M8891 First in Human in Solid Tumors

NCT03138538 | Terminated Phase 1 Results FDA Drug

• 1 other identifier: MS100015_0019
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 7

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.

Conditions

Advanced Solid Tumors; Metastatic Renal Cell Carcinoma

Keywords

Advanced Solid Tumors; Metastatic Renal Cell Carcinoma; M8891; Methionine Aminopeptidase 2 Inhibitor

Outcome Measures

Primary Outcomes (1)

• 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

  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.

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

Secondary Outcomes (22)

• 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)

Study Arms (6)

M8891 7 mg

EXPERIMENTAL

Participant received M8891 at dose of 7 milligrams (mg) orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.

Drug: Part 1: M8891

M8891 12 mg

EXPERIMENTAL

Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.

Drug: Part 1: M8891

M8891 20 mg

EXPERIMENTAL

Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.

Drug: Part 1: M8891

M8891 35 mg

EXPERIMENTAL

Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.

Drug: Part 1: M8891

M8891 60 mg

EXPERIMENTAL

Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.

Drug: Part 1: M8891

M8891 80 mg

EXPERIMENTAL

Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.

Drug: Part 1: M8891

Interventions

Part 1: M8891 DRUG

Participants receives M8891 orally once daily at escalated dose levels under fasting condition for consecutive 21-day cycles of continuous treatment until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.

M8891 12 mg; M8891 20 mg; M8891 35 mg; M8891 60 mg; M8891 7 mg; M8891 80 mg

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

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

Study Sites (7)

Smilow Cancer Hospital - Yale

New Haven, Connecticut, 06510, United States

Location

Indiana University Health Hospital

Indianapolis, Indiana, 46202, United States

Location

Sidney Kimmel Cancer Center - Johns Hopkins

Baltimore, Maryland, 21205-1911, United States

Location

Henry Ford Health System

Detroit, Michigan, 48202, United States

Location

Nebraska Cancer Specialists

Omaha, Nebraska, 68130, United States

Location

Comprehensive Cancer Centers of Nevada

Las Vegas, Nevada, 89169, United States

Location

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, 08901, United States

Location

Related Publications (2)

• Lignet F, Friese-Hamim M, Jaehrling F, El Bawab S, Rohdich F. Preclinical Pharmacokinetics and Translational Pharmacokinetic/Pharmacodynamic Modeling of M8891, a Potent and Reversible Inhibitor of Methionine Aminopeptidase 2. Pharm Res. 2023 Dec;40(12):3011-3023. doi: 10.1007/s11095-023-03611-z. Epub 2023 Oct 5.

  PMID: 37798538 DERIVED

• Carducci MA, Wang D, Habermehl C, Bodding M, Rohdich F, Lignet F, Duecker K, Karpenko O, Pudelko L, Gimmi C, LoRusso P. A First-in-human, Dose-escalation Study of the Methionine Aminopeptidase 2 Inhibitor M8891 in Patients with Advanced Solid Tumors. Cancer Res Commun. 2023 Aug 24;3(8):1638-1647. doi: 10.1158/2767-9764.CRC-23-0048. eCollection 2023 Aug.

  PMID: 37637935 DERIVED

Related Links

• Trial Awareness and Transparency website
• US Medical Information website, Medical Resources

MeSH Terms

Conditions

Carcinoma, Renal Cell

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

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 Research & Development Institute, Inc., a business of Merck KGaA, Darmstadt, Germany

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 26, 2017
• First Posted: May 3, 2017
• Study Start: August 8, 2017
• Primary Completion: September 16, 2020
• Study Completion: September 16, 2020
• Last Updated: March 11, 2022
• Results First Posted: March 11, 2022

Record last verified: 2021-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (7)