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.
Recently published data shows that priming ASS1-deficient tumors with ADI-PEG 20 and
docetaxel improves the effect of gemcitabine. Therefore, a cohort of patients consisting of
ten patients diagnosed with either osteosarcoma or Ewing's sarcoma (ideally five of each),
and five patients diagnosed with small cell lung cancer will be included as an exploratory
cohort. Enrollment to Cohort 2 will occur concurrently with Cohort 1.
- Cohort 1: 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.
- Cohort 2: Histologically or cytologically confirmed osteosarcoma, Ewing's sarcoma, or
small cell lung cancer that is unresectable or metastatic that have either failed
standard of care therapy or would be standardly treated with gemcitabine or
gemcitabine and docetaxel.
- 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.
- Cohort 1: At least 16 years of age.
- Cohort 2: Patients with osteosarcoma or Ewing's sarcoma must be at least 10 years of
age. Patients with small cell lung cancer must be at least 18 years of age.
- Cohort 2 (SCLC group ONLY): Must be amenable to biopsy
- 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
- 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 (except for patients with SCLC, see below) because of their poor
prognosis and because they often develop progressive neurologic dysfunction that would
confound the evaluation of neurologic and other adverse events. Patients with SCLC are
allowed to enroll with brain metastases provided they are stable and they are at least
3 months post-treatment for brain metastases.
- 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
- 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.