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| Name | Class |
|---|---|
| National Pediatric Cancer Foundation | OTHER |
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The purpose of this study is to determine if the addition of infusions of a type of immune cell called a "natural killer", or NK cell to the sarcoma chemotherapy regimen GEM/DOX (gemcitabine and docetaxel) can improve outcomes in people with childhood sarcomas that have relapsed or not responded to prior therapies.
The goals of this study are:
Participants will receive study drugs that include chemotherapy and NK cells in cycles; each cycle is 21 days long and you can receive up to 8 cycles.
This is a multi-center study with rolling safety and toxicity analysis, to determine the safety and efficacy of the addition of adoptive transfer of universal donor, TGFβ imprinted (TGFβi), expanded NK cells to the pediatric sarcoma salvage chemotherapeutic regimen gemcitabine/docetaxel (GEM/DOX) for treatment of relapsed and refractory pediatric sarcomas, identify toxicities related to treatment with GEM/DOX + TGFβi expanded NK cells, and assess in vivo persistence of expanded, universal donor, TGFβi NK cells after adoptive transfer and correlate with clinical outcomes.
The planned therapy will involve 8 cycles of 21 days each consisting of gemcitabine, docetaxel, supportive dexamethasone and peg-filgrastim, and universal donor, TGFβi ex vivo expanded NK cells (Cycles 1-6).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment | Experimental | Part 1: Enrollment of 5 patients in each cohort (osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, and non-rhabdomyosarcoma). Part 2: Enrollment of 2 cohorts in 2 stages for a total of 40 patients. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| GEM/DOX + TGFBi expanded NK cells | Biological | 8 cycles consisting of gemcitabine, docetaxel, supportive dexamethasone and pegfilagrastim, and universal donor, TGFBi ex vivo expanded NK cells
|
| Measure | Description | Time Frame |
|---|---|---|
| Part 1 | Evaluation of DLT in patients enrolled during Part 1 enrollment
| 3-5 years |
| Part 2 | Determination of 6-month progression free survival (PFS) in study patients measured from initiation of treatment (Day 1 of the first cycle of therapy) Patients will be considered evaluable for tumor response if they:
| 3-5 years |
| Measure | Description | Time Frame |
|---|---|---|
| Treatment response of target lesions determined using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria | Assessments will be performed after every other cycle of treatment to determine antitumor effect of therapy. | Every two cycles (21 days per cycle) for 3-5 years |
| Frequency and characterization of DLT in study patients |
| Measure | Description | Time Frame |
|---|---|---|
| Exploratory Endpoint | Assessment of TGFβi NK cell persistence, phenotype, and retained cytolytic activity in patient peripheral blood via samples drawn on days 1, 8, and 12 of each cycle beginning with cycle 2 analyzed by flow cytometry. | Days 1, 8, and 12 of each cycle (21 days per cycle), starting with cycle 2 |
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 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:
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 starting protocol therapy as defined below:
Absolute Neutrophil Count ≥1000/mcL
Platelet count ≥100,000/mcL transfusion independent defined as no platelet transfusions 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) 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
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.
8) 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.
9) 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 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 WHO Classification of Soft Tissue Tumors are not eligible for this study:
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 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
Uncontrolled intercurrent illness including, but not limited to:
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.
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Jessica Crimella, BSN, RN, CCRP | Contact | 813-745-6250 | jessica.crimella@moffitt.org |
| Name | Affiliation | Role |
|---|---|---|
| Bhuvana Setty, MD | Nationwide Children's Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Alabama | Recruiting | South Birmingham | Alabama | 35233 | United States |
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Single arm, unblinded, phase I/II study
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|
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cycle = 21 days |
| 3-5 years |
| Phoenix Children's Hospital | Recruiting | Phoenix | Arizona | 85016 | United States |
|
| Arkansas Children's Hospital | Recruiting | Little Rock | Arkansas | 72202 | United States |
|
| Children's Hospital of Los Angeles | Recruiting | Los Angeles | California | 90027 | United States |
|
| Stanford University | Recruiting | Palo Alto | California | 94304 | United States |
|
| University of Florida | Recruiting | Gainesville | Florida | 32610 | United States |
|
| Nemours Jacksonville | Recruiting | Jacksonville | Florida | 32207 | United States |
|
| University of Miami | Recruiting | Miami | Florida | 33136 | United States |
|
| Johns Hopkins All Children's Hospital | Recruiting | St. Petersburg | Florida | 33701 | United States |
|
| Washington University/St Louis Childrens | Recruiting | St Louis | Missouri | 63110 | United States |
|
| Roswell Park Comprehensive Cancer Center | Recruiting | Buffalo | New York | 14263 | United States |
|
| Montefiore Medical Center | Recruiting | The Bronx | New York | 10467 | United States |
|
| University of North Carolina | Recruiting | Chapel Hill | North Carolina | 27599 | United States |
|
| Levine Cancer Institute | Recruiting | Charlotte | North Carolina | 28203 | United States |
|
| Duke Children's Hospital/Duke Health | Recruiting | Durham | North Carolina | 27710 | United States |
|
| Cleveland Clinic | Recruiting | Cleveland | Ohio | 44195 | United States |
|
| Nationwide Children's Hospital | Recruiting | Columbus | Ohio | 43205 | United States |
|
| Children's Hospital of Philadelphia | Recruiting | Philadelphia | Pennsylvania | 19104 | United States |
|
| Vanderbilt University Medical Center | Recruiting | Nashville | Tennessee | 37232 | United States |
|
| UT Southwestern | Recruiting | Dallas | Texas | 75390 | United States |
|
| University of Texas MD Anderson Cancer Center | Recruiting | Houston | Texas | 77030 | United States |
|
| Primary Children's Hospital | Recruiting | Salt Lake City | Utah | 84113 | United States |
|
| ID | Term |
|---|---|
| D012008 | Recurrence |
| ID | Term |
|---|---|
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D000077143 | Docetaxel |
| D003907 | Dexamethasone |
| C455861 | pegfilgrastim |
| D000093542 | Gemcitabine |
| ID | Term |
|---|---|
| D043823 | Taxoids |
| D043822 | Cyclodecanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D004224 | Diterpenes |
| D013729 | Terpenes |
| D011246 | Pregnadienetriols |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D013259 | Steroids, Fluorinated |
| D006571 | Heterocyclic Compounds |
| D003841 | Deoxycytidine |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
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