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

NCT03449901 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 201912062-10011R01CA227115-01A1
• Study Type: interventional
• Target: 98
• Locations: 1 country
• Sites: 4

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. 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.

Conditions

Soft Tissue Sarcoma

Outcome Measures

Primary Outcomes (1)

• Progression-free Survival (PFS) (Cohort 1 Only)

  * 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).

  Through completion of follow-up (median follow-up 494 days, full range of 5-1500 days).

Secondary Outcomes (4)

• Overall Survival (OS) (Cohort 1 Only)

  Through completion of follow-up (median follow-up 494 days, full range of 5-1500 days).

• Clinical Benefit Rate (CBR) (Cohort 1 Only)

  Through completion of treatment (median treatment of 9 months)

• Safety and Tolerability of Regimen as Measured by Number and Grade of Adverse Events

  From start of treatment through 30 days after completion of treatment (median treatment of 9 months + 1 month follow-up)

• Number of Participants With Cancer-related Mortality (Cohort 1 Only)

  Through completion of follow-up (median follow-up 494 days, full range of 5-1500 days).

Study Arms (2)

Cohort 1: ADI-PEG 20 + Gemcitabine + Docetaxel

EXPERIMENTAL

* 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 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 * After Cycle 8, patients may continue on ADI-PEG 20 alone (without gemcitabine and docetaxel) upon request. * Treatment may continue for up to 34 cycles (103 weeks)

Drug: pegylated arginine deiminase; Drug: Gemcitabine; Drug: Docetaxel; Procedure: Tumor biopsy; Procedure: Research blood draw

Cohort 2: ADI-PEG 20 + Gemcitabine + Docetaxel

EXPERIMENTAL

* 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 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 * After Cycle 8, patients may continue on ADI-PEG 20 alone (without gemcitabine and docetaxel) upon request. * Treatment may continue for up to 34 cycles (103 weeks)

Drug: pegylated arginine deiminase; Drug: Gemcitabine; Drug: Docetaxel; Procedure: Tumor biopsy; Procedure: Research blood draw

Interventions

pegylated arginine deiminase DRUG

-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.

Also known as: ADI-PEG 20

Cohort 1: ADI-PEG 20 + Gemcitabine + Docetaxel; Cohort 2: ADI-PEG 20 + Gemcitabine + Docetaxel

Gemcitabine DRUG

-Gemcitabine is a nucleoside metabolic inhibitor that exhibits antitumor activity.

Also known as: Gemzar

Cohort 1: ADI-PEG 20 + Gemcitabine + Docetaxel; Cohort 2: ADI-PEG 20 + Gemcitabine + Docetaxel

Docetaxel DRUG

-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.

Also known as: Taxotere

Cohort 1: ADI-PEG 20 + Gemcitabine + Docetaxel; Cohort 2: ADI-PEG 20 + Gemcitabine + Docetaxel

Tumor biopsy PROCEDURE

* 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

Cohort 1: ADI-PEG 20 + Gemcitabine + Docetaxel; Cohort 2: ADI-PEG 20 + Gemcitabine + Docetaxel

Research blood draw PROCEDURE

-Day -7 (pre-treatment), Day -1, and Days 1 and 8 of each cycle

Cohort 1: ADI-PEG 20 + Gemcitabine + Docetaxel; Cohort 2: ADI-PEG 20 + Gemcitabine + Docetaxel

Eligibility Criteria

• Age: 10 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• National Institutes of Health (NIH): collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (4)

Stanford Medicine

Palo Alto, California, 94304, United States

Location

Sarcoma Oncology Center

Santa Monica, California, 90403, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Sarcoma

Interventions

ADI PEG20; Gemcitabine; Docetaxel

Condition Hierarchy (Ancestors)

Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Results Point of Contact

• Title: Mia Weiss, M.D.
• Organization: Washington University School of Medicine

m.c.weiss@wustl.edu

314-362-5737

Study Officials

• Mia Weiss, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 20, 2018
• First Posted: February 28, 2018
• Study Start: May 9, 2018
• Primary Completion: July 8, 2022
• Study Completion: July 8, 2022
• Last Updated: December 11, 2025
• Results First Posted: September 8, 2023

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (4)