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

Inclusion 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
• •Phase II:
• •* Relapsed/refractory Neuroblastoma
• •* Relapsed/refractory Ewing sarcoma
• •3. Tumor assessment:
• •Disease assessment is required for eligibility and must be done after last dose of previous therapy and prior to first dose of study drug.
• •4. Disease Status:
• •Relapsed/Refractory Neuroblastoma Relapsed disease defined as neuroblastoma that was previously in remission after standard therapy (at least 4 cycles of aggressive multi-drug induction chemotherapy, with or without radiation and surgery, followed by immunotherapy, or according to a standard high-risk treatment/neuroblastoma protocol) and has now relapsed and is in any number of relapses.
• •Refractory disease defined as High-risk neuroblastoma (as defined by INRG) that failed to achieve CR after at least 4 cycles of aggressive multi-drug induction chemotherapy, progression during upfront therapy or with disease remaining after standard immunotherapy.
• •International Neuroblastoma Risk Group Staging System (INRG) High Risk NB defined as one of the following:
• •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
• •Relapsed/refractory Sarcoma Subjects that have relapsed following standard of care therapy or having progressed during standard of care therapy. Standard of care therapy for sarcoma includes multi-agent chemotherapy with local control consisting of either surgery or radiation therapy.
• •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:
• •Subjects must have fully recovered from the acute toxic effects of all prior anti- cancer therapy and be within the following timelines:
• •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. Subjects must have adequate organ function at the time of enrollment:
• •* Cardiac: Subjects must have a QTcF ≤ 480 msc.
• •* 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 an estimated Glomerular Filtration rate (eGFR) as calculated from the Bedside Schwartz equation (in units of mL/min/1.73 m2) or via radioisotope GFR ≥ 70.
• •The Bedside Schwartz equation is: \[(0.413) X (Height in cm)\] / SCr
• •9. Subjects of childbearing potential must have a negative serum pregnancy test. Subjects of childbearing potential must agree to use effective measures to avoid pregnancy.
• •10. Written informed consent in accordance with institutional and FDA guidelines must be obtained from all subjects (or subjects' legal representative).