Safety and Efficacy of Trans Sodium Crocetinate (TSC) With Radiation and Temozolomide in Newly Diagnosed Glioblastoma

• Sponsor: Diffusion Pharmaceuticals Inc (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01465347
• Collaborator: (none)
• Enrollment: 59
• Locations: 18
• Arm: 1
• Duration (Months): 48
• Patients Per Site: 3.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This open-label study evaluated the safety and efficacy of TSC when dosed concomitantly with the standard of care (radiation therapy and temozolomide) for newly diagnosed glioblastoma in adults. All patients received TSC in the study. The objective of the study was to evaluate the effect of TSC on survival and tumor response in patients with GBM while establishing an acceptable patient risk profile.

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma; GBM; Glioma	Drug: Trans Sodium Crocetinate (TSC)	Phase 1/Phase 2

Detailed Description

The overall objectives of this Phase 1/2 clinical study in newly diagnosed GBM patients was to evaluate the safety and tolerability, efficacy, PK profile, PFS/time to disease progression, QoL, and overall survival in adults when TSC is added to the standard of care regimen of radiation therapy and temozolomide. All patients received TSC in this study. The primary objective of the Phase 1 portion of the study was to evaluate the safety (DLT rate) and to define the dosing regimen of TSC for the larger Phase 2 study. The primary clinical endpoint was overall survival at 24 months and patients will be followed for up to 3 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 59 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open-label Phase 1/2 (Safety Lead-in) Study of Trans Sodium Crocetinate (TSC) With Concomitant Treatment of Fractionated Radiation Therapy and Temozolomide in Newly Diagnosed Glioblastoma (GBM) Patients to Evaluate Safety and Efficacy
• Study Start Date: Feb 1, 2012
• Actual Primary Completion Date: Nov 1, 2015
• Actual Study Completion Date: Feb 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: TSC 0.25 mg/kg for 9 or 18 doses This was an open-label, sequential-cohort, dose-escalation study in two phases. Phase 1 was a safety run-in evaluating Trans Sodium Crocetinate (TSC) in 3 subjects who received 3 doses per week for 3 weeks (9 doses in total). Phase 2 engaged 56 subjects who received 3 doses per week for 6 weeks (18 doses in total). TSC was consistently dosed at 0.25mg/kg in both phases.

Drug: Trans Sodium Crocetinate (TSC); TSC administered intravenously as a bolus injection prior to radiation therapy sessions during 6 weeks of radiotherapy.; Other Names: TSC

Outcome Measures

Primary Outcome Measures

1. Dose Limiting Toxicities (DLTs) [During phase 1]

   Number of Participants in Phase 1 with Dose Limiting Toxicities (DLTs)

2. Overall Survival [6, 12, 18, 24 months]

   Participants in phase 2 (18 dose group, 6 weeks treatment with TSC) were monitored for up to 3 years (last follow-up - February 16, 2016). Overall Survival (OS) was defined as the length of time from the date of tumor resection surgery or definitive biopsy to the date of death. The OS analyses were performed using the Kaplan-Meier estimate method. The OS rates at 6, 12, 18 and 24 months were estimated. Median OS values were calculated; a corresponding 95% confidence interval for each median value was determined using a log rank analysis. The length of OS (in months) was calculated as follows: date of death or censored - date of surgery or definitive biopsy / 30.4375.

Secondary Outcome Measures

1. Progression-Free Survival (PFS) [6,12,18, 24 months]

   The PFS analyses were performed using the Kaplan-Meier estimate method. The PFS rates at 6, 12, 18 and 24 months were estimated. Median PFS values were calculated; a corresponding 95% confidence interval for each median value was determined using a log rank analysis. Time to disease progression (in months) was calculated as follows: date of event* or censoring - date of surgery or definitive biopsy / 30.4375; *event = first tumor progression or death.

