Clinical trial NCT03138538: M8891 First in Human in Solid Tumors
Official title: An Open-label, Phase I Dose Escalation Trial of Methionine Aminopeptidase 2 Inhibitor M8891 in Subjects With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Advanced Solid Tumors
Metastatic Renal Cell Carcinoma
Keywords: Advanced Solid Tumors
Metastatic Renal Cell Carcinoma
M8891
Methionine Aminopeptidase 2 Inhibitor
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
Collaborators: name: Merck KGaA, Darmstadt, Germany
First posted: 2017-05-03
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: 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
timeFrame: At the end of Cycle 1 (each Cycle is of 21 days)
Secondary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAE) and TEAEs Leading to Death
timeFrame: Up to 1136 Days
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAE) by Severity
timeFrame: Up to 1136 Days
measure: Maximum Observed Plasma Concentration (Cmax) of M8891
timeFrame: 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)
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) of M8891
timeFrame: 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)
measure: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M8891
timeFrame: 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)
measure: Area Under the Concentration-time Curve From Zero Extrapolated to Infinity (AUC0-inf) of M8891
timeFrame: 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)
measure: Area Under the Plasma Concentration Versus Time Curve Within One Dosing Interval (AUC0-tau) of M8891
timeFrame: 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)
measure: Apparent Terminal Half Life (t1/2) of M8891
timeFrame: 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)
measure: Terminal Elimination Rate Constant (Lambda z) of M8891
timeFrame: 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)
measure: Apparent Total Body Clearance (CL/f) of M8891
timeFrame: 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)
measure: Apparent Body Clearance of Drug Following Extravascular Administration At Steady State (CLss/f) of M8891
timeFrame: 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)
measure: Apparent Volume of Distribution During Terminal Phase (VZ/f) of M8891
timeFrame: 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)
measure: Accumulation Ratios of AUC (Racc AUC) of M8891
timeFrame: 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)
measure: Accumulation Ratio of Cmax (Racc Cmax) of M8891
timeFrame: 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)
measure: Number of Participants With Best Overall Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria
timeFrame: Up to 1136 Days
measure: Number of Participants With Clinical Benefit
timeFrame: Up to 1136 Days
measure: Progression-Free Survival (PFS)
timeFrame: Up to 1136 Days
measure: Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03
timeFrame: Up to 1136 Days
measure: Number of Participants With Clinically Meaningful Changes From Baseline in Vital Signs
timeFrame: Up to 1136 Days
measure: Number of Participants With Clinically Meaningful Changes From Baseline in Electrocardiogram (ECG) Values
timeFrame: Up to 1136 Days
measure: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PF) Score of 2 or Higher Than 2
timeFrame: Up to 1136 Days
measure: Percentage of Participants With Objective Response
timeFrame: Up to 1136 Days
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Smilow Cancer Hospital - Yale
state: Connecticut
city: Indianapolis
country: United States
facility: Indiana University Health Hospital
state: Indiana
city: Baltimore
country: United States
facility: Sidney Kimmel Cancer Center - Johns Hopkins
state: Maryland
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Omaha
country: United States
facility: Nebraska Cancer Specialists
state: Nebraska
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey
state: New Jersey
Study officials:
affiliation: EMD Serono Research & Development Institute, Inc., a business of Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References: