An Open-label, Phase I Dose Escalation Trial of Methionine Aminopeptidase 2 Inhibitor M8891 in Subjects With Advanced Solid Tumors

EMD Serono Research & Development Institute, Inc.7 sites in 1 country27 target enrollmentAugust 8, 2017

ConditionsAdvanced Solid Tumors Metastatic Renal Cell Carcinoma

DrugsPart 1: M8891

Overview

Phase: Phase 1
Intervention: Not specified
Conditions: Advanced Solid Tumors
Sponsor: EMD Serono Research & Development Institute, Inc.
Enrollment: 27
Locations: 7
Primary Endpoint: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.03
Status: Terminated
Last Updated: 4 years ago

Overview Investigators Eligibility Criteria Outcomes Sites Similar Trials

Overview

Brief Summary

The purpose of this study was to determine the maximum tolerated dose (MTD), safety, tolerability, Pharmacokinetic (PK), pharmacodynamic and clinical activity of M8891 as single agent in participants with advanced solid tumors in Part 1.

Registry

clinicaltrials.gov

Start Date

August 8, 2017

End Date

September 16, 2020

Last Updated

4 years ago

Study Type

Interventional

Study Design

Single Group

Sex

All

Investigators

Sponsor

EMD Serono Research & Development Institute, Inc.

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•Participants must be refractory to or intolerant of existing cancer therapy(ies) known to provide clinical benefit.
•Histologically confirmed advanced solid tumors with no clear curative treatment options available after at least 1 prior systemic anticancer therapy.
•Tumor accessible for biopsies and agreement to conduct pre-dose and post-dose fresh tumor biopsies.
•Male or female subjects at least 18 years of age
•Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1 at Screening
•Histologic or cytologic evidence/proven of metastatic renal cell carcinoma (mRCC) with clear cell component
•Part 2A: Participants should have progressed to 1 or more previous lines of systemic anticancer therapy, excluding treatment with cabozantinib
•Part 2B: Participants should have progressed to 1 or 2 previous lines of systemic anticancer therapy, excluding treatment with cabozantinib. Participants should have failed to only 1 previous TKI for metastatic disease. Adjuvant therapy with sunitinib will be considered as 1 line of therapy for metastatic disease in the case that disease progression occurs during or within 3 months of the completion of the treatment.
•Other protocol defined inclusion criteria could apply

Exclusion Criteria

•ECOG PS \>= 2
•Extensive prior radiotherapy on more than 30% of bone marrow reserves, or prior bone marrow/stem cell transplantation within 5 years of study start.
•Severe bone marrow, renal or liver impairment.
•Tumor in contact with, invading or encasing major blood vessels or radiographic evidence of significant cavitary pulmonary lesions
•Uncontrolled hypertension defined as sustained Blood Pressure (BP) \> 150 millimeters of mercury (mm Hg) systolic or \> 100 mm Hg diastolic despite optimal antihypertensive treatment
•Participant is pregnant or breastfeeding
•Part 2A and 2B: Previous use of cabozantinib or a MetAP2 inhibitor, tumor in contact with invading or encasing major blood vessels or radiographic evidence of significant cavitary pulmonary lesions
•Other protocol defined exclusion criteria could apply

Outcomes

Primary Outcomes

Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.03

Time Frame: At the end of Cycle 1 (each Cycle is of 21 days)

A DLT was defined as the occurrence of any of following events that were judged by the study investigator, to be related to the study medication: Grade 4 liver enzyme elevation; Grade 4 neutropenia lasting \>5 days or Grade \>= 3 neutropenia with fever; Grade 4 thrombocytopenia lasting \>5 days or Grade \>=3 thrombocytopenia with clinically significant bleeding; Any treatment interruption \>7 days or \>30% of total dose in Cycle 1 due to AEs not related to the underlying disease or concomitant medication; Grade \>=3 non-hematologic toxicity excluding Grade 3 nausea or vomiting lasting \<48 hours, and resolves to \<= Grade 1 either spontaneously or with medication, Grade 3 fatigue \<= 3 days, Grade 3 hypertension in the absence of maximal medical therapy, Grade 3 rash \<= 3 days, Grade 3 electrolyte abnormality that lasts \<72 hours, is not clinically complicated, and resolves spontaneously or responds to conventional medication and Grade \>=3 single lab value increase without clinical correlate.

Secondary Outcomes

Number of Participants With Treatment-Emergent Adverse Events (TEAE) and TEAEs Leading to Death(Up to 1136 Days)
Number of Participants With Treatment-Emergent Adverse Events (TEAE) by Severity(Up to 1136 Days)
Maximum Observed Plasma Concentration (Cmax) of M8891(Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days))
Time to Reach Maximum Observed Plasma Concentration (Tmax) of M8891(Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days))
Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M8891(Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days))
Area Under the Concentration-time Curve From Zero Extrapolated to Infinity (AUC0-inf) of M8891(Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days))
Area Under the Plasma Concentration Versus Time Curve Within One Dosing Interval (AUC0-tau) of M8891(Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days))
Apparent Terminal Half Life (t1/2) of M8891(Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days))
Terminal Elimination Rate Constant (Lambda z) of M8891(Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days))
Apparent Total Body Clearance (CL/f) of M8891(Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days))
Apparent Body Clearance of Drug Following Extravascular Administration At Steady State (CLss/f) of M8891(Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days))
Apparent Volume of Distribution During Terminal Phase (VZ/f) of M8891(Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days))
Accumulation Ratios of AUC (Racc AUC) of M8891(Pre-dose and at 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 of Cycle 1 (each cycle is 21 days))
Accumulation Ratio of Cmax (Racc Cmax) of M8891(Pre-dose and at 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 of Cycle 1 (each cycle is 21 days))
Number of Participants With Best Overall Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria(Up to 1136 Days)
Number of Participants With Clinical Benefit(Up to 1136 Days)
Progression-Free Survival (PFS)(Up to 1136 Days)
Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03(Up to 1136 Days)
Number of Participants With Clinically Meaningful Changes From Baseline in Vital Signs(Up to 1136 Days)
Number of Participants With Clinically Meaningful Changes From Baseline in Electrocardiogram (ECG) Values(Up to 1136 Days)
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PF) Score of 2 or Higher Than 2(Up to 1136 Days)
Percentage of Participants With Objective Response(Up to 1136 Days)