Symptoms and General Pathology

All Conditions

Neoplasms

Nervous System Diseases

Rare Diseases

Recurrence

Brain Neoplasms

Medulloblastoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Brain Tumor, Childhood

Medulloblastoma, Childhood

Neuroepithelioma

Skeletally-immature children with refractory or recurrent medulloblastoma of the SHH group

Skeletally-mature subjects with refractory or recurrent medulloblastoma of the SHH group

Subjects who are eligible for the Phase I or Phase II arm of the trial and are candidates for surgery, may be enrolled in the surgical arm prior to initiation of the Phase I or Phase II treatment.

CX-4945 is supplied as 200 mg capsules delivered orally as a formulated API

CX 4945

Ralph Salloum, MD

This is a multi center, Phase I, Phase II and surgical study of the CX-4945 drug (silmitasertib sodium) for patients with recurrent SHH (Sonic Hedgehog) medulloblastoma

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and/or the recommended phase II dose (RP2D) of CX-4945 administered orally daily to skeletally-immature children with recurrent SHH (sonic hedgehog) medulloblastoma (Phase I) II. To describe the toxicity profile and define the dose-limiting toxicities (DLTs) of CX-4945 in skeletally-immature children with recurrent SHH (sonic hedgehog) medulloblastoma. (Phase I) III. To characterize the pharmacokinetics of CX-4945 administered orally daily to skeletally-immature children with recurrent SHH (sonic hedgehog) medulloblastoma. (Phase I) IV. To characterize the concentrations of CX-4945 in tumor after administration of CX-4945 and surgical resection (Surgical Study). V. To establish the safety and characterize the toxicity of 1000mg BID continuous dosing of CX-4945 in skeletally-mature patients with recurrent SHH medulloblastoma (Phase II). VI. To estimate the objective response rate associated with CX-4945 in skeletally-mature patients with recurrent SHH medulloblastoma

SECONDARY OBJECTIVES:

I. To document preliminary antitumor activity of CX-4945 in skeletally-immature children with recurrent SHH medulloblastoma (Phase I). II. To perform a genomic analysis within the confines of a Phase I study to investigate correlation between response to treatment and the presence of specific genomic alterations. and/or specific subgroups of disease (Phase I). III. To explore the ability of CX-4945 at the MTD/ RP2D to inhibit CK2-mediated signaling in tumor (Surgical Study). IV. To characterize the pharmacokinetics of CX-4945 in skeletally-mature patients with recurrent SHH medulloblastoma (Phase II). V. To perform a genomic analysis within the confines of a Phase II study to investigate correlation between response to treatment and the presence of specific genomic alterations and/or specific subgroups of disease (Phase II).

OUTLINE: Phase I component is a dose-escalation study. The Phase II component is to establish the safety of 1000mg BID given continuously.

The study will open with a safety cohort of 3 subjects who are considered skeletally-mature. The initial 3 subjects will be administered CX-4945 twice a day at the adult RP2D of 1000 mg BID or at its BSA adjusted equivalent; however, the dose will be given continuously. If there are not excessive toxicities in this cohort, the study will proceed following the Phase II design for subjects who are skeletally-mature.

Following the safety lead in, the Phase 1 component of this trial will be initiated. Skeletally-immature children with refractory or recurrent medulloblastoma of the SHH subgroup, will be administered CX-4945 twice a day on a continuous basis at a starting dose of 600mg/m2 BID which corresponds approximately to the BSA adjusted recommended Phase 2 dose (RP2D) of 1000mg. The Phase 1 study will escalate doses to determine the maximum tolerated dose skeletally-immature children.

The surgical study will be initiated after the first 3 patients in the skeletally-mature cohort are treated for initial assessment of safety and did not experience excessive toxicity. Skeletally-mature subjects with recurrent or refractory SHH medulloblastoma will be eligible as soon the surgical study is initiated and will receive drug at 1000mg BID or its BSA adjusted equivalent depending upon age and BSA. Skeletally-immature subjects will only be eligible to enroll on the surgical trial once the MTD is defined in the Phase 1 component and will receive drug at the established MTD for this cohort.

After completion of study treatment, patients are followed up to 2 years.

Testing the Safety and Tolerability of CX-4945 in Patients With Recurrent Medulloblastoma Who May or May Not Have Surgery

PBTC-053: A Pediatric Brain Tumor Consortium Phase I/ II and Surgical Study of CX-4945 in Patients With Recurrent SHH Medulloblastoma

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.

To report the plasma drug concentration of CX-4945 on this schedule in skeletally-immature children

Percentage of patients who achieve sustained objective response.

Interval of time between the date of initiation of protocol treatment and minimum date of documentation of PD, second malignancy, death due to any cause or date of last follow-up.

Percentage of patients who achieve objective response in the skeletally-immature cohort

To report the plasma drug concentration of CX-4945 in skeletally-mature subjects

Percentage of various genomic alterations will be reported

Change in CK2 activity in tumor tissue from patients on the surgical are at baseline and after treatment.

Spots Global Cancer Trial Database for sonic hedgehog (shh) positive