Evaluation of LY2606368 Therapy in Combination With Cyclophosphamide or Gemcitabine for Children and Adolescents With Refractory or Recurrent Group 3/Group 4 or SHH Medulloblastoma Brain Tumors

NCT04023669 | Completed Phase 1 FDA Drug

• 2 other identifiers: SJELIOTNCI-2019-04787
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

Brief Summary

SJELIOT is a phase 1 trial that aims to explore the combination of prexasertib with established DNA-damaging agents used in medulloblastoma to evaluate tolerance and pharmacokinetics in recurrent or refractory disease. Additionally, a small expansion cohort will be incorporated into the trial at the combination MTD/RP2D (maximum tolerated dose/recommended phase two dose) to detect a preliminary efficacy signal. Stratum A: Prexasertib and Cyclophosphamide Primary Objectives

• To determine the safety and tolerability and estimate the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of combination treatment with prexasertib and cyclophosphamide in participants with recurrent/refractory Group 3 and Group 4 medulloblastoma and recurrent/refractory sonic hedgehog (SHH) medulloblastoma.
• To characterize the pharmacokinetics of prexasertib in combination with cyclophosphamide. Secondary Objectives
• To estimate the rate and duration of objective response and progression free survival (PFS) associated with prexasertib and cyclophosphamide treatment in this patient population.
• To characterize the pharmacokinetics of cyclophosphamide and metabolites. Stratum B: Prexasertib and Gemcitabine Primary Objectives
• To determine the safety and tolerability and estimate the MTD/RP2D of combination treatment with prexasertib and gemcitabine in participants with recurrent/refractory Group 3 and Group 4 medulloblastoma.
• To characterize the pharmacokinetics of prexasertib in combination with gemcitabine. Secondary Objectives
• To estimate the rate and duration of objective response and PFS associated with prexasertib and gemcitabine treatment in this patient population.
• To characterize the pharmacokinetics of gemcitabine and gemcitabine triphosphate (only at St. Jude Children's Research Hospital).

Conditions

Brain Tumor; Brain Tumor, Recurrent; Brain Tumor, Refractory; Brain Tumor, Pediatric; Medulloblastoma; Medulloblastoma Recurrent; Medulloblastoma, Non-WNT/Non-SHH; Medulloblastoma, Non-WNT/Non-SHH, Group 3; Medulloblastoma, Non-WNT/Non-SHH, Group 4; Brain Cancer; CNS Cancer; CNS Tumor; CNS Neoplasm

Keywords

Brain Tumors in Adolescents; Brain Tumors in Children; Brain Tumors in Young Adults; CHK1/2 Inhibitor; Combination therapy; Indeterminate molecular subgroup; Medulloblastoma, Group 3; Medulloblastoma, Group 4; Medulloblastoma, G3/G4; Progressive brain tumor; Recurrent brain tumor; Refractory brain tumor; Sonic hedgehog; SHH Medulloblastoma; St. Jude Brain Tumor Studies; St. Jude Studies; St. Jude Treatment; Molecular; Molecular therapy

Outcome Measures

Primary Outcomes (4)

• Estimate the Maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D) of each doublet by stratum

  The maximum tolerated dose (MTD) is empirically defined as the highest dose level at which six patients have been treated with at most one patient experiencing a dose-limiting toxicity (DLT) and the next higher dose level has been determined to be too toxic. The MTD estimate will not be available if the lowest dose level studied is too toxic or the highest dose level studied is considered safe. In the latter case, the highest studied safe dose may be considered as the recommended phase 2 dose (RP2D). The MTD estimation will be limited to evaluable patients and toxicity assessments from course 1 (28 days).

  1 month after start of prexasertib and cyclophosphamide or gemcitabine treatment

• To determine the safety and tolerability of combination treatment with prexasertib and cyclophosphamide or gemcitabine.

  Incidence of adverse event data at least possibly related to treatment will be summarized in tables by treatment combination and by dose level.

  Up to 2 years after start of prexasertib and cyclophosphamide or gemcitabine treatment

• To characterize the area under the concentration-time curve (AUC0-∞) of prexasertib in combination with cyclophosphamide or gemcitabine.

  Prexasertib area under the curve (AUC0-∞) is estimated based on course 1, days 2 through 7 PK samples.

  prexasertib and cyclophosphamide or gemcitabine treatment course 1 days 2 through 7

• To characterize the systemic clearance (CL) of prexasertib in combination with cyclophosphamide or gemcitabine.

  Prexasertib systemic clearance (CL) is estimated based on course 1, days 2 through 7 pharmacokinetic samples.

  prexasertib and cyclophosphamide or gemcitabine treatment course 1 days 2 through 7

Secondary Outcomes (10)

• Rate of objective response (complete or partial response) by stratum

  Up to 1 year after completion of prexasertib and cyclophosphamide or gemcitabine treatment

• Duration of objective response by stratum

  Up to 1 year after completion of prexasertib and cyclophosphamide or gemcitabine treatment

• Progression-free survival for patients treated with prexasertib and cyclophosphamide or gemcitabine

  Up to 3 years from diagnosis

• To characterize the area under the concentration-time curve (AUC0-24h) of cyclophosphamide.

  prexasertib and cyclophosphamide treatment course 1, days 1 and 2

• To characterize the systemic clearance (CL) of cyclophosphamide.

  prexasertib and cyclophosphamide treatment course 1, days 1 and 2

Study Arms (2)

A: prexasertib + cyclophosphamide

EXPERIMENTAL

Stratum A: Participants receive combination treatment with cyclophosphamide given intravenously (IV) on days 1 and 15 and prexasertib given intravenously (IV) on days 2 and 16. Cycles repeat every 28 days for up to 24 months (26 cycles) in the absence of disease progression or unacceptable toxicity. They may also receive growth therapy support with filgrastim or peg-filgrastim. Note: Only if absolutely necessary, cyclophosphamide may be given on day 16 and prexasertib may be given on day 17.

