Prexasertib in Treating Pediatric Patients With Recurrent or Refractory Solid Tumors

• ClinicalTrials.gov Identifier: NCT02808650
• Recruitment Status: Completed
• First Posted: June 22, 2016
• Last Update Posted: April 15, 2021
• Sponsor: Children's Oncology Group
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Children's Oncology Group

Tracking Information

• First Submitted Date: June 15, 2016
• First Posted Date: June 22, 2016
• Last Update Posted Date: April 15, 2021
• Actual Study Start Date: February 27, 2017
• Actual Primary Completion Date: December 31, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 8, 2018)

• Maximum tolerated dose (MTD) of prexasertib based on incidence of dose limiting toxicity assessed National Cancer Institute (NCI) CTCAE version 4.0 [ Time Frame: Up to 28 days ]
• Incidence of adverse events (toxicities) according to NCI CTCAE version 4.0 [ Time Frame: Up to 28 days ]
• Pharmacodynamic parameters of prexasertib [ Time Frame: Pre-dose and at 1, 1.5, 2, 4 and 8 hours after on day 1; at 24 hours on day 2 and 96 hours on day 5 after beginning the infusion; on day 8 during complete blood count evaluation; pre-dose and end of infusion on day 15 of course 1 ]
  Plasma will be collected and LY2606368 concentrations will be determined by a validated liquid chromatography/tandem mass spectrometry method. Summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).

Original Primary Outcome Measures (submitted: June 21, 2016)

• Recommended phase 2 dose (RP2D) or the maximum tolerated dose (MTD) [ Time Frame: 28 Days ]
• Adverse events as assessed by (CTCAE) version 4.0 [ Time Frame: 28 Days ]
  DLT will be defined as possibly, probably or definitely attributable to LY2606368. The DLT observation period for the purposes of dose-escalation will be the first cycle of therapy.
• Pharmacokinetic Assessment of LY2606368 Concentrations in Plasma Samples [ Time Frame: Cycle 1, Days 1, 2, 5, 8, and 15 ]
  A descriptive analysis of pharmacokinetic (PK) parameters of LY2606368 will be performed and summarized with simple summary statistics

Current Secondary Outcome Measures (submitted: August 8, 2018)

• Antitumor activity of prexasertib [ Time Frame: Up to 2 years ]
• CHK1/2 expression status [ Time Frame: Up to 2 years ]
  Tumor tissue will be analyzed by immunohistochemistry.
• TP53 deletion and/or mutation in tumor tissue as a potential biomarker of Chk1 inhibition [ Time Frame: Up to 2 years ]
  Will be assessed by immunohistochemistry or sequencing.
• Pharmacodynamic markers of prexasertib [ Time Frame: Up to 2 years ]
  Tumor tissue will be evaluated for deletion and/or mutation of Trp53 and peripheral blood mononuclear cells for autophosphorylation of Chk1 and H2AX.

Original Secondary Outcome Measures (submitted: June 21, 2016)

• Evaluation of disease response to preliminarily define the antitumor activity of LY2606368 [ Time Frame: Every Other Cycle x 2 then Every 3 Cycles for up to 1 year ]
  Patients will have tumor disease evaluations performed at the end of cycles 1, 3, and 5 and then every 3 cycles. Disease response will be assessed according to RECIST criteria and will be reported descriptively.
• PBMC Studies [ Time Frame: Cyce 1, Days 1 and 2 ]
  Peripheral blood mononuclear cells (PBMCs) will be evaluated in consenting patients for autophosphorylation of Chk1 and H2AX. Blood samples will be collected at baseline prior to infusion and at 24 hours after start of infusion
• Evaluation of CHK 1/2 Expression in Tumor Tissue [ Time Frame: Cycle 1 Day 1 ]
  Tissue will be collected either from diagnosis or relapse to evaluate CHK1/2 expression
• Evaluation of TP53 in Tumor Tissue [ Time Frame: Cycle 1 Day 1 ]
  Tissue will be collected either from diagnosis or relapse to evaluate TP53 by immunohistochemistry

