Pevonedistat and Pembrolizumab for the Treatment of dMMR/MSI-H Metastatic or Locally Advanced Unresectable Solid Tumor

NCT04800627 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 2020-1065NCI-2020-13862
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I/II trial identifies the side effects and best dose of pevonedistat when given together with pembrolizumab in treating mismatch repair deficiency (dMMR)/high-frequency microsatellite instability (MSI-H) solid tumor that has spread to other places in the body (metastatic) or has spread to nearby tissue or lymph nodes (locally advanced) and cannot removed by surgery (unresectable). Pevonedistat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving pevonedistat and pembrolizumab may kill more tumor cells.

Conditions

Locally Advanced Malignant Solid Neoplasm; Metastatic Malignant Solid Neoplasm; Unresectable Malignant Solid Neoplasm

Outcome Measures

Primary Outcomes (2)

• Recommended Phase 2 Dose of Pevonedistat When Combined With Pembrolizumab (Phase I)

  21 days

• Objective Response (Partial Response [PR] or Complete Response [CR]) (Phase II)

  Will be assessed by immune modified Response Evaluation Criteria in Solid Tumors (iRECIST) version (v) 1.1.

  Through study completion, an average of 1 year

Secondary Outcomes (5)

• Changes in Protein Misfolding

  Up to 24 weeks

• Progression Free Survival (PFS)

  Through study completion, an average of 1 year

• Duration of Response

  Through study completion, an average of 1 year

• Overall Survival

  Through study completion, an average of 1 year

• Incidence of Adverse Events

  Through study completion, an average of 1 year

Study Arms (1)

Treatment (pevonedistat, pembrolizumab)

EXPERIMENTAL

Patients receive pevonedistat IV over 60 minutes on days 1, 3, and 5, and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Biological: Pembrolizumab; Drug: Pevonedistat

Interventions

Pembrolizumab BIOLOGICAL

Given IV

Also known as: Keytruda, Lambrolizumab, MK-3475, SCH 900475

Treatment (pevonedistat, pembrolizumab)

Pevonedistat DRUG

Given IV

Also known as: MLN4924, Nedd8-Activating Enzyme Inhibitor MLN4924

Treatment (pevonedistat, pembrolizumab)

Eligibility Criteria

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

You may qualify if:

• Patients 18 years or older
• Patients must have metastatic or locally advanced unresectable solid tumor
• Tumor that is deficient in mismatch repair (dMMR) or microsatellite instability high (MSI-H) as determined by one of three methods:
• Immunohistochemistry determined dMMR by complete loss of MLH1, PMS2, MSH2 or MSH6
• Polymerase chain reaction (PCR) determined microsatellite instability at \> 30% of tested microsatellites
• Next-generation determined MSI-H based upon instability at multiple microsatellites as determined by the specific next generation sequencing panel
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Hemoglobin \>= 8 g/dL (may transfuse to achieve this threshold)
• Absolute neutrophil count (ANC) \>= 1,500/mm\^3
• Platelet count \>= 100,000/mm\^3
• Albumin \> 2.7 g/dL
• Total bilirubin =\< 1.5 x upper limit of normal (ULN) except in patients with Gilbert's syndrome. Patients with Gilbert's syndrome may enroll if direct bilirubin =\< 3 x ULN of the direct bilirubin
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 3.0 x ULN
• Creatinine clearance \>= 30 mL/min according to MD Anderson standard, automated laboratory calculation
• Human immunodeficiency virus (HIV) patients may be considered as long as they meet the following criteria:

You may not qualify if:

• Treatment with any investigational products within 4 weeks before the first dose of any study drug
• Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of study procedures
• Active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia
• Major surgery within 14 days before the first dose of any study drug or a scheduled surgery during study period
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Life-threatening illness unrelated to cancer
• Patients with uncontrolled coagulopathy or bleeding disorder
• Known hepatitis B surface antigen seropositive or known or suspected active hepatitis C infection
• Note: Patients who have isolated positive hepatitis B core antibody (i.e., in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load. Patients who have positive hepatitis C antibody may be included if they have an undetectable hepatitis C viral load
• Known hepatic cirrhosis or severe pre-existing hepatic impairment
• Known cardiopulmonary disease defined as:
• Unstable angina;
• Congestive heart failure (New York Heart Association \[NYHA\] Class III or IV);
• Myocardial infarction (MI) within 6 months prior to first dose (patients who had ischemic heart disease such as a (ACS), MI, and/or revascularization greater than 6 months before screening and who are without cardiac symptoms may enroll);
• Symptomatic cardiomyopathy;

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Links

• MD Anderson Cancer Center

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

pembrolizumab; pevonedistat

Condition Hierarchy (Ancestors)

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

Limitations and Caveats

Company stopped development of the drug and shut down the entire program with pevonedistat. Takeda had a negative phase III of the agent in liquid tumors and thus shut the program. It was not due to any toxicity, but lack of path for FDA indication.

Results Point of Contact

• Title: Dr. Michael Overman,MD- Assoc VP, CN Research, SVP, Cancer NW Clin & Acad Dev
• Organization: UT MD Anderson Cancer Center

moverman@mdanderson.org

(713) 792-2828

Study Officials

• Michael J Overman

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

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

Study Record Dates

• First Submitted: January 12, 2021
• First Posted: March 16, 2021
• Study Start: March 29, 2021
• Primary Completion: November 3, 2022
• Study Completion: November 3, 2022
• Last Updated: December 27, 2022
• Results First Posted: December 21, 2022

Record last verified: 2022-12

Locations

US (1)