Silmitasertib (CX-4945) in Combination With Chemotherapy for Relapsed Refractory Solid Tumors

Eligibility Criteria

• 1. Age: Less than 30 years old at initial diagnosis
• 2. Pathology All subjects must have a confirmed diagnosis of tumor type. Phase I: Relapsed/refractory solid tumors: Neuroblastoma, Ewing Sarcoma, Osteosarcoma, Rhabdomyosarcoma, Liposarcoma
• * Relapsed/refractory Neuroblastoma
• * Relapsed/refractory Ewing sarcoma
• 3. Tumor assessment:
• 4. Disease Status:
• 1. Any age with International Neuroblastoma Risk Group (INRG) Stage L2, MS, or M with MYCN amplification
• 2. Age ≥ 547 days and INRG Stage M regardless of biologic features
• 3. Any age initially diagnosed with INRG Stage L1 MYCN amplified NBL who have progressed to Stage M without systemic chemotherapy
• 4. Age ≥ 547 days of age initially diagnosed with INRG Stage L1, L2, or MS who have progressed to Stage M without systemic chemotherapy
• 5. Measurable or evaluable disease, including at least one of the following:
• * Measurable tumor by CT or MRI
• * MIBG or PET that is positive for disease
• * Bone Marrow biopsy/aspirate that is positive for disease
• 6. Timing from prior therapy:
• 1. Myelosuppressive chemotherapy: Must not have received within 2 weeks of enrollment onto this study.
• 2. Small Molecule Inhibitors (anti-neoplastic agent): At least 2 weeks from the completion of therapy with a small molecule inhibitor.
• 3. Immunotherapy: At least 4 weeks since the completion of any type of immunotherapy, e.g. tumor vaccines, CAR-T cells, anti-GD2 Monoclonal antibodies (ex. naxitamab, dinutuximab, etc.).
• 4. Radiotherapy: At least 30 days since the last treatment except for radiation delivered with palliative intent to a non-target site.
• 5. Stem Cell Transplant:
• * Allogeneic: No evidence of active graft vs. host disease
• * Allogeneic/Autologous: ≥ 2 months must have elapsed since transplant.
• 6. MIBG Therapy: At least 6 weeks since treatment with MIBG therapy.
• 7. Subjects must have a Lansky or Karnofsky Performance Scale score of \>/= 50.
• 8. Subject must be able to swallow capsules.
• 9. Subjects must have adequate organ function at the time of enrollment:
• * Cardiac- Corrected QT (QTc) interval \<480ms (calculated using Bazett formula)
• * Hematological: Hematological recovery as defined by ANC ≥750/μL
• * Liver: Adequate liver function as defined by AST and ALT \<5x upper limit of normal
• * Renal: Subjects must have adequate renal function defined as Creatinine clearance (in units ml/min) or radioisotope GFR ≥ 70.
• 10. Subjects of childbearing potential must have a negative serum pregnancy test. Subjects of childbearing potential must agree to use effective measures to avoid pregnancy.
• 11. Written informed consent in accordance with institutional and FDA guidelines must be obtained from all subjects (or subjects' legal representative).
• 1. Investigational Drugs: Subjects who are currently receiving another investigational drug are excluded from participation.
• 2. Anti-cancer Agents: Subjects who are currently receiving other anticancer agents are not eligible. Subjects must have fully recovered from the hematological and bone marrow suppression effects of prior therapy.
• 3. Subjects who are currently receiving Vitamin K antagonists (warfarin).
• 4. Subjects who are currently receiving the class of lipid-lowering medications HMG-CoA reductase inhibitors (statins).
• 5. Infection: Subjects who have an uncontrolled infection are not eligible until the infection is judged to be well controlled in the opinion of the investigator.
• 6. Subjects who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study, or in whom compliance is likely to be suboptimal, should be excluded.
• 7. Subjects 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 subject's ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results.
• 8. Subjects with any of the following gastrointestinal disorders:
• 1. Difficulty with swallowing or active malabsorption (e.g. short gut) syndrome.
• 2. Uncontrolled diarrhea (excess of 4 stools/day)
• 3. Gastritis, ulcerative colitis, Chron's disease or hemorrhagic coloproctitis
• 4. History of gastric or small bowel surgery involving any extent of gastric or small bowel resection
• 9. Lactating subjects are not eligible unless they have agreed to not breastfeed their infants. There is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the nursing subject with silmitasertib. (NOTE: breast milk cannot be stored for future use while the nursing subject is being treated on study.)
• 10. Subjects with a history of any other malignancy.