ADI-PEG 20 in Combination With Gemcitabine and Docetaxel for the Treatment of Soft Tissue Sarcoma
Trial ID or NCT#
The investigators have recently demonstrated that argininosuccinate synthase 1 (ASS1) expression is silenced in 88% of all sarcomas (n=708), and that this loss is associated with a decreased overall survival. Using the extracellular arginine depleting enzyme PEGylated arginine deiminase (ADI-PEG20), an extracellular arginine depleting enzyme, the investigators demonstrated ADI-PEG20 induces a prosurvival metabolic reprogramming in ASS1-deficient sarcomas that redirects glucose into the serine/folate pathway directing the carbons from glucose into pyrimidine biosynthesis, thus sensitizing cells to death by the pyrimidine antimetabolite gemcitabine by using metabolomics. The synthetic lethality was increased by the addition of docetaxel. Therefore a phase II clinical trial of ADI with gemcitabine and docetaxel, a standard second line therapy for soft tissue sarcoma will be conducted to determine if the clinical benefit rate of gemcitabine and docetaxel is improved by the metabolic changes induced by ADI-PEG20
A Phase II Trial of ADI-PEG 20 in Combination With Gemcitabine and Docetaxel for the Treatment of Soft Tissue Sarcoma
- - Histologically or cytologically confirmed grade 2 or 3 soft tissue sarcoma that is unresectable or metastatic that would be standardly treated with gemcitabine or gemcitabine and docetaxel. For all others, please contact the principal investigator. Prior surgery for primary or metastatic disease after chemotherapy following a response is allowed.
- - Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam.
- - Treated with at least one line of systemic therapy. The allowable window between treatments is 21 days for chemotherapy or a TKI, or 5 ½ half-lives for a TKI (whichever is shorter), 21 days and progression by CT for immunotherapy, 21 days for RT, 21 days for surgery, or 28 days for an investigational agent.
- - At least 16 years of age.
- - Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
- - Normal bone marrow and organ function as defined below:
- - Leukocytes ≥ 3,000/mcL
- - Absolute neutrophil count ≥ 1,500/mcl
- - Platelets ≥ 100,000/mcl
- - Total bilirubin ≤ 2 x institutional upper limit of normal (IULN)
- - AST(SGOT)/ALT(SGPT) ≤ 3 x IULN (or ≤ 5 x IULN if liver metastases are present)
- - Creatinine ≤ 1.5 x IULN OR
- - Creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
- - Serum uric acid ≤ 8 mg/dL (with or without medication control)
- - Women of childbearing potential and men 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 participating in this study, she must inform her treating physician immediately.
- - Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).
- - A history of other high grade malignancy ≤ 5 years previous. Exceptions include basal cell or squamous cell carcinoma of the skin which were treated with local resection only or carcinoma in situ of the cervix, or other tumors discussed with the study PI
- - Currently receiving any other investigational agents.
- - Prior treatment with ADI-PEG 20, gemcitabine, or docetaxel. Patients treated > one year ago in the adjuvant/neoadjuvant setting with gemcitabine or docetaxel would be allowed to be enrolled on the trial.
- - Known brain metastases. Patients with known brain metastases must be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
- - A history of allergic reactions attributed to compounds of similar chemical or biologic composition to ADI-PEG 20, gemcitabine, pegylated compounds, or other agents used in the study.
- - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- - History of seizure disorder not related to underlying cancer.
- - Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.
- - Known HIV-positivity on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with the study treatment. 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.
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