Description:
The purpose of this study is 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 and to determine the safety,
tolerability, PK and antitumor activity of M8891 combined with cabozantinib in participants
with metastatic renal cell carcinoma (mRCC) in Part 2 (Part 2a and Part 2b) of the study.
Title
- Brief Title: 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
Clinical Trial IDs
- ORG STUDY ID:
MS100015_0019
- NCT ID:
NCT03138538
Conditions
- Advanced Solid Tumors
- Metastatic Renal Cell Carcinoma
Interventions
| Drug | Synonyms | Arms |
|---|
| Part 1: M8891 | | Part 1: M8891 |
| Part 2A: M8891 | | Part 2A: Dose Escalation Cohort: M8891 and Cabozantinib |
| Part 2B: M8891 | | Part 2B: Dose Expansion Cohort: M8891 and Cabozantinib |
| Cabozantinib | | Part 2A: Dose Escalation Cohort: M8891 and Cabozantinib |
Purpose
The purpose of this study is 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 and to determine the safety,
tolerability, PK and antitumor activity of M8891 combined with cabozantinib in participants
with metastatic renal cell carcinoma (mRCC) in Part 2 (Part 2a and Part 2b) of the study.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Part 1: M8891 | Experimental | | |
| Part 2A: Dose Escalation Cohort: M8891 and Cabozantinib | Experimental | | - Part 2A: M8891
- Cabozantinib
|
| Part 2B: Dose Expansion Cohort: M8891 and Cabozantinib | Experimental | | - Part 2B: M8891
- Cabozantinib
|
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
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Part 1: Number of Participants Experienced Any Dose-Limiting Toxicity (DLT) Over the DLT period |
| Time Frame: | From Cycle 1 Day 1 up to Cycle 1 Day 21 (Each cycle is of 21 days) |
| Safety Issue: | |
| Description: | DLTs are defined as any pre-defined set of adverse events (AEs) which are defined in the protocol, observed in the first 21-day treatment cycle and judged to be M8891 related or clinically relevant (excluding events to be related to underlying disease, medical history or concomitant medications/ procedures in the opinion of the safety monitoring committee). |
Secondary Outcome Measures
| Measure: | Part 1: Number of Participants With Treatment-Emergent Adverse Events (TEAE), Serious TEAEs, TEAEs Leading to Discontinuation and Death |
| Time Frame: | Up to 7 months |
| Safety Issue: | |
| Description: | AE is defined as any untoward medical occurrence which does not necessarily have a causal relationship with this the study drug. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE is any untoward medical occurrence that at any dose results in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or considered medically important. |
| Measure: | Part 1: Number of Participants With Clinical Significant Changes From Baseline in Laboratory, Electrocardiogram measures, vital signs, Eastern Cooperative Oncology Group Performance status (ECOG PS) |
| Time Frame: | Baseline up to 8 months |
| Safety Issue: | |
| Description: | Clinical laboratory assessments will include hematology, biochemistry and coagulation parameters. Vital sign assessments will include assessments of heart rate, diastolic blood pressure, systolic blood pressure, weight and temperature, ECG and ECOG PS will also be assessed. Number of participants with clinical significant changes from baseline in laboratory, electrocardiogram measures, vital signs and in Eastern Cooperative Oncology Group Performance status (ECOG PS) will be reported. |
| Measure: | Part 1: Maximum Observed Plasma Concentration (Cmax) of M8891 |
| Time Frame: | Part 1: Day 1, 2, 8, 15, 16 of Cycle 1; Day 1 of Cycle 2 and Cycle 3 (each Cycle is of 21 days) |
| Safety Issue: | |
| Description: | Cmax will be obtained directly from the concentration versus time curve. |
