Clinical trial NCT02395692
Conditions: Adult Brain Glioblastoma
Sponsor: National Cancer Institute (NCI)
Start date: 2015-12-18; Completion date: 2017-02-16
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well methoxyamine works when added to standard temozolomide in treating patients with glioblastoma that has come back. Drugs used in chemotherapy, such as methoxyamine and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the efficacy of TRC102 (methoxyamine) and temozolomide, as measured by response rate, in bevacizumab naïve glioblastoma. (Arm I) II. To estimate the efficacy of TRC102 and temozolomide, as measured by response rate, in bevacizumab refractory glioblastoma. (Arm II)

SECONDARY OBJECTIVES:

I. Evaluate the toxicities of oral TRC102 and temozolomide in this patient population.

II. Estimate the efficacy of TRC102 and temozolomide, as measured by progression-free survival, progression-free survival at 6 months and overall survival, in bevacizumab naïve glioblastoma.

III. Estimate the efficacy of TRC102 and temozolomide, as measured by progression-free survival in bevacizumab refractory glioblastoma.

TERTIARY OBJECTIVES:

I. Assess the tissue correlates of N-methylpurine-deoxyribonucleic acid (DNA) glycosylase (MPG), topoisomerase II-alpha (topo II a), and O-6-methylguanine-DNA methyltransferase (MGMT) status, with response, progression-free survival (PFS), and overall survival.

OUTLINE:

Patients receive methoxyamine orally (PO) once daily (QD) and temozolomide PO QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days, every 2 months for 2 years, and then every 6 months thereafter.

Arms: arm 1: Patients receive methoxyamine PO QD and temozolomide PO QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Treatment intervention 2: Methoxyamine intervention 3: Temozolomide
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given PO intervention 3: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
 
 
 
 
 
 
 
                                           ABTC #: 1402 
 
 
 
 
 
 
 
 
 
 
NCI #: ABTC-1402 
  
 
 
 
 
 
 
 
 
            NCT #: TBD  
 
  
Version Date – 09/28/15 
 
Phase II Study of TRC102 in Combination with Temozolomide for Recurrent 
Glioblastoma 
 
A Protocol of the Adult Brain Tumor Consortium (ABTC)  
 
Coordinating Center: 
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins  
 
 
NCI-Supplied Agent: TRC102, NSC 3801 
IND# TBD 
IND Sponsor: CTEP, DCTD, NCI 
Other Agent: Temozolomide, commercially available 
Study Chair 
Manmeet Ahluwalia, MD 
Cleveland Clinic 
 
Phone: 216-444-6145  
Fax: 216-444-0924 
Email: ahluwam@ccf.org 
Biostatistician 
Xiaobu Ye, MD, MS 
Johns Hopkins University 
Phone: 410-614-6261 
Email: xye3@jhmi.edu 
 
Study Co-Chair 
Lisa Rogers, DO 
University Hospitals  
Phone: 216-844-3717 
Fax: 216-844-4785 
Email: Lisa.Rogers1@UHhospitals.org 
Pharmacology Laboratories 
Michelle A. Rudek, PharmD, PhD 
Johns Hopkins University 
Phone: 443-287-6476 
Email: mrudek2@jhmi.edu 
 
Study Co-Chair 
Jan Drappatz, MD 
University of Pittsburgh  
Phone: 412-648-6507 
Fax: 412-648-6579 
Email: drappatzj@upmc.edu 
Jeffrey G. Supko, PhD 
Massachusetts General Hospital 
Phone: 617-724-1970 
Email: jsupko@partners.org 
 
Nursing Contact  
Cathy Schilero, RN, BSN 
 
Cleveland Clinic 
Phone: 216-444-4068 
Fax: 216-636-1371 
 
 
 
Email: schilec@ccf.org 
Pharmacy Contact 
Anne Delisa, PharmD, BCOP 
Sidney Kimmel Comprehensive 
Cancer  Center at Johns Hopkins 
Phone: 410-502-1036 
Email: adelisa@jhmi.edu 


Phase II Study of TRC102 in Combination with Temozolomide for Recurrent Glioblastoma 
 
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PARTICIPATING INVESTIGATORS: Adult Brain Tumor Consortium participating 
members 
 
 
 
 
 
 
 
 
ABTC Manager 
Joy Fisher 
Johns Hopkins University 
Phone: 410-955-3657 
Email: jfisher@jhmi.edu 
ABTC Data Coordinator 
Serena Desideri, M.D. 
Johns Hopkins University 
Phone: 410-614-4400 
Email: sdeside1@jhmi.edu 
Protocol Development 
Coordinator 
Megan Sims 
Johns Hopkins University 
Phone: 410-614-3086 
Email: msims3@jhmi.edu 
 
 
 
 
 
 
 
 


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Table of Contents 
1.0 
OBJECTIVES .................................................................................................................................................. 5 
2.0 
BACKGROUND AND RATIONALE ........................................................................................................... 6 
2.1 
GLIOBLASTOMA ............................................................................................................................................. 6 
2.2  
TRC102 ......................................................................................................................................................... 6 
2.3 
RATIONALE .................................................................................................................................................. 11 
3.0 
PATIENT ELIGIBILITY CRITERIA ........................................................................................................ 12 
3.1  
PATIENT SAMPLE ......................................................................................................................................... 12 
3.2 
ELIGIBILITY CRITERIA .................................................................................................................................. 12 
3.3 
INELIGIBILITY CRITERIA ............................................................................................................................... 14 
4.0 
TREATMENT PLAN .................................................................................................................................... 16 
4.1 
TREATMENT SCHEMA ................................................................................................................................... 16 
4.2 
TREATMENT REQUIREMENTS ....................................................................................................................... 17 
4.3 
DRUG ADMINISTRATION .............................................................................................................................. 17 
4.4 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ............................................. 19 
5.0 
DOSING DELAYS/DOSE MODIFICATION FOR TOXICITY .............................................................. 20 
5.1 
DOSE MODIFICATION FOR TRC102 .............................................................................................................. 21 
5.2 
DOSE MODIFICATION FOR TEMOZOLOMIDE ................................................................................................. 21 
5.3 
MAJOR EVENTS ............................................................................................................................................ 22 
5.4 
USE OF HEMATOLOGIC GROWTH FACTORS .................................................................................................. 23 
5.5 
TOXICITY CRITERIA ..................................................................................................................................... 23 
6.0 
PHARMACEUTICAL INFORMATION .................................................................................................... 24 
6.1 
TRC102 ....................................................................................................................................................... 24 
6.2 
TEMOZOLOMIDE ........................................................................................................................................... 25 
7.0 
PROCEDURES FOR PATIENT ENTRY ON STUDY ............................................................................. 27 
8.0 
RESPONSE ASSESSMENT / SAFETY AND QUALITY ASSURANCE ................................................ 28 
8.1 
CRITERIA FOR RESPONSE ASSESSMENT ........................................................................................................ 28 
8.2 
ASSESSMENT OF RESPONSE .......................................................................................................................... 30 
8.3 
SAFETY ASSESSMENTS .................................................................................................................................. 30 
8.4 
QUALITY ASSURANCE .................................................................................................................................. 30 
9.0 
MONITORING OF PATIENTS .................................................................................................................. 32 
9.1       TABLE OF REQUIRED OBSERVATIONS .......................................................................................................... 32 
9.2 
ADVERSE EVENTS: LISTS AND REPORTING REQUIREMENTS ......................................................................... 33 
9.3 
SERIOUS ADVERSE EVENTS AND EXPEDITED ADVERSE EVENT REPORTING ................................................ 36 
9.4       ROUTINE ADVERSE EVENT AND DATA REPORTING ...................................................................................... 40 
9.5  
EXPLORATORY CORRELATIVE STUDIES ....................................................................................................... 41 
10.0    OFF TREATMENT/OFF STUDY CRITERIA .......................................................................................... 42 
10.1 
 OFF TREATMENT CRITERIA ......................................................................................................................... 42 
10.2 
OFF STUDY CRITERIA ................................................................................................................................... 43 
11.0   STATISTICAL CONSIDERATIONS ......................................................................................................... 44 
12.0   RECORDS TO BE KEPT ............................................................................................................................. 46 
13.0  REFERENCES .............................................................................................................................................. 46 


