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

Inclusion Criteria:

1. Patients must be between the ages ≥ 2 years and ≤ 40 years of age and have had arelapsed or refractory osteosarcoma, Ewing sarcoma, rhabdomyosarcoma ornon-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 cytotoxicsystemic treatment for relapse sarcoma. Local control with surgical resection orradiation therapy of the primary tumor and any metastatic sites as clinicallyindicated as standard of care per the treating physician must be considered prior toenrollment.

4. Prior Therapy: Therapy may not have been received more recently than the timeframesdefined below:

• Myelosuppressive chemotherapy: Patients must not have received myelosuppressivetherapy within 14 days of protocol therapy

• Radiation: At least 2 weeks must have elapsed from the start of protocoltherapy since local palliative XRT (small port); 4 weeks must have elapsed forall other radiation therapy

• Hematopoietic Cell Transplant (HCT): Patients must have at least 6 weekselapsed 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 sincethe completion of therapy with a biologic agent.

• Monoclonal antibodies: At least 3 weeks must have elapsed from the start ofprotocol therapy since prior therapy that included a monoclonal antibody.

• Prior use of Gemcitabine and/or Docetaxel: Patients who have received theseagents for prior treatment may be included if previous treatments were given ≥ 6 months prior to enrollment on this study, and there were no allergicreactions, pulmonary edema or fibrosis, Grade 3 or higher neuropathy or othernon-hematologic Grade 4 adverse events related to gemcitabine and/or docetaxeltherapies.

4. Performance status: Karnofsky ≥ 60 for patients ≥16 years of age. Lansky score of ≥ 60 for patients < 16 years of age (see Appendix A) 5) Organ Function Requirements:Patients must have normal organ and marrow function within 7 days of startingprotocol therapy as defined below:

• Absolute Neutrophil Count ≥1000/mcL

• Platelet count ≥100,000/mcL transfusion independent defined as no platelettransfusions within the last 72 hours

• 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) ORcreatinine clearance ≥70 mL/min/1.73 m2 for patients with creatinine levels aboveinstitutional normal

• Shortening fraction ≥ 27% by ECHO OR ejection fraction of ≥ 50% by ECHO or gatedradionuclide study

• Echocardiogram done within 12 months of study entry will be acceptable. Ifpatient has required anthracycline chemotherapy since last ECHO and enrollmenton this study, echocardiogram should be repeated.

• No evidence for dyspnea at rest, no chronic oxygen requirement, and room air pulseoximetry >94% if there is a clinical indication for pulse oximetry 6) Neuropathy:Patients must have ≤ Grade 2 neuropathy at enrollment 7) Patients with seizuredisorders may be enrolled if seizures are well controlled on anti-convulsant, withthe exception of diazepam given its potential deleterious effects on NK cellactivity.

8. Contraception: The effects of expanded NK cells on the developing human fetusare unknown. For this reason and because the chemotherapeutic preparativeagents as well as other therapeutic agents used in this trial are known to beteratogenic, women of child-bearing potential must agree to use adequatecontraception (hormonal or barrier method of birth control; abstinence) priorto study entry and for the duration of study participation. Should a womanbecome pregnant or suspect she is pregnant while she or her partner isparticipating in this study, she should inform her treating physicianimmediately. Men treated or enrolled on this protocol must also agree to useadequate contraception prior to the study, for the duration of studyparticipation, and 4 months after completion of preparatory regimenadministration.

9. All patients and/or their parents or legal guardians must have the ability tounderstand and the willingness to sign a written informed consent/assentdocument.

Exclusion Criteria:

1. Patients who are receiving any other investigational agents.

2. Patients must not be receiving any additional medicines being given for the specificpurpose 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 orother expanded or manufactured cellular products.

5. Patients with bone marrow only disease are not eligible for this study.

6. Patients with any of the following "Intermediate" (rarely metastasizing) or "malignant" Grade 2 or Grade 3 tumors of any size, as defined in the WHOClassification of Soft Tissue Tumors are not eligible for this study:

• So-called fibrohistiocytic tumors - plexiform fibrohistiocytic tumor, giantcell tumor of soft tissues

• Fibroblastic/myofibroblastic tumors - solitary fibrous tumor, malignantsolitary fibrous tumor, inflammatory myofibroblastic tumor, low grademyofibroblastic sarcoma, myxoinflammatory fibroblastic sarcoma, atypicalmyxoinflammatory fibroblastic tumor, myxofibrosarcoma, low grade fibromyxoidsarcoma, sclerosing epithelioid fibrosarcoma

• Tumors of uncertain differentiation - epithelioid sarcoma, alveolar soft partsarcoma, clear cell sarcoma of soft tissue, angiomatoid fibrous histiocytoma,ossifying fibromyxoid tumour, myoepithelioma, myoepithelial carcinoma,extraskeletal myxoid chondrosarcoma, neoplasms with perivascular epithelioidcell differentiation (PEComa), initial sarcoma, atypical fibroxanthoma, mixedtumor NOS, phosphaturic mesenchymal tumor, malignant ossifying fibromyxoidtumor, malignant mixed tumor, malignant phosphaturic mesenchymal tumor

• Chondro-osseous tumors - extraskeletal osteosarcoma

• Pericytic (perivascular) tumors - malignant glomus tumor

• Nerve sheath tumors - malignant peripheral nerve sheath tumor, malignantgranular cell tumor, epithelioid malignant peripheral nerve sheath tumor,malignant Triton tumor

• Undifferentiated sarcomas (with a specific pathologic category in the WHOclassification) - undifferentiated round cell sarcoma, undifferentiatedepithelioid sarcoma, undifferentiated spindle cell sarcoma

7. Patients who, in the judgment of the treating physician, has tumors near criticalstructures for which transient swelling would cause substantial symptoms, such astumor within the bowel mucosa

8. Patients with CNS metastatic disease will not be eligible for this study.

9. Concomitant Medications:

• Due to their effect on NK cell function, systemic corticosteroids outside ofthe supportive dexamethasone given from day 7 through 9 should be used ONLY forlife-threatening conditions (i.e., life-threatening allergic reactions andanaphylaxis such as bronchospasm, stridor) unresponsive to other measures. Theuse of dexamethasone as an anti-emetic is not permitted. Corticosteroid therapycan be used as a premedication for transfusion in patients known to have ahistory of transfusion reactions or for treatment of an unexpected transfusionreaction (hydrocortisone 2 mg/kg or less or an equivalent dose of analternative corticosteroids). The use of steroids during protocol therapy otherthan the study- required prophylactic dexamethasone doses requires clearjustification 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 constantlychanging, it is important to regularly consult a frequently-updated listsuch as http://medicine.iupui.edu/clinpharm/ddis/; medical reference textssuch as the Physicians' Desk Reference may also provide this information.

• Diazepam

• Chemotherapeutic agents other than the study drugs

10. Uncontrolled intercurrent illness including, but not limited to:

• ongoing or active infection

• psychiatric illness/social situations that would limit compliance with studyrequirements

11. Pregnancy or Breast-Feeding: Pregnant or breast-feeding woman will not be entered onthis study due to risks of fetal and teratogenic adverse events as seen inanimal/human studies with Gemcitabine and Docetaxel

12. HIV Infection: HIV-positive patients on combination antiretroviral therapy areineligible because of the potential for pharmacokinetic interactions with the studymedications. In addition, these patients are at increased risk of lethal infectionswhen treated with marrow-suppressive therapy. Appropriate studies will be undertakenin patients receiving combination antiretroviral therapy when indicated

13. Patients who in the opinion of the investigator may not be able to comply with thesafety monitoring requirements of the study are not eligible.