| Measure: | Part 1: Time to Reach Maximum Plasma Concentration (Tmax) of M8891 |
| Time Frame: | Part 1: Day 1, 2, 8, 15, 16 of Cycle 1; Day 1 of Cycle 2 and Cycle 3 (each Cycle is of 21 days) |
| Safety Issue: | |
| Description: | Time to reach the maximum plasma concentration (Tmax) will be obtained directly from the concentration versus time curve. |
| Measure: | Part 1: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of M8891 |
| Time Frame: | Part 1: Day 1, 2, 8, 15, 16 of Cycle 1; Day 1 of Cycle 2 and Cycle 3 (each Cycle is of 21 days) |
| Safety Issue: | |
| Description: | Area under the plasma concentration vs time curve from time zero to the last sampling time t at which the concentration is at or above the lower limit of quantification (LLQ). AUC0-t will be to be calculated according to the mixed log-linear trapezoidal rule. |
| Measure: | Part 1: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of M8891 |
| Time Frame: | Day 1, 2, 8, 15, 16 of Cycle 1; Day 1 of Cycle 2 and Cycle 3 (Each cycle is of 21 days) |
| Safety Issue: | |
| Description: | AUC0-inf will be calculated by combining AUC0-t and AUCextra. AUC extra represents an extrapolated value obtained by Clast/ λz, where Clast is the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLQ) and λz is the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase. |
| Measure: | Part 1: Area under the plasma concentration versus time curve within one dosing interval (AUC0-tau) of M8891 |
| Time Frame: | Day 1, 2, 8, 15, 16 of Cycle 1; Day 1 of Cycle 2 and Cycle 3 (Each cycle is of 21 days) |
| Safety Issue: | |
| Description: | AUC 0-tau is defined as the area under the concentration-time curve from 0 to dosing interval. |
| Measure: | Part 1: Apparent Terminal Half-life (t1/2) of M8891 |
| Time Frame: | Day 1, 2, 8, 15, 16 of Cycle 1; Day 1 of Cycle 2 and Cycle 3 (Each cycle is of 21 days) |
| Safety Issue: | |
| Description: | Terminal half-life is the time measured for the concentration of drug to decrease by one half. |
| Measure: | Part 1: Apparent Body Clearance From Plasma Following Extravascular Administration (CL/f) of M8891 |
| Time Frame: | Day 1, 2, 8, 15, 16 of Cycle 1; Day 1 of Cycle 2 and Cycle 3 (Each cycle is of 21 days) |
| Safety Issue: | |
| Description: | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent clearance after oral dose (CL/f) is influenced by the fraction absorbed. |
| Measure: | Part 1: Apparent Volume of Distribution Following Extravascular Administration of M8891 |
| Time Frame: | Day 1, 2, 8, 15, 16 of Cycle 1; Day 1 of Cycle 2 and Cycle 3 (Each cycle is of 21 days) |
| Safety Issue: | |
| Description: | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. |
| Measure: | Part 1: Apparent Terminal Rate Constant of M8891 |
| Time Frame: | Day 1, 2, 8, 15, 16 of Cycle 1; Day 1 of Cycle 2 and Cycle 3 (Each cycle is of 21 days) |
| Safety Issue: | |
| Description: | Apparent Terminal Rate Constant is defined as the rate at which drug is cleared from the body. |
| Measure: | Part 1: Accumulation ratio for AUCtau (Racc(AUCtau)) of M8891 |
| Time Frame: | Day 1, 2, 8, 15, 16 of Cycle 1; Day 1 of Cycle 2 and Cycle 3 (Each cycle is of 21 days) |
| Safety Issue: | |
| Description: | Accumulation ratio will be calculated from AUCtau at steady state and AUCtau after single dosing. |
| Measure: | Part 1: Accumulation ratio for Cmax (Racc(Cmax))of M8891 |
| Time Frame: | Day 1, 2, 8, 15, 16 of Cycle 1; Day 1 of Cycle 2 and Cycle 3 (Each cycle is of 21 days) |
| Safety Issue: | |
| Description: | Accumulation ratio will be calculated from Cmax at steady state and Cmax after single dosing. |
| Measure: | Part 1: Apparent Body Clearance of Drug Following Extravascular Administration at Steady State (CLss/F) of M8891 |
| Time Frame: | Day 1, 2, 8, 15, 16 of Cycle 1; Day 1 of Cycle 2 and Cycle 3 (Each cycle is of 21 days) |