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14.0 
COLLABORATIVE AGREEMENTS LANGUAGE ................................................................................. 48 
15.0  ETHICAL AND LEGAL CONSIDERATIONS ......................................................................................... 50 
APPENDIX I – PATIENT MEDICATION DIARIES ........................................................................................... 51 
 
 


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1.0 
OBJECTIVES  
 
Primary Objectives 
 
Arm 1 
• To estimate the efficacy of TRC102 and temozolomide, as measured by response 
rate, in bevacizumab naïve glioblastoma  
Arm 2 (opens only if Arm 1 meets efficacy criteria) 
• To estimate the efficacy of TRC102 and temozolomide, as measured by response 
rate, in bevacizumab refractory glioblastoma   
 
Secondary Objectives 
 
1. Evaluate the toxicities of oral TRC102 and temozolomide in this patient 
population  
2. Estimate the efficacy of TRC102 and temozolomide, as measured by progression-
free survival, progression-free survival at 6 months and overall survival, in 
bevacizumab naïve glioblastoma 
3. Estimate the efficacy of TRC102 and temozolomide, as measured by progression-
free survival in bevacizumab refractory glioblastoma 
  
Exploratory Objective 
 
• Assess the tissue correlates of methylpurine DNA-glycosylase (MPG) and 
topoisomerase IIα (Topo IIα), and O6-methylguanine DNA methyltransferase 
(MGMT) status, with response, PFS, and overall survival 
 


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2.0 
BACKGROUND AND RATIONALE 
 
2.1 
Glioblastoma 
 
Although the recent addition of temozolomide (TMZ) to radiation therapy for the 
treatment of glioblastoma (GBM) has resulted in improved outcomes, the estimated 2-
year survival with maximal therapy remains only 27% (Stupp 2005, Stupp 2009). Almost 
all GBMs progress, with a median time to progression of approximately 7 months. The 
prognosis is very poor for patients who have progressive/recurrent GBM. There is 
currently no standard therapy for recurrence. Salvage chemotherapies are largely 
ineffective, with progression-free survival at 6 months (PFS6) rates of 10-15%.  
Bevacizumab therapy at recurrence is associated with a high response rate, but not 
significantly increased survival. Survival after failure of bevacizumab administered for 
GBM recurrence is very poor with a median survival of 4-6 months and PFS 6 of 0 
(Reardon 2012). Hence, new therapies for recurrent GBM are urgently needed. 
 
2.2  
TRC102 
 
An NCI phase I study of TRC102 and temozolomide in relapsed solid tumors and 
lymphomas evaluated the safety of the combination of TRC102 and temozolomide 
(P9483, NCT01851369). Based on this dose escalation trial, the recommended doses for 
the phase II study are 150mg/m2 for temozolomide and 150mg flat dose for TRC102. No 
dose limiting toxicity was seen at 150mg/m2 of temozolomide and a TRC102 dose of 
150mg administered days 1-5 of a 28-day cycle (personal communication, Naoko 
Takebe). We propose to evaluate efficacy of TRC102 at 150mg flat dose combined with 
TMZ 150mg/m2 in a phase II trial of recurrent GBM.  
 
We hypothesize that oral TRC102 can be safely administered with TMZ and that it will 
potentiate DNA damage caused by TMZ, resulting in increased tumor response and 
improved survival as compared with historic controls. A dose escalation trial of 
intravenous TRC102 in combination with TMZ has been performed in relapsed systemic 
and central nervous system tumors at Case Comprehensive Cancer Center. A variety of 
dose-intense schedules of TMZ at recurrence have been evaluated. As compared with the 
standard 5 days every 28 days schedule, the dose- intense regimens have not shown 
greater efficacy and are associated with increased incidence and severity of 
lymphocytopenia (Weller 2013.). Therefore, we selected the standard schedule of TMZ.   
 
We hypothesize that biologic markers obtained in tumor tissue collected at the time of 
tumor progression will correlate with treatment response.  N-methylpurine DNA 
glycosylase (MPG) overexpression, together with inhibition of base excision repair 
(BER), sensitizes glioma cells to TMZ (Tang 2011). As an exploratory aim, we propose 
to  determine expression of MPG by IHC in resected tumor tissue from initial diagnosis, 
and correlate this with treatment response, a design  similar to the study of Weeks et al 
(Weeks 2013) in which expression of uracil-DNA glycosylase in lung cancer was found 
to correlate with pemetrexed response.  Because overexpression of topoisomerase 2a 


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(topo2a) correlates with increased sensitivity to the TRC102 potentiation of cytotoxicity 
of DNA damaging agents, we propose to determine expression of topo2a in resected 
tumor tissue and correlate its expression with treatment response. O6-methylguanine 
DNA methyltransferase (MGMT) is a strong predictor of response to TMZ.  MGMT 
methylation status will be collected to correlate response with TMZ, independent of 
TRC102 co-administration. 
 
Resistance to TMZ 
 
A major obstacle to effective treatment with TMZ in GBM is the presence of elaborate 
mechanisms of DNA repair. For instance, TMZ forms O6-methylguanine (O6mG), 7-
methylguanine (N7mG), and 3- methyladenine (N3mA) DNA adducts that are repaired by 
at least two mechanisms. The O6mG DNA adduct, a cytotoxic and genotoxic lesion, is 
repaired by MGMT. MGMT activity is a major mechanism of resistance to methylating 
agents. In contrast, cell death caused by O6mG adducts is promoted by mismatch repair 
(MMR) system, such that deficiency in MMR is associated with pronounced resistance to 
methylating agents. N7mG and N3mA DNA adducts are removed by the BER pathway 
(Liu 1999, Liu 2002). 
 
Base excision repair (BER) pathway 
 
BER is an important drug resistant factor because it recognizes a variety of substrates and 
has the ability to rapidly and efficiently repair N7mG and N3mA DNA adducts. BER is 
the major pathway that protects cells against the potentially harmful effects of 
spontaneously and chemically occurring DNA damage, including (i) inappropriate bases; 
(ii) abasic sites that are formed by enzyme-catalyzed, spontaneous or chemical-induced 
base release; and (iii) DNA single strand breaks produced during the processing of 
damaged DNA. Efficient BER minimizes the impact of these lesions in normal and tumor 
cells. Thus, when BER is disrupted, these abundant N-methylated DNA adducts and 
intermediates generated in the repair process become highly cytotoxic. Most importantly, 
BER disruption is able to bypass other resistance factors such as MMR defects and high 
MGMT activity. 
 
Base excision repair efficiently repairs DNA bases through a series of enzymatic steps, 
starting with the action of a glycosylase to excise the damaged base.  TRC102 interrupts 
this process because TRC102 binds to the apurinic site created through the action of the 
glycosylase, thereby interrupting normal repair.  As well, TRC102 bound DNA is a 
substrate for topo IIa which results in DNA strand breaks that then trigger cellular 
apoptosis. 
 
Introduction to TRC102 
 
TRC102 (NSC-3801), a biochemical inhibitor of the BER pathway developed and studied 
by investigators from Case Comprehensive Cancer Center (CCCC), Cleveland Ohio,  
reverses TMZ resistance in preclinical models at doses that are well tolerated. The ability 
of TRC102 to interrupt the BER pathway was demonstrated in vitro (Yan 2007). 


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Pharmacology studies demonstrated its ability to inhibit BER induced by treatment with 
alkylating agents, including TMZ, and anti-metabolite chemotherapy. When administered 
with TMZ, TRC102 covalently binds to apurinic/apyrimidinic (AP) sites generated by 
DNA glycosylase, in an attempt to replace DNA bases damaged by TMZ.  TRC102-
bound AP sites are refractory to the catalytic activity of the apurinic/apyrimidinic 
endonuclease (APE), leading to the interruption of BER. 
 
