Enzastaurin in Treating Young Patients With Refractory Primary CNS Tumors

Neuroblastoma Clinical Trial

Official title:

Phase I and Pharmacokinetic Study of Enzastaurin (LY317615) in Children and Adolescents With Refractory Primary CNS Tumors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00503724
• Other study ID #: CDR0000557572
• Secondary ID: U01CA081457PBTC-
• Status: Completed
• Phase: Phase 1
• First received: July 17, 2007
• Last updated: March 2, 2012
• Start date: June 2007
• Est. completion date: May 2010

Study information

• Verified date: March 2012
• Source: Pediatric Brain Tumor Consortium
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Enzastaurin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

PURPOSE: This phase I trial is studying the side effects and best dose of enzastaurin in treating young patients with refractory primary brain tumors.

Description:

OBJECTIVES:

Primary

• To estimate the maximum tolerated dose (MTD) and/or recommend a phase II dose of enzastaurin hydrochloride in children with recurrent or refractory CNS tumors who are not receiving enzyme-inducing anticonvulsants.

• To further characterize the pharmacokinetics and toxicity of the recommended phase II dose of enzastaurin hydrochloride given twice daily in these patients.

Secondary

• To characterize the pharmacokinetics of enzastaurin hydrochloride at the recommended phase II dose given once a day or twice a day in children.

• To document and describe toxicities associated with enzastaurin hydrochloride.

• To document antitumor activity in children with recurrent or refractory CNS tumors.

• To explore changes in MR perfusion scans obtained within 15 ± 2 days after initiation of enzastaurin hydrochloride therapy as compared to baseline and to correlate these changes with clinical outcome.

• To evaluate a panel of biological surrogate markers in this patient population at baseline and following enzastaurin hydrochloride administration.

OUTLINE: This is a multicenter study.

Patients receive oral enzastaurin hydrochloride once daily until the maximum tolerated dose (MTD) is determined. Patients then receive enzastaurin hydrochloride at the MTD twice daily on days 1-28. Treatment repeats every 28 days for 13 courses in the absence of disease progression or unacceptable toxicity. Patients may receive 13 additional courses (for a total of 26 courses) of oral enzastaurin hydrochloride if the patient is benefitting from the treatment and the investigator and subject agree to continue treatment.

Patients undergo blood sample collection periodically for pharmacokinetic studies.

After completion of study treatment, patients are followed periodically.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: May 2010
• Est. primary completion date: May 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 21 Years

Eligibility

DISEASE CHARACTERISTICS:

• Histologically confirmed primary CNS malignancy including low-grade glioma

• All tumors, except intrinsic brain stem and diffuse optic pathway tumors, must have histological verification at either the time of diagnosis or recurrence

• Patients with intrinsic brain stem or diffuse optic pathway tumors must have clinical and/or radiographic evidence of progression

• Recurrent or progressive disease or disease refractory to standard therapy and for which there is no known curative therapy

PATIENT CHARACTERISTICS:

Inclusion Criteria:

• Karnofsky performance scale (for > 16 years of age) or Lansky performance score (for = 16 years of age) = 60% assessed within two weeks prior to registration

• Peripheral absolute neutrophil count (ANC) = 1,000/µL

• Platelet count = 100,000/µL (transfusion independent)

• Hemoglobin = 8.0 g/dL (may receive RBC transfusions)

• Creatinine clearance or radioisotope GFR = 70 mL/min OR maximum serum creatinine based on age as follows:

• 0.8 mg/dL (= 5 years of age)

• 1.0 mg/dL (6 to 10 years of age)

• 1.2 mg/dL (11 to 15 years of age)

• 1.5 mg/dL (= 16 years of age)

• Total bilirubin = 1.5 x upper limit of normal (ULN) for age

• ALT = 5 x ULN for age

• Serum albumin = 2.5 g/dL

• Patients of childbearing or child-fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study

• Negative pregnancy test

• Patients must have a normal QTc for age and no evidence of a clinically significant arrhythmia on ECG

• No evidence of active graft-versus-host disease

Exclusion Criteria:

• Pregnant or lactating

• Body surface area < 0.5 m^2

• Clinically significant unrelated systemic illness that would compromise the patient's ability to tolerate protocol therapy or would likely interfere with the study procedures or results

