Safety and Efficacy Study of TH-302 CNS Penetration in Recurrent High Grade Astrocytoma Following Bevacizumab

• Sponsor: The University of Texas Health Science Center at San Antonio (Other)
• Overall Status: Completed
• CT.gov ID: NCT01403610
• Collaborator: (none)
• Enrollment: 28
• Location: 1
• Arms: 4
• Duration (Months): 52
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The Primary Objectives are:

• To determine the extent by which TH-302 is able to penetrate the blood brain barrier and affect tumor tissue

• To assess the safety of single dose TH-302 in patients with high grade glioma undergoing surgery

• To assess the safety of TH-302 in combination with bevacizumab for patients with high grade glioma

• To determine the MTD and DLT(s) of TH-302 in combination with bevacizumab

The Secondary Objectives are:

To determine the progression-free survival with or without debulking craniotomy for patients treated with combination bevacizumab and TH-302 following recurrence on single agent bevacizumab

Condition or Disease	Intervention/Treatment	Phase
HIGH GRADE GLIOMA	Drug: TH-302 preoperative; Drug: Placebo; Drug: TH-302 (escalating) with bevacizumab 10mg/kg	Phase 2

Detailed Description

Single center, dose-escalation, prospective study with TH-302 single dose at 575 mg/m2 or placebo administered preoperatively, followed by postoperative combination therapy bevacizumab at 10mg/kg every 2 weeks and TH-302 at 240 - 670 mg/m2 every 2 weeks (4 week cycle) until disease progression. Subjects will be randomized (2:1) to receive pre-operative dose of TH-302 (surgical subjects only). Subjects not receiving surgery will receive combination therapy of bevacizumab at 10 mg/kg every 2 weeks and TH-302 at 240-670 mg/m2 every 2 weeks (4 week cycle) starting from Cycle 1, Day 1 until disease progression.

This study will use a classic dose escalation design to determine the MTD of TH-302 when used in combination with bevacizumab. The dose of TH-302 will be escalated in cohorts of 3-6 subjects. The initial dose of TH-302 will be 240 mg/m2. A dose level minus 1 will be built into the study in the event that subjects experience excessive toxicity at Dose Level 1. Dose escalation will continue to 340 mg/m2 and 670 mg/m2.

Study Design

• Study Type: Interventional
• Actual Enrollment: 28 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Investigator Initiated Study to Determine the Safety, Efficacy and CNS Penetration of TH-302 in Recurrent High Grade Astrocytoma Following Bevacizumab
• Study Start Date: Jun 1, 2011
• Actual Primary Completion Date: Oct 1, 2015
• Actual Study Completion Date: Oct 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1 Subjects received TH-302 single dose at 575 mg/m2 or placebo administered preoperative in a 2:1 randomization and were then administered 240 mg/m2 of TH-302 post-operative.	Drug: TH-302 preoperative; TH-302 single dose at 575 mg/m2 administered preoperatively, followed by postoperative combination therapy bevacizumab at 10mg/kg every 2 weeks and TH-302 at 240 - 480 mg/m2 every 2 weeks (4 week cycle) until disease progression. Subjects will be randomized (2:1) to receive pre-operative dose of TH-302.; Other Names: Study drug ; Drug: Placebo; Placebo administered preoperatively, followed by postoperative combination therapy bevacizumab at 10mg/kg every 2 weeks and TH-302 at 240 - 480 mg/m2 every 2 weeks (4 week cycle) until disease progression. Subjects will be randomized (2:1) to receive pre-operative dose of TH-302.; Other Names: Study placebo ; Drug: TH-302 (escalating) with bevacizumab 10mg/kg; Combination of 10mg/m2 of bevacizumab with an escalating dose of TH-302 from 240 to 670 mg/m2; Other Names: Study drug escalating dose
Experimental: Cohort 2 Surgical subjects will receive TH-302 at 340 mg/m2 every 2 weeks (4 week cycles) starting after surgery from Cycle 1, Day 1 until disease progression.	Drug: TH-302 preoperative; TH-302 single dose at 575 mg/m2 administered preoperatively, followed by postoperative combination therapy bevacizumab at 10mg/kg every 2 weeks and TH-302 at 240 - 480 mg/m2 every 2 weeks (4 week cycle) until disease progression. Subjects will be randomized (2:1) to receive pre-operative dose of TH-302.; Other Names: Study drug ; Drug: TH-302 (escalating) with bevacizumab 10mg/kg; Combination of 10mg/m2 of bevacizumab with an escalating dose of TH-302 from 240 to 670 mg/m2; Other Names: Study drug escalating dose
Experimental: Cohort 3 Surgical or Non-Surgical subjects will receive TH-302 at 480 mg/m2 every 2 weeks (4 week cycles) starting after surgery from Cycle 1, Day 1 until disease progression.	Drug: TH-302 (escalating) with bevacizumab 10mg/kg; Combination of 10mg/m2 of bevacizumab with an escalating dose of TH-302 from 240 to 670 mg/m2; Other Names: Study drug escalating dose
Experimental: Cohort 4 Non-surgical subjects will receive a dose up to 670 mg/m2 of TH-302	Drug: TH-302 (escalating) with bevacizumab 10mg/kg; Combination of 10mg/m2 of bevacizumab with an escalating dose of TH-302 from 240 to 670 mg/m2; Other Names: Study drug escalating dose

