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

NCT03306420 | Terminated Phase 1 Results FDA Drug

• 1 other identifier: MS201408-0005
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 3

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).

Conditions

Metastatic or Locally Advanced Unresectable Solid Tumors

Keywords

MS201408-0005A; MS201408-0005B; MS201408-0005C; First-in-Human; Advanced solid tumors

Outcome Measures

Primary Outcomes (6)

• 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.

  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.

  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

  The laboratory measurements included hematology, biochemistry and hormonal tests. Number of participants with any clinically significant abnormalities in laboratory measurements were reported. Clinical significance was determined by the investigator.

  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 Vital Signs

  Vital signs assessment included blood pressure, pulse rate and body temperature. Number of Participants with any clinically significant abnormalities in vital signs were reported. Clinical significance was determined by the investigator.

  Baseline up to safety follow-up visit, assessed up to 15.4 months

• Part 1A Dose Escalation: Number of Participants With On-Treatment Shift in Eastern Cooperative Oncology Performance Status (ECOG PS) Score From 0 to 1

  ECOG PS score is widely used by doctors and researchers to assess how a participants' disease is progressing, and is used to assess how the disease affects the daily living abilities of the participant, and determine appropriate treatment and prognosis. The score ranges from Grade 0 to Grade 4, where Grade 0 = Fully active, able to carry on all pre-disease performance without restriction, Grade 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (like light house work, office work), Grade 2 = Ambulatory and capable of all self-care but unable to carry out any work activities, Grade 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours and Grade 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. Number of participants with on-treatment shift in ECOG PS Score from 0 to 1 were reported.

  Baseline up to safety follow-up visit, assessed up to 15.4 months

• Part 1A Dose Escalation: Number of Participants With Clinically Significant Change From Baseline in Physical Examination Abnormalities

  A complete physical examination (including, general appearance, skin, pulmonary, cardiovascular, gastrointestinal, external genitourinary only as medically relevant, lymphatic, neurologic and musculoskeletal systems, head/neck, extremities, eyes, ears, nose, throat, and cognitive status) was performed. Number of participants with clinical significant change from baseline in physical examination abnormalities were reported. Clinical significance was determined by the investigator.

  Baseline up to safety follow-up visit, assessed up to 15.4 months

Secondary Outcomes (15)

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

  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)

• Part 1A Dose Escalation: Maximum Observed Plasma Concentration (Cmax) of M4112

  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)

• Part 1A Dose Escalation: Time to Reach Maximum Plasma Concentration (Tmax) of M4112

  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)

• 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

  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)

• Part 1A Dose Escalation: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4112

  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)

Study Arms (5)

Part IA Dose Escalation: M4112 100 mg

EXPERIMENTAL

Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).

Drug: M4112

Part IA Dose Escalation: M4112 200 mg

EXPERIMENTAL

Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).

Drug: M4112

Part IA Dose Escalation: M4112 400 mg

EXPERIMENTAL

Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).

Drug: M4112

Part IA Dose Escalation: M4112 600 mg

EXPERIMENTAL

Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).

Drug: M4112

Part IA Dose Escalation: M4112 800 mg

EXPERIMENTAL

Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).

Drug: M4112

Interventions

M4112 DRUG

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).

Part IA Dose Escalation: M4112 100 mg; Part IA Dose Escalation: M4112 200 mg; Part IA Dose Escalation: M4112 400 mg; Part IA Dose Escalation: M4112 600 mg; Part IA Dose Escalation: M4112 800 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• EMD Serono Research & Development Institute, Inc.: lead
• Merck KGaA, Darmstadt, Germany: collaborator

Study Sites (3)

Yale Cancer Center

New Haven, Connecticut, 06510, United States

Location

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

Houston, Texas, 77030, United States

Location

South Texas Accelerated Research Therapeutics (START)

San Antonio, Texas, 78229, United States

Location

Related Publications (1)

• 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.

  PMID: 32843490 DERIVED

MeSH Terms

Conditions

Neoplasm Metastasis

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Limitations and Caveats

Part IB and Part IC for this study were never initiated as the study was terminated early due to lackluster pharmacodynamic data that showed no significant reduction of plasma kynurenine at steady state at a range of tested dose levels of M4112.

Results Point of Contact

• Title: Communication Center
• Organization: Merck KGaA, Darmstadt, Germany

service@emdgroup.com

+49-6151-72-5200

Study Officials

• Medical Responsible

  EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 5, 2017
• First Posted: October 11, 2017
• Study Start: October 3, 2017
• Primary Completion: January 14, 2019
• Study Completion: January 14, 2019
• Last Updated: February 6, 2020
• Results First Posted: February 6, 2020

Record last verified: 2020-01

Locations

US (3)