Clinical Trials /

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

NCT03449901

Description:

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

Related Conditions:
  • Soft Tissue Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: ADI-PEG 20 in Combination With Gemcitabine and Docetaxel for the Treatment of Soft Tissue Sarcoma
  • Official Title: A Phase II Trial of ADI-PEG 20 in Combination With Gemcitabine and Docetaxel for the Treatment of Soft Tissue Sarcoma

Clinical Trial IDs

  • ORG STUDY ID: 201803202
  • SECONDARY ID: 1R01CA227115-01A1
  • NCT ID: NCT03449901

Conditions

  • Soft Tissue Sarcoma

Interventions

DrugSynonymsArms
pegylated arginine deiminaseADI-PEG 20ADI-PEG 20 + Gemcitabine + Docetaxel
GemcitabineGemzarADI-PEG 20 + Gemcitabine + Docetaxel
DocetaxelTaxotereADI-PEG 20 + Gemcitabine + Docetaxel

Purpose

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

Trial Arms

NameTypeDescriptionInterventions
ADI-PEG 20 + Gemcitabine + DocetaxelExperimentalADI-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 600 mg/m2 over 90 minutes on Days 1 and 8 of each cycle. Docetaxel will be given intravenously at a dose of 60 mg/m2 over 60 minutes on Day 8 of each cycle. Patients started on gemcitabine at a dose of 900 mg/m2 or 750 mg/m2 or docetaxel at a dose of 75 mg/m2 per previous protocol version will be allowed to continue at that dose level Treatment may continue for up to 34 cycles (103 weeks)
  • pegylated arginine deiminase
  • Gemcitabine
  • Docetaxel

Eligibility Criteria

        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. 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).

        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 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:16 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:Through completion of follow-up (median treatment of 9 months + 6 months of follow-up)
Safety Issue:
Description: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

Measure:Overall survival (OS)
Time Frame:Through 5 years after completion of treatment (median treatment of 9 months)
Safety Issue:
Description:-OS: defined as time on study to time of death due to any reasons or latest follow-up (whichever is earlier)
Measure:Clinical benefit rate (CBR)
Time Frame:Through completion of treatment (median treatment of 9 months)
Safety Issue:
Description: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.
Measure: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)
Safety Issue:
Description:-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.
Measure:Cancer-related mortality
Time Frame:Through 5 years after completion of treatment (median treatment of 9 months)
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Washington University School of Medicine

Last Updated

September 19, 2019