AzTrials
AzTrials

Locally Advanced Malignant Solid NeoplasmPhase 1/2NCT04800627

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

A Phase 1/2 study testing Pembrolizumab and Pevonedistat in people with Locally Advanced Malignant Solid Neoplasm and Metastatic Malignant Solid Neoplasm, run by M.D. Anderson Cancer Center at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
Search all trials

Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Pembrolizumab and Pevonedistat
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
2 participants
Where
1 siteUnited States
Study dates
29 Mar 2021to 3 Nov 2022
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 33Show fewer
  • 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:
  • CD4 count > 350 cells/mm^3
  • Undetectable viral load
  • No history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections
  • Female patients who:
  • Are postmenopausal for at least 1 year before the screening visit, OR
  • Are surgically sterile, OR If they are of childbearing potential:
  • Agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug (female and male condoms should not be used together), or
  • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)
  • Male patients, even if surgically sterilized (i.e., status post-vasectomy), who:
  • Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug (female and male condoms should not be used together), or
  • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)
  • Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care
  • Demonstrated prior progression on or after anti-PD1/L1 based therapy by radiographic progression. The potential for psuedoprogression should be excluded by concurrent tumor marker (for example carcinoembryonic antigen) or circulating tumor deoxyribonucleic acid [ctDNA] elevation, or clinical symptom progression, or short interval repeat imaging confirming progression. (if uncertain if patient meets eligibility please discuss with study principal investigator [PI])
  • Must have received at least 2 doses of a PD1/PD-L1 inhibitor
  • Progressive disease either during therapy or within 2 months of last dose of therapy
  • Measurable disease by immune modified Response Evaluation Criteria in Solid Tumors (iRECIST) version (v)1.1 by treating investigator or study PI
  • Tumor that is accessible to biopsy and patient is willing to undergone mandatory tumor biopsies at pre-treatment and on-treatment (unless exception granted by study PI)
  • Life expectancy >= 12 weeks as judged by treating physician

Who cannot join

  • 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
Show all 34Show fewer
  • 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;
  • Clinically significant arrhythmia:
  • History of polymorphic ventricular fibrillation or torsade de pointes,
  • Permanent atrial fibrillation [a fib], defined as continuous a fib for >= 6 months,
  • Persistent a fib, defined as sustained a fib lasting > 7 days and/or requiring cardioversion in the 4 weeks before screening,
  • Grade 3 a fib, within 6 months of starting protocol therapy, defined as symptomatic and incompletely controlled medically, and
  • Patients with paroxysmal a fib or < Gr 3 a fib for period of at least 6 months are permitted to enroll provided that their rate is controlled on a stable regimen.
  • Clinically significant pulmonary hypertension requiring pharmacologic therapy
  • Uncontrolled high blood pressure (i.e., systolic blood pressure >= 160 mm Hg, diastolic blood pressure >= 100 mm Hg)
  • Prolonged rate corrected QT (QTc) interval >= 500 msec, calculated according to institutional guidelines
  • Left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiogram or radionuclide angiography
  • Known moderate to severe chronic obstructive pulmonary disease, interstitial lung disease, and pulmonary fibrosis
  • Known central nervous system (CNS) involvement unless controlled with surgery or radiation therapy and has demonstrated no progression over 3 months from last local modality therapy
  • Systemic antineoplastic therapy or radiotherapy for other malignant conditions within 14 days before the first dose of any study drug
  • Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on day 1 before first dose of study drug
  • Female patients who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s)
  • Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s)
  • Known hypersensitivity to a study agent(s)
  • Residual adverse events from prior therapy (other than endocrinopathies or alopecia or neuropathy due to chemotherapy) that have not resolved to grade 0-1
  • Serious adverse immune related adverse events (grade 3 or 4) with previous immune checkpoint therapy, that were symptomatic and required prolong immunosuppression (> 6 weeks)

Trial locations and contacts

1 site in 1 country.

United States1 site

  • M D Anderson Cancer Center

    Houston, Texas, 77030

Other trials in United States

About this study

Official title: A Phase I/II Trial of Pevonedistat in Combination With Pembrolizumab in Patients With dMMR/MSI-H Cancers

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. Determine safety and phase II dose of pevonedistat in combination with pembrolizumab. (Phase I) II. To assess the efficacy of pevonedistat in combination with pembrolizumab in patients with dMMR/MSI-H cancers.

SECONDARY OBJECTIVES:

  1. To assess additional efficacy endpoints of the combination of pevonedistat and pembrolizumab in dMMR/MSI-H cancers.

II. To assess the safety of pevonedistat and pembrolizumab in the dMMR/MSI-H patient cohort.

III. To assess the pharmacodynamics impact of pevonedistat and pembrolizumab on tumor and immune-related components.

EXPLORATORY OBJECTIVES:

  1. Immune context evaluation of tumor microenvironment. II. Determine clinical benefit. III. Evaluate pevonedistat pharmacokinetics and resistance mechanisms in combination therapy.

OUTLINE: This is a phase I, dose escalation study of pevonedistat followed by a phase II study.

Patients receive pevonedistat intravenously (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.

After completion of study treatment, patients are followed up every 3-6 months.

Being tested
Pembrolizumab, Pevonedistat
Medical subject headings
Neoplasm Metastasis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PembrolizumabBiological

    Also called Keytruda, Lambrolizumab, MK-3475, SCH 900475

    Given IV

  • PevonedistatDrug

    Also called MLN4924, Nedd8-Activating Enzyme Inhibitor MLN4924

    Given IV

Study groups in NCT04800627
Study groupRoleWhat they receive
Treatment (pevonedistat, pembrolizumab)ExperimentalPatients 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.
Receives: Biological: Pembrolizumab; Drug: Pevonedistat

What is being measured

The primary outcome is the main question the study is designed to answer.

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

    Measured: 21 days

  2. 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.

    Measured: Through study completion, an average of 1 year

Secondary outcomes (5)

  1. Changes in Protein Misfolding

    Will analyze the pharmacodynamics impact of pevonedistat by evaluating changes in protein misfolding between pre-treatment and on-treatment tumor biopsies.

    Measured: Up to 24 weeks

  2. Progression Free Survival (PFS)

    Will be assessed by iRECIST v1.1. Will be estimated using the method of Kaplan and Meier.

    Measured: Through study completion, an average of 1 year

  3. Duration of Response

    Measured: Through study completion, an average of 1 year

  4. Overall Survival

    Will be estimated using the method of Kaplan and Meier.

    Measured: Through study completion, an average of 1 year

  5. Incidence of Adverse Events

    Measured: Through study completion, an average of 1 year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted16 Mar 2021
  2. Study start29 Mar 2021
  3. Primary completion3 Nov 2022
  4. Study completion3 Nov 2022

Why it stopped: Per PI

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
2 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04800627
Sponsor's protocol ID
2020-1065
Other IDs
NCI-2020-13862, 2020-1065
Status last verified
Dec 2022
First submitted
12 Jan 2021
Last updated
27 Dec 2022
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Pembrolizumab and Pevonedistat in people with Locally Advanced Malignant Solid Neoplasm and Metastatic Malignant Solid Neoplasm, run by M.D. Anderson Cancer Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 33 inclusion and 34 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 27 Dec 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 21 Dec 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Recommended Phase 2 Dose of Pevonedistat When Combined With Pembrolizumab (Phase I) (time frame: 21 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04800627.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Dec 2022.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in