Safety and Efficacy Study of Trans Sodium Crocetinate (TSC) in Newly Diagnosed Glioblastoma (GBM) Biopsy-Only Subjects

Study Overview
=================
Brief Summary
-----------------
Open-label, randomized, controlled, phase 3 safety and efficacy registration trial. Subjects will be randomized at baseline to the standard of care for first-line treatment of glioblastoma plus Trans Sodium Crocetinate (TSC) or the standard of care. The standard of care for GBM will consist of temozolomide plus radiation therapy for 6 weeks followed by 28 days of rest followed by 6 cycles of post-radiation temozolomide treatment.

Detailed Description
-----------------
During the radiation treatment period subjects will receive: Focal radiation delivered as 60 Gray/30 fractions scheduled at 2 Gray/day for 5 days each week (Monday through Friday) for 6 weeks. Temozolomide 75mg/m2 orally once daily (usually administered the night preceding each radiation session) starting the evening before the first radiation session over a period of 42 calendar days with a maximum of 49 days. TSC 0.25 mg/kg IV for 3 days each week (Monday, Wednesday, Friday) administered between 45 to 60 minutes prior to each radiation session. Pneumocystis carinii pneumonia (PCP) prophylaxis is required during Temozolomide + radiation administration, regardless of lymphocyte count and is to continue until recovery of lymphocyte count to less than or equal to Grade 1. During the 28-day rest period all subjects will receive no treatment. During the post-radiation 6-cycle temozolomide treatment period subjects will receive: All subjects will receive: 28-day oral temozolomide (150 mg/m2 first cycle and 200 mg/m2 all subsequent cycles as tolerated) administered on Day 1-5 (Monday through Friday) of each 28-day cycle. Controls: Will receive oral temozolomide at night at home per the standard of care. Subjects randomized to TSC: Will receive TSC 1.5 mg/kg (or the dose recommended by the Data Safety Monitoring Board) 1.5 to 2 hours before their temozolomide dose during the daytime for 3 days during the first week of each 28-day cycle (Days 1, 3, 5: Monday, Wednesday, Friday). The Tuesday, Thursday doses will be given at night at home. Long-acting antiemetics may be administered prior to daytime temozolomide dosing on Days 1, 3, 5. In accordance with the FDA directive of August 22, 2017 the safety, tolerability and pharmacokinetics of TSC at doses between 0.25 mg/kg and up to 1.5 mg/kg in combination with concomitant temozolomide will be assessed via a dose escalation run-in prior to initiating the randomized trial. The first eight (8) subjects enrolled in the 100-206 trial will be assigned (not randomized between treatments) at Baseline to undergo radiation plus temozolomide plus TSC treatment (0.25 mg/kg) for 6 weekly cycles followed by 4 weeks of rest in standard fashion. At the Week 10 clinic visit the same eight (8) subjects will be assigned to treatment with 2 subjects each assigned to TSC at doses of 0.25, 0.50, 1.0 and 1.5 mg/kg. The first eight (8) subjects will be studied in parallel and all for two full 28-day cycles with inclusion of appropriate blood sampling collection for TSC and temozolomide pharmacokinetics. The Data Safety Monitoring Board will examine the resultant safety data after 2 full cycles (Weeks 11 through 18 of post-radiation temozolomide treatment period; Days 1 to 56). The eight (8) subjects that are a part of the dose-escalation run-in will continue at their assigned TSC dose (0.25, 0.5, 1.0, 1.5 mg/kg) for the Week 19 TSC dosing period. The Data Safety Monitoring Board will recommend an acceptable TSC dose, if different than 1.5 mg/kg, for the post-radiation temozolomide treatment period prior to the Week 23 TSC dosing period for the eight (8) subjects that are a part of the dose-escalation run-in. Thereafter, subjects will enter the 100-206 trial and be randomized at Baseline between TSC plus standard of care or the standard of care.

Official Title
-----------------
Open-label, Randomized, Controlled, Phase 3 Safety and Efficacy Study of Trans Sodium Crocetinate With Radiation Therapy and Temozolomide in Newly Diagnosed Glioblastoma (GBM) Biopsy-Only Subjects

Conditions
-----------------
Glioblastoma

Intervention / Treatment
-----------------
* Drug: Trans Sodium Crocetinate plus SOC
* Other: Standard of Care (SOC)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female subjects who are at least 18 to 70 years of age Have histologically confirmed GBM The only surgical consideration is biopsy. Subjects who had gross total resection, partial resection and/or debulking are excluded. Measurable (>10mm x 10mm) contrast enhancing disease. Limited disturbance of tumor during biopsy. Surgical and pathology reports that document surgery was limited to biopsy and histologic confirmation. Life expectancy of at least 3 months. Subjects must have a Karnofsky score (KPS) of ≥ 60 at Screening. Glucocorticoid therapy allowed. Tumor Treatment Field (TT Fields) therapy allowed. If female, the subject must have a negative serum or urine pregnancy test at Screening unless meeting non-productive potential criteria. Subjects must have hematologic and renal functions as specified: Absolute neutrophil count ≥ 1500/mm3, platelets ≥ 100,000/mm3, Hgb ≥ 9.0g/dL, creatinine ≤ 1.7mg/dL, total bilirubin ≤ 1.5mg/dL, blood urea nitrogen (BUN) within 2 times the upper limit of normal, transaminases ≤ 4 times above the upper limits of the institutional norm. The subject or subject's medical power of attorney has provided written consent to participate in this study. Exclusion Criteria: Subjects who had gross total tumor resection, partial resection, and/or debulking surgery. Subjects must not have had prior RT, chemotherapy (including Gliadel wafer), immunotherapy or therapy with a biologic agent, or hormonal therapy. Subject who is pregnant or lactating. Subject with a serious concurrent infection or medical illness that would jeopardize the ability of the subject to receive study treatment with reasonable safety. Subject who cannot undergo MRI. Subject receiving concurrent chemotherapeutics or investigational agents within 30 days of study entry, including gliadel wafers or gliasite application. Subjects with other uncontrolled medical conditions, e.g. myocardial infarction, cerebrovascular accident, diabetes or hypertension. Subjects diagnosed with another malignancy within 3 years prior to study start with the exception of adequately treated basal cell carcinoma, squamous cell carcinoma, non-melanomatous skin cancer or carcinoma in situ of the uterine cervix. CTCAE Version 4, Grade 4 non-hematological toxicity (except for alopecia, nausea, vomiting).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open-label, randomized, controlled
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trans Sodium Crocetinate plus SOC<br>Trans Sodium Crocetinate plus the Standard of Care (SOC): SOC composed of radiation and temozolomide for 6 weeks followed by 4 weeks of rest followed by six (6) 28-day cycles of temozolomide | Drug: Trans Sodium Crocetinate plus SOC<br>* Trans Sodium Crocetinate (TSC) plus the Standard of Care (SOC): SOC composed of radiation and temozolomide for 6 weeks followed by 4 weeks of rest followed by six (6) 28-day cycles of temozolomide<br>* Other names: Trans Sodium Crocetinate (TSC) plus Standard of Care;|
| Active Comparator: Standard of Care (SOC)<br>Standard of Care (SOC): SOC composed of radiation and temozolomide for 6 weeks followed by 4 weeks of rest followed by six (6) 28-day cycles of temozolomide | Other: Standard of Care (SOC)<br>* Standard of Care (SOC): SOC composed of radiation and temozolomide for 6 weeks followed by 4 weeks of rest followed by six (6) 28-day cycles of temozolomide<br>* Other names: Standard of Care;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival will be calculated from randomization to the time of death from any cause | All subjects will be followed for 24 months |