2. Number of Participants With Reduction in Tumor Size, According to Percentage of Tumor Reduction [From Baseline to Week 110]

   The sum of the product of the diameters of the tumor (using recorded tumor diameter measurements made from brain MRI images) was used to express tumor size. Results were summarized for actual and percentage change from baseline. Individual subjects results were listed, including tumor volume and tumor response from independent reviewers. Investigator data were listed but not used in the analysis. Percent response (according to independent reviewer assessments) by percentage tumor reduction from tumor resection or definitive biopsy to the last MRI were summarized.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Aged at least 18 years of age; male or female. A patient who is 70 years of age or older may be considered for enrollment after review of patient clinical and laboratory data by the Protocol Medical Monitor.

• Histologically confirmed diagnosis of GBM.

• Contrast enhancing disease on MRI within 21 days prior to screening.

• Karnofsky score (KPS) of ≥ 60 at Screening.

• No prior RT, chemotherapy (including Gliadel wafer), immunotherapy or therapy with a biologic agent, or hormonal therapy. Glucocorticoid therapy is allowed.

• Within 2 weeks of baseline visit, 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.

• Sexually active patients must use an acceptable method of contraception while receiving doses of study medication.

• Females of childbearing potential must have a negative serum or urine pregnancy test at screening and have additional pregnancy tests during study.

Exclusion Criteria:

• Patient who cannot undergo MRI.

• Pregnant or lactating.

• Serious concurrent infection or medical illness that would jeopardize the ability of the patient to receive study treatment with reasonable safety.

• Patient receiving concurrent chemotherapeutics or investigational agents within 30 days of baseline assessments, including gliadel wafers or gliasite application.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St. Joseph's Medical Center Barrow Neurology Clinics	Phoenix	Arizona	United States	85013
2	University of Arkansas Winthrop P. Rockefeller Cancer Institute	Little Rock	Arkansas	United States	72205
3	USC/Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
4	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
5	The George Washington University Medical Center	Washington, D.C.	District of Columbia	United States	20037
6	University of Florida McKnight Brain Institute	Gainesville	Florida	United States	32611
7	Emory University Winship Cancer Institute	Atlanta	Georgia	United States	30322
8	Northwestern University Robert H. Lurie Comprehensive Cancer Center	Chicago	Illinois	United States	60611
9	Rush University Medical Center	Chicago	Illinois	United States	60612
10	University of Kentucky Markey Cancer Center	Lexington	Kentucky	United States	40536
11	North Shore University Hospital	Manhasset	New York	United States	11030
12	Forsyth Regional Cancer Center	Winston-Salem	North Carolina	United States	27103
13	Penn State University Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033
14	Medical University of South Carolina	Charleston	South Carolina	United States	29425
15	Baylor University Medical Center	Dallas	Texas	United States	75246
16	University of Texas Health Science Center Memorial Hermann Medical Center	Houston	Texas	United States	77030
17	UVA Health Sciences Center Emily Couric Clinical Cancer Center	Charlottesville	Virginia	United States	22908
18	Froedtert & Medical College of Wisconsin Cancer Center	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Diffusion Pharmaceuticals Inc

Investigators

• Study Chair: David R. Jones, M.D., Diffusion Pharmaceuticals Inc

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Diffusion Pharmaceuticals Inc
• ClinicalTrials.gov Identifier: NCT01465347
• Other Study ID Numbers: DP100-202
• First Posted: Nov 4, 2011
• Last Update Posted: Jul 14, 2017
• Last Verified: Jun 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Diffusion Pharmaceuticals Inc: Primary brain tumor; Glioblastoma; Glioma; GBM; Radiation therapy
• Additional relevant MeSH terms: Glioblastoma; Glioma; Trans-sodium crocetinate

Study Results

Participant Flow

Recruitment Details	Treatment naive patients with a histologically confirmed diagnosis of GBM who were scheduled to receive standard-of-care radiation and temozolomide treatment per Stupp et al (2005) were enrolled in the study at 18 academic clinical sites in the U.S.
Pre-assignment Detail	Open-label, historical control (Stupp et al; N Engl J Med 2005; 352: 987-996, March 10, 2005, DOI: 10.1056/NEJMoa043330); patients received standard-of-care radiation/temozolomide treatment plus Trans Sodium Crocetinate (TSC); three (3) patients completed 9 doses (phase 1) as a safety run-in followed by 56 patients who received 18 doses (phase 2).

