A Multi-Institution Study of TGFβ Imprinted, Ex Vivo Expanded Universal Donor NK Cell Infusions As Adoptive Immunotherapy in Combination with Gemcitabine and Docetaxel in Patients with Relapsed or Refractory Pediatric Bone and Soft Tissue

Eligibility Criteria

• 1. Patients must be between the ages \> 12 years and ≤ 40 years of age and have had a relapsed or refractory osteosarcoma, Ewing sarcoma, rhabdomyosarcoma or non-rhabdomyosarcoma soft tissue sarcoma.
• 2. Patients must have measurable disease using RECIST 1.1 criteria
• 3. Patients must have had at least one and no more than four total lines of systemic treatment for relapse sarcoma. Local control with surgical resection or radiation therapy of the primary tumor and any metastatic sites as clinically indicated as standard of care per the treating physician must be considered prior to enrollment.
• 4. Prior Therapy: Therapy may not have been received more recently than the timeframes defined below:
• * Myelosuppressive chemotherapy: Patients must not have received myelosuppressive therapy within 14 days of protocol therapy
• * Radiation: At least 2 weeks must have elapsed from the start of protocol therapy since local palliative XRT (small port); 4 weeks must have elapsed for all other radiation therapy
• * Hematopoietic Cell Transplant (HCT): Patients must have at least 6 weeks elapsed after autologous and allogeneic hematopoietic cell transplant
• * Biologic (anti-neoplastic agent): At least 7 days or 5 half-lives of the drug, whichever is longer, must have elapsed from the start of protocol therapy since the completion of therapy with a biologic agent.
• * Monoclonal antibodies: At least 3 weeks must have elapsed from the start of protocol therapy since prior therapy that included a monoclonal antibody.
• * Prior use of Gemcitabine and/or Docetaxel: Patients who have received these agents for prior treatment may be included if previous treatments were given ≥ 6 months prior to enrollment on this study, and there were no allergic reactions, pulmonary edema or fibrosis, Grade 3 or higher neuropathy or other non-hematologic Grade 4 adverse events related to gemcitabine and/or docetaxel therapies.
• * Absolute Neutrophil Count ≥1000/mcL
• * Platelet count ≥100,000/mcL independent of transfusion
• * Total bilirubin \< 1.5x upper limit of normal for age
• * AST(SGOT)/ALT(SGPT) ≤ 2.5 x institutional upper limit of normal
• * Serum creatinine \< 1.5 x upper limit of normal based on age/gender (Table 3) OR creatinine clearance ≥70 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
• * Shortening fraction ≥ 27% by ECHO OR ejection fraction of ≥ 50% by ECHO or gated radionuclide study
• * Echocardiogram done within 12 months of study entry will be acceptable. If patient has required anthracycline chemotherapy since last ECHO and enrollment on this study, echocardiogram should be repeated.
• * No evidence for dyspnea at rest, no chronic oxygen requirement, and room air pulse oximetry \>94% if there is a clinical indication for pulse oximetry 6) Neuropathy: Patients must have ≤ Grade 2 neuropathy at enrollment 7) Patients with seizure disorders may be enrolled if seizures are well controlled on anti-convulsant, with the exception of diazepam given its potential deleterious effects on NK cell activity.
• 1. Patients who are receiving any other investigational agents.
• 2. Patients must not be receiving any additional medicines being given for the specific purpose of treating cancer
• 3. Patients with a history of allergic reactions attributed to docetaxel, gemcitabine, or peg-filgrastim or biosimilar
• 4. Patients who have received any prior cellular therapies, such as CAR-T cells or other expanded or manufactured cellular products.
• 5. Patients with bone marrow only disease are not eligible for this study.
• 6. Patients who, in the judgment of the treating physician, has tumors near critical structures for which transient swelling would cause substantial symptoms, such as tumor within the bowel mucosa
• 7. Patients with CNS metastatic disease will not be eligible for this study.
• 8. Concomitant Medications:
• * Due to their effect on NK cell function, systemic corticosteroids outside of the supportive dexamethasone given from day 7 through 9 should be used ONLY for life-threatening conditions (i.e., life-threatening allergic reactions and anaphylaxis such as bronchospasm, stridor) unresponsive to other measures. The use of dexamethasone as an anti-emetic is not permitted. Corticosteroid therapy can be used as a premedication for transfusion in patients known to have a history of transfusion reactions or for treatment of an unexpected transfusion reaction (hydrocortisone 2 mg/kg or less or an equivalent dose of an alternative corticosteroids). The use of steroids during protocol therapy other than the study- required prophylactic dexamethasone doses requires clear justification and documentation of use for a life-threatening condition.
• * The following are also prohibited while on study treatment
• * Strong CYP3A4 inducers. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/; medical reference texts such as the Physicians' Desk Reference may also provide this information.
• * Diazepam
• * Chemotherapeutic agents other than the study drugs
• 9. Uncontrolled intercurrent illness including, but not limited to:
• * ongoing or active infection
• * psychiatric illness/social situations that would limit compliance with study requirements
• 10. Pregnancy or Breast-Feeding: Pregnant or breast-feeding woman will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies with Gemcitabine and Docetaxel
• 11. HIV Infection: HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with the study medications. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
• 12. Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.