ADI-PEG 20 in Combination With Gemcitabine and Docetaxel for the Treatment of Soft Tissue Sarcoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03449901
Recruitment Status : Recruiting
First Posted : February 28, 2018
Last Update Posted : October 31, 2018
Polaris Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Washington University School of Medicine

Brief 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

Condition or disease Intervention/treatment Phase
Soft Tissue Sarcoma Drug: pegylated arginine deiminase Drug: Gemcitabine Drug: Docetaxel Procedure: Tumor biopsy Procedure: Research blood draw Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 75 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Trial of ADI-PEG 20 in Combination With Gemcitabine and Docetaxel for the Treatment of Soft Tissue Sarcoma
Actual Study Start Date : May 9, 2018
Estimated Primary Completion Date : May 9, 2020
Estimated Study Completion Date : February 9, 2025

Arm Intervention/treatment
Experimental: ADI-PEG 20 + Gemcitabine + Docetaxel
  • ADI-PEG 20 will be given on Day -7 of Cycle 1 and then on Days 1, 8, and 15 of each subsequent cycle. Cycles are 21 days. ADI-PEG 20 will be given on an outpatient basis at a dose of 36 mg/m2 via intramuscular injection into either the deltoid or gluteal muscle.
  • Gemcitabine will be given intravenously at a dose of 900 mg/m2 over 90 minutes on Days 1 and 8 of each cycle. Docetaxel will be given intravenously at a dose of 75 mg/m2 over 60 minutes on Day 8 of each cycle.
  • Treatment may continue for up to 34 cycles (103 weeks)
Drug: pegylated arginine deiminase
-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.
Other Name: ADI-PEG 20

Drug: Gemcitabine
-Gemcitabine is a nucleoside metabolic inhibitor that exhibits antitumor activity.
Other Name: Gemzar

Drug: Docetaxel
-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.
Other Name: Taxotere

Procedure: Tumor biopsy
  • Day -7 (pre-treatment) and Day -1 prior to the start of Cycle 1
  • Tumor biopsies are mandatory for the first 10 patients amendable to biopsy enrolled at Washington University only

Procedure: Research blood draw
-Day -7 (pre-treatment), Day -1, and Days 1 and 8 of each cycle

Primary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: Through completion of follow-up (median treatment of 9 months + 6 months of follow-up) ]
    • PFS: defined as time on study to time patients progressed on the drug combination or death or latest follow-up if progression/death is not observed yet
    • Progressive disease: At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).

Secondary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: Through 5 years after completion of treatment (median treatment of 9 months) ]
    -OS: defined as time on study to time of death due to any reasons or latest follow-up (whichever is earlier)

  2. Clinical benefit rate (CBR) [ Time Frame: Through completion of treatment (median treatment of 9 months) ]
    • CBR = proportion of patients who have experienced complete response (CR)+ partial response (PR) + stable disease (SD) lasting 24 weeks or longer
    • CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).
    • PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
    • SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

  3. Safety and tolerability of regimen as measured by number and grade of adverse events [ Time Frame: From start of treatment through 30 days after completion of treatment (median treatment of 9 months + 1 month follow-up) ]
    -The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.

  4. Cancer-related mortality [ Time Frame: Through 5 years after completion of treatment (median treatment of 9 months) ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • 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. 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 in the palliative setting or with neoadjuvant or adjuvant chemotherapy within the prior six months. 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 18 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).

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
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03449901

Contact: Brian A Van Tine, M.D., Ph.D. 314-362-5817

United States, California
Sarcoma Oncology Center Not yet recruiting
Santa Monica, California, United States, 90403
Contact: Sant P Chawla, M.D.    310-552-9999      
Principal Investigator: Sant P Chawla, M.D.         
United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Brian A Van Tine, M.D., Ph.D.    314-362-5817   
Principal Investigator: Brian A Van Tine, M.D., Ph.D.         
Sub-Investigator: Douglas Adkins, M.D.         
Sub-Investigator: Angie Hirbe, M.D.         
Sub-Investigator: Jingqin (Rosy) Luo, Ph.D.         
Sponsors and Collaborators
Washington University School of Medicine
Polaris Pharmaceuticals, Inc.
Principal Investigator: Brian A Van Tine, M.D., Ph.D. Washington University School of Medicine

Additional Information:
Responsible Party: Washington University School of Medicine Identifier: NCT03449901     History of Changes
Other Study ID Numbers: 201803202
First Posted: February 28, 2018    Key Record Dates
Last Update Posted: October 31, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators