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Recurrent LymphomaPhase 1NCT03323034

Pevonedistat, Irinotecan, and Temozolomide in Treating Patients With Recurrent or Refractory Solid Tumors or Lymphoma

A Phase 1 study testing Irinotecan, Pevonedistat and Temozolomide in people with Recurrent Lymphoma and Recurrent Malignant Solid Neoplasm, run by Children's Oncology Group at 20 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

This phase I trial studies the side effects and best dose of pevonedistat when given together with irinotecan hydrochloride and temozolomide in treating patients with solid tumors, central nervous system (CNS) tumors, or lymphoma that have come back after a period of improvement (recurrent) or that do not respond to… Read more about this study

Who is it for?
Ages 6 months to 21 years
What is being tested?
Irinotecan, Pevonedistat and Temozolomide
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
30 participants
Where
20 sitesUnited States
Study dates
11 Jan 2018to 30 Sep 2024
Phase
Phase 1
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 6 months to 21 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • Part A1: Patients must be >= 12 months and =< 21 years of age at the time of study enrollment
  • Part A2: Patients must be >= 6 months and < 12 months of age at the time of study enrollment; patients will enroll one dose level behind the dose level at which patients in Part A1 are enrolling
  • Patients with recurrent or refractory solid tumors, including CNS tumors and lymphoma, for which no standard therapy is available are eligible; patients must have had histologic verification of malignancy at original diagnosis or relapse except in patients with intrinsic brain stem tumors, optic pathway gliomas, or patients with pineal tumors and elevations of cerebrospinal fluid (CSF) or serum tumor markers including alpha-fetoprotein or beta-human chorionic gonadotropin (HCG)
  • Patients must have either measurable or evaluable disease
  • Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
  • Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age; NOTE: neurologic deficits in patients with CNS tumors must have been relatively stable for at least 7 days prior to study enrollment; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
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  • Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment; if after the required time frame, the numerical eligibility criteria are met, e.g. blood count criteria, the patient is considered to have recovered adequately
  • Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive; at least 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea); the duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment
  • Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil counts [ANC] counts): >= 7 days after the last dose of agent; the duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment
  • Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
  • Corticosteroids: if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
  • Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair and the study-assigned research coordinator
  • Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)
  • Stem cell Infusions (with or without total body irradiation [TBI]):
  • Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion: >= 84 days after infusion and no evidence of graft versus host disease (GVHD)
  • Autologous stem cell infusion including boost infusion: >= 42 days
  • Cellular therapy: >= 42 days after the completion of any type of cellular therapy (e.g. modified T cells, natural killer [NK] cells, dendritic cells, etc.)
  • Radiation therapy (XRT)/external beam irradiation including protons: >= 14 days after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial brain metastases (BM) radiation
  • Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-metaiodobenzylguanidine [MIBG]): >= 42 days after systemically administered radiopharmaceutical therapy
  • Patients must not have received prior exposure to pevonedistat; patients with prior exposure to irinotecan or temozolomide are eligible
  • For patients with solid tumors without known bone marrow involvement:
  • Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
  • Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
  • Hemoglobin >= 8 g/dL
  • Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions); these patients will not be evaluable for hematologic toxicity; at least 5 of every cohort of 6 patients on Part A1 must be evaluable for hematologic toxicity for the dose-escalation part of the study; if dose-limiting hematologic toxicity is observed, all subsequent patients enrolled must be evaluable for hematologic toxicity
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
  • Age: 6 months to < 1 years maximum serum creatinine (mg/dL): male: 0.5; female: 0.5
  • Age: 1 to < 2 years maximum serum creatinine (mg/dL): male: 0.6; female: 0.6
  • Age: 2 to < 6 years maximum serum creatinine (mg/dL): male: 0.8; female: 0.8
  • Age: 6 to < 10 years maximum serum creatinine (mg/dL): male: 1; female: 1
  • Age: 10 to < 13 years maximum serum creatinine: (mg/dL): male: 1.2; female: 1.2
  • Age: 13 to < 16 years maximum serum creatinine: (mg/dL): male: 1.5; female: 1.4
  • Age: >= 16 years maximum serum creatinine: (mg/dL) male: 1.7; female: 1.4
  • Bilirubin (sum of conjugated + unconjugated) =< upper limit of normal (ULN) for age
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransaminase [ALT]) =< 135 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L
  • Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase) [AST]); =< 150 U/L; for the purpose of this study, the ULN for SGOT is 50 U/L
  • Serum albumin >= 2.7 g/dL
  • Shortening fraction of >= 27% by echocardiogram, or
  • Ejection fraction of >= 50% by gated radionuclide study
  • No supraventricular arrhythmia on electrocardiogram (EKG)
  • Prolonged rate corrected QT (QTc) interval < 500 msec
  • Pulse oximetry > 94% on room air if there is clinical indication for determination (e.g. dyspnea at rest)
  • Patients with seizure disorder may be enrolled if on non-enzyme inducing anti-convulsants and well controlled
  • Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] version 5.0) resulting from prior therapy must be =< grade 2, with the exception of decreased tendon reflex (DTR); any grade of DTR is eligible
  • International normalized ratio (INR) =< 1.5
  • All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines

Who cannot join

  • Pregnant or breast-feeding women will not be entered on this study because there is not yet available information regarding human fetal or teratogenic toxicities; pregnancy tests must be obtained in girls who are post-menarchal
  • Males or females of reproductive potential may not participate unless they have agreed to practice 1 highly effective and 1 additional effective (barrier) method of contraception at the same time during the entire study treatment period and through 4 months after the last dose of study drug, 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, post-ovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception
  • Patients with uncontrolled high blood pressure (i.e., systolic/diastolic blood pressure > 99th percentile) are not eligible
  • Patients with known cardiopulmonary disease are not eligible; cardiopulmonary disease is defined as:
  • Cardiomyopathy other than chemotherapy related changes in cardiac function that meet the eligibility requirements
  • Clinically significant arrhythmia:
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  • 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 defined as symptomatic and incompletely controlled medically, or controlled with device (e.g. pacemaker), or ablation and
  • Patients with paroxysmal a fib or < grade (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
  • Implantable cardioverter defibrillator;
  • Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing);
  • Pulmonary hypertension
  • Congestive heart failure class III or IV
  • Patients with known hepatic cirrhosis or severe pre-existing hepatic impairment are not eligible
  • Patients with uncontrolled coagulopathy or bleeding disorder are not eligible
  • Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible; if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
  • Patients who are currently receiving another investigational drug are not eligible
  • Patients who are currently receiving other anti-cancer agents are not eligible
  • Patients must not have received enzyme-inducing anticonvulsants for at least 7 days prior to enrollment
  • Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial
  • Patients who are receiving any investigational agent other than pevonedistat, including but not limited to androgens, supraphysiologic doses of corticosteroids, erythropoietin, eltrombopag, or romiplostim
  • Patients who have received drugs that are strong inducers of CYP3A4 within 14 days prior to study enrollment are not eligible; while on study, concomitant use of strong CYP3A4 inhibitors, BCRP inhibitors (cyclosporine, eltrombopag, gefitinib), and UGT1A1 inhibitors, (diclofenac, ketoconazole, probenecid, silibinin, nilotinib and atazanavir) should be avoided because of potential for increased irinotecan toxicity
  • Patients who have an uncontrolled infection are not eligible
  • Patients who have received a prior solid organ transplantation are not eligible
  • Patients with known human immunodeficiency virus (HIV) seropositive are not eligible
  • Patients with known hepatitis B surface antigen seropositive or known or suspected active hepatitis C infection are not eligible; 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
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition as the study agents
  • Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible

Trial locations and contacts

20 sites in 1 country.

20 sites in 1 country

United States20 sites

  • C S Mott Children's Hospital

    Ann Arbor, Michigan, 48109

  • Children's Healthcare of Atlanta - Arthur M Blank Hospital

    Atlanta, Georgia, 30329

  • Children's Hospital Colorado

    Aurora, Colorado, 80045

  • Children's Hospital of Alabama

    Birmingham, Alabama, 35233

  • Dana-Farber Cancer Institute

    Boston, Massachusetts, 02215

  • Lurie Children's Hospital-Chicago

    Chicago, Illinois, 60611

  • Cincinnati Children's Hospital Medical Center

    Cincinnati, Ohio, 45229

  • Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center

    Houston, Texas, 77030

  • Riley Hospital for Children

    Indianapolis, Indiana, 46202

  • Children's Hospital Los Angeles

    Los Angeles, California, 90027

  • Saint Jude Children's Research Hospital

    Memphis, Tennessee, 38105

  • University of Minnesota/Masonic Cancer Center

    Minneapolis, Minnesota, 55455

  • NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center

    New York, New York, 10032

  • Children's Hospital of Orange County

    Orange, California, 92868

  • Children's Hospital of Philadelphia

    Philadelphia, Pennsylvania, 19104

  • Children's Hospital of Pittsburgh of UPMC

    Pittsburgh, Pennsylvania, 15224

  • UCSF Medical Center-Mission Bay

    San Francisco, California, 94158

  • Seattle Children's Hospital

    Seattle, Washington, 98105

  • Washington University School of Medicine

    St Louis, Missouri, 63110

  • Children's National Medical Center

    Washington D.C., District of Columbia, 20010

Other trials in United States

About this study

Official title: A Phase 1 Study of Pevonedistat (MLN4924), a NEDD8 Activating Enzyme (NAE) Inhibitor, in Combination With Temozolomide and Irinotecan in Pediatric Patients With Recurrent or Refractory Solid Tumors

This phase I trial studies the side effects and best dose of pevonedistat when given together with irinotecan hydrochloride and temozolomide in treating patients with solid tumors, central nervous system (CNS) tumors, or lymphoma that have come back after a period of improvement (recurrent) or that do not respond to treatment (refractory). Pevonedistat and irinotecan may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving pevonedistat, irinotecan hydrochloride, and temozolomide may work better in treating patients with solid tumors, central nervous system (CNS) tumors, or lymphoma compared to irinotecan and temozolomide alone.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of pevonedistat administered as an intravenous infusion on days 1, 8, 10, and 12 of a 28-day cycle (cycle 1), and on days 1, 3, and 5 of a 21-day cycle (cycle 2 and beyond) in combination with irinotecan (administered as an intravenous infusion on days 8-12 of cycle 1 and days 1-5 of cycles 2+) and temozolomide (administered orally on days 8-12 in cycle 1 and days 1-5 of cycles 2+) in children with recurrent or refractory solid tumors, including central nervous system (CNS) tumors and lymphoma.

II. To define and describe the toxicities of pevonedistat administered on this schedule.

III. To characterize the pharmacokinetics of pevonedistat in children with recurrent or refractory cancer.

SECONDARY OBJECTIVES:

  1. To preliminarily define the antitumor activity of pevonedistat within the confines of a phase 1 study.

II. To assess the biologic activity of pevonedistat.

OUTLINE: This is a dose escalation study of pevonedistat.

Patients receive pevonedistat intravenously (IV) over 60 minutes on days 1, 8, 10, and 12, temozolomide orally (PO) daily on days 8-12, and irinotecan IV over 90 minutes on days 8-12 of cycle 1. Beginning cycle 2, patients receive pevonedistat IV over 60 minutes on days 1, 3, and 5, temozolomide PO daily on days 1-5, and irinotecan IV over 90 minutes on days 1-5. Treatment repeats every 28 days for cycle 1 and 21 days for subsequent cycles for up to 17 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Being tested
Irinotecan, Pevonedistat, Temozolomide
Medical subject headings
Lymphoma, Central Nervous System Neoplasms

What participants receive

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

  • IrinotecanDrug

    Given IV

  • PevonedistatDrug

    Also called MLN4924, Nedd8-Activating Enzyme Inhibitor MLN4924

    Given IV

  • TemozolomideDrug

    Also called CCRG-81045, Gliotem, Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-, M & B 39831