Outcome Measures

Primary Outcome Measures

1. Time to Progression [2 years]

   Time from initiation study until radiographic progression by RANO criteria

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. At least 18 years of age

2. Ability to understand the purposes and risks of the study and has signed a written informed consent form approved by the investigator's IRB/Ethics Committee

3. Histologically confirmed high grade astrocytoma

4. Progression following both standard combined modality treatment with radiation and temozolomide chemotherapy, as well as anti-angiogenic therapy (ie, bevacizumab)

5. Recovered from toxicities of prior therapy to grade 0 or 1

6. ECOG performance status of 0 or 1

7. Life expectancy of at least 3 months

8. Acceptable liver function

9. Acceptable renal function

10. Acceptable hematologic status

11. All women of childbearing potential must have a negative serum pregnancy test and male and female subjects must agree to use effective means of contraception (surgical sterilization or the use or barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel or an IUD) with their partner from entry into the study through 6 months after the last dose

Exclusion Criteria:

1. The subject is receiving warfarin (or other coumarin derivatives) and is unable to switch to low molecular weight heparin (LMWH) before the first dose of study drug.

2. The subject has evidence of acute intracranial or intratumoral hemorrhage either by MRI or computerized tomography (CT) scan. Subjects with resolving hemorrhage changes, punctate hemorrhage, or hemosiderin are eligible.

3. The subject is unable to undergo MRI scan (eg, has pacemaker).

4. The subject has received enzyme-inducing anti-epileptic agents within 14 days of study drug (eg, carbamazepine, phenytoin, phenobarbital, primidone).

5. The subject has not recovered to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 Grade ≤ 1 from AEs (except alopecia, anemia and lymphopenia) due to surgery, antineoplastic agents, investigational drugs, or other medications that were administered prior to study drug.

6. The subject has evidence of wound dehiscence

7. Severe chronic obstructive or other pulmonary disease with hypoxemia (requires supplementary oxygen, symptoms due to hypoxemia or oxygen saturation <90% by pulse oximetry after a 2 minute walk) or in the opinion of the investigator any physiological state likely to cause normal tissue hypoxia

8. The subject is pregnant or breast-feeding.

9. The subject has serious intercurrent illness

10. The subject has inherited bleeding diathesis or coagulopathy with the risk of bleeding.

11. The subject has received any of the following prior anticancer therapy:

• Non-standard radiation therapy such as brachytherapy, systemic radioisotope therapy (RIT), or intra-operative radiotherapy (IORT). Note: stereotactic radiosurgery (SRS) is allowed

• Antiangiogenic agents whose primary mode of action is through the VEGF signaling within 21 days prior to first dose of study drug (surgical subjects only)

• Non-bevacizumab systemic therapy (including investigational agents and small-molecule kinase inhibitors) or non-cytotoxic hormonal therapy (eg, tamoxifen) within 7 days or 5 half-lives, whichever is shorter, prior first dose of study drug

• Biologic agents (antibodies, immune modulators, vaccines, cytokines) within 21 days prior to first dose of study drug

• Nitrosoureas or mitomycin C within 42 days, or metronomic/protracted low-dose chemotherapy within 14 days, or other cytotoxic chemotherapy within 28 days, prior to first dose of study drug

• Prior treatment with carmustine wafers

• Prior treatment with TH-302

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cancer Therapy & Research Center at UTHSCSA	San Antonio	Texas	United States	78229

Sponsors and Collaborators

• The University of Texas Health Science Center at San Antonio

Investigators

• Principal Investigator: Andrew Brenner, MD,, Institute for Drug Development

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: The University of Texas Health Science Center at San Antonio
• ClinicalTrials.gov Identifier: NCT01403610
• Other Study ID Numbers: CTRC 11-24; CTRC 11-24
• First Posted: Jul 27, 2011
• Last Update Posted: Jul 24, 2019
• Last Verified: Mar 1, 2019

• Keywords provided by The University of Texas Health Science Center at San Antonio: TH-302; Bevacizumab; Phase 2; Glioma; High Grade Glioma; CNS
• Additional relevant MeSH terms: Glioma; Astrocytoma; Bevacizumab; Phosphoramide Mustards

