| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| This trial studies the side effects and best dose of pevonedistat when given together with irinotecan and temozolomide in treating patients with solid tumors or lymphoma that have come back after a period of improvement or that do not respond to treatment. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Drugs used in chemotherapy work in different ways to stop cancer growth. Giving pevonedistat, irinotecan hydrochloride, and temozolomide together may work better in treating solid tumors or lymphoma. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049516 |
| E.1.2 | Term | Malignant tumor |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
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. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 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
- Patients 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
- 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
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) >= 50 mL/min/1.73 m^2 or a serum creatinine based on age/gender
- 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 |
|
| E.4 | Principal 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 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:
- 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
- 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Maximum tolerated dose (MTD) and/or RP2D of pevonedistat [Time frame: Up to 28 days]
2. Incidence of adverse events
3. Pharmacokinetics of pevonedistat [ Time Frame: Pre-dose, end of infusion, 1, 2, 4, 6-8, and 24 hours post-dose infusion on days 1, 8, and 10 of cycle 1 For patients >/= 10 kg; for patients < 10 kg: pre-dose, end of infusion 2, 6-8, and 24 hours post-dose infusion on days 1, 8, and 10 of cycle 1 ] On day 10 samples are collected only at pre-dose. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Multiple time points occurring as stated in Section E.5.1 |
|
| E.5.2 | Secondary end point(s) |
1. Anti-tumor activity of pevonedistat [ Time Frame: Up to 4 years ]
2. Biologic activity of pevonedistat [ Time Frame: Up to 4 years ]
3. Disease response [ Time Frame: Up to 4 years ] |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Multiple time points occurring as stated in Section E.5.2 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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