Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 1 of 1 for:    medulloblastoma CHK inhibitor
Previous Study | Return to List | Next Study

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04023669
Recruitment Status : Recruiting
First Posted : July 17, 2019
Last Update Posted : October 15, 2019
Sponsor:
Collaborator:
Eli Lilly and Company
Information provided by (Responsible Party):
St. Jude Children's Research Hospital

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).

Condition or disease Intervention/treatment Phase
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 Drug: Prexasertib Drug: Cyclophosphamide Drug: Gemcitabine Biological: filgrastim Biological: peg-filgrastim Phase 1

Detailed Description:

Participants will be stratified by the biological characteristics of their tumor to one of two treatment strata:

STRATUM A

  • Combination Treatment: prexasertib and cyclophosphamide
  • Patient population: Participants with recurrent/refractory Group 3 and Group 4 (G3/G4) medulloblastoma, recurrent/refractory sonic hedgehog (SHH) medulloblastoma and medulloblastoma participants with Indeterminate molecular subgroup

STRATUM B

  • Combination Treatment: prexasertib and gemcitabine
  • Patient population: Participants with recurrent/refractory Group 3 and Group 4 medulloblastoma

Participants with a diagnosis of G3/G4 medulloblastoma who qualify for both treatment strata will be assigned per slot availability as well as institutional PI preference. If slots are available in both stratum A and stratum B, patients will be assigned to the dose level nearest completion.

The Rolling 6 design will be used separately in each stratum to estimate the maximum tolerated dose (MTD) or recommended phase two dose (RP2D). Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in the absence of disease progression or unacceptable toxicity.

Participants will receive doublet therapy in cycles of 28 days. The dose-limiting toxicity (DLT)-evaluation period will consist of the first cycle (i.e. first 5 weeks of therapy). Participants will be evaluated at least once a week during the DLT-evaluation period and at regular intervals thereafter. Standard tests (i.e. physical exams, blood tests, and disease evaluations) will be undertaken at regular intervals. Research-associated evaluations (i.e. pharmacokinetic studies, etc.) will also be carried out during therapy. Treatment may be continued for up to 2 years in the absence of disease progression or unacceptable toxicity.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: St. Jude ELIOT: Phase 1 Evaluation of LY2606368, a Molecularly-Targeted CHK1/2 Inhibitor Therapy, in Combination With Cyclophosphamide or Gemcitabine for Children and Adolescents With Refractory or Recurrent Group 3/Group 4 or SHH Medulloblastoma Brain Tumors
Actual Study Start Date : August 8, 2019
Estimated Primary Completion Date : June 2025
Estimated Study Completion Date : June 2026


Arm Intervention/treatment
Experimental: A: prexasertib + cyclophosphamide
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.
Drug: Prexasertib
IV
Other Name: LY2606368

Drug: Cyclophosphamide
IV
Other Name: Cytoxan

Biological: filgrastim
Given subcutaneously (SQ). Alternatively, pegfilgrastim may be given.
Other Name: G-CSF

Biological: peg-filgrastim
Given subcutaneously (SQ). Alternatively, filgrastim may be given.
Other Names:
  • pegylated filgrastim
  • PEG filgrastim
  • Neulasta®

Experimental: B: prexasertib + gemcitabine
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.
Drug: Prexasertib
IV
Other Name: LY2606368

Drug: Gemcitabine
IV
Other Names:
  • 2'-deoxy-2',2' difluorocytidine monohydrochloride
  • LY18801
  • Gemzar®

Biological: filgrastim
Given subcutaneously (SQ). Alternatively, pegfilgrastim may be given.
Other Name: G-CSF

Biological: peg-filgrastim
Given subcutaneously (SQ). Alternatively, filgrastim may be given.
Other Names:
  • pegylated filgrastim
  • PEG filgrastim
  • Neulasta®




Primary Outcome Measures :
  1. Estimate the Maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D) of each doublet by stratum [ Time Frame: 1 month after start of prexasertib and cyclophosphamide or gemcitabine treatment ]
    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).

  2. To determine the safety and tolerability of combination treatment with prexasertib and cyclophosphamide or gemcitabine. [ Time Frame: Up to 2 years after start of prexasertib and cyclophosphamide or gemcitabine treatment ]
    Incidence of adverse event data at least possibly related to treatment will be summarized in tables by treatment combination and by dose level.

