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
- Conditions
- Interventions
- Registration Number
- NCT04023669
- Lead Sponsor
- 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 ph...
- 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
...
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 21
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.
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
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Participant must be ≥1 year and <25 years of age at time of screening.
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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.
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Participant must have measurable or evaluable disease as defined in the protocol.
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Participant must have received their last dose of myelosuppressive anticancer chemotherapy at least 3 weeks prior to study enrollment.
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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.)
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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.
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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.
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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
- 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
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Female participants of childbearing age must have a negative pregnancy test at the time of enrollment.
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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.
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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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description A: prexasertib + cyclophosphamide Prexasertib 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. A: prexasertib + cyclophosphamide 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. A: prexasertib + cyclophosphamide peg-filgrastim 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. A: prexasertib + cyclophosphamide filgrastim 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. B: prexasertib + gemcitabine Prexasertib 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. B: prexasertib + gemcitabine 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. B: prexasertib + gemcitabine filgrastim 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. B: prexasertib + gemcitabine peg-filgrastim 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.
- Primary Outcome Measures
Name Time Method Estimate the Maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D) of each doublet by stratum 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 d...
To characterize the systemic clearance (CL) of prexasertib in combination with cyclophosphamide or gemcitabine. 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.
To determine the safety and tolerability of combination treatment with prexasertib and cyclophosphamide or gemcitabine. 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.
To characterize the area under the concentration-time curve (AUC0-∞) of prexasertib in combination with cyclophosphamide or gemcitabine. 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.
- Secondary Outcome Measures
Name Time Method Rate of objective response (complete or partial response) by stratum 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.
Duration of objective response by stratum 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.
To characterize the systemic clearance (CL) of cyclophosphamide. 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.
To characterize the systemic clearance (CL) of gemcitabine. prexasertib and cyclophosphamide treatment course 1, day 1 Gemcitabine systemic clearance (CL) is estimated based on course 1, day 1 PK samples.
To characterize the area under the concentration-time curve (AUC0-4h) of gemcitabine. 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.
To characterize the area under the concentration-time curve (AUC0-24h) of cyclophosphamide. 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.
Progression-free survival for patients treated with prexasertib and cyclophosphamide or gemcitabine 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...
To characterize the area under the concentration-time curve (AUC0-24h) of 4-hydroxy-cyclophosphamide. 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.
To characterize the area under the concentration-time curve (AUC0-24h) of carboxyethylphosphoramide mustard. 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.
To characterize the area under the concentration-time curve (AUC0-4h) of gemcitabine triphosphate (only at St. Jude Children's Research Hospital). 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.
Trial Locations
- Locations (1)
St. Jude Children's Research Hospital
🇺🇸Memphis, Tennessee, United States
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