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
Condition: Soft Tissue Sarcoma
MeSH terms: Sarcoma; Small Cell Lung Carcinoma; Osteosarcoma; Sarcoma, Ewing
Intervention: pegylated arginine deiminase; Gemcitabine; Docetaxel; Tumor biopsy; Research blood draw
Intervention description: -Arginine deiminase (ADI) is a recombinant protein cloned from M. hominis, produced in E. coli, and conjugated with PEG of 20,000 mw using a succinimidyl succinate linker. Thus ADI-PEG 20 is an arginine degrading enzyme, ADI, coupled to PEG.; -Gemcitabine is a nucleoside metabolic inhibitor that exhibits antitumor activity.; -Docetaxel is an antineoplastic agent belonging to the taxoid family. It is prepared by semisynthesis beginning with a precursor extracted from the renewable needle biomass of yew plants.; Up to 21 days prior to initiation of ADI-PEG 20 Day -1 (+/- 1 day as long as performed prior to initiation of gemcitabine.
Tumor biopsies are mandatory for the first 20 patients amendable to biopsy enrolled at Washington University only (completed as of 05/14/2019) and for all patients enrolled to the SCLC cohort; -Day -7 (pre-treatment), Day -1, and Days 1 and 8 of each cycle
Intervention MeSH terms: Gemcitabine; Docetaxel
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 98.0
Sex: All
Minimum age: 10 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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
             immediately.

          -  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.