Clinical Trials /

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

Description:

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).

Related Conditions:
  • Medulloblastoma
  • Medulloblastoma, Non-WNT/Non-SHH
  • Medulloblastoma, SHH-Activated
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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
  • 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

Clinical Trial IDs

  • ORG STUDY ID: SJELIOT
  • SECONDARY ID: NCI-2019-04787
  • NCT ID: NCT04023669

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

Interventions

DrugSynonymsArms
PrexasertibLY2606368A: prexasertib + cyclophosphamide
CyclophosphamideCytoxanA: prexasertib + cyclophosphamide
Gemcitabine2'-deoxy-2',2' difluorocytidine monohydrochloride, LY18801, Gemzar®B: prexasertib + gemcitabine
filgrastimG-CSFA: prexasertib + cyclophosphamide
peg-filgrastimpegylated filgrastim, PEG filgrastim, Neulasta®A: prexasertib + cyclophosphamide

Purpose

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).

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.
    

Trial Arms

NameTypeDescriptionInterventions
A: prexasertib + cyclophosphamideExperimentalStratum 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.
  • Prexasertib
  • Cyclophosphamide
  • filgrastim
  • peg-filgrastim
B: prexasertib + gemcitabineExperimentalStratum 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.
  • Prexasertib
  • Gemcitabine
  • filgrastim
  • peg-filgrastim

Eligibility 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.
      
Maximum Eligible Age:24 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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).

Secondary Outcome Measures

Measure: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
Safety Issue:
Description: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.
Measure:Duration of objective response by stratum
Time Frame:Up to 1 year after completion of prexasertib and cyclophosphamide or gemcitabine treatment
Safety Issue:
Description: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.
Measure:Progression-free survival for patients treated with prexasertib and cyclophosphamide or gemcitabine
Time Frame:Up to 3 years from diagnosis
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:Cyclophosphamide area under the curve (AUC0-24h) is estimated based on course 1, days 1 and 2 PK samples.
Measure:To characterize the systemic clearance (CL) of cyclophosphamide.
Time Frame:prexasertib and cyclophosphamide treatment course 1, days 1 and 2
Safety Issue:
Description:Cyclophosphamide systemic clearance (CL) is estimated based on course 1, days 1 and 2 PK samples.
Measure: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
Safety Issue:
Description:4-hydroxy-cyclophosphamide are under the curve AUC0-24h is estimated based on course 1, days 1 and 2 PK samples.
Measure: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
Safety Issue:
Description:Carboxyethylphosphoramide mustard area under the curve (AUC0-24h) is estimated based on course 1, days 1 and 2. PK samples.
Measure:To characterize the area under the concentration-time curve (AUC0-4h) of gemcitabine.
Time Frame:prexasertib and gemcitabine treatment course 1, day 1.
Safety Issue:
Description:Gemcitabine area under the curve (AUC0-4h) is estimated based on course 1, day 1 PK samples.
Measure:To characterize the systemic clearance (CL) of gemcitabine.
Time Frame:prexasertib and cyclophosphamide treatment course 1, day 1
Safety Issue:
Description:Gemcitabine systemic clearance (CL) is estimated based on course 1, day 1 PK samples.
Measure: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
Safety Issue:
Description:Gemcitabine triphosphate are under the curve AUC0-4h is estimated based on course 1, day 1 PK samples.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:St. Jude Children's Research Hospital

Trial 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

Last Updated

October 11, 2019