Drug: Prexasertib; Drug: Cyclophosphamide; Biological: filgrastim; Biological: peg-filgrastim

B: prexasertib + gemcitabine

EXPERIMENTAL

Stratum B: Participants receive combination treatment with gemcitabine given intravenously (IV) on days 1 and 15 and prexasertib given intravenously (IV) on days 2 and 16. Cycles repeat every 28 days for up to 24 months (26 cycles) in the absence of disease progression or unacceptable toxicity. They may also receive growth therapy support with filgrastim or peg-filgrastim. Note: Only if absolutely necessary, gemcitabine may be given on day 16 and prexasertib may be given on day 17.

Drug: Prexasertib; Drug: Gemcitabine; Biological: filgrastim; Biological: peg-filgrastim

Interventions

Prexasertib DRUG

IV

Also known as: LY2606368

A: prexasertib + cyclophosphamide; B: prexasertib + gemcitabine

Cyclophosphamide DRUG

IV

Also known as: Cytoxan

A: prexasertib + cyclophosphamide

Gemcitabine DRUG

IV

Also known as: 2'-deoxy-2',2' difluorocytidine monohydrochloride, LY18801, Gemzar®

B: prexasertib + gemcitabine

filgrastim BIOLOGICAL

Given subcutaneously (SQ). Alternatively, pegfilgrastim may be given.

Also known as: G-CSF

A: prexasertib + cyclophosphamide; B: prexasertib + gemcitabine

peg-filgrastim BIOLOGICAL

Given subcutaneously (SQ). Alternatively, filgrastim may be given.

Also known as: pegylated filgrastim, PEG filgrastim, Neulasta®

A: prexasertib + cyclophosphamide; B: prexasertib + gemcitabine

Eligibility Criteria

• Age: 1 Year - 24 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Participants with recurrent, refractory, or progressive medulloblastoma.
• Age ≥ 1 year and \< 25 years at the time of screening.
• Participants and/or guardian can understand and is willing to sign a written informed consent document according to institutional guidelines.

You may not qualify if:

• Previous exposure to any CHK1 inhibitor.
• Participants with a history of clinically significant, uncontrolled heart disease and/or repolarization abnormalities.
• Participants with any history of QTc prolongation (i.e. QTc interval of \> 480 msec).
• Participant must be ≥1 year and \<25 years of age at time of screening.
• Participant must have recurrent, progressive or refractory Group 3/Group 4 or SHH medulloblastoma (per central pathology confirmation of primary tissue and/or relapsed tissue). Central pathology review previously completed at St. Jude Children's Research Hospital using equivalent methods can be used for enrollment. Note: Group 3/Group 4 may be referred to as Non-WNT Non-SHH (NWNS) in pathology reports. Medulloblastoma patients with indeterminate molecular subgroup after central pathology review are eligible for enrollment on stratum A.
• Participant must have measurable or evaluable disease as defined in the protocol.
• Participant must have received their last dose of myelosuppressive anticancer chemotherapy at least 3 weeks prior to study enrollment.
• Participants must have had their last fraction of radiation (including CSI) at least 4 weeks prior to study enrollment. Participants who received radiation therapy for palliation must have had their last fraction of radiation at least 2 weeks prior to study enrollment.
• \-- Note: Participants must have relapsed with recurrent, progressive or refractory disease after any prior radiation therapy that is not considered palliative. Palliative radiation therapy is defined as local small port RT to alleviate and/or palliate symptoms. (CSI, whole brain RT, large field/port RT, or large field/port multilevel spinal RT will not be considered palliative at any dose.)
• Participant who are receiving corticosteroids must be on a stable or decreasing dose for at least 1 week prior to enrollment with no plans for escalation.
• Participant must have a Lansky (≤ 16 years) or Karnofsky (\> 16 years) performance score of ≥50 and, in the opinion of the investigator, a minimum life expectancy of at least 6 weeks.
• \-- Note: Participants 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.
• Participant must have adequate bone marrow and organ function as defined as:
• ANC ≥ 1.0 x 10\^9/L without growth factor support within 7 days
• Platelet count ≥ 75x 10\^9/L without support of a platelet transfusion within 7 days

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead
• Eli Lilly and Company: collaborator

Study Sites (1)

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Related Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude
• St. Jude Brain Tumor Studies

MeSH Terms

Conditions

Brain Neoplasms; Medulloblastoma; Central Nervous System Neoplasms; Microphthalmia, Isolated, with Coloboma 5

Interventions

prexasertib; Cyclophosphamide; Gemcitabine; Filgrastim; Granulocyte Colony-Stimulating Factor; pegfilgrastim

Condition Hierarchy (Ancestors)

Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neuroectodermal Tumors, Primitive; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Study Officials

• Giles W. Robinson, MD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 11, 2019
• First Posted: July 17, 2019
• Study Start: August 8, 2019
• Primary Completion: May 1, 2023
• Study Completion: January 13, 2025
• Last Updated: February 7, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data will be made available at the time of article publication.
• Access Criteria: Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.

Locations

US (1)