Study Results

Participant Flow

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Arm/Group Description	Prior to surgery subjects will be assigned to this group in a 2:1 randomization, ie. 2 subjects will be assigned to TH-302 and one to placebo. A single dose of 575 mg/m2 or placebo will be administered pre-operatively with hypoxyprobe-1 at 500 mg/m2 over 20 minutes. Subjects in this group receive TH-302 at a dose of 240mg/m2 post surgery.	Subjects received 340mg/m2 of TH-302 post surgery	Subjects were dosed with 480mg/m2 of TH-302 regardless of whether or not surgery was performed. 3 subjects in this arm had surgery prior to this dose of TH-302.	Subjects in this cohort did not undergo any surgery, a dose of 670mg/m2 was administered to all.
Period Title: Overall Study
STARTED	5	6	4	13
COMPLETED	3	3	4	13
NOT COMPLETED	2	3	0	0

Baseline Characteristics

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Total
Arm/Group Description	Prior to surgery subjects will be assigned to this group in a 2:1 randomization, ie. 2 subjects will be assigned to TH-302 and one to placebo. A single dose of 575 mg/m2 or placebo will be administered pre-operatively with hypoxyprobe-1 at 500 mg/m2 over 20 minutes. Subjects in this group receive TH-302 at a dose of 240mg/m2 post surgery.	Subjects received 340mg/m2 of TH-302 post surgery	Subjects were dosed with 480mg/m2 of TH-302 regardless of whether or not surgery was performed. 3 subjects in this arm had surgery prior to this dose of TH-302.	Subjects in this cohort did not undergo any surgery, a dose of 670mg/m2 was administered to all.	Total of all reporting groups
Overall Participants	3	3	4	13	23
Age (Years) [Mean (Full Range) ]
Mean (Full Range) [Years]	56	47	50	61	56
Sex: Female, Male (Count of Participants)
Female	1 33.3%	2 66.7%	3 75%	3 23.1%	9 39.1%
Male	2 66.7%	1 33.3%	1 25%	10 76.9%	14 60.9%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
United States	3 100%	3 100%	4 100%	13 100%	23 100%

Outcome Measures

1. Primary Outcome

Title	Time to Progression
Description	Time from initiation study until radiographic progression by RANO criteria
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

See full published data at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071657/

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Arm/Group Description	Bevacizumab (Bev) 10mg/kg every 2 weeks plus TH-302 240mg/m2 every 2 weeks (in a 4 week cycle)	Bevacizumab (Bev) 10mg/kg every 2 weeks plus TH-302 340mg/m2 every 2 weeks (in a 4 week cycle)	Bevacizumab (Bev) 10mg/kg every 2 weeks plus TH-302 480 mg/m2 every 2 weeks (in a 4 week cycle)	Bevacizumab (Bev) 10mg/kg every 2 weeks plus TH-302 470 mg/m2 every 2 weeks (in a 4 week cycle)
Measure Participants	3	3	4	13
Median (Full Range) [months]	11.3	9	15.6	4.5

Adverse Events

Time Frame	2 years
Adverse Event Reporting Description	Common Terminology Criteria for Adverse Events version 4.0, Grade 3 or higher reported as serious adverse events. Grade 1: Mild; asymptomatic or mild symptoms 2: Moderate; minimal, local or noninvasive intervention indicated 3: Severe or medically significant but not immediately life threatening 4: Life-threatening consequences; urgent intervention indicated. 5: Death
Arm/Group Title	Cohort 1		Cohort 2		Cohort 3		Cohort 4
Arm/Group Description	240 mg/m2 dosage		340 mg/m2 dosage		480 mg/m2 dosage		670 mg/m2
All Cause Mortality
	Cohort 1		Cohort 2		Cohort 3		Cohort 4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/13 (0%)
Serious Adverse Events
	Cohort 1		Cohort 2		Cohort 3		Cohort 4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		1/3 (33.3%)		1/4 (25%)		0/13 (0%)
Blood and lymphatic system disorders
Thrombocytopenia	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/13 (0%)	0
Skin and subcutaneous tissue disorders
Rash	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/13 (0%)	0
Other (Not Including Serious) Adverse Events
	Cohort 1		Cohort 2		Cohort 3		Cohort 4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		2/3 (66.7%)		1/4 (25%)		7/13 (53.8%)
Blood and lymphatic system disorders
thrombocytopenia	0/3 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	1	0/13 (0%)	0
Cardiac disorders
Hypertension	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/13 (7.7%)	1
Gastrointestinal disorders
anal inflammation	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	4/13 (30.8%)	4
nausea	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	2/13 (15.4%)	2
stomatitis	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0	2/13 (15.4%)	2
Constipation	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/13 (7.7%)	1
General disorders
proctitis	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	2/13 (15.4%)	2
Skin and subcutaneous tissue disorders
rash	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	3/13 (23.1%)	3

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.