Clinical trial NCT03219268: A Study of MGD013 in Patients With Unresectable or Metastatic Neoplasms
Official title: A Phase 1, First-in-Human, Open-Label, Dose Escalation Study of MGD013, A Bispecific DART® Protein Binding PD-1 and LAG-3 in Patients With Unresectable or Metastatic Neoplasms
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced Solid Tumors
Hematologic Neoplasms
Ovarian Cancer
HER2-positive Advanced Solid Tumors
Non Small Cell Lung Cancer
Small-cell Lung Cancer
Squamous Cell Carcinoma of Head and Neck
Cholangiocarcinoma
Cervical Cancer
TNBC - Triple-Negative Breast Cancer
Lead sponsor: MacroGenics
Sponsor class: INDUSTRY
First posted: 2017-07-17
Enrollment: 277
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The primary goal of this Phase 1 study is to characterize the safety and tolerability of tebotelimab and establish the maximum tolerated dose (MTD) of tebotelimab in advanced solid tumors, and tebotelimab in combination with margetuximab in HER2+ advanced solid tumors. Pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and the anti-tumor activity of tebotelimab will also be assessed.


Eligibility criteria: Inclusion Criteria:

* Histologically proven, locally advanced unresectable or metastatic solid tumors (or hematologic malignancies, Cohort Expansion only) for whom no approved therapy with demonstrated clinical benefit is available or standard treatment was declined.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Life expectancy ≥ 12 weeks
* Measurable disease
* Tissue specimen available for retrospective analysis of PD-1, PD-L1, LAG-3, and MHC-II expression
* Acceptable laboratory parameters

HER2+ Cohort:

- Locally advanced or metastatic HER2+ locally advanced or metastatic solid tumors, regardless of organ of origin.

i. The cancer must have progressed following standard therapy, or has progressed during or after HER2-directed therapy if approved and available for patients with HER2+ breast, gastric, or gastroesophageal junction cancer.

ii. History of HER2 positivity defined as 3+ by IHC or 2+ by Immunohistochemistry (IHC) in combination with in situ hybridization (ISH) positivity most recent tumor biopsy.

* All patients in the HER2+ cohort must be willing to provide consent for a baseline and on-treatment tumor biopsy during the screening period and within 14 days prior to Cycle 3 Day 1. Exceptions may be made based on a medical contraindication at the discretion of the Sponsor's Medical Monitor. This requirement will be discontinued after an adequate number of samples are collected, as determined by the Sponsor.

Exclusion Criteria:

* Symptomatic central nervous system (CNS) metastases or primary CNS lymphoma
* History of allogeneic bone marrow, stem-cell, or solid organ transplant
* History of known or suspected autoimmune disease with the specific exceptions of vitiligo, resolved childhood atopic dermatitis, psoriasis not requiring systemic treatment (within the past 2 years), and patients with a history of Grave's disease that are now euthyroid clinically and by laboratory testing.
* Treatment with any systemic chemotherapy within 3 weeks prior to the initiation of study drug; treatment with biologics or investigational therapy within the 4 weeks prior to the initiation of study drug.
* Major surgery within 4 weeks prior to the initiation of study drug.
* Prior treatment with combination of monoclonal antibodies against PD-1 and LAG-3 (Cohort Expansion only).
* Treatment with radiation therapy within 2 weeks prior to the initiation of study drug.
* Clinically significant cardiovascular disease.
* QTcF prolongation \> 480 milliseconds
* HER2+ cohort: left ventricular ejection fraction less than 50%
* Clinically significant pulmonary compromise, including a requirement for supplemental oxygen use to maintain adequate oxygenation.
* Active pneumonitis or history of non-infectious pneumonitis.
* Clinically significant gastrointestinal disorders.
* Evidence of active viral, bacterial, or systemic fungal infection requiring parenteral treatment within 7 days prior to the initiation of study drug.
* Known history of positive testing for human immunodeficiency virus or history of acquired immune deficiency syndrome.
* Known history of hepatitis B (except in hepatocellular carcinoma) or hepatitis C infection or known positive test for hepatitis B surface antigen, hepatitis B core antigen, or hepatitis C polymerase chain reaction (PCR)
* Vaccination with any live virus vaccine within 4 weeks prior to the initiation of study drug administration. Inactivated annual influenza vaccination is allowed
* Dementia or altered mental status that would preclude understanding and rendering of informed consent
* Confirmed or presumed COVID-19/SARS-CoV-2 infection. While SARS-CoV-2 testing is not mandatory for study entry, testing should follow local clinical practice guidelines/standards. Patients with a positive test result for SARS-CoV-2 infection, known asymptomatic infection, or presumed infection are excluded. Patients may be considered eligible after a resolved SARS-CoV-2 infection once he or she remains afebrile for at least 72 hours and after other SARS-CoV-2-related symptoms have fully recovered to baseline for a minimum of 72 hours.

Primary outcomes:
measure: Number of participants with Treatment-Emergent Adverse Events (TEAE) as assessed by CTCAE v4.03 (tebotelimab monotherapy)
timeFrame: up to 24 months
measure: Number of participants with Treatment-Emergent Adverse Events as assessed by CTCAE v4.03 (tebotelimab plus margetuximab)
timeFrame: up to 24 months
Secondary outcomes:
measure: Area Under the Plasma Concentration versus Time Curve (AUC) of tebotelimab
timeFrame: From Day 1 to Day 15 after the first and second doses
measure: Maximum Plasma Concentration (Cmax) of tebotelimab and tebotelimab plus margetuximab
timeFrame: At the end of infusion on Study Days 1, 15, 29 and 43 in Cycles 1 and 2 and on Study Day 1 for all subsequent cycles until treatment discontinuation, up to 2 years
measure: Time to reach maximum (peak) plasma concentration (Tmax) of tebotelimab and tebotelimab plus margetuximab
timeFrame: At the end of infusion on Study Days 1, 15, 29 and 43 in Cycles 1 and 2 and on Study Day 1 for all subsequent cycles until treatment discontinuation, up to 2 years
measure: Trough plasma concentration (Ctrough) of tebotelimab
timeFrame: Study Days 1, 15, 29, 43 in Cycles 1 and 2 and Day 1 of each subsequent cycle s until treatment discontinuation, up to 2 years
measure: Total body clearance of the drug from plasma (CL) of tebotelimab
timeFrame: Cycle 1 Day 1 out to Cycle 1 Day 15
measure: Apparent volume of distribution at steady state (Vss) of tebotelimab
timeFrame: Cycle 1 Day 1 out to Cycle 1 Day 15
measure: Terminal half-life (t1/2) of tebotelimab
timeFrame: Cycle 1 Day 1 out to Cycle 1 Day 15
measure: Number of patients with anti-drug antibody
timeFrame: Study Day 1, 15, 29, 57, 85, 113, then every 56 days up to 2 years Tebotelimab plus margetuximab: Day 1, 22, 43, and then every 6 weeks until treatment discontinuation
measure: Objective response rate (ORR)
timeFrame: Throughout the study, up to 4 years.
measure: Median Duration of response (DoR)
timeFrame: Throughout the study, up to 4 years.
measure: Progression-free survival (PFS)
timeFrame: Throughout the study, up to 4 years.
measure: Median Overall survival (OS)
timeFrame: Throughout the study, up to 4 years.
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Los Angeles
country: United States
facility: USC/Norris Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: UCLA Hematology & Oncology Clinic
state: California
city: Newport Beach
country: United States
facility: Hoag Memorial Hospital Presbyterian
state: California
city: Sarasota
country: United States
facility: Florida Cancer Specialists & Research Institute
state: Florida
city: Chicago
country: United States
facility: University of Chicago Medicine
state: Illinois
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital and Dana-Farber Cancer Institute
state: Massachusetts
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: Stephenson Cancer Center, The University of Oklahoma
state: Oklahoma
city: Philadelphia
country: United States
facility: University of Pennsylvania, Abramson Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Houston
country: United States
facility: The University of Texas M.D. Anderson Cancer Center
state: Texas
city: Darlinghurst
country: Australia
facility: St Vincent's Hospital Sydney
state: New South Wales
city: Waratah
country: Australia
facility: Calvary Mater Newcastle
state: New South Wales
city: Wollongong
country: Australia
facility: Southern Medical Day Care Centre
state: New South Wales
city: Heidelberg
country: Australia
facility: Austin Health Melbourne
state: Victoria
city: Burgas
country: Bulgaria
facility: "Complex Oncology Center - Burgas" EOOD
city: Sofia
country: Bulgaria
facility: "Acibadem City Clinic Multiprofile Hospital for Active Treatment Tokuda" EAD, Sofia
city: Sofia
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment "Serdika" EOOD, Sofia
city: Shatin
country: Hong Kong
facility: Prince of Wales Hospital
city: Kraków
country: Poland
facility: Pratia MCM Kraków
state: Malopolskie
city: Józefów
country: Poland
facility: BioVirtus Research Site Sp. Z o.o. / Biovirtus Centrum Medyczne
state: Masovian
city: Warszawa
country: Poland
facility: Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie Państwowy Instytut Badawczy
state: Mazowieckie
city: Warszawa
country: Poland
facility: Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie Państwowy Instytut Badawczy
state: Mazowieckie
city: Poznań
country: Poland
facility: Med-Polonia Sp. z o.o.
city: Barcelona
country: Spain
facility: Vall d'Hebron Institute of Oncology
city: Madrid
country: Spain
facility: Hospital Ruber Internacional
city: Madrid
country: Spain
facility: START Madrid-CIOCC, Hospital HM Sanchinarro
city: Bangkok
country: Thailand
facility: King Chulalongkorn Memorial Hospital
city: Chiang Mai
country: Thailand
facility: Maharaj Nakorn Chiang Mai Hospital
city: Songkhla
country: Thailand
facility: Songklanagarind Hospital
city: Cherkassy
country: Ukraine
facility: Communal Nonprofit Enterprise "Cherkassy Regional Oncology Dispensary" of Cherkassy Regional Council
state: Cherkasy Region
city: Vinnytsia
country: Ukraine
facility: Communal Nonprofit Enterprise Podillia Regional Center of Oncology of Vinnytsia Regional Council
state: Vinnytsa Region
city: Dnipro
country: Ukraine
facility: Communal Non-profit Enterprise "City Clinical Hospital #4" of Dnipro City Council
city: Ivano-Frankivs'k
country: Ukraine
facility: Communal Nonprofit Enterprise "Prykarpatsky Clinical Oncological Centre of Ivano-Frankivska Regional Council"
city: Sumy
country: Ukraine
facility: Municipal Non-Profit Enterprise of Sumy Regional Council "Sumy Regional Clinical Oncology Dispensary"
city: Uzhgorod
country: Ukraine
facility: Communal Nonprofit Enterprise "Central City Clinical Hospital of Uzhhorod City Council", City Oncology Center, State Higher Educational Institution <<Uzhhorod National University>>
Study officials:
affiliation: MacroGenics
name: Ashley Ward, MD
role: STUDY_DIRECTOR
References: