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

Study Overview
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Brief Summary
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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.

Official Title
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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
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Soft Tissue Sarcoma

Intervention / Treatment
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* Drug: pegylated arginine deiminase
* Drug: Gemcitabine
* Drug: Docetaxel
* Procedure: Tumor biopsy
* Procedure: Research blood draw


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 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 (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.

Ages Eligible for Study
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Minimum Age: 10 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: ADI-PEG 20 + Gemcitabine + Docetaxel<br>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<br>* -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.<br>* Other names: ADI-PEG 20;Drug: Gemcitabine<br>* -Gemcitabine is a nucleoside metabolic inhibitor that exhibits antitumor activity.<br>* Other names: Gemzar;Drug: Docetaxel<br>* -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.<br>* Other names: Taxotere;Procedure: Tumor biopsy<br>* 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<br>Procedure: Research blood draw<br>* -Day -7 (pre-treatment), Day -1, and Days 1 and 8 of each cycle<br>|
| Experimental: Cohort 2: ADI-PEG 20 + Gemcitabine + Docetaxel<br>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<br>* -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.<br>* Other names: ADI-PEG 20;Drug: Gemcitabine<br>* -Gemcitabine is a nucleoside metabolic inhibitor that exhibits antitumor activity.<br>* Other names: Gemzar;Drug: Docetaxel<br>* -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.<br>* Other names: Taxotere;Procedure: Tumor biopsy<br>* 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<br>Procedure: Research blood draw<br>* -Day -7 (pre-treatment), Day -1, and Days 1 and 8 of each cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) (Cohort 1 Only) | -OS: defined as time on study to time of death due to any reasons or latest follow-up (whichever is earlier) | Through completion of follow-up (median follow-up 494 days, full range of 5-1500 days). | 
| Clinical Benefit Rate (CBR) (Cohort 1 Only) | 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. | Through completion of treatment (median treatment of 9 months) | 
| Safety and Tolerability of Regimen as Measured by Number and Grade of Adverse Events | -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. | 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). |