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

NCT03323034 | Completed Phase 1 Results DMC FDA Drug

• 3 other identifiers: ADVL1615NCI-2017-01229UM1CA097452
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 20

Brief 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.

Conditions

Recurrent Lymphoma; Recurrent Malignant Solid Neoplasm; Recurrent Primary Central Nervous System Neoplasm; Refractory Lymphoma; Refractory Malignant Solid Neoplasm; Refractory Primary Central Nervous System Neoplasm

Outcome Measures

Primary Outcomes (7)

• 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.

  Up to 28 days

• 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.

  Up to 3 years 8 months

• 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.

  Up to 10 days

• 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.

  Up to 10 days

• 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.

  Up to 10 days

• 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.

  Up to 10 days

• 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.

  Up to 10 days

Secondary Outcomes (1)

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

  Up to 4 years

Study Arms (1)

Treatment (pevonedistat, temozolomide, irinotecan)

EXPERIMENTAL

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

Irinotecan DRUG

Given IV

Treatment (pevonedistat, temozolomide, irinotecan)

Pevonedistat DRUG

Given IV

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

Treatment (pevonedistat, temozolomide, irinotecan)

Temozolomide DRUG

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

Treatment (pevonedistat, temozolomide, irinotecan)

Eligibility Criteria

• Age: 6 Months - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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
• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Children's Oncology Group: lead
• National Cancer Institute (NCI): collaborator

Study Sites (20)

Children's Hospital of Alabama

Birmingham, Alabama, 35233, United States

Location

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Children's Hospital of Orange County

Orange, California, 92868, United States

Location

UCSF Medical Center-Mission Bay

San Francisco, California, 94158, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Children's Healthcare of Atlanta - Arthur M Blank Hospital

Atlanta, Georgia, 30329, United States

Location

Lurie Children's Hospital-Chicago

Chicago, Illinois, 60611, United States

Location

Riley Hospital for Children

Indianapolis, Indiana, 46202, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

C S Mott Children's Hospital

Ann Arbor, Michigan, 48109, United States

Location

University of Minnesota/Masonic Cancer Center

Minneapolis, Minnesota, 55455, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

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

New York, New York, 10032, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, 15224, United States

Location

Saint Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center

Houston, Texas, 77030, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

MeSH Terms

Conditions

Lymphoma; Central Nervous System Neoplasms

Interventions

Irinotecan; pevonedistat; Temozolomide

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Nervous System Neoplasms; Neoplasms by Site; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Camptothecin; Alkaloids; Heterocyclic Compounds; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Results Reporting Coordinator
• Organization: Children's Oncology Group

resultsreportingcoordinator@childrensoncologygroup.org

16264470064

Study Officials

• Jennifer H Foster

  Pediatric Early Phase Clinical Trial Network

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 11, 2017
• First Posted: October 26, 2017
• Study Start: January 11, 2018
• Primary Completion: September 30, 2021
• Study Completion: September 30, 2024
• Last Updated: October 22, 2024
• Results First Posted: September 23, 2022

Record last verified: 2024-10

Locations

US (20)