ADI-PEG 20 in Combination With Gemcitabine and Docetaxel for the Treatment of Soft Tissue Sarcoma, Osteosarcoma, Ewing's Sarcoma, and Small Cell Lung Cancer

Not Recruiting

Trial ID: NCT03449901


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.

Official Title

A Phase II Trial of ADI-PEG 20 in Combination With Gemcitabine and Docetaxel for the Treatment of Soft Tissue Sarcoma Osteosarcoma, Ewing's Sarcoma, and Small Cell Lung Cancer

Stanford Investigator(s)

Nam Quoc Bui
Nam Quoc Bui

Clinical Assistant Professor, Medicine - Oncology

Kristen N Ganjoo
Kristen N Ganjoo

Professor of Medicine (Oncology)


Inclusion Criteria:

   - 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).

Exclusion Criteria:

   - 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
   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.


drug: pegylated arginine deiminase

drug: Gemcitabine

drug: Docetaxel

procedure: Tumor biopsy

procedure: Research blood draw

Not Recruiting

Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305
Behnaz Agahian

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