First-in-Human Study of MS201408-0005A as Single Agent and in Combinations

Phase 1TerminatedNCT03306420

EMD Serono Research & Development Institute, Inc.15 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Metastatic or Locally Advanced Unresectable Solid Tumors

Interventions

M4112DRUG

All participants who received M4112 100,200,400,600 and 800 mg twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (3)

Yale Cancer Center

New Haven, Connecticut, United States

University of TX M.D. Anderson Cancer Center-Investigational Cancer Therapeutics Partner

Houston, Texas, United States

South Texas Accelerated Research Therapeutics (START)

San Antonio, Texas, United States

Outcomes

Primary Outcomes

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

DLTs was assessed as per NCI CTCAE v 4.03. DLT defined as any Grade greater than or equal (\>=) 3 nonhematological AE or Immune-related adverse event (irAE) assessed by Investigator or Sponsor during first Cycle (first 28 days) of study treatment. Asymptomatic Grade \>= 3 lipase or amylase elevation not associated with clinical manifestations of pancreatitis. Any TEAE observed in subsequent cycle. Any Grade 4 neutropenia of \>= 5 days duration, Grade \>= 3 febrile neutropenia, Grade 3 hemoglobin decrease despite blood transfusion or erythroid growth factor. Grade 4 hemoglobin decrease assessed as related to study drug. Any Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding. Any Grade \>= 3 clinical signs and symptoms related to increased QTc.

Time frame: Cycle 1 (Each Cycle is of 28 days)

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

An adverse event (AE) was defined as any untoward medical occurrence in participant which does not necessarily have casual relationship with treatment was any unfavorable and unintended sign(including abnormal laboratory finding), symptom/disease temporally associated with use of medicinal product, whether/not considered related to medicinal product. A serious adverse event(SAE) was AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Term TEAE is defined as AEs starting/worsening after first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs. Treatment related AE was defined as having a "Possible" or "Related" relationship to study treatment, as assessed by the Investigator.

Time frame: Baseline up to safety follow-up visit, assessed up to 15.4 months

Part 1A Dose Escalation: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters

Data from ClinicalTrials.gov

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Secondary Outcomes

Part 1A Dose Escalation: Area Under the Plasma Concentration Curve From Time Zero to 8 Hours Post Dose AUC(0-8h) of M4112

Area under the drug concentration-time curve from 0 to 8 h post dosing for M4112. AUC0-8 was calculated according to the mixed log-linear trapezoidal rule.