Clinical trial NCT03306420: First-in-Human Study of MS201408-0005A as Single Agent and in Combinations
Official title: Phase I, First-in-Human, Open-Label, Multiple-Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Activity of MS201408-0005A as Single Agent and Sequentially in Combinations With MS201408-0005C or MS201408-0005B in Subjects With Metastatic or Locally Advanced Unresectable Solid Tumors
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Metastatic or Locally Advanced Unresectable Solid Tumors
Keywords: MS201408-0005A
MS201408-0005B
MS201408-0005C
First-in-Human
Advanced solid tumors
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
Collaborators: name: Merck KGaA, Darmstadt, Germany
First posted: 2017-10-11
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase I, open-label study to determine the safety, tolerability, pharmacokinetic (PK), pharmacodynamics (PD), and preliminary antitumor activity of MS201408-0005A as single agent (Part IA only) and in combination with MS201408-0005C or MS201408-0005B (Part IB, Part IC).


Eligibility criteria: Inclusion Criteria:

* Subjects with histologically or cytologically proven advanced or metastatic solid malignancies for whom no effective standard therapy exists or has failed or subjects who are intolerant to established therapy known to provide clinical benefit for their condition (dose escalation cohorts; Part I).
* An eastern cooperative oncology group performance status (ECOG PS) of 0 to 1 at screening and adequate hematological, renal and hepatic function as defined by protocol specified criteria.
* Other protocol defined inclusion criteria could apply.

Exclusion Criteria:

* Intolerance to immune checkpoint inhibitor therapy as defined by the occurrence of an adverse drug reaction requiring drug discontinuation (dose escalation cohorts), concurrent anticancer treatment or immunosuppressive agents.
* Prior organ transplantation including allogeneic stem cell transplantation, brain metastases (except those meeting certain protocol specified criteria which are acceptable), significant acute or chronic infections, a history of cardiovascular/cerebrovascular disease.
* Current significant cardiac conduction abnormalities and hypokalemia as specified in the protocol.
* Warfarin or other Vitamin K antagonists treatment, strong inhibitors or inducers of cytochrome P450 (CYP)3A4, and drugs with a narrow therapeutic index, which are predominantly metabolized by CYP3A4 and drugs known to have a high risk to prolong QTc as per label.
* Pregnancy or lactation.
* Severe hypersensitivity reactions to monoclonal antibodies, known hypersensitivity to the investigational medicinal products or to one or more of the excipients, autoimmune diseases (inflammatory bowel diseases, interstitial lung disease, or pulmonary fibrosis), and live vaccines within 28 days prior to study entry.
* Pneumonitis and history of pneumonitis.
* Other protocol defined exclusion criteria could apply.

Primary outcomes:
measure: Part 1A Dose Escalation: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) as Per National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03
timeFrame: Cycle 1 (Each Cycle is of 28 days)
measure: Part 1A Dose Escalation: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Who Experienced a Treatment Related Adverse Events (TRAE) According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03
timeFrame: Baseline up to safety follow-up visit, assessed up to 15.4 months
measure: Part 1A Dose Escalation: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters
timeFrame: Baseline up to safety follow-up visit, assessed up to 15.4 months
measure: Part 1A Dose Escalation: Number of Participants With Clinically Significant Abnormalities in Vital Signs
timeFrame: Baseline up to safety follow-up visit, assessed up to 15.4 months
measure: Part 1A Dose Escalation: Number of Participants With On-Treatment Shift in Eastern Cooperative Oncology Performance Status (ECOG PS) Score From 0 to 1
timeFrame: Baseline up to safety follow-up visit, assessed up to 15.4 months
measure: Part 1A Dose Escalation: Number of Participants With Clinically Significant Change From Baseline in Physical Examination Abnormalities
timeFrame: Baseline up to safety follow-up visit, assessed up to 15.4 months
Secondary outcomes:
measure: Part 1A Dose Escalation: Area Under the Plasma Concentration Curve From Time Zero to 8 Hours Post Dose AUC(0-8h) of M4112
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)
measure: Part 1A Dose Escalation: Maximum Observed Plasma Concentration (Cmax) of M4112
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)
measure: Part 1A Dose Escalation: Time to Reach Maximum Plasma Concentration (Tmax) of M4112
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)
measure: Part 1A Dose Escalation: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hour Post-dose (AUC0-8/Dose) of M4112
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)
measure: Part 1A Dose Escalation: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4112
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)
measure: Part 1A Dose Escalation: Accumulation Ratio for Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hour Post-dose (Racc[AUC0-8h]) of M4112
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)
measure: Part IA Dose Escalation: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4112
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)
measure: Part 1A Dose Escalation: Pre-dose Observed Plasma Concentration (Cpre) of M4112
timeFrame: Pre-dose on Days 8, 15 (Cycle 1) and Day 1 (Cycle 2) (Each Cycle is 28 days)
measure: Part 1A Dose Escalation: Dose Normalized Pre-dose Observed Plasma Concentration (Cpre/Dose) of M4112
timeFrame: Pre-dose on Days 8, 15 (Cycle 1) and Day 1 (Cycle 2) (Each Cycle is 28 days)
measure: Part 1A Dose Escalation: Slope of Concentration-QTc (cQTc) Regression of M4112
timeFrame: Baseline up to safety follow-up visit, assessed up to 15.4 months
measure: Part 1A Dose Escalation: Number of Participants With Best Overall Response (BOR)
timeFrame: From first dose of study drug administration until PD, assessed up to 15.4 months
measure: Part 1A Dose Escalation: Duration of Response
timeFrame: From first dose of study drug administration until PD, assessed up to 15.4 months
measure: Part 1A Dose Escalation: Disease Control Rate
timeFrame: From first dose of study drug administration until PD, assessed up to 15.4 months
measure: Part 1A Dose Escalation: Time to Tumor Response
timeFrame: From first dose of study drug administration until PD, assessed up to 15.4 months
measure: Part 1A Dose Escalation: Progression Free Survival Time (PFS)
timeFrame: From first dose of study drug administration until PD, assessed up to 15.4 months
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Houston
country: United States
facility: University of TX M.D. Anderson Cancer Center-Investigational Cancer Therapeutics Partner
state: Texas
city: San Antonio
country: United States
facility: South Texas Accelerated Research Therapeutics (START)
state: Texas
Study officials:
affiliation: EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References:
citation: Naing A, Eder JP, Piha-Paul SA, Gimmi C, Hussey E, Zhang S, Hildebrand V, Hosagrahara V, Habermehl C, Moisan J, Papadopoulos KP. Preclinical investigations and a first-in-human phase I trial of M4112, the first dual inhibitor of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2, in patients with advanced solid tumors. J Immunother Cancer. 2020 Aug;8(2):e000870. doi: 10.1136/jitc-2020-000870.