Donor NK Cell Therapy in Combination with Gemcitabine and Docetaxel for the Treatment of Relapsed or Refractory Sarcomas, The TINKS Trial
This phase II trial tests how well donor immune cells called natural killer (NK) cells, in combination with gemcitabine and docetaxel (GEMDOX), works in treating patients with sarcomas that have not responded to previous treatment (refractory), or sarcomas that have come back after a period of improvement (recurrent). NK cells are normally present in the body in small amounts. They are very good at recognizing viruses and cancers too. When they recognize a tumor cell, NK cells will try to kill the tumor cell. NK cells can be collected from healthy people and grown in the lab. Then they can be given by vein to people with cancer to try to help their immune system fight their cancer. Sarcomas can send out a signal that can make NK cells less effective, called TGF-beta. The NK cells from another person (donor) used in this trial have been exposed to TGF-beta when they were made, which may make these NK cells better at treating sarcoma. Gemcitabine is a chemotherapy drug that blocks the cells from making DNA and may kill tumor cells. Docetaxel is in a class of medications called taxanes. It stops tumor cells from growing and dividing and may kill them. Giving TGF-beta NK cells in combination with chemotherapy with GEMDOX may kill more tumor cells in patients with sarcomas.
Inclusion Criteria
- Patients must be between the ages >= 2 years and =< 40 years of age and have had a relapsed or refractory osteosarcoma, Ewing sarcoma, rhabdomyosarcoma or non-rhabdomyosarcoma soft tissue sarcoma
- Patients must have measurable disease using RECIST 1.1 criteria
- Patients must have had at least one and no more than four total lines of cytotoxic systemic treatment regimens 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
- 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 external radiation therapy (XRT) (smallport); 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
- Performance status: Karnofsky >= 60 for patients >=16 years of age. Lansky score of >= 60 for patients < 16 years of age
- Absolute neutrophil count >= 1000/mcL (within 7 days of starting protocol therapy)
- Platelet count >= 100,000/mcL (transfusion-independent, defined as no platelet transfusions within the last 72 hours) (within 7 days of starting protocol therapy)
- Total bilirubin < 1.5 x upper limit of normal for age (within 7 days of starting protocol therapy)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x institutional upper limit of normal (within 7 days of starting protocol therapy)
- Serum creatinine < 1.5 x upper limit of normal based on age/gender OR creatinine clearance >= 70 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal (within 7 days of starting protocol therapy)
- Shortening fraction >= 27% by ECHO OR ejection fraction of >= 50% by ECHO or gated radionuclide study (within 7 days of starting protocol therapy) * 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 (within 7 days of starting protocol therapy)
- Neuropathy: Patients must have =< grade 2 neuropathy at enrollment
- 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
- Contraception: The effects of expanded NK cells on the developing human fetus are unknown. For this reason and because the chemotherapeutic preparative agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of preparatory regimen administration
- All patients and/or their parents or legal guardians must have the ability to understand and the willingness to sign a written informed consent/assent document
Exclusion Criteria
- Patients who are receiving any other investigational agents
- Patients must not be receiving any additional medicines being given for the specific purpose of treating cancer
- Patients with a history of allergic reactions attributed to docetaxel, gemcitabine, or peg-filgrastim or biosimilar
- Patients who have received any prior cellular therapies, such as chimeric antigen receptor (CAR)-T cells or other expanded or manufactured cellular products
- Patients with bone marrow only disease are not eligible for this study
- Patients with any of the following “intermediate (rarely metastasizing)” or “malignant” grade 2 or grade 3 tumors of any size, as defined in the World Health Organization (WHO) classification of soft tissue tumors, are not eligible for this study: * So-called fibrohistiocytic tumors – plexiform fibrohistiocytic tumor, giant cell tumor of soft tissues * Fibroblastic/myofibroblastic tumors – solitary fibrous tumor, malignant solitary fibrous tumor, inflammatory myofibroblastic tumor, low grade myofibroblastic sarcoma, myxoinflammatory fibroblastic sarcoma, atypical myxoinflammatory fibroblastic tumor, myxofibrosarcoma, low grade fibromyxoid sarcoma, sclerosing epithelioid fibrosarcoma * Tumors of uncertain differentiation – epithelioid sarcoma, alveolar soft part sarcoma, clear cell sarcoma of soft tissue, angiomatoid fibrous histiocytoma, ossifying fibromyxoid tumor, myoepithelioma, myoepithelial carcinoma, extraskeletal myxoid chondrosarcoma, neoplasms with perivascular epithelioid cell differentiation (PEComa), intimal sarcoma, atypical fibroxanthoma, mixed tumor not otherwise specified (NOS), phosphaturic mesenchymal tumor, malignant ossifying fibromyxoid tumor, 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, malignant granular cell tumor, epithelioid malignant peripheral nerve sheath tumor, malignant Triton tumor * Undifferentiated sarcomas (with a specific pathologic category in the WHO classification) - undifferentiated round cell sarcoma, undifferentiated epithelioid sarcoma, undifferentiated spindle cell sarcoma
- 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
- Patients with central nervous system (CNS) metastatic disease will not be eligible for this study
- 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
- Uncontrolled intercurrent illness including, but not limited to: * ongoing or active infection * psychiatric illness/social situations that would limit compliance with study requirements
- 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
- 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
- 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
Additional locations may be listed on ClinicalTrials.gov for NCT05634369.