Arm/Group Title	TSC 0.25 mg/kg - 9 Dose Group	TSC 0.25 mg/kg - 18 Dose Group
Arm/Group Description	Phase 1: 3 weeks of TSC (9 doses in total) with concomitant RT and temozolomide for 6 weeks	Phase 2: 6 weeks of TSC (18 doses in total) with concomitant RT and temozolomide for 6 weeks
Period Title: Overall Study
STARTED	3	56
COMPLETED	2	53
NOT COMPLETED	1	3

Baseline Characteristics

Arm/Group Title	TSC 0.25 mg/kg for 9 or 18 Doses
Arm/Group Description	Trans Sodium Crocetinate (TSC): TSC administered intravenously as a bolus injection prior to radiation therapy sessions during 6 weeks of radiotherapy.
Overall Participants	56
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	41 73.2%
>=65 years	15 26.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.2 (10.79)
Sex: Female, Male (Count of Participants)
Female	24 42.9%
Male	32 57.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 1.8%
White	52 92.9%
More than one race	0 0%
Unknown or Not Reported	3 5.4%
Region of Enrollment (participants) [Number]
United States	56 100%
Count of participants (participants) [Number]
Number [participants]	56 100%

Outcome Measures

1. Primary Outcome

Title	Dose Limiting Toxicities (DLTs)
Description	Number of Participants in Phase 1 with Dose Limiting Toxicities (DLTs)
Time Frame	During phase 1

Outcome Measure Data

Analysis Population Description

Dose limiting toxicities were only assessed for Phase 1 participants

Arm/Group Title	TSC 0.25 mg/kg - 9 Dose Group	TSC 0.25 mg/kg - 18 Dose Group
Arm/Group Description	Phase 1: 3 weeks of TSC (9 doses in total) with concomitant RT and temozolomide for 6 weeks	Phase 2: 6 weeks of TSC (18 doses in total) with concomitant RT and temozolomide for 6 weeks
Measure Participants	3	0
Count of Participants [Participants]	0 0%

2. Primary Outcome

Title	Overall Survival
Description	Participants in phase 2 (18 dose group, 6 weeks treatment with TSC) were monitored for up to 3 years (last follow-up - February 16, 2016). Overall Survival (OS) was defined as the length of time from the date of tumor resection surgery or definitive biopsy to the date of death. The OS analyses were performed using the Kaplan-Meier estimate method. The OS rates at 6, 12, 18 and 24 months were estimated. Median OS values were calculated; a corresponding 95% confidence interval for each median value was determined using a log rank analysis. The length of OS (in months) was calculated as follows: date of death or censored - date of surgery or definitive biopsy / 30.4375.
Time Frame	6, 12, 18, 24 months

Outcome Measure Data

Analysis Population Description

All participants who received any amount of TSC and at least 1 session of RT (modified ITT)

Arm/Group Title	TSC 0.25 mg/kg - 18 Dose Group - Phase 2
Arm/Group Description	Trans Sodium Crocetinate (TSC): TSC administered intravenously for 18 doses as a bolus injection prior to radiation therapy sessions during 6 weeks of radiotherapy.
Measure Participants	56
6 month OS	89.3 159.5%
12 month OS	71.2 127.1%
18 month OS	43.8 78.2%
24 month OS	36.3 64.8%

3. Secondary Outcome

Title	Progression-Free Survival (PFS)
Description	The PFS analyses were performed using the Kaplan-Meier estimate method. The PFS rates at 6, 12, 18 and 24 months were estimated. Median PFS values were calculated; a corresponding 95% confidence interval for each median value was determined using a log rank analysis. Time to disease progression (in months) was calculated as follows: date of event* or censoring - date of surgery or definitive biopsy / 30.4375; *event = first tumor progression or death.
Time Frame	6,12,18, 24 months

Outcome Measure Data

Analysis Population Description

The analysis of PFS was performed in phase 2 only and included the modified ITT population which included 54 of the 56 subjects (98.2%) at the 2-year time point.