Available data support the hypothesis that TRC102-bound DNA is a substrate for topo II, 
which cleaves TRC102-bound DNA sites to produce strand breaks in cancer cells that 
cause cellular apoptosis.  
As a result, TRC102 is able to potentiate the activity of TMZ (and other 
chemotherapeutics that activate the BER pathway) in cancer cells that express high levels 
of topo II (both in vitro and in vivo), without increasing toxicity in non-cancer cells (i.e., 
bone marrow cells) that express low levels of topo II.  
 
Activity of TRC102 in Combination with Alkylating Chemotherapy  
 
The ability of TRC102 to potentiate chemotherapy was initially demonstrated using TMZ 
(Li 1999, Liu 2002, Taverna 2001). Collectively, the available data indicate that 
treatment of cancer cells with TMZ produced N7-methylguanine and N3-methyladenine 
DNA adducts that activated BER to generate AP sites within double-stranded DNA. 
TRC102 bound covalently to AP sites to form structurally modified AP sites that were 
then resistant to the repair activity of APE. The persistence of these lesions led to cell 
death through the generation of DNA strand breaks.  
 
The lethal toxicity induced by TMZ combined with TRC102 appears to be mediated 
through the poisoning effect of topo II. While TRC102-bound AP sites are refractory to 
the catalytic activity of APE (indicating their ability to block BER), they are cleaved by 
purified topo II or nuclear extracts from tumor cells expressing high levels of topo II, 
suggesting that TRC102-bound AP sites stimulate topo II-mediated DNA cleavage .  
 
Furthermore, cells treated with TMZ and TRC102 demonstrate increased expression of 
topo II and increased formation of γ-H2AX foci (a marker of DNA double strand breaks) 
that co-localizes with up-regulated topo II. The cleavage of TRC102-bound AP sites by 
topo II also explains the ability of TRC102 to potentiate the effects of TMZ in cancer 
cells (that have high levels of topo II) compared to normal cells (which have low levels of 
topo II). For example, in vitro addition of TRC102 effectively sensitized tumor cells, but 
not bone marrow cells, to the effects of TMZ 
 
Several preclinical studies have demonstrated improved therapeutic efficacy of alkylating 
agents by blocking BER with TRC102. In vivo studies have shown that TRC102 
potentiates the antitumor effect of TMZ in human tumor xenografts in nude mice. Mice 
carrying SW480 tumor (AGT expressing, MMR wt and p53 mutant) that were resistant to 
treatment with TMZ alone had cessation of tumor growth lasting 50 ± 13 days and very 
slow regrowth when treated with TRC102 (2 mg/kg) plus TMZ (120 mg/kg), yielding 
tumor growth delays of 70 ± 14 days (p < 0.002) compared with untreated tumors. Tumor 


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ABTC # 1402 
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regression following treatment with TMZ and TRC102 treatment reflected DNA strand 
breaks and a significant increase in tumor apoptosis. Therefore, TRC102 inhibition of 
DNA BER is a promising strategy to sensitize tumor cells to therapeutic alkylating 
agents. 
 
In the first in human phase I clinical trial, TRC102 was administered as a 5-day 
intravenous continuous infusion based on animal data. Dosing started at 15 mg/m2 
TRC102 daily for 5 days and plasma samples were collected and analyzed for TRC102 
using validated methods. Pharmacokinetic parameters were derived using a single 
compartment intravenous infusion model and plasma TRC102 concentrations from 5 
patients across 15 dosing cycles. Pharmacokinetic studies demonstrated an unexpected 
prolonged half-life of TRC102, estimated to be 45 hours (range: 32.1 - 68.8 hours) which 
represents a 10-fold increase when compared to the TRC102 half-life observed in dogs 
(t½ = 4.5 hours) and a 143-fold increase when compared to the half-life observed in rats 
(t½ = 19 min). The volume of distribution (Vss) was estimated to be 1,437 L and the 
clearance (CL) was estimated to be 22.47 L/h. The Cmax (across all patients) was 41.4 
ng/mL. Individual pharmacokinetic exposures and derived PK parameters demonstrated 
very little intra- and interpatient variability. (Savvides (a) abstract) The protocol was 
therefore revised with TRC102 administered as one hour continuous infusion. The 
average half-life of TRC102 at this schedule was 55.04 hours (range: 12.2 - 100.3 hours, 
n = 20), statistically not different from half-life of TRC102 administered as a five-day 
continuous infusion (Savvides (b) abstract).  
 
