CX-4945 in Treating Patients with Recurrent SHH Medulloblastoma

Inclusion Criteria

• PHASE I SKELETALLY-IMMATURE
• 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
• 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
• 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)
• PHASE II
• 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
• 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
• SURGICAL STUDY
• Disease status: Surgical resection of central nervous system (CNS) disease must be clinically indicated
• Patient must be >= 3 at the time of enrollment
• Therapy prior to resection: Patients must be amenable to receiving CX-4945 for 5-7 days prior to their resection
• ALL PHASES
• 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)
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Absolute neutrophil count >= 1.0 x 10^9 cells/ L
• Platelets >= 100 x 10^9 cells/ L (unsupported, defined as no platelet transfusion within 7 days)
• Hemoglobin >= 8 g/dl (may receive transfusions)
• Total bilirubin =< 1.5 times institutional upper limit of normal (ULN)
• Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =< 3 x institutional upper limit of normal (ULN)
• Albumin >= 2 g/dl
• Serum electrolytes (sodium, potassium, chloride) within institutional limits of normal (patients can be on enteral supplementation)
• 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)
• Corticosteroids: Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to enrollment
• 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
• 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
• 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

Exclusion Criteria

• Breast feeding: Nursing mothers are excluded from this study. There is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with CX-4945
• Concurrent illness * Patients with a history of any other malignancy, except patients with a secondary brain tumor if the patient’s prior malignancy has been in remission for at least 5 years from the end of treatment * Patients with any of the following gastrointestinal disorders: ** Difficulty with swallowing or active malabsorption (e.g., short gut) syndrome ** Uncontrolled diarrhea (excess of 2-3 stools/day above normal frequency) ** Gastritis, ulcerative colitis, Crohn’s disease, or hemorrhagic coloproctitis ** History of gastric or small bowel surgery involving any extent of gastric or small bowel resection * Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the patient’s ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results
• Cardiac: Corrected QT (QTc) interval is > 480ms
• Concomitant Medications * Patients who are receiving any other anti-cancer or investigational drug therapy are ineligible * Patients on warfarin * Patients on statins
• Prisoners: Prisoners will be excluded from this study
• Inability to participate: Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits or obtain follow-up studies required to assess toxicity to therapy or to adhere to drug administration plan, other study procedures, and study restrictions