Arm/Group Title	TSC 0.25 mg/kg - 18 Dose Group - Phase 2
Arm/Group Description	Trans Sodium Crocetinate (TSC): TSC administered intravenously for 18 doses as a bolus injection prior to radiation therapy sessions during 6 weeks of radiotherapy.
Measure Participants	56
6 months	30.9 55.2%
12 months	9.9 17.7%
18 months	4.0 7.1%
24 months	0.0 0%

4. Secondary Outcome

Title	Number of Participants With Reduction in Tumor Size, According to Percentage of Tumor Reduction
Description	The sum of the product of the diameters of the tumor (using recorded tumor diameter measurements made from brain MRI images) was used to express tumor size. Results were summarized for actual and percentage change from baseline. Individual subjects results were listed, including tumor volume and tumor response from independent reviewers. Investigator data were listed but not used in the analysis. Percent response (according to independent reviewer assessments) by percentage tumor reduction from tumor resection or definitive biopsy to the last MRI were summarized.
Time Frame	From Baseline to Week 110

Outcome Measure Data

Analysis Population Description

Of the 56 modified ITT population (subjects in the TSC 18 dose group) tumor size data exist for 37 subjects. Four (4) tumor-bearing subjects at baseline MRI did not have any post-baseline MRIs. Fourteen (14) subjects had a complete resection before baseline.

Arm/Group Title	TSC 0.25mg/kg - 9 Dose Group - Phase 1	TSC 0.25 mg/kg - 18 Dose Group - Phase 2
Arm/Group Description	Phase 1 was the safety lead-in portion of the study conducted to evaluate an initial TSC dosage regimen in a smaller number of subjects and for a shorter period before a larger number of subjects were studied for a longer period in phase 2. Three (3) subjects were dosed with TSC at 0.25mg/kg for 3 weeks for a total of 9 doses with monitoring for dose-limiting toxicity (DLT). A Safety Monitoring Committee (SMC) evaluated the safety data and recommended TSC 0.25mg/kg for phase 2.	Trans Sodium Crocetinate (TSC): TSC administered intravenously for 18 doses as a bolus injection prior to radiation therapy sessions during 6 weeks of radiotherapy.
Measure Participants	3	37
tumor not reduced	1 1.8%	10 NaN
0 to 39% tumor reduction	0 0%	6 NaN
40 to 63% tumor reduction	0 0%	2 NaN
64 to 93% tumor reduction	0 0%	6 NaN
94 to 99% tumor reduction	0 0%	2 NaN
100% tumor reduction	2 3.6%	11 NaN