  3. To characterize the area under the concentration-time curve (AUC0-∞) of prexasertib in combination with cyclophosphamide or gemcitabine. [ Time Frame: prexasertib and cyclophosphamide or gemcitabine treatment course 1 days 2 through 7 ]
    Prexasertib area under the curve (AUC0-∞) is estimated based on course 1, days 2 through 7 PK samples.

  4. To characterize the systemic clearance (CL) of prexasertib in combination with cyclophosphamide or gemcitabine. [ Time Frame: prexasertib and cyclophosphamide or gemcitabine treatment course 1 days 2 through 7 ]
    Prexasertib systemic clearance (CL) is estimated based on course 1, days 2 through 7 pharmacokinetic samples.


Secondary Outcome Measures :
  1. Rate of objective response (complete or partial response) by stratum [ Time Frame: Up to 1 year after completion of prexasertib and cyclophosphamide or gemcitabine treatment ]
    The incidence of objective responses (complete or partial response) observed during prexasertib and cyclophosphamide or gemcitabine treatment or during follow-up prior to progression or initiation of alternative cancer therapy.

  2. Duration of objective response by stratum [ Time Frame: Up to 1 year after completion of prexasertib and cyclophosphamide or gemcitabine treatment ]
    The duration of objective response is measured from the time the measurement criteria are met for complete response (CR) or partial response (PR), whichever is recorded first, until the first day on which recurrent or progressive disease is objectively documented.

  3. Progression-free survival for patients treated with prexasertib and cyclophosphamide or gemcitabine [ Time Frame: Up to 3 years from diagnosis ]
    Progression-free survival (PFS) is defined from the time of treatment initiation until disease progression or until death from any cause (whichever is earlier) for patients who experience an event and until the date of last follow-up for those who are alive and progression free at the time of analysis. PFS is estimated by Kaplan-Meier approach and median PFS is reported.

  4. To characterize the area under the concentration-time curve (AUC0-24h) of cyclophosphamide. [ Time Frame: prexasertib and cyclophosphamide treatment course 1, days 1 and 2 ]
    Cyclophosphamide area under the curve (AUC0-24h) is estimated based on course 1, days 1 and 2 PK samples.

  5. To characterize the systemic clearance (CL) of cyclophosphamide. [ Time Frame: prexasertib and cyclophosphamide treatment course 1, days 1 and 2 ]
    Cyclophosphamide systemic clearance (CL) is estimated based on course 1, days 1 and 2 PK samples.

  6. To characterize the area under the concentration-time curve (AUC0-24h) of 4-hydroxy-cyclophosphamide. [ Time Frame: prexasertib and cyclophosphamide treatment course 1, days 1 and 2 ]
    4-hydroxy-cyclophosphamide are under the curve AUC0-24h is estimated based on course 1, days 1 and 2 PK samples.

  7. To characterize the area under the concentration-time curve (AUC0-24h) of carboxyethylphosphoramide mustard. [ Time Frame: prexasertib and cyclophosphamide treatment course 1, days 1 and 2 ]
    Carboxyethylphosphoramide mustard area under the curve (AUC0-24h) is estimated based on course 1, days 1 and 2. PK samples.

  8. To characterize the area under the concentration-time curve (AUC0-4h) of gemcitabine. [ Time Frame: prexasertib and gemcitabine treatment course 1, day 1. ]
    Gemcitabine area under the curve (AUC0-4h) is estimated based on course 1, day 1 PK samples.

  9. To characterize the systemic clearance (CL) of gemcitabine. [ Time Frame: prexasertib and cyclophosphamide treatment course 1, day 1 ]
    Gemcitabine systemic clearance (CL) is estimated based on course 1, day 1 PK samples.

  10. To characterize the area under the concentration-time curve (AUC0-4h) of gemcitabine triphosphate (only at St. Jude Children's Research Hospital). [ Time Frame: prexasertib and cyclophosphamide treatment course 1, day 1 ]
    Gemcitabine triphosphate are under the curve AUC0-4h is estimated based on course 1, day 1 PK samples.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   1 Year to 24 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria: Screening Phase

  • 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.

