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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT04023669


Additional trial details provided through ANZCTR are available at the end of this record.


Registration number
NCT04023669
Ethics application status
Date submitted
1/03/2020
Date registered
16/07/2019
Date last updated
10/03/2020

Titles & IDs
Public 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
Scientific 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
Secondary ID [1] 0 0
NCI-2019-04787
Secondary ID [2] 0 0
SJELIOT
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Brain Tumor 0 0
Brain Tumor, Recurrent 0 0
Brain Tumor, Refractory 0 0
Brain Tumor, Pediatric 0 0
Medulloblastoma 0 0
Medulloblastoma Recurrent 0 0
Medulloblastoma, Non-WNT/Non-SHH 0 0
Medulloblastoma, Non-WNT/Non-SHH, Group 3 0 0
Medulloblastoma, Non-WNT/Non-SHH, Group 4 0 0
Brain Cancer 0 0
CNS Cancer 0 0
CNS Tumor 0 0
CNS Neoplasm 0 0
Condition category
Condition code
Cancer 0 0 0 0
Brain
Cancer 0 0 0 0
Children's - Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Prexasertib
Treatment: Drugs - Cyclophosphamide
Treatment: Drugs - Gemcitabine
Other interventions - filgrastim
Other interventions - peg-filgrastim

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.
Note: Only if absolutely necessary, cyclophosphamide may be given on day 16 and prexasertib may be given on day 17.

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.
Note: Only if absolutely necessary, gemcitabine may be given on day 16 and prexasertib may be given on day 17.


Treatment: Drugs: Prexasertib
IV

Treatment: Drugs: Cyclophosphamide
IV

Treatment: Drugs: Gemcitabine
IV

Other interventions: filgrastim
Given subcutaneously (SQ). Alternatively, pegfilgrastim may be given.

Other interventions: peg-filgrastim
Given subcutaneously (SQ). Alternatively, filgrastim may be given.

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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).
Timepoint [1] 0 0
1 month after start of prexasertib and cyclophosphamide or gemcitabine treatment
Primary outcome [2] 0 0
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.
Timepoint [2] 0 0
Up to 2 years after start of prexasertib and cyclophosphamide or gemcitabine treatment
Primary outcome [3] 0 0
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.
Timepoint [3] 0 0
prexasertib and cyclophosphamide or gemcitabine treatment course 1 days 2 through 7
Primary outcome [4] 0 0
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.
Timepoint [4] 0 0
prexasertib and cyclophosphamide or gemcitabine treatment course 1 days 2 through 7
Secondary outcome [1] 0 0
Rate of objective response (complete or partial response) by stratum - 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.
Timepoint [1] 0 0
Up to 1 year after completion of prexasertib and cyclophosphamide or gemcitabine treatment
Secondary outcome [2] 0 0
Duration of objective response by stratum - 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.
Timepoint [2] 0 0
Up to 1 year after completion of prexasertib and cyclophosphamide or gemcitabine treatment
Secondary outcome [3] 0 0
Progression-free survival for patients treated with prexasertib and cyclophosphamide or gemcitabine - 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.
Timepoint [3] 0 0
Up to 3 years from diagnosis
Secondary outcome [4] 0 0
To characterize the area under the concentration-time curve (AUC0-24h) of cyclophosphamide. - Cyclophosphamide area under the curve (AUC0-24h) is estimated based on course 1, days 1 and 2 PK samples.
Timepoint [4] 0 0
prexasertib and cyclophosphamide treatment course 1, days 1 and 2
Secondary outcome [5] 0 0
To characterize the systemic clearance (CL) of cyclophosphamide. - Cyclophosphamide systemic clearance (CL) is estimated based on course 1, days 1 and 2 PK samples.
Timepoint [5] 0 0
prexasertib and cyclophosphamide treatment course 1, days 1 and 2
Secondary outcome [6] 0 0
To characterize the area under the concentration-time curve (AUC0-24h) of 4-hydroxy-cyclophosphamide. - 4-hydroxy-cyclophosphamide are under the curve AUC0-24h is estimated based on course 1, days 1 and 2 PK samples.
Timepoint [6] 0 0
prexasertib and cyclophosphamide treatment course 1, days 1 and 2
Secondary outcome [7] 0 0
To characterize the area under the concentration-time curve (AUC0-24h) of carboxyethylphosphoramide mustard. - Carboxyethylphosphoramide mustard area under the curve (AUC0-24h) is estimated based on course 1, days 1 and 2. PK samples.
Timepoint [7] 0 0
prexasertib and cyclophosphamide treatment course 1, days 1 and 2
Secondary outcome [8] 0 0
To characterize the area under the concentration-time curve (AUC0-4h) of gemcitabine. - Gemcitabine area under the curve (AUC0-4h) is estimated based on course 1, day 1 PK samples.
Timepoint [8] 0 0
prexasertib and gemcitabine treatment course 1, day 1.
Secondary outcome [9] 0 0
To characterize the systemic clearance (CL) of gemcitabine. - Gemcitabine systemic clearance (CL) is estimated based on course 1, day 1 PK samples.
Timepoint [9] 0 0
prexasertib and cyclophosphamide treatment course 1, day 1
Secondary outcome [10] 0 0
To characterize the area under the concentration-time curve (AUC0-4h) of gemcitabine triphosphate (only at St. Jude Children's Research Hospital). - Gemcitabine triphosphate are under the curve AUC0-4h is estimated based on course 1, day 1 PK samples.
Timepoint [10] 0 0
prexasertib and cyclophosphamide treatment course 1, day 1