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PRIMARY OBJECTIVES:
I. To determine the safety of the addition of adoptive transfer of universal donor expanded TGF-beta-imprinted NK cells (universal donor, TGFbeta imprinted [TGFbetai], expanded NK cells) to gemcitabine/docetaxel (GEM/DOX) for treatment of relapsed and refractory sarcomas.
II. To determine the 6-month progression free survival achieved with this treatment in patients within cohorts of relapsed or refractory osteosarcoma, Ewing sarcoma, rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma.
SECONDARY OBJECTIVES:
I. To identify the toxicities related to this treatment regimen using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
II. To evaluate response rates across sarcoma histologies using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
III. To assess overall survival for patients with relapsed sarcoma treated with this regimen.
IV. To evaluate the persistence of TGFbetai NK cells in patient peripheral blood during therapy.
V. To quantify circulating tumor deoxyribonucleic acid (ctDNA) in patients with relapse or refractory sarcomas before, during and after therapy.
VI. To evaluate the effect of chemotherapy regimen on enhancing tumor targets for NK cell-mediated lysis in circulating tumor cells and in resected tumor tissue.
VII. To evaluate the density, phenotype, and function of TGFbetai NK cells that have successfully invaded the tumor microenvironment in patients undergoing surgical local control during or immediately after completing planned therapy.
VIII. To evaluate the 1-year progression free survival for patients within cohorts of relapsed or refractory osteosarcoma, Ewing sarcoma, rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma who receive continuation therapy.
IX. To evaluate the feasibility and safety of monotherapy NK infusions as continuation therapy.
EXPLORATORY OBJECTIVE:
I. To compare radiographic response with RECIST 1.1 versus (vs.) Immune-Modified (i)RECIST for evaluation of response to cellular therapy in patients determined to have pseudoprogression by treating physician.
OUTLINE:
INITIAL THERAPY: Patients receive gemcitabine intravenously (IV) over 90 minutes on days 1 and 8, docetaxel IV over 60 minutes on day 8, and TGF-beta NK cells IV over 30 minutes or less from time of thaw on day 12 of each cycle. Cycles repeat every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Patients may undergo local control with surgery or radiation therapy following cycle 2 as clinically indicated.
CONTINUATION THERAPY: Patients with complete response (CR), partial response (PR) or stable disease (SD) after cycle 8 may optionally continue study treatment for an additional 8 cycles. Patients may optionally continue study treatment non-randomly with 1 of 2 regimens.
REGIMEN A: Patients receive gemcitabine IV over 90 minutes on days 1 and 8, docetaxel IV over 60 minutes on day 8, and TGF-beta NK cells IV over 30 minutes or less from time of thaw on day 12 of each cycle. Cycles repeat every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity.
REGIMEN B: Patients receive TGF-beta NK cells IV over 30 minutes or less from time of thaw on day 1 of each cycle. Cycles repeat every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity.
Additionally, patients undergo echocardiography (ECHO) during screening and computed tomography (CT) scan or magnetic resonance imaging (MRI) as well as blood sample collection throughout the study. Patients may undergo tissue sample collection as clinically indicated.
After completion of study treatment, patients are followed up at 30 days and then every 3 – 12 months for up to 5 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationNationwide Children's Hospital
Principal InvestigatorBhuvana Anantha Setty
- Primary IDMCC21704
- Secondary IDsNCI-2023-00498
- ClinicalTrials.gov IDNCT05634369