Protocol Number: 09-C-0112

Title:

A Phase I Study of MK-0752 in Pediatric Patients with Recurrent or Refractory CNS Malignancies

Number:

09-C-0112

Summary:

Background:

-A subset of patients with pediatric CNS tumors continue to have a poor prognosis despite advances in surgery and radiation. Novel strategies are required for improving outcome for these patients.

-Advances in cancer biology have allowed the identification of key tumorigenic signal transduction pathways, such as the NOTCH signaling pathway, and the development of novel therapies that target these pathways. NOTCH signaling plays a central role in normal neural stem cell regulation and maintenance, and may be important in brain tumor stem cell biology.

-Recent research has implicated dysregulation of the NOTCH signaling pathway in pediatric CNS tumors including high-grade gliomas, ependymomas and medulloblastomas.

-MK-0752 is an orally active inhibitor of the enzyme, gamma secretase, which is necessary for NOTCH signaling. Inhibition prevents activation of a key transcription factor, and thereby prevents cell signaling by NOTCH.

Objectives:

-To estimate the maximum tolerated dose (MTD) and recommend a Phase II dose of MK-0752 administered for 3 consecutive days weekly to children with recurrent or refractory CNS malignancies.

-To characterize the pharmacokinetics of MK-0752 administered on this schedule.

-To document and describe toxicities associated with MK-0752 administrated on this schedule.

Eligibility:

-Patient must be greater than or equal to 3 and less than or equal to 21 years of age at registration.

-Patients with a histologically confirmed diagnosis of a primary malignant CNS tumor that is recurrent, or refractory to standard therapy. All tumors must have histologic verification at either the time of diagnosis or recurrence except patients with intrinsic brain stem tumors. The institutional PI will review the pathology reports (source documentation) from the outside institutions to document the diagnosis of a malignant CNS tumor. Progression and recurrence will be documented by review of MRI scans. If time permits we will have the diagnosis confirmed by the NCI Laboratory of Pathology. Patients with intrinsic brain stem tumors must have radiographic evidence of progression.

-Karnofsky Performance Scale (KPS for > 16 yrs of age) or Lansky Performance Score (LPS for less than or equal to 16 years of age) greater than or equal to 60 assessed within two weeks prior to registration.

-Patients must have recovered from the toxic effects of all prior therapy.

-Patients on anticonvulsants must be on nonenzyme inducing anticonvulsants

Design:

-MK-0752 will be administered orally for 3 consecutive days weekly for 4 weeks. Therapy may continue for 6 courses. If patients are deriving benefit from therapy and have at least clinical and radiographic stable disease at the end of course 6, they may continue for 13 additional courses.

-The starting dose is 200 mg/m2/d and inter-patient dose escalation or reduction will occur in set increments (to an estimated maximum of 400 mg/m2/d).

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA:

1 Age

Patient must be greater than or equal to 3 years less than or equal to 21 years of age at registration.

2 Tumor

Patients with a histologically confirmed diagnosis of a primary CNS tumor (excluding histologically benign brain tumors (e.g. low-grade glioma)) that is recurrent, or refractory to standard therapy. All tumors must have histologic verification at either the time of diagnosis or recurrence except patients with intrinsic brain stem tumors. These patients must have radiographic evidence of progression.

3 Neurological Status

Patients with neurological deficits should have deficits that are stable for a minimum of 2 weeks prior to registration. A baseline neurological exam by a neurologist should clearly document the neurological status of the patient at the time of registration on the study.

4 Performance Status

Karnofsky Performance Scale (KPS for > 16 yrs of age) or Lansky Performance Score (LPS for less than or equal to 16 years of age) greater than or equal to 60 assessed within two weeks prior to registration.

5 Prior/Concurrent Therapy: Patients must have received standard therapy, refused standard therapy or have no other standard therapy options.

6 Baseline Adverse Events: Patient must have recovered from the toxic effects of all prior therapy before entering this study. For those baseline adverse events attributable to prior therapy, recovery is defined as a toxicity grade less than or equal to 2, using CTCAE v. 3.0, unless otherwise specified in the Inclusion and Exclusion Criteria.

7 Prior Therapy

7.1 Myelosuppressive chemotherapy: Patients must have received their last dose of known myelosuppressive anticancer chemotherapy at least three (3) weeks prior to study registration or at least six (6) weeks if nitrosourea.

7.2 Investigational / Biologic agent: Patient must have received their last dose of other investigational or biologic agent greater than or equal to 7 days prior to study registration.

-In the event that a patient has received another investigational or biologic agent and has experienced greater than or equal to grade 2 myelosuppression, then at least three (3) weeks must have elapsed prior to registration.

-If the investigational or biologic agent has a prolonged half-life then at least three (3) weeks must have elapsed prior to registration. Such patients should be discussed with the study chair prior to registration.

7.3 Monoclonal antibody treatment: Patient must have received their last dose of monoclonal antibody greater than or equal to 4 weeks prior to registration.

7.4 Radiation: Patients must have received their last dose of radiation:

- greater than or equal to 2 wks prior to study registration for local palliative XRT (small volume)

- greater than or equal to 6 months prior to study registration for total body irradiation (TBI), or craniospinal XRT

- greater than or equal to 6 wks prior to study registration for other substantial bone marrow irradiation

7.5 Bone Marrow Transplant: Patient must be:

- greater than or equal to 6 months since allogeneic bone marrow transplant prior to registration

- greater than or equal to 3 months since autologous bone marrow/stem cell prior to registration

- No evidence of active graft versus host disease.

7.6 Corticosteroids: Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 2 weeks prior to registration.

7.7 Growth factors: At least 7 days since the completion of therapy with a hematopoietic growth agent (filgrastim, sargramostim, and erythropoietin) and 14 days for long-acting formulations.

7.8 Anticonvulsants: If taking anticonvulsants, patients must be on anticonvulsants which are not considered enzyme inducing anticonvulsants.

8 Organ Function: Documented within 14 days of registration and within 7 days of the start of treatment.

8.1 Bone Marrow:

-Absolute neutrophil count greater than or equal to 1000/microl

-Platelets greater than or equal to 100,000/microl (unsupported)

-Hemoglobin greater than or equal to 8 g/dL (may receive RBC transfusions)

8.2 Renal: Normal serum creatinine for age or GFR greater than or equal to 70 ml/min/1.73m(2).

8.3 Hepatic:

- Bilirubin less than or equal to 1.5 times upper limit of normal for age

- SGPT (ALT) less than or equal to 2.5 times institutional upper limit of normal for age

8.4 Nutrition: Albumin greater than or equal to 2.5 g/dL.

8.5 Other: Normal Sodium, Potassium, Magnesium & Calcium values. If serum Calcium is below the institutional lower limits of normal, then ionized serum Calcium needs to be above the institutional lower limits of normal.

9 Pregnancy Status

Female patients of childbearing potential must not be pregnant or breast-feeding. Female patients of childbearing potential must have a negative serum or urine pregnancy test.

10 Pregnancy Prevention

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.

11 Informed Consent

Signed informed consent according to institutional guidelines must be obtained.

EXCLUSION CRITERIA:

1 Concurrent Illness

Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that would compromise the patient's ability to tolerate protocol therapy or would likely interfere with the study procedures or results.

2 Current Therapy

Patients receiving any other concurrent anticancer or investigational drug therapy.

3 Patients is taking enzyme inducing anticonvulsant drugs.

4 Inability to Participate

Patients with inability to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy.

5 Prior therapy with MK-0752

Special Instructions:

Currently Not Provided

Keywords:

Recurrent or Refractory

Pediatric Brain Tumors

NOTCH Inhibitor

Recruitment Keyword(s):

None

Condition(s):

Medulloblastoma

Ependymoma

Glioma

CNS Tumor

Investigational Drug(s):

MK-0752

Investigational Device(s):

None

Intervention(s):

Drug: MK-0752

Supporting Site:

National Cancer Institute

Contact(s):

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
Phone: 1-888-NCI-1937
Fax: Not Listed
Electronic Address: ncicssc@mail.nih.gov

Citation(s):

Cohen KJ, Broniscer A, Glod J. Pediatric glial tumors. Curr Treat Options Oncol. 2001 Dec;2(6):529-36.

Packer RJ. Brain tumors in children. Arch Neurol. 1999 Apr;56(4):421-5.

Reddy AT, Packer RJ. Pediatric central nervous system tumors. Curr Opin Oncol. 1998 May;10(3):186-93.

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