Clinical trial NCT03449901: 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
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
Conditions: Soft Tissue Sarcoma
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.
Interventions:
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.
name: pegylated arginine deiminase
other_name: ADI-PEG 20
type: Drug
description: -Gemcitabine is a nucleoside metabolic inhibitor that exhibits antitumor activity.
name: Gemcitabine
other_name: Gemzar
type: Drug
description: -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.
name: Docetaxel
other_name: Taxotere
type: Drug
description: * Up to 21 days prior to initiation of ADI-PEG 20 Day -1 (+/- 1 day as long as performed prior to initiation of gemcitabine.<br/>* 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
name: Tumor biopsy
type: Procedure
description: -Day -7 (pre-treatment), Day -1, and Days 1 and 8 of each cycle
name: Research blood draw
type: Procedure
Study arms:
design_group_description: * 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.<br/>* 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<br/>* After Cycle 8, patients may continue on ADI-PEG 20 alone (without gemcitabine and docetaxel) upon request.<br/>* Treatment may continue for up to 34 cycles (103 weeks)
design_group_title: Cohort 1: ADI-PEG 20 + Gemcitabine + Docetaxel
design_group_type: Experimental
design_group_description: * 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.<br/>* 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<br/>* After Cycle 8, patients may continue on ADI-PEG 20 alone (without gemcitabine and docetaxel) upon request.<br/>* Treatment may continue for up to 34 cycles (103 weeks)
design_group_title: Cohort 2: ADI-PEG 20 + Gemcitabine + Docetaxel
design_group_type: Experimental
Sponsor: Washington University School of Medicine
Collaborators: National Cancer Institute
National Institutes of Health
Drug name mappings:
name: 盐酸吉西他滨
lang: CN
name: Gemcitabine Hydrochloride
lang: EN
name: ゲムシタビン塩酸塩
lang: JP
name: 多西他赛
lang: CN
name: Docetaxel
lang: EN
name: ドセタキセル
lang: JP