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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 21
- 试验地点
- 1
- 主要终点
- Estimate the Maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D) of each doublet by stratum
研究概览
简要总结
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).
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 24 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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 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 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
- •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.
研究组 & 干预措施
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.
干预措施: Prexasertib (Drug)
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.
干预措施: Cyclophosphamide (Drug)
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.
干预措施: filgrastim (Biological)
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.
干预措施: peg-filgrastim (Biological)
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.
干预措施: Prexasertib (Drug)
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.
干预措施: Gemcitabine (Drug)
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.
干预措施: filgrastim (Biological)
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.
干预措施: peg-filgrastim (Biological)
结局指标
主要结局
Estimate the Maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D) of each doublet by stratum
时间窗: 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).
To characterize the systemic clearance (CL) of prexasertib in combination with cyclophosphamide or gemcitabine.
时间窗: 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.
时间窗: 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.
时间窗: 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.
次要结局
- Rate of objective response (complete or partial response) by stratum(Up to 1 year after completion of prexasertib and cyclophosphamide or gemcitabine treatment)
- Duration of objective response by stratum(Up to 1 year after completion of prexasertib and cyclophosphamide or gemcitabine treatment)
- To characterize the systemic clearance (CL) of cyclophosphamide.(prexasertib and cyclophosphamide treatment course 1, days 1 and 2)
- To characterize the systemic clearance (CL) of gemcitabine.(prexasertib and cyclophosphamide treatment course 1, day 1)
- To characterize the area under the concentration-time curve (AUC0-4h) of gemcitabine.(prexasertib and gemcitabine treatment course 1, day 1.)
- To characterize the area under the concentration-time curve (AUC0-24h) of cyclophosphamide.(prexasertib and cyclophosphamide treatment course 1, days 1 and 2)
- Progression-free survival for patients treated with prexasertib and cyclophosphamide or gemcitabine(Up to 3 years from diagnosis)
- 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)
- To characterize the area under the concentration-time curve (AUC0-24h) of carboxyethylphosphoramide mustard.(prexasertib and cyclophosphamide treatment course 1, days 1 and 2)
- 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)