| Safety Issue: | |
| Description: | Clearance (CLss/F) of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes at steady state. |
| Measure: | Part 1: Best Overall Response (BOR) |
| Time Frame: | Time from date of randomization up to end of the treatment or until disease progression (assessed up to 8 months) |
| Safety Issue: | |
| Description: | BOR will be determined according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) as assessed by investigators. BOR is defined as the best response of any of the complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from the date of randomization until disease progression. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is defined as at least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. |
| Measure: | Part 1: Number of Participants With Clinical Benefit |
| Time Frame: | Time from date of randomization up to end of the treatment or until disease progression (assessed up to 8 months) |
| Safety Issue: | |
| Description: | Clinical benefit defined as Complete Response [CR], Partial Response [PR] or Stable Disease [SD] for >= 12 weeks. Clinical benefit will be assessed according to RECIST Version 1.1. CR: defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: defined as at least a 30% decrease in sum of longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Progressive disease (PD) :defined as at least a 20% increase in sum of longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study) or unequivocal progression of existing non-target lesions. SD: defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of longest diameter while on study. |
| Measure: | Part 1: Progression-free survival |
| Time Frame: | Time from date of randomization until disease progression or death (assessed up to 8 months) |
| Safety Issue: | |
| Description: | Progression-free survival time (PFS) is defined as the time from first study drug administration to either first observation of disease progression (as assessed by RECIST v 1.1) or occurrence of death due to any cause, whichever occurs first. |
| Measure: | Part 2A and 2B: Duration of Response According to Response evaluation criteria in solid tumors (RECIST) v1.1 as Assessed by Investigators |
| Time Frame: | Part 2A and 2B: Up to 12 months |
| Safety Issue: | |
| Description: | |
| Measure: | Part 2A and 2B: Progression Free Survival (PFS) Time According to Response evaluation criteria in solid tumors (RECIST) v1.1 as Assessed by Investigators |
| Time Frame: | Part 2A and 2B: up to 12 months |
| Safety Issue: | |
| Description: | |
| Measure: | Part 2B: Plasma Concentrations of M8891 and cabozantinib |
| Time Frame: | Day 1, 8, 15 of Cycle 1 and Day 1 of Cycle 2 (each Cycle is of 21 days) |
| Safety Issue: | |
| Description: | |
| Measure: | Part 2A: Maximum Observed Plasma Concentration (Cmax) of M8891 and Cabozantinib |
| Time Frame: | Part 2A: Day -1, 1, 8, 15 of Cycle 1; Day 1 of Cycle 2 (each Cycle is of 22 days) |
| Safety Issue: | |
| Description: | |
| Measure: | Part 2A: Time to Reach Maximum Plasma Concentration (Tmax) of M8891 and Cabozantinib |
| Time Frame: | Part 2A: Day 1, 8, 15 of Cycle 1; Day 1 of Cycle 2 (each Cycle is of 22 days) |
| Safety Issue: | |
| Description: | |
| Measure: | Part 2A: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of M8891 and Cabozantinib |
| Time Frame: | Part 2A: Day -1, 1, 8, 15 of Cycle 1; Day 1 of Cycle 2 (each Cycle is of 22 days) |
| Safety Issue: | |
| Description: | |
Details
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Active, not recruiting |
| Lead Sponsor: | EMD Serono Research & Development Institute, Inc. |
Trial Keywords
- Advanced Solid Tumors
- Metastatic Renal Cell Carcinoma
- M8891
- Methionine Aminopeptidase 2 Inhibitor
Last Updated
October 30, 2020
