: Research Site
city: Manila
country: Philippines
facility: Research Site
city: Manila
country: Philippines
facility: Research Site
city: Quezon City
country: Philippines
facility: Research Site
city: Quezon City
country: Philippines
facility: Research Site
city: San Juan
country: Philippines
facility: Research Site
city: Taguig City
country: Philippines
facility: Research Site
city: Gdańsk
country: Poland
facility: Research Site
city: Kraków
country: Poland
facility: Research Site
city: Olsztyn
country: Poland
facility: Research Site
city: Tomaszów Mazowiecki
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Singapore
country: Singapore
facility: Research Site
city: Singapore
country: Singapore
facility: Research Site
city: Singapore
country: Singapore
facility: Research Site
city: Badalona
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Sevilla
country: Spain
facility: Research Site
city: Valencia
country: Spain
facility: Research Site
city: Kaohsiung city
country: Taiwan
facility: Research Site
city: Taichung City
country: Taiwan
facility: Research Site
city: Taichung
country: Taiwan
facility: Research Site
city: Tainan
country: Taiwan
facility: Research Site
city: Taipei
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: Bangkok
country: Thailand
facility: Research Site
city: Bangkok
country: Thailand
facility: Research Site
city: Hat Yai
country: Thailand
facility: Research Site
city: Khon Kaen
country: Thailand
facility: Research Site
city: Muang
country: Thailand
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Bornova-Izmir
country: Turkey
facility: Research Site
Study officials:
References: