Clinical trial NCT05275868: Study of MGY825 in Patients With Advanced Non-small Cell Lung Cancer
Official title: An Open-label, Phase I, Dose Escalation, Expansion Study of MGY825 in Adult Patients With Advanced Non-small Cell Lung Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Non-small Cell Lung Cancer
Keywords: non-small cell lung cancer (NSCLC)
NFE2L2
NRF2
KEAP1
CUL3
MGY825
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2022-03-11
Enrollment: 140
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Study of MGY825 single agent in adult patients with advanced non-small cell lung cancer.

Detailed description: First in human, phase I, multicenter, open-label study of MGY825 single agent with a dose escalation and a dose expansion in adult patients with advanced non-small cell lung cancer (NSCLC).

The dose escalation part will investigate the safety and tolerability of MGY825 in adult patients with advanced NSCLC harboring NFE2L2, or KEAP1 or CUL3 (NFE2L2/KEAP1/CUL3) mutations. Patient enrollment will be based on locally available test results of mutation status.

An exploratory assessment on the effect of food may be investigated during the dose escalation part.

The dose expansion part will assess the preliminary anti-tumor activity and further assess the safety and tolerability of MGY825 in adult patients with advanced NSCLC divided in two patient groups.

Group 1: Patients with advanced NSCLC harboring NFE2L2/KEAP1/CUL3 mutations enrolled based on locally available test results of mutation status.

Group 2: Patients with advanced NSCLC irrespective of prior knowledge of NFE2L2/KEAP1/CUL3 mutational status.

Eligibility criteria: Inclusion Criteria:

* Signed informed consent must be obtained prior to participation in the study.
* Dose escalation and dose expansion group 1:

Patients with histologically or cytologically confirmed diagnosis of advanced (metastatic or unresectable) NFE2L2/KEAP1/CUL3 mutant NSCLC. Local data confirming the NFE2L2/KEAP1/CUL3 mutation status in tissue must be available for enrollment.

* Dose expansion group 2:

Patients with histologically or cytologically confirmed diagnosis of advanced (metastatic or unresectable) NSCLC irrespective of NFE2L2/KEAP1/CUL3 mutation status.

* All patients:

Patients must have progressed after 1 platinum-based chemotherapy regimen and PD-(L)1 antibody therapy either sequentially or concurrent with chemotherapy, where indicated, for Stage IV NSCLC.

Patients treated with neo-adjuvant / adjuvant platinum-based therapy that progressed within 6 months of treatment are permitted to participate.

Prior therapy with VEGF/VEGFR targeting agents is permitted. Prior treatment with approved targeted drugs (e.g., EGFRi, ALKi, METi) is mandatory in patients with NSCLC whose tumor bears actionable mutations.

* Presence of at least one measurable lesion according to RECIST v1.1.
* Patient must have a site of disease amenable to biopsy and be a candidate for tumor biopsy according to the treating institution's guidelines. Patient must be willing to undergo a new tumor biopsy at screening and during study treatment. A recent biopsy collected after the last systemic treatment and within 3 months before study entry may be submitted at screening.

Exclusion Criteria:

* Having out of range laboratory values defined as:

Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) \< 60 mL/min Total bilirubin \> 1.5 x ULN, except for patients with Gilbert's syndrome who are excluded if total bilirubin \> 3.0 x ULN or direct bilirubin \> 1.5 x ULN ALT \> 3 x ULN AST \> 3 x ULN ANC \< 1.0 x 109/L Platelet count \< 75 x 109/L Hemoglobin \< 9 g/dL

* Impaired cardiac function or clinically significant cardiac disease, including any of the following:

Clinically significant and/or uncontrolled heart disease such as congestive heart failure requiring treatment (NYHA Grade ≥2), uncontrolled hypertension or clinically significant arrhythmia.

QTcF \> 470 msec on screening ECG or congenital long QT syndrome. Acute myocardial infarction or unstable angina pectoris \< 3 months prior to study entry.

* Presence of symptomatic CNS metastases, or CNS metastases that require local CNS-directed therapy (such as radiotherapy or surgery) or increasing doses of corticosteroids within 2 weeks prior to study entry. Patients with treated symptomatic brain metastases should be neurologically stable (for 4 weeks post-treatment and prior to study entry) and at a dose of ≤ 10 mg per day prednisone or equivalent for at least 2 weeks before administration of any study treatment.
* Known active COVID-19 infection.
* Unable or unwilling to swallow capsules as per dosing schedule. Other protocol-defined inclusion/exclusion criteria may apply.

Primary outcomes:
measure: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)
timeFrame: 28 months
measure: Frequency of dose interruptions and reductions
timeFrame: 28 months
measure: Dose intensity
timeFrame: 28 months
measure: Incidence and nature of dose limiting toxicities (DLTs) during the first 28 days of treatment with the study drug
timeFrame: 28 days
Secondary outcomes:
measure: Area under the concentration-time curve (AUC)
timeFrame: 20 months
measure: Peak concentration (Cmax)
timeFrame: 20 months
measure: Time to reach maximum drug concentrations in systemic circulation (Tmax)
timeFrame: 20 months
measure: Overall response rate (ORR) per RECIST 1.1
timeFrame: 28 months
measure: Progression free survival (PFS) per RECIST 1.1
timeFrame: 28 months
measure: Duration of response (DOR) per RECIST 1.1
timeFrame: 28 months
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Saint Louis
country: United States
facility: Wash U School of Medicine
state: Missouri
city: New York
country: United States
facility: NYU School of Medicine
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Onc. Dept
state: New York
city: Houston
country: United States
facility: Uni Of TX MD Anderson Cancer Cntr
state: Texas
city: Frankfurt am Main
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Koeln
country: Germany
facility: Novartis Investigative Site
city: Chuo ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Geneve 14
country: Switzerland
facility: Novartis Investigative Site
city: St Gallen
country: Switzerland
facility: Novartis Investigative Site
Study officials:
References: