SM-88 Maintenance Therapy for Advanced Ewing's Sarcoma and as Salvage Therapy for Sarcoma

Study Overview
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Brief Summary
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The primary objective is to evaluate the efficacy of SM-88, a combination metabolic cancer treatment, in two study cohorts: Clinically advanced Ewing's Sarcoma patients who have not progressed at the conclusion of systemic treatment Clinically advanced sarcoma patients in the salvage treatment setting Up to 24 efficacy evaluable patients (up to 12 per cohort) will be enrolled. Study patients will receive oral SM-88, with scheduled safety and efficacy evaluations.

Detailed Description
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This prospective, open-label, two stage, pilot phase 2 trial evaluates the efficacy and safety of SM-88 in two cohorts of patients: 1) as maintenance therapy following standard primary or palliative treatments for Ewing's sarcoma patients with high risk of relapse or disease progression; and 2) as salvage therapy for patients with clinically advanced sarcomas. The primary objective is to evaluate the efficacy of SM-88, a combination metabolic cancer treatment, measured as positive efficacy events, including overall response, maintaining stable disease for ≥ 3 months, or progression free survival at least 1.5 times longer than the last prior line of treatment. Eligible patients will receive daily oral treatment with SM-88, which consists of D,L-alpha-metyrosine, used with methoxsalen, phenytoin, and sirolimus in continuous treatment cycles of 28 days. Treatment will continue until: 1) Symptomatic, clinical progression with radiographic progressive disease; 2) 48 weeks after documented complete response; or 3) evidence of unacceptable toxicity, or other decision to discontinue treatment

Official Title
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Phase 2 Clinical Trial to Evaluate Efficacy and Safety of SM-88 Used With Methoxsalen, Phenytoin, and Sirolimus (MPS) as Maintenance Therapy Following Standard Treatments for Ewing's Sarcoma or as Salvage Therapy for Advanced Sarcomas

Conditions
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Sarcoma, Ewing, Sarcoma

Intervention / Treatment
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* Drug: Combination metyrosine-derivative, low-dose methoxsalen, phenytoin and sirolimus (MPS)


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Ability to understand and willingness to provide written informed consent to participate in this study ≥12 years of age Diagnosis: Maintenance treatment cohort: Histologic or cytologic diagnosis of Ewing's sarcoma, including non-resected, locally advanced or metastatic disease Salvage treatment cohort: Non-resected, locally advanced or metastatic sarcoma (including Ewing's sarcoma) for which there is no standard of care treatment and no curative other option Radiographic disease assessment within 35 days prior to enrollment and planned treatment start with study drug Prior treatment: Maintenance treatment cohort : 1-3 prior lines of systemic treatment (including current treatment) Salvage cohort: Any number of prior treatments Maintenance treatment cohort only: Patient completed current line of treatment (systemic, surgery, radiation) prior to enrollment, without disease progression as compared to baseline AND has achieved at least one of the following CR in response to current second or third line treatment PR in response to current line of treatment (after at least 4 cycles, if treatment included systemic therapy) SD in response to current line of treatment (after at least 4 cycles, if treatment included systemic therapy) Measurable disease, except for patients in Cohort A who have achieved CR at the conclusion of current 2nd or 3rd line of treatment ECOG performance status 0-2 Adequate organ function defined as all laboratory parameters ≤ Grade 2 NCI CTCAE criteria Patients must be able to swallow and retain whole capsules Key Exclusion Criteria: Systemic anticancer agents within 14 days prior to treatment on study Major surgery within 30 days Prior treatment with SM-88 Any screening laboratory, electrocardiogram (ECG), other clinical finding, comorbidity or clinical history that, in the opinion of the investigator, indicates an unacceptable risk for patient to participate in the study or would limit patient's ability to comply with study requirements History of any drug allergies or significant adverse reactions to any of the components of SM-88 History of light sensitive diseases for which methoxsalen would be contraindicated Current or anticipated treatment with a contraindicated medication Evidence of viral infections including human immunodeficiency virus (HIV), hepatitis B, and hepatitis C

Ages Eligible for Study
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Minimum Age: 12 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: Maintenance Treatment: Ewing's Sarcoma<br>Combination metyrosine-derivative, low-dose methoxsalen, phenytoin and sirolimus | Drug: Combination metyrosine-derivative, low-dose methoxsalen, phenytoin and sirolimus (MPS)<br>* Daily oral combination therapy for cancer<br>* Other names: SM-88;|
| Experimental: Salvage Treatment: Sarcoma<br>Combination metyrosine-derivative, low-dose methoxasalen, phenytoin and sirolimus | Drug: Combination metyrosine-derivative, low-dose methoxsalen, phenytoin and sirolimus (MPS)<br>* Daily oral combination therapy for cancer<br>* Other names: SM-88;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Complete response (CR) + partial response (PR) as evaluated using RECIST 1.1 | Every 3 months for up to 2 years | 
| Stable Disease for at Least 3 Months | Stable disease (SD) as evaluated using RECIST 1.1 | Every 3 months for up to 2 years | 
| Progression Free Survival on Study of at Least 1.5 Times the Duration of PFS for the Last Prior Treatment | From date of enrollment until the date of first documented progression, as evaluated using RECIST 1.1, or date of death, whichever occurs first | Every 3 months for up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response | From date of CR or PR until the date of first documented progression, as evaluated using RECIST 1.1 | Every 3 months for up to 2 years | 
| Overall Survival | From date enrollment until the date of death | Every 3 months for up to 2 years | 
| Clinical Benefit Rate | CR+PR+SD as evaluated using RECIST 1.1 | Every 3 months for up to 2 years | 
| Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v5 | Adverse events will be assessed at each visit and at unscheduled visits as clinically indicated | From date of enrollment until 28 days after last treatment with SM-88 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ewing's Sarcoma, Locally advanced sarcoma, Metastatic sarcoma, SM-88, D.L-alpha-metyrosine