Summary

This phase I/II trial studies the best dose and side effects of CX-4945, and how well it works in treating patients with sonic hedgehog (SHH) medulloblastoma that has come back (recurrent). CX-4945 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Objectives

PRIMARY OBJECTIVES:
I. To estimate the maximum tolerated dose (MTD) and recommend a Phase II dose of silmitasertib sodium (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 associated with CX-4945 in children with recurrent SHH (sonic hedgehog) medulloblastoma. (Phase I)
III. To characterize the pharmacokinetics of CX-4945 administered on this schedule in skeletally-immature children with recurrent SHH 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 1000 mg twice daily (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. (Phase II)

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 MTD/ recommended phase II dose (RP2D) inhibits 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: This is a phase I, dose-escalation study of silmitasertib sodium followed by a phase II study.

Patients receive silmitasertib sodium orally (PO) BID. Treatment repeats every 28 days for up to 52 cycles (26 for phase I and 26 for phase II) in the absence of disease progression or unacceptable toxicity.

SURGICAL STUDY: Patients receive silmitasertib sodium PO BID for 5-7 days prior to surgery. Within 2-4 weeks after surgery, patients receive silmitasertib sodium PO BID every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Eligibility

1. PHASE I SKELETALLY-IMMATURE
2. Skeletal maturity: Patient must be skeletally-immature at the time of study enrollment, defined as females with a bone age < 14 years and males with a bone age < 16 years
3. Disease status: Patients who participate in the expansion cohort must have bi-dimensionally measurable disease, defined as at least one lesion that can be accurately measured in at least two dimensions. Patients with measurable extraneural disease only are also eligible
4. BSA: Patients enrolled on the Phase 1 study must have a bovine serum albumin (BSA) as noted below Dose level 0 (400 mg/m^2 BID): minimum (0.84m^2), maximum (2.25m^2) Dose level 1 (600 mg/m^2 BID): minimum (0.60m^2), maximum (2.00m^2) Dose level 2 (800 mg/m^2 BID): minimum (0.63m^2), maximum (2.00m^2)
5. PHASE II
6. Skeletal maturity: Patients must be skeletally-mature at the time of study enrollment, defined as females with a bone age >= 14 years and males with a bone age >= 16 years OR have a chronologic age > 18 years
7. Disease status: Patients must have bi-dimensionally measurable disease, defined as at least one lesion that can be accurately measured in at least two dimensions; patients with measurable extraneural disease only are also eligible
8. SURGICAL STUDY
9. Disease status: Surgical resection of central nervous system (CNS) disease must be clinically indicated
10. Patient must be >= 3 at the time of enrollment
11. Therapy prior to resection: Patients must be amenable to receiving CX-4945 for 5-7 days prior to their resection
12. ALL PHASES
13. Tumor: Patient must have a diagnosis of SHH medulloblastoma that is recurrent or progressive, confirmed histologically and by Clinical Laboratory Improvement Act (CLIA)-certified methylation-based subgroup testing at Cincinnati Children’s Hospital Medical Center (CCHMC)
14. Prior therapy: Patients must have received prior disease directed therapy which included radiation therapy and must have recovered from the acute treatment related toxicities (defined as =< grade 1 if not otherwise defined in eligibility criteria) prior to entering this study
15. Chemotherapy: Patients must have received their last dose of known myelosuppressive anticancer therapy at least 21 days prior to enrollment or at least 42 days if nitrosourea
16. Investigational/Biologic Agent * Biologic or investigational agent (anti-neoplastic): Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the investigational or biologic agent >= 7 days prior to study enrollment ** 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. * Monoclonal Antibodies and agents with known prolonged half-lives: Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the agent >= 28 days prior to study enrollment
17. Radiation: Patients must have had their last fraction of * Craniospinal irradiation or total body irradiation or radiation to >= 50% of pelvis > 3 months prior to enrollment * Focal irradiation > 4 weeks prior to enrollment
18. Stem cell transplant: Patient must be * >= 6 months since allogeneic stem cell transplant prior to enrollment with no evidence of active graft versus (vs.) host disease * >= 3 months since autologous stem cell transplant prior to enrollment
19. Growth factors: Patients must be off all colony- forming growth factor(s) for at least 1 week prior to enrollment (e.g. filgrastim, sargramostim or erythropoietin). 2 weeks must have elapsed if patients received long-acting formulations
20. Neurologic status: * Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment, documented by a detailed neurological exam * Patients with seizure disorders may be enrolled if seizures are well controlled
21. Performance status: Karnofsky performance scale (KPS for > 16 years of age) or Lansky performance score (LPS for =< 16 years of age) assessed within two weeks of enrollment must be >= 50. Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
22. Absolute neutrophil count >= 1.0 x 10^9 cells/ L
23. Platelets >= 100 x 10^9 cells/ L (unsupported, defined as no platelet transfusion within 7 days)
24. Hemoglobin >= 8 g/dl (may receive transfusions)
25. Total bilirubin =< 1.5 times institutional upper limit of normal (ULN)
26. Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal (ULN)
27. Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =< 3 x institutional upper limit of normal (ULN)
28. Albumin >= 2 g/dl
29. Serum electrolytes (sodium, potassium, chloride) within institutional limits of normal (patients can be on enteral supplementation)
30. Serum creatinine based on age/gender as noted below. Patients that do not meet the criteria below but have a 24 hour creatinine clearance or glomerular filtration rate (GFR) (radioisotope or iothalamate) >= 70 mL/min/1.73 m^2 are eligible * Age: Maximum Serum Creatinine (mg/dL) * 3 to < 6 years: 0.8 (male), 0.8 (female) * 6 to < 10 years: 1 (male), 1 (female) * 10 to < 13 years: 1.2 (male), 1.2 (female) * 13 to < 16 years: 1.5 (male), 1.4 (female) * >= 16 years: 1.7 (male), 1.4 (female)
31. Corticosteroids: Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to enrollment
32. Pregnancy status: Female patients of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
33. 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 and for 3 months after drug cessation
34. Informed consent: The patient or parent/guardian is able to understand the consent and is willing to sign a written informed consent document according to institutional guidelines

Treatment Sites in Georgia