Eligibility
Key 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.
Minimum age
1 Year
Maximum age
24 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.

-- 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 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.

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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Tennessee

Funding & Sponsors
Primary sponsor type
Other
Name
St. Jude Children's Research Hospital
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Eli Lilly and Company
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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).
Trial website
https://clinicaltrials.gov/show/NCT04023669
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Giles W. Robinson, MD
Address 0 0
St. Jude Children's Research Hospital
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Tabatha E. Doyle, RN
Address 0 0
Country 0 0
Phone 0 0
901-595-2544
Fax 0 0
Email 0 0
tabatha.doyle@stjude.org
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT04023669

Additional trial details provided through ANZCTR
Accrual to date
1
Recruiting in Australia
Recruitment state(s)
WA
Funding & Sponsors
Primary sponsor
Primary sponsor name
Primary sponsor address
Primary sponsor country
Secondary sponsor category [1] 28
Other Collaborative groups
Name [1] 28
ANZCHOG
Address [1] 28
27-31 Wright Street, Clayton VIC 3168
Country [1] 28
Australia
Ethics approval
Ethics application status
 
Public notes
Perth Children's Hospital

Contacts
Principal investigator
Title 141 0
Dr
Name 141 0
Nick Gottardo
Address 141 0
15 Hospital Ave, Nedlands WA 6009
Country 141 0
Australia
Phone 141 0
+618 6456 0241
Fax 141 0
+618 6456 0241
Email 141 0
Nick.Gottardo@health.wa.gov.au
Contact person for public queries
Title 142 0
Mrs
Name 142 0
Robyn Strong
Address 142 0
27-31 Wright Street, Clayton VIC 3168
Country 142 0
Australia
Phone 142 0
+613 8572 2684
Fax 142 0
+613 9902 4810
Email 142 0
Robyn.strong@hudson.org.au
Contact person for scientific queries
Title 143 0
Dr
Name 143 0
Nick Gottardo
Address 143 0
15 Hospital Ave, Nedlands WA 6009
Country 143 0
Australia
Phone 143 0
+618 6456 0241
Fax 143 0
+618 6456 0241
Email 143 0
Nick.Gottardo@health.wa.gov.au