MGD019 DART® Protein in Unresectable/Metastatic Cancer

Colorectal Cancer Clinical Trial

Official title:

A Phase 1, First-in-Human, Open-Label, Dose Escalation and Cohort Expansion Study of MGD019, a Bispecific DART® Protein Binding PD-1 and CTLA-4 in Patients With Unresectable or Metastatic Neoplasms

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03761017
• Other study ID #: CP-MGD019-01
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: December 12, 2018
• Est. completion date: December 2024

Study information

• Verified date: February 2024
• Source: MacroGenics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the safety and tolerability, pharmacokinetics (PK) pharmacodynamics and preliminary antitumor activity of lorigerlimab. This Phase 1, open-label study will characterize safety, dose-limiting toxicities (DLTs), and maximum tolerated/administered dose (MTD/MAD) of MGD019. Dose escalation will occur in a 3+3+3 design in patients with advanced solid tumors of any histology. Once the MTD/MAD is determined, a Cohort Expansion Phase will be enrolled to further characterize safety and initial anti-tumor activity in patients with specific tumor types anticipated to be sensitive to dual checkpoint blockade.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 162
• Est. completion date: December 2024
• Est. primary completion date: July 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Dose escalation: Patients with histologically proven, unresectable, locally advanced or metastatic solid tumors for whom no approved therapy with demonstrated clinical benefit is available or patients who are intolerant to standard therapy.
• Cohort Expansion Phase:
• Checkpoint inhibitor-naïve squamous cell NSCLC, including:

1. Patients that have progressed during or following treatment with platinum-based chemotherapy for advanced disease. Patients harboring an activating epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement must have progressed following at least one available EGFR or ALK targeted therapy. ROS1 rearrangement or BRAF mutation must have progressed following at least 1 available EGFR (including osimertinib for EGFR T790M-mutated NSCLC), ALK, ROS1 or BRAF targeted therapy, respectively

2. Patients that have progressed during or following treatment with platinum-based chemotherapy for advanced disease and patients with previously untreated squamous cell NSCLC without activating mutations for whom checkpoint inhibitor therapy is not approved or available.

• Advanced non-microsatellite instability-high colorectal cancer (CRC) with recurrence, progression, or intolerance to standard therapy consisting of at least 2 prior standard regimens. CRC harboring an activating EGFR mutation must have progressed during or following at least one available EGFR targeted therapy. Patients who are inappropriate candidates for or have refused treatment with these regimens are also eligible. Patients should have received no more than 4 prior lines of systemic therapy.
• Checkpoint inhibitor-naïve mCRPC that has progressed during or following no more than 2 prior lines of an androgen receptor antagonist or androgen synthesis inhibitor (e.g., enzalutamide or abiraterone, respectively), if approved and available, with a

PSA value of at least 2 ng/mL and meeting at least one of the following:

• Progression in measurable disease (RECIST v1.1).
• Appearance of 2 or more new bone lesions according to Prostate Cancer Working Group 2 (PCWG-2).
• Rising PSA defined as at least two sequential rises in PSA.
• Eligible patients may have received prior chemotherapy (i.e. docetaxel), and patients with known homologous recombination (HRR) pathway gene alterations must have received the applicable approved therapy (e.g. olaparib).
• Cutaneous melanoma that has progressed during or following systemic treatment for unresectable, locally advanced, or metastatic disease. Patients will have received PD-(L)1 and/or CTLA-4 pathway inhibitors where available and indicated.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Life expectancy = 12 weeks.
• Measurable disease as per RECIST 1.1 for the purpose of response assessment must either (a) not reside in a field that has been subjected to prior radiotherapy or (b) have demonstrated clear evidence of radiographic progression since the completion of prior radiotherapy and prior to study enrollment.
• All patients must have an identified formalin-fixed, paraffin embedded (FFPE) tumor specimen (up to 20 slides or a block) for immunohistochemical evaluation of pharmacodynamic markers of interest. Patients may undergo a fresh tumor biopsy during the screening period if a tumor sample is not available. Patients in the mCRPC expansion cohort with bone only disease not amenable to fresh biopsy may be eligible in consultation with the Sponsor.
• Acceptable laboratory parameters and adequate organ reserve.

Exclusion Criteria:

• In patients who have previously received an immune checkpoint inhibitor (e.g., anti-PD-L1, anti-PD-1, anti-CTLA-4), toxicities related to the checkpoint inhibitor must have resolved to = Grade 1 or baseline. Patients with well controlled immune endocrinopathies secondary to prior checkpoint therapy are eligible.
• Patients with symptomatic CNS metastases. Patients with history of prior CNS metastasis must have been treated, must be asymptomatic, and must not have concurrent treatment for the CNS disease, progression of CNS metastases on magnetic resonance imaging (MRI) or computed tomography (CT) for at least 14 days after last day of prior therapy for the CNS metastases, or concurrent leptomeningeal disease or cord compression.
• Patients who sustained the following Grade 3 immune checkpoint inhibitor related AEs are ineligible: Ocular AE, changes in liver function tests that met the criteria for Hy's law (> 3 × ULN of either ALT or AST with concurrent > 2 × ULN of total bilirubin and without alternate etiology), neurologic toxicity, colitis, renal toxicity, pneumonitis.
• Patients who have received prior therapy with a combination of monoclonal antibodies against PD-1/PD-L1 and CTLA-4 will be excluded in the Cohort Expansion (this does not apply to the melanoma expansion cohort).
• Patients with any history of known or suspected autoimmune disease with certain exceptions
• History of prior allogeneic bone marrow, stem-cell, or solid organ transplantation.
• History of trauma or major surgical procedure within 4 weeks prior to initiation of study drug administration.
• Systemic antineoplastic therapy, or investigational therapy (for all tumor types) or androgen receptor antagonist/androgen synthesis inhibitor for mCRPC (e.g., enzalutamide or abiraterone, respectively) within the 4 weeks prior to initiation of study drug administration.
• Treatment with radiation therapy within 2 weeks prior to initiation of study drug administration.
• Radioligand (e.g., radium-223) within 6 months prior to initiation of study drug administration for mCRPC in the Cohort Expansion Phase.
• Serum testosterone > 50 ng/dl or > 1.7 nmol/L for mCRPC in the Cohort Expansion Phase.
• 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

Related Conditions & MeSH terms

• Advanced Cancer
• Colorectal Cancer
• Cutaneous Melanoma
• Melanoma
• Prostate Cancer Metastatic
• Solid Tumor, Adult
• Squamous Cell Non Small Cell Lung Cancer

Intervention

Biological:
• Lorigerlimab
Bispecific DART protein binding PD-1 and CTLA-4

Locations

Country	Name	City	State
Bulgaria	Complex Oncology Center - Burgas" EOOD, Department of Medical Oncology	Burgas
Bulgaria	Multiprofile Hospital for Active Treatment-Uni Hospital	Panagyurishte
Bulgaria	Multiprofile Hospital for Active Treatment "Heart and Brain"" EAD, Clinic of Medical Oncology	Pleven
Bulgaria	Complex Oncology Center - Ruse EOOD	Ruse
Bulgaria	University Mulitprofile Hospital for Active Treatment "Sv. Ivan Rilski	Sofia
Poland	University Clinical Centre, Early Clinical Trials Unit	Gdansk
Poland	Pratia MCM Krakow	Kraków
Poland	Europejskie Centrum Zdrowia Otwock	Otwock
Poland	Med-Polonia Sp. z.o.o.	Poznan
Poland	LUX MED Onkologia Sp. z.o.o.	Warszawa
Poland	Narodowy Instytut Onkologii im	Warszawa
Poland	Mazovian Onkological Hospital	Wieliszew
Spain	ICO Badalona / Hospital Universitari Germans Trias i Pujol	Badalona	Barcelona
Spain	Hospital Ruber Internacional	Madrid
Spain	Hospital Universitario La Princesa	Madrid
Ukraine	Communal Non-profit Enterprise "City Clinical Hospital #4" of Dnipro	Dnipro
Ukraine	Communal Non-Profit Enterprise "Regional Center of Oncology", Oncosurgical Department of Head and Neck	Kharkiv
Ukraine	Communal Nonprofit Enterprise "Regional Clinical Oncology Center of Kirovohrad Regional Council"	Kirovohrad
Ukraine	Kyiv City Clinical Oncological Centre	Kyiv
Ukraine	National Cancer Institute of Ukraine	Kyiv
Ukraine	Sumy Clinical Oncological Hospital	Sumy
Ukraine	Communal Nonprofit Enterprise "Podilsky Regional Center of Oncology"	Vinnytsia
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	UPMC Hillman Cancer Center	Camp Hill	Pennsylvania
United States	UPMC Hillman Cancer Center	Carlisle	Pennsylvania
United States	University of Chicago Medical Center	Chicago	Illinois
United States	UPMC Hillman Cancer Center	Erie	Pennsylvania
United States	Oncology Hematology West p.c. dba Nebraska Cancer Specialists	Grand Island	Nebraska
United States	START Midwest	Grand Rapids	Michigan
United States	UPMC Pinnacle - Community Osteopathic Medical Sciences Pavilion (MSP)	Harrisburg	Pennsylvania
United States	UPMC Pinnacle Harrisburg	Harrisburg	Pennsylvania
United States	UPMC Pinnacle - Ortenzio Cancer Center (OCC)	Mechanicsburg	Pennsylvania
United States	The Sarah Cannon Research Institute / Tennessee Oncology	Nashville	Tennessee
United States	Nebraska Cancer Specialists	Omaha	Nebraska
United States	UPMC Hillman Cancer Center	Pittsburgh	Pennsylvania
United States	Providence Portland Medical Center	Portland	Oregon
United States	UPMC Hillman Cancer Center at UPMC Memorial	York	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
MacroGenics

Countries where clinical trial is conducted

United States,  Bulgaria,  Poland,  Spain,  Ukraine, 

References & Publications (1)

Berezhnoy A, Sumrow BJ, Stahl K, Shah K, Liu D, Li J, Hao SS, De Costa A, Kaul S, Bendell J, Cote GM, Luke JJ, Sanborn RE, Sharma MR, Chen F, Li H, Diedrich G, Bonvini E, Moore PA. Development and Preliminary Clinical Activity of PD-1-Guided CTLA-4 Blocking Bispecific DART Molecule. Cell Rep Med. 2020 Dec 22;1(9):100163. doi: 10.1016/j.xcrm.2020.100163. eCollection 2020 Dec 22. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of treatment-emergent adverse events	Safety is based on evaluation of adverse events (AEs) and serious adverse events (SAEs) from the time of study drug administration through the End of Study visit.	30 days after last dose
Secondary	Cmax	Maximum Plasma Concentration of lorigerlimab	up to 108 weeks
Secondary	Tmax	Time to reach maximum (peak) plasma concentration of lorigerlimab	up to 108 weeks
Secondary	AUC	Area Under the Plasma Concentration versus Time Curve of lorigerlimab	up to 108 weeks
Secondary	Ctrough	Trough plasma concentration of lorigerlimab	up to 108 weeks
Secondary	CL	Total body clearance of the drug from plasma of lorigerlimab	up to 108 weeks
Secondary	Vss	Apparent volume of distribution at steady state of lorigerlimab	up to 108 weeks
Secondary	t1/2	Terminal half life of lorigerlimab	up to 108 weeks
Secondary	Percent of patients with anti-drug antibodies against lorigerlimab	Immunogenicity	up to 108 weeks
Secondary	Objective response rate (ORR)	The number of participants who have a complete response (CR) or partial response (PR) to treatment. Efficacy assessed using conventional Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)	Every 12 weeks, up to 4 years
Secondary	Duration of Response (DoR)	DoR is defined as the time from the date of initial response (CR or PR) to the date of first documented PD or death from any cause, whichever occurs first	Every 12 weeks until withdrawal of consent, lost to follow up, death, or end of the study, up to 4 years
Secondary	Progression free survival (PFS)	PFS is defined as the time from the first dose date to the date of first documented PD or death from any cause, whichever occurs first.	Tumor status assessed every 12 weeks. Survival status is assessed approximately every 12 weeks after the last dose of study treatment until withdrawal of consent, lost to follow up, death, or end of the study, up to 4 years
Secondary	Overall survival (OS)	OS is defined as the time from the first dose date to the date of death from any cause.	OS status is assessed approximately every 12 weeks after the last dose of study treatment until withdrawal of consent, lost to follow up, death, or end of the study, up to 4 years
Secondary	Prostate specific antigen (PSA) response rate in mCRPC	Percent of patients with 50% or more decline in PSA and confirmed 3 weeks later	Every 3 weeks on treatment, then every 3 months up to 2 years post last treatment
Secondary	Best PSA percent change in mCRPC	Best percent change in PSA from baseline	Every 3 weeks on treatment, then every 3 months up to 2 years post last treatment
Secondary	Duration of PSA response	Time from PSA response to time of PSA progression	Every 3 weeks on treatment, then every 3 months up to 2 years post last treatment
Secondary	Radiographic progression-free survival (PFS) in metastatic castration-resistant prostate cancer (mCRPC)	Time from first dose to first occurrence of radiographic progression, or death	up to 2 years post last treatment
Secondary	Time to PSA progression in mCRPC	The time from the first dose of MGD019 to the first documented PSA progression. PSA progression is defined as an increase that is = 25% and = 2 ng/mL the baseline or lowest value observed, and which confirmed by a second value at least 3 weeks later	PSA is assessed every 3 weeks while on treatment, every 3 months for up to 2 years post-treatment

External Links

•   Link to published 2020 manuscript