ClinicalTrials.gg
CompletedNCT03323034Updated Oct 22, 2024Results posted

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

A Phase 1 interventional study of Irinotecan and Pevonedistat in Recurrent Lymphoma, Recurrent Malignant Solid Neoplasm and Recurrent Primary Central Nervous System Neoplasm, sponsored by Children's Oncology Group. Completed at 20 sites in United States. Open to participants aged 6 Months to 21 Years. Per ClinicalTrials.gov, last updated 2024-10-22.

Sponsored by Children's Oncology Group · Phase 1, Interventional, and Treatment

Phase
Phase 1
Study type
Interventional
Enrollment
30
Allocation
Not applicable
Ages
6 Months to 21 Years
Sex
All
01

Study 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 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:

I. 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:

I. 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.

02

Conditions studied

  • Recurrent Lymphoma
  • Recurrent Malignant Solid Neoplasm
  • Recurrent Primary Central Nervous System Neoplasm
  • Refractory Lymphoma
  • Refractory Malignant Solid Neoplasm
  • Refractory Primary Central Nervous System Neoplasm
03

In context

Lymphoma

3,018 studies on the registry are indexed under Lymphoma; 434 are open to participants now.

This study's enrollment of 30 is below the median of 43 across 2,319 interventional studies indexed under Lymphoma.

Browse Lymphoma studies →

Lead sponsor

Children's Oncology Group is the lead sponsor of 448 studies on the registry; 36 are open to participants now.

Of its 12 completed or terminated interventional studies of FDA-regulated products, 11 (92%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
6 Months to 21 Years
Sexes eligible
All
Accepts healthy volunteers
No

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

Inclusion criteria

  • 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 solid tumors, including CNS tumors and lymphoma, for which no standard therapy is available are eligible; patients must have had histologic verification of 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
  • >= 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
  • 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 or [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
    • : 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 (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 (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)
    • >= 8 g/dL
  • Patients with known bone marrow 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
  • or radioisotope (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
  • (sum of conjugated + unconjugated) =\< (ULN) for age
  • Serum glutamate pyruvate transaminase () (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
  • of >= 50% by gated radionuclide study
  • No supraventricular arrhythmia on (EKG)
  • Prolonged rate (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 ( [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
  • (INR) =\< 1.5
  • All patients and/or their parents or legally authorized representatives must sign a written ; assent, when appropriate, will be obtained according to institutional guidelines

Exclusion criteria

Exclusion Criteria:

  • 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 may not participate unless they have agreed to practice 1 highly effective and 1 additional effective (barrier) method of 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
    • 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 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 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 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 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 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 (HIV) seropositive are not eligible
  • Patients with known surface antigen seropositive or known or suspected active 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
Terms in these criteria, in plain language(29)

Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.

Relapsed and refractory

Relapsed: the illness came back after treatment had worked. Refractory: it did not respond to treatment, or stopped responding while still on it.

Cancer (malignancy)

Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.

Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.

Karnofsky performance status (KPS)

A 0–100 scale of how well someone can carry out everyday activities. 100 is no complaints and no signs of illness; 70 is able to look after yourself but not to work or keep up normal activity; 50 is needing considerable help and frequent medical care.

Studies often ask for 60 or 70 and above. Your doctor gives the score.

Platelets

Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.

Absolute neutrophil count (ANC)

The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.

It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.

Corticosteroids (steroids)

Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.

Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.

GVHD (graft-versus-host disease)

After a transplant from a donor, the donor’s immune cells attack the recipient’s body, often the skin, gut or liver.

Brain metastases

Cancer deposits in the brain from a cancer that started elsewhere in the body (CNS metastases include the spinal cord).

Studies differ: some leave out any brain metastases, some accept ones treated and stable for some weeks. Check what this study allows.

Hemoglobin (Hb)

The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).

Metastases

Cancer that has spread from where it began to other parts of the body. “Metastatic” cancer is cancer that has spread this way.

Creatinine clearance (CrCl)

How quickly the kidneys clear creatinine, a waste product, from the blood. A study may estimate it from a blood test with age, weight and sex (often by the Cockcroft–Gault formula), or measure it using blood and urine collected over a set time. Given in mL/min; higher is better.

GFR and eGFR (kidney filtering)

GFR (glomerular filtration rate) is how much blood the kidneys filter each minute. It is usually estimated from a blood test — eGFR, by formulas such as CKD-EPI or MDRD — and some studies ask for it to be measured directly instead. Usually given in mL/min/1.73 m².

Check the method, the units and the minimum the study states. A value of 90 or above is in the normal-or-high range, but kidney damage can show in other tests too.

Bilirubin

A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.

Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.

ULN (upper limit of normal)

The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.

“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.

ALT and AST (liver enzymes)

Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.

Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.

LVEF (left ventricular ejection fraction)

The share of blood the heart’s main pumping chamber (the left ventricle) pushes out with each beat, measured by an echocardiogram (heart ultrasound) or a MUGA scan. About 50–70% is normal.

ECG (electrocardiogram)

A recording of the heart’s electrical activity, taken with stickers on the chest, arms and legs. It takes a few minutes and does not hurt.

QT and QTc

On an ECG, the QT interval is the time the heart’s lower chambers take to activate electrically and recover in each beat. QTc is that time adjusted for heart rate (QTcF by Fridericia’s formula, QTcB by Bazett’s). Some medicines lengthen it, and a long QTc can raise the risk of a dangerous heart rhythm.

The study may name a correction formula and a limit in milliseconds, often around 450–480.

CTCAE grade

The US National Cancer Institute’s scale of how severe an adverse event is — any unwanted medical event during a study, such as a symptom, an illness or an abnormal test result, whether or not a treatment caused it. Whether it did is judged separately.

1
Mild.
2
Moderate.
3
Severe.
4
Life-threatening.
5
Death due to the event.

“Side effects of earlier treatment resolved to grade 1 or less” means they have settled to mild or gone.

INR, PT and aPTT (clotting tests)

Blood tests of how long blood takes to clot. The INR is the prothrombin time (PT) put on a common scale; about 1 is usual for someone not taking a blood thinner.

Criteria often make an exception for people on a blood thinner such as warfarin, whose INR is raised on purpose.

Informed consent

Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.

You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.

Reproductive potential

Able to have children. For women this usually means from the first period until menopause, unless permanently unable to through surgery; for men, unless permanently sterile. Read who the line is about — participants, women, men, or their partners.

Criteria about it usually ask for contraception during the study and for a time after it.

Contraception

Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.

Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.

Clinically significant

Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.

Investigational drug or device

A drug or device being studied in a clinical trial.

It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.

CYP3A (CYP3A4) inhibitors and inducers

CYP3A is a group of enzymes, mainly CYP3A4, in the liver and gut that break down many medicines. Some medicines, supplements and foods (grapefruit, St John’s wort) slow them down or speed them up, which changes how much of a study drug stays in the body.

Studies list them so they can be avoided or switched; bring a list of everything you take, including supplements.

HIV

The human immunodeficiency virus, which weakens the immune system.

Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.

Hepatitis B tests

Hepatitis B is a virus that infects the liver. These are separate tests: HBsAg positive usually means a current infection (a recent vaccination can briefly cause it too); total anti-HBc (HBcAb) positive means an infection now or in the past; HBV DNA measures how much virus is in the blood.

Some studies accept a past infection if HBV DNA is undetectable, sometimes with antiviral medicine during the study. Check what this study allows.

Hepatitis C tests

Hepatitis C is a virus that infects the liver. An HCV antibody test can stay positive after an infection has cleared (and is occasionally positive without one); an HCV RNA test shows whether the virus is there now.

After treatment, hepatitis C counts as cured when HCV RNA is still undetectable 12 weeks or more after the treatment ended. Studies often accept people cured this way.

05

Study design

Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrollment
30 participants (actual)

Study arms

  • Experimental
    Treatment (pevonedistat, temozolomide, irinotecan)

    Patients 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.

    Drug: Irinotecan · Drug: Pevonedistat · Drug: Temozolomide

Interventions

  • Given IV

  • Given IV

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

  • Given PO

    Also known as: CCRG-81045, Gliotem, Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-, M & B 39831, M and B 39831, Methazolastone, RP-46161, SCH 52365, Temcad, Temizole, Temodal, Temodar, Temomedac, TMZ

06

What researchers measure

Primary outcomes

  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.

    Time frame: 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.

    Time frame: 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.

    Time frame: 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.

    Time frame: 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.

    Time frame: 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.

    Time frame: 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.

    Time frame: Up to 10 days

Secondary outcomes

  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.

    Time frame: Up to 4 years

07

Results

Posted Sep 23, 2022

Participant flow

Participant flow — Overall Study
MilestonePart A Dose Level 1: 15 mg/m^2Part A Dose Level 2: 20 mg/m^2Part A Dose Level 3: 25 mg/m^2Part A Dose Level 4: 35 mg/m^2Part A PK Dose Level 4: 35 mg/m^2
Started66666
Completed00000
Not completed66666
Withdrew: Lack of efficacy55655
Withdrew: Physician decision00001
Withdrew: Withdrawal by subject11010

Outcome measures

PrimaryMTD/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.

Time frame:
Up to 28 days
Reported as:
Number · mg/m^2
MTD/RP2D of Pevonedistat in Combination With Irinotecan and Temozolomide
mg/m^2Treatment (Pevonedistat, Temozolomide, Irinotecan)
MTD/RP2D of Pevonedistat in Combination With Irinotecan and Temozolomide35
PrimaryNumber 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.

Time frame:
Up to 3 years 8 months
Reported as:
Count of participants · Participants
Number of Participants With Grade 3 or Greater Toxicities Associated With Pevonedistat in Combination With Irinotecan and Temozolomide
ParticipantsPart A Dose Level 1: 15 mg/m^2Part A Dose Level 2: 20 mg/m^2Part A Dose Level 3: 25 mg/m^2Part A Dose Level 4: 35 mg/m^2Part A PK Dose Level 4: 35 mg/m^2
Number of Participants With Grade 3 or Greater Toxicities Associated With Pevonedistat in Combination With Irinotecan and Temozolomide54624
PrimaryHalf-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.

Time frame:
Up to 10 days
Reported as:
Median · hours
Half-life of Pevonedistat in Combination With Irinotecan and Temozolomide
hoursPart A Dose Level 1: 15 mg/m^2Part A Dose Level 2: 20 mg/m^2Part A Dose Level 3: 25 mg/m^2Part A Dose Level 4: 35 mg/m^2Part A PK Dose Level 4: 35 mg/m^2
Half-life of Pevonedistat in Combination With Irinotecan and Temozolomide5.3 (4.7 to 7.4)5 (4.1 to 6.0)5.2 (4.0 to 5.5)4.7 (4.0 to 6.7)6.1 (3.9 to 7.9)
PrimaryT 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.

Time frame:
Up to 10 days
Reported as:
Median · hours
T Max of Pevonedistat in Combination With Irinotecan and Temozolomide
hoursPart A Dose Level 1: 15 mg/m^2Part A Dose Level 2: 20 mg/m^2Part A Dose Level 3: 25 mg/m^2Part A Dose Level 4: 35 mg/m^2Part A PK Dose Level 4: 35 mg/m^2
T Max of Pevonedistat in Combination With Irinotecan and Temozolomide1. (1.0 to 1.6)1 (1.0 to 2.5)1 (0.9 to 1.4)1.1 (1.0 to 1.1)1.1 (1.0 to 1.5)
PrimaryC 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.

Time frame:
Up to 10 days
Reported as:
Median · ng/mL
C Max of Pevonedistat in Combination With Irinotecan and Temozolomide
ng/mLPart A Dose Level 1: 15 mg/m^2Part A Dose Level 2: 20 mg/m^2Part A Dose Level 3: 25 mg/m^2Part A Dose Level 4: 35 mg/m^2Part A PK Dose Level 4: 35 mg/m^2
C Max of Pevonedistat in Combination With Irinotecan and Temozolomide156 (87.9 to 208.0)218.5 (170.5 to 335.0)303.5 (174.0 to 365.5)419 (238.0 to 689.0)363.8 (214.0 to 2367.0)
PrimaryAUC 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.

Time frame:
Up to 10 days
Reported as:
Median · hr*ng/mL
AUC of Pevonedistat in Combination With Irinotecan and Temozolomide
hr*ng/mLPart A Dose Level 1: 15 mg/m^2Part A Dose Level 2: 20 mg/m^2Part A Dose Level 3: 25 mg/m^2Part A Dose Level 4: 35 mg/m^2Part A PK Dose Level 4: 35 mg/m^2
AUC of Pevonedistat in Combination With Irinotecan and Temozolomide803 (608.0 to 1010.0)973.5 (865.0 to 1928.0)1340 (990.0 to 1890.0)2018.5 (1505.0 to 2535.0)1957 (1583.0 to 5733.0)
PrimaryClearance 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.

Time frame:
Up to 10 days
Reported as:
Median · L/hr/m^2
Clearance of Pevonedistat in Combination With Irinotecan and Temozolomide
L/hr/m^2Part A Dose Level 1: 15 mg/m^2Part A Dose Level 2: 20 mg/m^2Part A Dose Level 3: 25 mg/m^2Part A Dose Level 4: 35 mg/m^2Part A PK Dose Level 4: 35 mg/m^2
Clearance of Pevonedistat in Combination With Irinotecan and Temozolomide18.8 (14.8 to 24.7)20.8 (10.6 to 23.3)18.9 (13.2 to 25.4)17.5 (13.8 to 23.3)17.9 (10.2 to 22.1)
SecondaryAnti-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.

Time frame:
Up to 4 years
Reported as:
Count of participants · Participants
Anti-tumor Activity of Pevonedistat in Combination With Irinotecan and Temozolomide
ParticipantsPart A Dose Level 1: 15 mg/m^2Part A Dose Level 2: 20 mg/m^2Part A Dose Level 3: 25 mg/m^2Part A Dose Level 4: 35 mg/m^2Part A PK Dose Level 4: 35 mg/m^2
Anti-tumor Activity of Pevonedistat in Combination With Irinotecan and Temozolomide11000

Adverse events

Collected over Up to 4 years. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Part A Dose Level 1: 15 mg/m^20/6 (0%)5/6 (83.3%)6/6 (100%)
Part A Dose Level 2: 20 mg/m^20/6 (0%)4/6 (66.7%)6/6 (100%)
Part A Dose Level 3: 25 mg/m^20/6 (0%)6/6 (100%)6/6 (100%)
Part A Dose Level 4: 35 mg/m^20/6 (0%)2/6 (33.3%)6/6 (100%)
Part A PK Dose Level 4: 35 mg/m^20/6 (0%)4/6 (66.7%)6/6 (100%)
Most frequent serious events
Showing 10 of 35
Most frequent serious events
EventPart A Dose Level 1: 15 mg/m^2Part A Dose Level 2: 20 mg/m^2Part A Dose Level 3: 25 mg/m^2Part A Dose Level 4: 35 mg/m^2Part A PK Dose Level 4: 35 mg/m^2
Lymphocyte count decreasedInvestigations5/60/62/61/63/6
White blood cell decreasedInvestigations5/60/61/61/61/6
Neutrophil count decreasedInvestigations3/61/62/62/61/6
Alanine aminotransferase increasedInvestigations0/62/61/60/61/6
HyperglycemiaMetabolism and nutrition disorders0/60/62/60/60/6
HypokalemiaMetabolism and nutrition disorders0/60/62/60/61/6
Abdominal painGastrointestinal disorders0/60/60/60/61/6
AnemiaBlood and lymphatic system disorders0/61/60/61/60/6
AnorexiaMetabolism and nutrition disorders1/60/61/60/60/6
Aspartate aminotransferase increasedInvestigations0/60/61/60/60/6
Most frequent other events
Showing 10 of 189
Most frequent other events
EventPart A Dose Level 1: 15 mg/m^2Part A Dose Level 2: 20 mg/m^2Part A Dose Level 3: 25 mg/m^2Part A Dose Level 4: 35 mg/m^2Part A PK Dose Level 4: 35 mg/m^2
AnemiaBlood and lymphatic system disorders6/64/66/66/65/6
Aspartate aminotransferase increasedInvestigations1/66/65/62/64/6
DiarrheaGastrointestinal disorders4/64/66/63/62/6
NauseaGastrointestinal disorders6/65/64/63/64/6
Platelet count decreasedInvestigations3/64/64/61/66/6
White blood cell decreasedInvestigations5/66/65/66/65/6
Alanine aminotransferase increasedInvestigations4/65/65/64/63/6
FatigueGeneral disorders4/63/62/63/65/6
HypoalbuminemiaMetabolism and nutrition disorders3/60/64/62/65/6
VomitingGastrointestinal disorders5/64/64/62/65/6

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)Part A Dose Level 1: 15 mg/m^2Part A Dose Level 2: 20 mg/m^2Part A Dose Level 3: 25 mg/m^2Part A Dose Level 4: 35 mg/m^2Part A PK Dose Level 4: 35 mg/m^2Total
<=18 years6646628
Between 18 and 65 years002002
>=65 years000000
Age, Continuous
Age, Continuous(years)Part A Dose Level 1: 15 mg/m^2Part A Dose Level 2: 20 mg/m^2Part A Dose Level 3: 25 mg/m^2Part A Dose Level 4: 35 mg/m^2Part A PK Dose Level 4: 35 mg/m^2Total
Median14.5 (6 to 18)12 (1 to 17)11 (2 to 21)7 (5 to 15)16.5 (4 to 18)13 (1 to 21)
Sex: Female, Male
Sex: Female, Male(Participants)Part A Dose Level 1: 15 mg/m^2Part A Dose Level 2: 20 mg/m^2Part A Dose Level 3: 25 mg/m^2Part A Dose Level 4: 35 mg/m^2Part A PK Dose Level 4: 35 mg/m^2Total
Female1241311
Male5425319
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Part A Dose Level 1: 15 mg/m^2Part A Dose Level 2: 20 mg/m^2Part A Dose Level 3: 25 mg/m^2Part A Dose Level 4: 35 mg/m^2Part A PK Dose Level 4: 35 mg/m^2Total
Hispanic or Latino001225
Not Hispanic or Latino5654424
Unknown or Not Reported100001
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Part A Dose Level 1: 15 mg/m^2Part A Dose Level 2: 20 mg/m^2Part A Dose Level 3: 25 mg/m^2Part A Dose Level 4: 35 mg/m^2Part A PK Dose Level 4: 35 mg/m^2Total
American Indian or Alaska Native000000
Asian010012
Native Hawaiian or Other Pacific Islander000000
Black or African American012036
White5335218
More than one race001001
Unknown or Not Reported110103
08

Study locations

20 sites
  • Children's Hospital of Alabama
    Birmingham, Alabama 35233, United States
  • Children's Hospital Los Angeles
    Los Angeles, California 90027, United States
  • Children's Hospital of Orange County
    Orange, California 92868, United States
  • UCSF Medical Center-Mission Bay
    San Francisco, California 94158, United States
  • Children's Hospital Colorado
    Aurora, Colorado 80045, United States
  • Children's National Medical Center
    Washington, District of Columbia 20010, United States
  • Children's Healthcare of Atlanta - Arthur M Blank Hospital
    Atlanta, Georgia 30329, United States
  • Lurie Children's Hospital-Chicago
    Chicago, Illinois 60611, United States
  • Riley Hospital for Children
    Indianapolis, Indiana 46202, United States
  • Dana-Farber Cancer Institute
    Boston, Massachusetts 02215, United States
  • C S Mott Children's Hospital
    Ann Arbor, Michigan 48109, United States
  • University of Minnesota/Masonic Cancer Center
    Minneapolis, Minnesota 55455, United States
  • Washington University School of Medicine
    Saint Louis, Missouri 63110, United States
  • NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
    New York, New York 10032, United States
  • Cincinnati Children's Hospital Medical Center
    Cincinnati, Ohio 45229, United States
  • Children's Hospital of Philadelphia
    Philadelphia, Pennsylvania 19104, United States
  • Children's Hospital of Pittsburgh of UPMC
    Pittsburgh, Pennsylvania 15224, United States
  • Saint Jude Children's Research Hospital
    Memphis, Tennessee 38105, United States
  • Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
    Houston, Texas 77030, United States
  • Seattle Children's Hospital
    Seattle, Washington 98105, United States
09

References and documents

Study documents

PDFs hosted by the registry, ClinicalTrials.gov.

10

Timeline

Tracking since Sep 25, 2026
ElapsedEstimatedEstimated, not yet reachedSimilar studies: half by the dot; the band is the middle halfHalf of similar studies reached it by the dot; the band is the middle half, from a quarter to three quarters

Ran from Jan 2018 to primary completion in Sep 2021, 44 months.

Results were first posted in Sep 2022, 11 months after primary completion.

Of 138 non-industry phase 1 interventional studies under Lymphoma, half reached primary completion within 64 months of starting (the median), counting those still running; a quarter within 39 and three quarters within 88. This study's 44 months is below that.

Counting every sponsor, half of 281 studies reached it within 53 months; a quarter within 34 and three quarters within 77.

How these figures are worked out, and which studies are left out of them.

Registered
Oct 11, 2017
First posted
Oct 26, 2017
StartActual
Jan 11, 2018
Primary completionActual
Sep 30, 2021
CompletionActual
Sep 30, 2024
Results first posted
Sep 23, 2022
Last update
Oct 22, 2024
What these dates mean
Start.
When the first participant enrolled; while estimated, when the study expects to open to recruitment.
Primary completion.
When the last participant was examined or treated to collect data for the study's main question, its primary outcome. A study that stopped early gives the date its data collection stopped.
Completion.
When the last participant's last visit took place, for every outcome, secondary ones and side effects included: the end of the study. Often later than primary completion, sometimes the same day.
Actual and Est.
Actual means the registry says the date has happened. Est. (estimated) is a date the sponsor plans or expects. It can still move, and the sponsor is expected to change it to actual once it has passed.
No changes since tracking began. The registry record was last updated on Oct 22, 2024, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT03323034
Responsible party
Sponsor
First posted
Oct 26, 2017
Start date
Jan 11, 2018
Primary completion
Sep 30, 2021
Completion
Sep 30, 2024
Results posted
Sep 23, 2022
Last update
Oct 22, 2024

Study contacts

Jennifer H Foster
principal investigator · Pediatric Early Phase Clinical Trial Network

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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Studies of the drugs tested here: Irinotecan · Pevonedistat · Temozolomide

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