Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Skin and Connective Tissue Diseases

Rare Diseases

Lung Neoplasms

Small Cell Lung Carcinoma

Sarcoma

Osteosarcoma

Sarcoma, Ewing

Carcinoma

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Carcinoma, Bronchogenic

Bronchial Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Neoplasms, Bone Tissue

Neoplasms, Connective Tissue

Small Cell Lung Cancer

Soft Tissue Sarcoma

Ewing Sarcoma

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Gemcitabine

Docetaxel

Taxane

Antimetabolites

Tubulin Modulators

Antimitotic Agents

Arginine

* 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)

-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.

pegylated arginine deiminase

-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

Tumor biopsy

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

Research blood draw

Brian A Van Tine, M.D., Ph.D.

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.

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

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

* 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).

-OS: defined as time on study to time of death due to any reasons or latest follow-up (whichever is earlier)

* 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.

-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.

National Institutes of Health (NIH)

National Cancer Institute (NCI)

Washington University School of Medicine

Patients enrolling to Cohort 1 must be diagnosed with soft tissue sarcoma.

* 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)

Cohort 1, 600mg/m2 Gemcitabine Dose Level: ADI-PEG 20 + Gemcitabine + Docetaxel

Patients enrolling to Cohort 1 must be diagnosed with soft tissue sarcoma.

* 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 750 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)

Cohort 1, 750 mg/m2 Gemcitabine Dose Level: ADI-PEG 20 + Gemcitabine + Docetaxel

Patients enrolling to Cohort 1 must be diagnosed with soft tissue sarcoma.

* 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 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)

Cohort 1, 900 mg/m2 Gemcitabine Dose Level: ADI-PEG 20 + Gemcitabine + Docetaxel

Patients enrolling to Cohort 2 must be diagnosed with osteosarcoma, Ewing's sarcoma, or small cell lung cancer.

* 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)

Cohort 2, 600mg/m2 Gemcitabine Dose Level: ADI-PEG 20 + Gemcitabine + Docetaxel

Cohort 1: ADI-PEG 20 + Gemcitabine + Docetaxel

Cohort 2: ADI-PEG 20 + Gemcitabine + Docetaxel

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Brian A. Van Tine, M.D., Ph.D.

PFS was evaluated only for Cohort 1; therefore, no participants in Cohort 2 were analyzed for this outcome measure. 2 participants in Cohort 1 were not evaluable for this outcome measure.

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

OS was evaluated only for Cohort 1; therefore, no participants in Cohort 2 were analyzed for this outcome measure. 7 participants in Cohort 1 were not evaluable for this outcome measure.

Overall Survival (OS) (Cohort 1 Only)

CBR was evaluated only for Cohort 1; therefore, no participants in Cohort 2 were analyzed for this outcome measure. 8 participants in Cohort 1 were not evaluable for this outcome measure.

Clinical Benefit Rate (CBR) (Cohort 1 Only)

Grade 1-2 anemia

Grade 3-5 anemia

Grade 3-5 febrile neutropenia

Grade 1-2 eosiniphilia

Grade 3-5 mitral valve disease

Grade 1-2 atrial fibrillation

Grade 3-5 atrial fibrillation

Grade 1-2 palpitations

Grade 3-5 pericardial effusion

Grade 1-2 sinus bradycardia

Grade 1-2 sinus tachycardia

Grade 3-5 sinus tachycardia

Grade 1-2 chest pain - cardiac

Grade 1-2 ear pain

Grade 1-2 vertigo

Grade 3-5 tinnitus

Grade 1-2 hyperthyroidism

Grade 1-2 cataract

Grade 1-2 blurred vision

Grade 1-2 watering eyes

Grade 1-2 retinal tear

Grade 1-2 dry eye

Grade 1-2 abdominal distension

Grade 1-2 abdominal pain

Grade 3-5 abdominal pain

Grade 1-2 anal hemorrhage

Grade 1-2 anal mucositis

Grade 1-2 ascites

Grade 3-5 ascites

Grade 1-2 bloating

Grade 1-2 colitis

Grade 1-2 colonic hemorrhage

Grade 3-5 colonic perforation

Grade 1-2 constipation

Grade 1-2 dental caries

Grade 3-5 dental caries

Grade 1-2 diarrhea

Grade 3-5 diarrhea

Grade 1-2 dry mouth

Grade 1-2 dyspepsia

Grade 1-2 dysphagia

Grade 1-2 fecal incontinence

Grade 1-2 flatulence

Grade 1-2 gastroesophageal reflux disease

Grade 1-2 hematochezia

Grade 3-5 generalized GI bleed

Grade 1-2 tooth extraction

Grade 1-2 hemorrhoids

Grade 3-5 lower gastrointestinal hemorrhage

Grade 1-2 lip pain

Grade 1-2 mucositis oral

Grade 1-2 nausea

Grade 1-2 oral pain

Grade 1-2 rectal hemorrhage

Grade 3-5 small intestinal obstruction

Grade 3-5 typhlitis

Grade 3-5 upper gastrointestinal hemorrhage

Grade 1-2 vomiting

Grade 3-5 vomiting

Grade 1-2 chills

Grade 5 death NOS

Grade 1-2 edema face

Grade 1-2 edema limbs

Grade 3-5 edema limbs

Grade 1-2 edema trunk

Grade 3-5 edema trunk

Grade 1-2 facial pain

Grade 1-2 fatigue

Grade 3-5 fatigue

Grade 1-2 fever

Grade 1-2 flu-like symptoms

Grade 1-2 generalized edema

Grade 1-2 infusion related reaction

Grade 1-2 injection site reaction

Grade 1-2 localized edema

Grade 1-2 malaise

Grade 1-2 non-cardiac chest pain

Grade 3-5 non-cardiac chest pain

Grade 1-2 pain at injection site

Grade 1-2 pain

Grade 3-5 hepatic hemorrhage

Grade 1-2 allergic reaction

Grade 3-5 allergic reaction

Grade 3-5 Celiac disease

Grade 1-2 bladder infection

Grade 1-2 bronchial infection

Grade 1-2 enterocolitis infectious

Grade 3-5 enterocolitis infectious

Grade 1-2 eye infection

Grade 1-2 folliculitis

Grade 1-2 gum infection

Grade 3-5 influenza A infection

Grade 1-2 lung infection

Grade 3-5 lung infection

Grade 1-2 papulopustular rash

Grade 1-2 paronychia

Grade 3-5 pleural infection

Grade 3-5 sepsis

Grade 1-2 sinusitis

Grade 1-2 skin infection

* 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 750 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)

* 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 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)

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

Cancer-related mortality was evaluated only for Cohort 1; therefore, no participants in Cohort 2 were analyzed for this outcome measure. 7 participants in Cohort 1 were not evaluable for this outcome measure.

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

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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	Soft Tissue Sar...	pegylated argin... Gemcitabine Docetaxel Tumor biopsy Research blood ...	10 Years -	Washington University School of Medicine
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	Soft Tissue Sar...	pegylated argin... Gemcitabine Docetaxel Tumor biopsy Research blood ...	10 Years -	Washington University School of Medicine
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	Soft Tissue Sar...	pegylated argin... Gemcitabine Docetaxel Tumor biopsy Research blood ...	10 Years -	Washington University School of Medicine

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