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).
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 until day 1 criteria of cycle 2 has been met. 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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
21
IV
IV
IV
Given subcutaneously (SQ). Alternatively, pegfilgrastim may be given.
Given subcutaneously (SQ). Alternatively, filgrastim may be given.
St. Jude Children's Research Hospital
Memphis, Tennessee, United States
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).
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: prexasertib and cyclophosphamide or gemcitabine treatment course 1 days 2 through 7
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.
Time frame: Up to 1 year after completion of prexasertib and cyclophosphamide or gemcitabine treatment
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.
Time frame: 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
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.
Time frame: Up to 3 years from diagnosis
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.
Time frame: prexasertib and cyclophosphamide treatment course 1, days 1 and 2
To characterize the systemic clearance (CL) of cyclophosphamide.
Cyclophosphamide systemic clearance (CL) is estimated based on course 1, days 1 and 2 PK samples.
Time frame: prexasertib and cyclophosphamide treatment course 1, days 1 and 2
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.
Time frame: prexasertib and cyclophosphamide treatment course 1, days 1 and 2
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.
Time frame: prexasertib and cyclophosphamide treatment course 1, days 1 and 2
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.
Time frame: prexasertib and gemcitabine treatment course 1, day 1.
To characterize the systemic clearance (CL) of gemcitabine.
Gemcitabine systemic clearance (CL) is estimated based on course 1, day 1 PK samples.
Time frame: prexasertib and cyclophosphamide treatment course 1, day 1
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.
Time frame: prexasertib and cyclophosphamide treatment course 1, day 1
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.