• Known hypersensitivity to enzastaurin hydrochloride or its components

• Inability to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy

PRIOR CONCURRENT THERAPY:

Inclusion Criteria:

• Must have recovered from the acute toxic effects (grade = 2) of all prior therapy before entering this study

• Must not have received myelosuppressive chemotherapy within 3 weeks of entry onto this study (6 weeks for prior nitrosourea)

• At least 7 days since the completion of therapy with a hematopoietic growth agent (i.e., filgrastim [G-CSF], sargramostim [GM-CSF], or erythropoietin)

• At least 14 days since long-acting formulations

• Therapeutic use of myeloid growth factors in patients with serious neutropenic conditions, such as sepsis, may be considered at the investigator's discretion

• At least 7 days since the completion of therapy with a biologic agent

• At least 2 weeks since prior local palliative radiotherapy (small port)

• At least 6 months must have elapsed after prior total body irradiation (TBI) or craniospinal radiotherapy

• At least 6 weeks must have elapsed after other substantial bone marrow irradiation

• At least 6 months since prior allogeneic bone marrow transplantation

• At least 3 months since prior autologous bone marrow or stem cell transplantation

• Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to registration

• Corticosteroids should be used at the lowest dose to control symptoms of edema and mass effect

Exclusion Criteria:

• Routine concurrent use of growth factors (i.e., G-CSF, GM-CSF, or erythropoietin)

• Any other concurrent anticancer or investigational drug therapy

• Concurrent enzyme-inducing anticonvulsants (EIACDs)

• Concurrent gents that prolong the QTc

• Concurrent drugs that are substrates or inhibitors of CYP3A4 or CYP2C9

• Other concurrent drugs that are sensitive substrates of CYP2C8, CYP2C9, or CYP2C19 and/or have a narrow therapeutic window

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Brain and Central Nervous System Tumors
• Central Nervous System Neoplasms
• Nervous System Neoplasms
• Neuroblastoma

Intervention

Drug:
• enzastaurin hydrochloride
Participants receive 200, 260, 340, or 440 mg/m2/day of enzastaurin orally once daily for 28 days (one course) during the dose escalation phase of the study. To study the toxicity profile of the MTD or phase II recommended dose established during the dose escalation phase, participants receive twice daily doses of enzastaurin orally at the phase II recommended dose for 28 days (one course). In the absence of unacceptable toxicity or disease progression, treatment may continue for 13 courses (approximately one year).

Locations

Country	Name	City	State
United States	Children's Memorial Hospital - Chicago	Chicago	Illinois
United States	Duke Comprehensive Cancer Center	Durham	North Carolina
United States	Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital	Houston	Texas
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	UCSF Medical Center at Parnassus	San Francisco	California
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Pediatric Brain Tumor Consortium	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum tolerated dose	The maximum tolerated dose or recommended phase II dose will be based on the dose-limiting toxicities observed during the first 28 days of therapy in those participants receiving enzastaurin on a once per day dosing schedule.	First 28 days of therapy	Yes
Primary	Number of participants treated with the maximum tolerated dose or phase II recommended dose on a twice daily dosage schedule with dose-limiting toxicities		First 28 days of therapy	Yes
Secondary	Pharmacokinetics	Blood samples for pharmacokinetic studies will be drawn 3 days prior to course 1 and on day 28 of course 1.	Three days prior to course 1 and day 28 of course 1	No
Secondary	Toxicity		From day 1 of therapy until 30 days after the last dose of the drug	Yes
Secondary	Tumor response	Brain images to assess tumor response (complete response, partial response, or stable disease) are taken pre-treatment, at day 15 of course 1, and at the end of courses 3, 5, 8, 11, and 13.	Pre-treatment, day 15 of course 1, and at the end of courses 3, 5, 8, 11, and 13.	No
Secondary	Change in MR perfusion parameters obtained within 15 ± 2 days after initiation of enzastaurin hydrochloride therapy as compared to baseline		Baseline and day 15 of course 1	No
Secondary	Change from baseline in the inhibition of Akt cell signaling at day 14 and day 28		Pre-treatment and at days 14 and 28 of course 1	No
Secondary	Akt pathway activity in pre-study tumor samples		Pre-treatment	No