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Prexasertib in Treating Pediatric Patients With Recurrent or Refractory Solid Tumors
• Official Title: A Phase 1 Study of LY2606368 (Prexasertib Mesylate Monohydrate) a CHK1/2 Inhibitor, in Pediatric Patients With Recurrent or Refractory Solid Tumors, Including CNS Tumors
• Brief Summary: This phase I trial studies the side effects and best dose of prexasertib in treating pediatric patients with solid tumors that have come back after a period of time during which the tumor could not be detected or does not respond to treatment. Checkpoint kinase 1 inhibitor LY2606368 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose of prexasertib (LY2606368) administered as an intravenous (IV) infusion over 60 minutes, every 14 days of a 28-day cycle to children with recurrent or refractory solid tumors.

II. To define and describe the toxicities of LY2606368 administered on this schedule.

III. To characterize the pharmacokinetics of LY2606368 in children with recurrent or refractory cancer.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of LY2606368 within the confines of a phase 1 study.

II. To examine checkpoint kinase (CHK)1/2 expression status in archival tumor tissue from solid tumor pediatric patients using immunohistochemistry.

III. To evaluate tumor tissue for deletion and/or mutation of tumor protein 53 (Trp53) as a potential biomarker of Chk1 inhibition.

IV. To evaluate autophosphorylation of Chk1 and H2A histone family, member x (H2AX) in peripheral blood mononuclear cells as a potential pharmacodynamic marker of LY2606368 activity.

OUTLINE: This is a dose-escalation study.

Patients receive prexasertib IV over 60 minutes on days 1 and 15. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Childhood Solid Neoplasm
• Recurrent Malignant Solid Neoplasm
• Recurrent Primary Central Nervous System Neoplasm
• Refractory Malignant Solid Neoplasm
• Refractory Primary Central Nervous System Neoplasm

Intervention

• Other: Laboratory Biomarker Analysis
  Correlative studies
• Other: Pharmacological Study
  Correlative studies
• Drug: Prexasertib
  Given IV
  Other Name: LY2606368

Study Arms

Experimental: Treatment (prexasertib)

Patients receive prexasertib IV over 60 minutes on days 1 and 15. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity.

Interventions:

• Other: Laboratory Biomarker Analysis
• Other: Pharmacological Study
• Drug: Prexasertib

• Publications *: Cash T, Fox E, Liu X, Minard CG, Reid JM, Scheck AC, Weigel BJ, Wetmore C. A phase 1 study of prexasertib (LY2606368), a CHK1/2 inhibitor, in pediatric patients with recurrent or refractory solid tumors, including CNS tumors: A report from the Children's Oncology Group Pediatric Early Phase Clinical Trials Network (ADVL1515). Pediatr Blood Cancer. 2021 Sep;68(9):e29065. doi: 10.1002/pbc.29065. Epub 2021 Apr 21.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 13, 2020): 30
• Original Estimated Enrollment (submitted: June 21, 2016): 36
• Actual Study Completion Date: March 31, 2021
• Actual Primary Completion Date: December 31, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patients with recurrent or refractory solid tumors, including central nervous system (CNS) tumors, are eligible; patients must have had histologic verification of malignancy at original diagnosis or relapse except in patients with intrinsic brain stem tumors, optic pathway gliomas, or in patients with pineal tumors and elevations of cerebrospinal fluid (CSF) or serum tumor markers including alpha-fetoprotein or beta-human chorionic gonadotropin (HCG)
• Patients must have either measurable or evaluable disease
• Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life

• Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age

  • Note: Neurologic deficits in patients with CNS tumors must have been relatively stable for at least 7 days prior to study enrollment; patients 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

• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment; if after the required timeframe, the defined eligibility criteria are met, e.g. blood count criteria, the patient is considered to have recovered adequately

  • Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive; the duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment

    • >= 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea)
  • Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days must have elapsed from last dose of agent; the duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment
  • Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
  • Corticosteroids: If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
  • Hematopoietic growth factors: >= 14 days must have elapsed since the last dose of a long-acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair and the study-assigned research coordinator
  • Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days must have elapsed since the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)

  • Stem cell infusions (with or without total body irradiation [TBI]):

    • Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion: >= 84 days must have elapsed after infusion, and no evidence of graft-versus-host disease (GVHD)
    • Autologous stem cell infusion including boost infusion: >= 42 days must have elapsed after completion
  • Cellular therapy: >= 42 days must have elapsed since the completion of any type of cellular therapy (e.g. modified T cells, natural killer [NK] cells, dendritic cells, etc.)
  • X ray (XRT)/external beam irradiation including protons: >= 14 days must have elapsed after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial bone marrow (BM) radiation
  • Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131 iodine metaiodobenzylguanidine [131I-MIBG]): >= 42 days must have elapsed since systemically administered radiopharmaceutical therapy
  • Patients must not have received prior exposure to LY2606368

• For patients with solid tumors without known bone marrow involvement:

  • Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
  • Platelet count >= 75,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
  • Hemoglobin >= 8.0 g/dl at baseline (may receive packed red blood cell [PRBC] transfusions)
• Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions); these patients will not be evaluable for hematologic toxicity; at least 5 of every cohort of 6 patients must be evaluable for hematologic toxicity for the dose-escalation part of the study; if dose-limiting hematologic toxicity is observed, all subsequent patients enrolled must be evaluable for hematologic toxicity

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

  • Age: maximum serum creatinine (mg/dL)
  • 1 to < 2 years: 0.6 (male and female)
  • 2 to < 6 years: 0.8 (male and female)
  • 6 to < 10 years: 1 (male and female)
  • 10 to < 13 years: 1.2 (male and female)
  • 13 to < 16 years: 1.5 (male), 1.4 (female)
  • >= 16 years: 1.7 (male), 1.4 (female)
• Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (3x ULN); for the purpose of this study, the ULN for SGPT is 45 U/L
• Serum albumin >= 2 g/dL
• Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by gated radionuclide study

• Corrected QT (QTc) =< 480 msec

  • Note: Patients should avoid concomitant medication known or suspected to prolong QTc interval or cause Torsades De Pointes; If possible, alternative agents should be considered
  • Patients who are receiving drugs that prolong the QTc are eligible if the drug is necessary and no alternatives are available
• Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
• Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] version [v]4) resulting from prior therapy must be =< grade 2
• For patients with CNS tumors, any baseline neurologic deficit, including seizures, must be stable for at least one week prior to initiating study treatment
• All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines
• Tissue blocks or slides must be sent if available; if tissue blocks or slides are unavailable, the study chair must be notified prior to study enrollment

Exclusion Criteria:

• Pregnant or breast-feeding women will not be entered on this study; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method both during and for 3 months after participation in this study; abstinence is an acceptable method of contraception
• Corticosteroids: Patients receiving corticosteroids must have been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment; if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Investigational drugs: Patients who are currently receiving another investigational drug are not eligible
• Anti-cancer agents: Patients who are currently receiving other anti-cancer agents are not eligible
• Anti-GVHD agents post-transplant: Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial
• Strong CYP1A2 inhibitors: Patients must not have received strong CYP1A2 inhibitors (ciprofloxacin, fluvoxamine, zafirlukast) for at least 7 days prior to enrollment and must not receive them for the duration of the study
• Patients who have an uncontrolled infection are not eligible
• Patients who have received a prior solid organ transplantation are not eligible
• Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to LY2606368 or to its formulation are not eligible
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Months to 21 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02808650
• Other Study ID Numbers: ADVL1515; NCI-2016-00643 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); ADVL1515; ADVL1515 ( Other Identifier: Pediatric Early Phase Clinical Trial Network ); ADVL1515 ( Other Identifier: CTEP ); UM1CA097452 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Children's Oncology Group
• Original Responsible Party: Same as current
• Current Study Sponsor: Children's Oncology Group
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Cynthia J Wetmore; COG Phase I Consortium

• PRS Account: Children's Oncology Group
• Verification Date: April 2021