Exclusion Criteria: Screening Phase

  • 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).

Inclusion Criteria: Strata A and B

  • 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 or Hopp Children's Cancer Center Heidelberg (KiTZ) 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.
  • 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. (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 109/L without growth factor support within 7 days
    • Platelet count ≥ 75x 109/L without support of a platelet transfusion within 7 days
    • Hemoglobin ≥8.0 g/dL without support of a blood transfusion within 7 days
    • Potassium, total calcium (corrected for serum albumin), magnesium, sodium and phosphorus within institutional normal limits or corrected to within normal limits with supplements before first dose of study medication
    • Serum creatinine ≤ the maximum serum creatinine based on age/gender: Age: 1 to < 2 years; maximum serum creatinine (mg/dL): 0.6 (male, female); Age: 2 to < 6 years; maximum serum creatinine (mg/dL): 0.8 (male, female); Age: 6 to < 10 years; maximum serum creatinine (mg/dL): 1 (male, female); Age: 10 to < 13 years; maximum serum creatinine (mg/dL): 1.2 (male, female); Age: 13 to < 16 years; maximum serum creatinine (mg/dL): 1.5 (male), 1.4 (female); Age :≥ 16 years; maximum serum creatinine (mg/dL): 1.7 (male), 1.4 (female).
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN. For the purposes of this study the ULN of ALT and AST is 45 U/L.
    • Total bilirubin ≤ ULN; or if > ULN then direct bilirubin ≤ 1.5 x ULN
  • Female participants of childbearing age must have a negative pregnancy test at the time of enrollment.
  • Participants of childbearing or child fathering potential must be willing to use medically acceptable form of birth control during treatment and for 16 weeks after stopping treatment.
  • Participants and/or guardian have the ability to understand and the willingness to sign a written informed consent document according to institutional guidelines.

Exclusion Criteria: Strata A and B

  • Participant who is receiving any other investigational agents.
  • Participants with other clinically significant medical disorders (i.e. serious infections or significant cardiac, pulmonary, hepatic, psychiatric, or other organ dysfunction) that could compromise their ability to tolerate protocol therapy or would interfere with the study procedures or results.
  • Participant with a history of clinically significant, uncontrolled heart disease and/or repolarization abnormalities as documented by a standard 12-lead ECG.
  • Shortening fraction of <27% by ECHO or ejection fraction of <50% by gated radionuclide study.
  • Prior history of QTc prolongation or QTc interval of > 480 msec.
  • Female participants who are breastfeeding a child.
  • Participants are excluded if unable to comply with guidelines listed in appendix I.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04023669


Contacts
Layout table for location contacts
Contact: Tabatha E. Doyle, RN 901-595-2544 tabatha.doyle@stjude.org

Locations
Layout table for location information
United States, Tennessee
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Tabatha E. Doyle, RN    901-595-2544    tabatha.doyle@stjude.org   
Principal Investigator: Giles W. Robinson, MD         
Sponsors and Collaborators
St. Jude Children's Research Hospital
Eli Lilly and Company
Investigators
Layout table for investigator information
Principal Investigator: Giles W. Robinson, MD St. Jude Children's Research Hospital

Additional Information:
Layout table for additonal information
Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT04023669     History of Changes
Other Study ID Numbers: SJELIOT
NCI-2019-04787 ( Registry Identifier: NCI Clinical Trial Registration Program )
First Posted: July 17, 2019    Key Record Dates
Last Update Posted: October 15, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (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.

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by St. Jude Children's Research Hospital:
CHK1/2 Inhibitor
Medulloblastoma, Group 3
Medulloblastoma, Group 4
Medulloblastoma, G3/G4
SHH Medulloblastoma
Brain Tumors in Adolescents
Brain Tumors in Children
Brain Tumors in Young Adults
Combination therapy
Indeterminate molecular subgroup
Progressive brain tumor
Recurrent brain tumor
Refractory brain tumor
Sonic hedgehog
St. Jude Brain Tumor Studies
St. Jude Studies
St. Jude Treatment
Molecular
Molecular therapy
Additional relevant MeSH terms:
Layout table for MeSH terms
Medulloblastoma
Enzyme Inhibitors
Brain Neoplasms
Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
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
Gemcitabine
Cyclophosphamide
Lenograstim
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs