A Phase 1 Study of Pevonedistat (MLN4924) a Cullin Ligase Inhibitor in Combination With Temozolomide and Irinotecan in Pediatric Patients With Recurrent or Refractory Solid Tumors

J
James Croop, MD, PhD

Primary Investigator

Overview

This phase I trial studies the side effects and best dose of pevonedistat when giving together with irinotecan hydrochloride 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.

Description

The purpose of this study is 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 hydrochloride (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 day 1 alone and on days 8, 10 and 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; to define and describe the toxicities of pevonedistat administered on this schedule; and to characterize the pharmacokinetics of pevonedistat in children with recurrent or refractory cancer.

Eligibility

You may be eligible for this study if you meet the following criteria:

  • Conditions:
    Pediatric Cancer,Solid Tumor,Recurrent Central Nervous System Neoplasm,Recurrent Lymphoma,Recurrent Malignant Solid Neoplasm,Refractory Central Nervous System Neoplasm,Refractory Lymphoma,Refractory Malignant Solid Neoplasm
  • Age: Between 1 Years - 21 Years
  • Gender: All

Inclusion Criteria
Patients with recurrent or refractory solid tumors, including CNS tumors and lymphoma, 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
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 == 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. Neulasta) 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)
Patients must not have received prior exposure to pevonedistat; patients with prior exposure to irinotecan or temozolomide are eligible
Exclusion Criteria
Pregnant or breast-feeding women will not be entered on this study; 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 blood pressure > 99th percentile) are not eligible
Patients with known cardiopulmonary disease 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 or moderate inhibitors and/or inducers of CYP3A4 within 14 days prior to enrollment are not eligible; while on study, the following BCRP inhibitors (cyclosporine, eltrombopag, gefitinib) should be avoided if possible, and concomitant use of UGT1A1 inhibitors, such as 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
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

Additional Information:
Participants will not be paid for their participation.

Updated on 20 Nov 2022. Study ID: 1712549832 (PHO-CROOP-COG-ADVL1615)

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