    Given PO

Study groups in NCT03323034
Study groupRoleWhat they receive
Treatment (pevonedistat, temozolomide, irinotecan)ExperimentalPatients receive pevonedistat IV over 60 minutes on days 1, 8, 10, and 12, temozolomide PO daily on days 8-12, and irinotecan IV over 90 minutes on days 8-12 of cycle 1. Beginning cycle 2, patients receive pevonedistat IV over 60 minutes on days 1, 3, and 5, temozolomide PO daily on days 1-5, and irinotecan IV over 90 minutes on days 1-5. Treatment repeats every 28 days for cycle 1 and 21 days for subsequent cycles for up to 17 cycles in the absence of disease progression or unacceptable toxicity.
Receives: Drug: Irinotecan; Drug: Pevonedistat; Drug: Temozolomide

What is being measured

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

  1. MTD/RP2D of Pevonedistat in Combination With Irinotecan and Temozolomide

    The maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) will be the maximum dose at which fewer than one-third of patients experience dose limiting toxicities.

    Measured: Up to 28 days

  2. Number of Participants With Grade 3 or Greater Toxicities Associated With Pevonedistat in Combination With Irinotecan and Temozolomide

    Frequency of patients who experience at least one grade 3 or higher toxicity that is at least possibly attributable to pevonedistat using the Common Terminology Criteria for Adverse Events version 5.0 by dose level stratified by study part and dose level.

    Measured: Up to 3 years 8 months

  3. Half-life of Pevonedistat in Combination With Irinotecan and Temozolomide

    Median (Range) for the time required for the serum concentration to fall to 50% of its starting dose by dose level stratified by study part and dose level.

    Measured: Up to 10 days

  4. T Max of Pevonedistat in Combination With Irinotecan and Temozolomide

    Median (Range) for the time at which the maximum (peak) serum concentration occurs by dose level stratified by study part and dose level.

    Measured: Up to 10 days

  5. C Max of Pevonedistat in Combination With Irinotecan and Temozolomide

    Median (Range) for the maximum (peak) serum concentration by dose level stratified by study part and dose level.

    Measured: Up to 10 days

  6. AUC of Pevonedistat in Combination With Irinotecan and Temozolomide

    Median (range) of the area under the drug concentration over time (pre-dose and then 0, 1, 2, 4, 6-8, and 24-hours post-dose infusion) curve stratified by study part and dose level.

    Measured: Up to 10 days

  7. Clearance of Pevonedistat in Combination With Irinotecan and Temozolomide

    Median (Range) for the rate of elimination of the drug by dose level stratified by study part and dose level.

    Measured: Up to 10 days

Secondary outcomes (1)

  1. Anti-tumor Activity of Pevonedistat in Combination With Irinotecan and Temozolomide

    Frequency of disease response (best overall response of partial or complete response) assessed per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR by dose level.

    Measured: Up to 4 years

Timeline

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

  1. First posted26 Oct 2017
  2. Study start11 Jan 2018
  3. Primary completion30 Sep 2021
  4. Study completion30 Sep 2024

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
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
30 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03323034
Sponsor's protocol ID
ADVL1615
Other IDs
NCI-2017-01229, ADVL1615, ADVL1615, ADVL1615, UM1CA097452
Status last verified
Oct 2024
First submitted
11 Oct 2017
Last updated
22 Oct 2024
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Irinotecan, Pevonedistat and Temozolomide in people with Recurrent Lymphoma and Recurrent Malignant Solid Neoplasm, run by Children's Oncology Group at 20 sites 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 46 inclusion and 30 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: finished, as of the sponsor's last update on 22 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 20 sites 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 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.

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 23 Sep 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?

MTD/RP2D of Pevonedistat in Combination With Irinotecan and Temozolomide (time frame: Up to 28 days). The study lists 7 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 NCT03323034.

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 22 Oct 2024.

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