Adverse Events

Time Frame	The first subject was enrolled February 27, 2012 and the last subject completed treatment on April 28, 2015. The last follow-up of the last subject was February 16, 2016. Adverse events were collected from the first dose of TSC to 30 days following the last dose (week 10 study visit). Subjects who experienced multiple events with the same preferred term were counted once for that preferred term.
Adverse Event Reporting Description	This was an open-label, sequential cohort, dose escalation study designed to evaluate the safety and efficacy of TSC administered concomitantly with standard-of-care RT and temozolomide in adults with GBM. The study included two phases. Phase 1 was a safety run-in wherein 3 subjects received 9 doses at 3 doses per week for 3 weeks. Phase 2 engaged 56 patients who received 18 doses at 3 doses per week for 6 weeks. The dose of TSC was consistently 0.25mg/kg.
Arm/Group Title	TSC 0.25 mg/kg - 9 Dose Group		TSC 0.25 mg/kg - 18 Dose Group
Arm/Group Description	Phase 1: 3 weeks of TSC (9 doses in total) with concomitant RT and temozolomide for 6 weeks		Phase 2: 6 weeks of TSC (18 doses in total) with concomitant RT and temozolomide for 6 weeks
All Cause Mortality
	TSC 0.25 mg/kg - 9 Dose Group		TSC 0.25 mg/kg - 18 Dose Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	TSC 0.25 mg/kg - 9 Dose Group		TSC 0.25 mg/kg - 18 Dose Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		10/56 (17.9%)
Blood and lymphatic system disorders
Febrile neutropenia	0/3 (0%)	0	1/56 (1.8%)	1
Cardiac disorders
Tachycardia	0/3 (0%)	0	1/56 (1.8%)	1
Immune system disorders
Drug hypersensitivity	0/3 (0%)	0	1/56 (1.8%)	1
Infections and infestations
Neutropenia sepsis	1/3 (33.3%)	1	0/56 (0%)	0
Tooth abscess	1/3 (33.3%)	1	0/56 (0%)	0
Skin infection	0/3 (0%)	0	1/56 (1.8%)	1
Urinary tract infection	0/3 (0%)	0	1/56 (1.8%)	1
Musculoskeletal and connective tissue disorders
Muscular weakness	0/3 (0%)	0	2/56 (3.6%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor hemorrhage	0/3 (0%)	0	1/56 (1.8%)	1
Nervous system disorders
Hydrocephalus	0/3 (0%)	0	2/56 (3.6%)	2
Brain edema	0/3 (0%)	0	1/56 (1.8%)	1
Somnolence	0/3 (0%)	0	1/56 (1.8%)	1
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/3 (0%)	0	2/56 (3.6%)	2
Atelectasis	0/3 (0%)	0	1/56 (1.8%)	1
Pleural effusion	0/3 (0%)	0	1/56 (1.8%)	1
Vascular disorders
Deep vein thrombosis	0/3 (0%)	0	1/56 (1.8%)	1
Other (Not Including Serious) Adverse Events
	TSC 0.25 mg/kg - 9 Dose Group		TSC 0.25 mg/kg - 18 Dose Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		56/56 (100%)
Gastrointestinal disorders
Nausea	0/3 (0%)	0	16/56 (28.6%)	17
Constipation	0/3 (0%)	0	16/56 (28.6%)	16
Vomiting	0/3 (0%)	0	5/56 (8.9%)	5
Diarrhea	0/3 (0%)	0	3/56 (5.4%)	3
Dry mouth	0/3 (0%)	0	3/56 (5.4%)	3
General disorders
Fatigue	0/3 (0%)	0	24/56 (42.9%)	25
Edema peripheral	1/3 (33.3%)	1	7/56 (12.5%)	7
Gait disturbance	1/3 (33.3%)	1	3/56 (5.4%)	4
Injection site bruising	1/3 (33.3%)	1	3/56 (5.4%)	3
Face edema	0/3 (0%)	0	3/56 (5.4%)	3
Irritability	0/3 (0%)	0	3/56 (5.4%)	3
Infections and infestations
Oral candidiasis	0/3 (0%)	0	5/56 (8.9%)	5
Sinusitis	0/3 (0%)	0	3/56 (5.4%)	3
Injury, poisoning and procedural complications
Radiation skin injury	0/3 (0%)	0	5/56 (8.9%)	6
Metabolism and nutrition disorders
Decreased appetite	0/3 (0%)	0	7/56 (12.5%)	7
Musculoskeletal and connective tissue disorders
Muscular weakness	0/3 (0%)	0	10/56 (17.9%)	13
Pain in extremity	0/3 (0%)	0	4/56 (7.1%)	4
Back pain	0/3 (0%)	0	3/56 (5.4%)	4
Nervous system disorders
Headache	0/3 (0%)	0	12/56 (21.4%)	13
Dysgeusia	0/3 (0%)	0	5/56 (8.9%)	5
Cognitive disorder	0/3 (0%)	0	3/56 (5.4%)	3
Convulsion	0/3 (0%)	0	3/56 (5.4%)	3
Psychiatric disorders
Insomnia	0/3 (0%)	0	9/56 (16.1%)	9
Anxiety	0/3 (0%)	0	4/56 (7.1%)	4
Confusional state	0/3 (0%)	0	4/56 (7.1%)	4
Depression	0/3 (0%)	0	3/56 (5.4%)	3
Skin and subcutaneous tissue disorders
Alopecia	3/3 (100%)	3	18/56 (32.1%)	20
Erythema	0/3 (0%)	0	6/56 (10.7%)	11
Dry skin	1/3 (33.3%)	1	3/56 (5.4%)	3
Vascular disorders
Deep vein thrombosis	0/3 (0%)	0	3/56 (5.4%)	4
Hypertension	1/3 (33.3%)	1	2/56 (3.6%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.