Tegavivint with Gemcitabine for the Treatment of Relapsed or Refractory Osteosarcoma

Inclusion Criteria

• Patients must be ≥ 1 year to ≤ 30 years of age at the time of study enrollment
• Patients must have had histologic verification of osteosarcoma at original diagnosis or relapse * All patients with relapsed or refractory osteosarcoma are eligible provided they received front line treatment with a regimen that contained at least 3 of the following agents: methotrexate, doxorubicin, cisplatin, and ifosfamide
• Dose Escalation: Patients must have either measurable or evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 * Note: Patients with no evidence of disease on imaging (e.g. following pulmonary metastasectomy) are NOT eligible during the dose escalation phase
• Dose Expansion: Patients with measurable or evaluable disease per RECIST 1.1 AND those with no evidence of disease on imaging following pulmonary metastasectomy are eligible during the dose expansion phase
• Patients must have a Lansky (≤ 16 years) or Karnofsky (> 16 years) score of ≥ 60, or Eastern Cooperative Oncology Group (ECOG) ≤ 2 * Note: Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Subjects must have fully recovered from the clinically significant acute effects of all prior anti-cancer chemotherapy, immunotherapy, surgery, or radiation therapy prior to enrollment * Myelosuppressive chemotherapy: ≥ 14 days after the last dose of myelosuppressive chemotherapy * Hematopoietic growth factors: ≥ 14 days after the last dose of a long-acting growth factor (e.g. pegfilgrastim) or ≥ 7 days for a short acting growth factor. 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 * Biologic (anti-neoplastic) agent: ≥ 7 days after the last dose of a biologic agent ** 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 * Cellular therapy: ≥ 21 days must have elapsed from last dose of any type of cellular therapy (e.g. modified T cells, gamma-delta T cells, natural killer [NK] cells, dendritic cells, etc.) with recovery of any associated toxicities * Interleukins, interferons, and cytokines (other than hematopoietic growth factors): ≥ 21 days must have elapsed from the last dose of interleukins, interferon or cytokines (other than hematopoietic growth factors) * Antibodies: 7 days or 3 half-lives (whichever is longer) but not longer than 30 days, and toxicity related to prior antibody therapy must be recovered to grade ≤ 1 * External beam radiation therapy (XRT): ≥ 14 days after local palliative XRT (small port); ≥ 150 days if radiation to ≥ 50% of the pelvis or bone marrow; ≥ 6 weeks must have elapsed if other substantial bone marrow (BM) radiation * Prior nucleoside analogue (gemcitabine) usage: Patients who have previously received a nucleoside analogue, including gemcitabine, are eligible * Investigational agents not otherwise specified: ≥ 30 days must have elapsed since the last dose of any agents not specified above * Surgery: ≥ 2 weeks from last major surgery, including pulmonary metastasectomy, with the exclusion of central line placement and core needle or small open biopsies
• Peripheral absolute neutrophil count (ANC) ≥ 750/mm^3 (0.75 x 10^9/L)
• Platelet count ≥ 75,000/mm^3 (75 x 10^9/L) * Transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 ml/min/1.73 m^2 OR a serum creatinine based on age/gender as follows: * Age 1 to < 2 years: Male 0.6 mg/dL, female 0.6 mg/dL * Age 2 to < 6 years: Male 0.8 mg/dL, female 0.8 mg/dL * Age 6 to < 10 years: Male 1.0 mg/dL, female 1.0 mg/dL * Age 10 to < 13 years: Male 1.2 mg/dL, female 1.2 mg/dL * Age 13 to < 16 years: Male 1.5 mg/dL, female 1.4 mg/dL * Age ≥ 16 years: Male 1.7 mg/dL, female 1.4 mg/dL
• Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x the upper limit of normal (ULN) for age
• Alanine aminotransferase (ALT) ≤ 5 x the ULN * For the purpose of this study, the ULN for ALT is 45 U/L
• No dyspnea at rest, no exercise intolerance, and no oxygen requirement (pulse oximetry > 93% on room air)
• Corrected QT interval (QTc) ≤ 470 ms using Fridericia formula

Exclusion Criteria

• Patients with a history of intraparenchymal central nervous system (CNS) disease (osteosarcoma) are not eligible unless they have imaging documenting stability of CNS lesions for ≥ 3 months prior to enrollment
• Female patients who are pregnant
• Lactating females are not eligible unless they have agreed not to breastfeed their infants
• Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained
• Males or females of reproductive potential are not eligible unless they have agreed to use two effective methods of birth control, including a medically accepted barrier or contraceptive method (e.g. male or female condom) for the duration of their study participation. Abstinence is an acceptable method of birth control. Patients should maintain adequate contraception for a minimum of 1 month after the last dose of treatment
• Subjects who are currently receiving another investigational drug are not eligible
• Subjects who are currently receiving other anti-cancer agents are not eligible
• Patients who are currently receiving drugs that are strong inducers or inhibitors of CYP3A4 are not eligible. Strong inducers or inhibitors of CYP3A4 should be avoided from 14 days prior to the 1st dose of tegavivint to the end of the study
• Patients who have received bisphosphonates within 4 weeks prior to study enrollment are not eligible
• Patients who have received denosumab within 180 days prior to study enrollment are not eligible
• Subjects who have an active, uncontrolled infection
• Subjects who have received prior solid organ or allogeneic stem cell transplantation
• Subjects who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study
• Patients with a known metabolic bone disease (ex: hyperparathyroidism, Paget’s disease, osteomalacia)
• Patients with a disorder associated with abnormal bone metabolism
• Patients with ≥ 2 grade hypocalcemia that is not corrected with oral calcium supplementation
• Patients with vitamin D < 20 ng/mL will require supplementation or will otherwise be excluded. Patients must agree to take vitamin D +/- calcium supplements (if necessary) according to institutional or published guidelines. Additional calcium supplementation is not required if adequate dietary intake can be ascertained