Subsequently PK of the oral formulation of TRC102 was assessed in a phase I study of 
TRC102 and pemetrexed in advanced solid tumors. TRC102 was administered as 
monotherapy on days 1 to 4 of a two-week cycle. Plasma for PK parameters was 
collected prior to dosing and 5, 15, and 30 minutes, and one, 2, 3, 4, 6, 8, and 24 hours 
following the first and fourth doses of TRC102.  The overall mean half-life of 28 hours 
was unchanged with increasing doses or cycle and the exposure increased proportionally 
with dose. The target AUC was exceeded in all patients who received at least 4 doses of 
TRC102. TRC102 accumulated with daily, dosing. The target Cmax of 50 ng/mL for in 
vivo activity was achieved by the fourth daily dose in 2 of 3 patients at 15 mg/M2/day 
and in all patients receiving 30 mg/M2/day and higher doses. The variability and PKs 
between patients were significantly influenced by both gender and baseline serum 
creatinine (Gordon 2012). 
 
Pharmacodynamic markers, including analysis of AP sites measured on DNA extracted 
from patients’ mononuclear cells (PBMCs) as well as DNA strand break determined by 
comet assay at multiple time points were obtained in the Phase I clinical trial of TRC102 
and TMZ. PD results, performed on 22 patients, showed that administration of the 
combination of TMZ and TRC102 resulted in 10-40% reduction in detectable AP sites. 
Comet assay results, performed on 20 patients revealed that the combination of TMZ and 
TRC102 2 to 3-fold higher levels of DNA strand breaks compared to TMZ alone 
(Savvides (a) abstract). 
 


Phase II Study of TRC102 in Combination with Temozolomide for Recurrent Glioblastoma 
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In several preclinical studies of human tumor xenografts in nude mice, improved 
therapeutic efficacy of TMZ by blocking BER with TRC102 has been demonstrated. 
Mice carrying SW480 colon cancer tumors (MGMT-expressing, MMR wt and p53 
mutant) treated with TRC102 (2 mg/kg) plus TMZ (120 mg/kg) had cessation of tumor 
growth lasting 50±13 days and very slow regrowth, yielding tumor growth delays of 
70±14 days (p < 0.002) compared with untreated tumors. Importantly, a survival benefit 
from TMZ combined with TRC102 has been demonstrated in CD133+ GBM stem cell 
orthotopic xenografts in mice. Combination therapy significantly (p<.001) increased the 
median survival (not reached after 230 days, with 65% survival at this time point) as 
compared with MX alone (79 days) and saline controls (75 days). Survival after the 
combination treatment was also significantly (<0.01) better than TMZ alone (120 days) 
(Figure 1, unpublished data courtesy, Andrew Sloan, University Hospital-Case Medical 
Center, Cleveland, Ohio). 
Figure 1. Survival of CD 133+ GBM CW 357 orthotopic xenografts receiving varying 
treatments: S= saline (control), T=TMZ (75 mg/kg), M = TRC102 alone, TM = TMZ + 
TRC102. 
The first in human Phase I trial of intravenous TRC102 and TMZ is ongoing at CCCC in 
relapsed solid tumor patients (Arm A) and in relapsed CNS tumor (primary and 
metastatic) patients (Arm B) (Principal Investigator Lisa Rogers).  The escalation dose of 
TMZ in Arm A is from 100 to 200 mg/m2/day in combination with TRC102 dose 
escalation from 15 to 150 mg/ m2/day, each given days 1-5 every 28 days. The current 
Arm A cohort is dosed at 200mg/m2/day TMZ and 150 mg/ m2/day TRC102). The Arm B 
design and doses are identical, except that TMZ dose escalation begins at 75 mg/ m2/day 
(Table 1). The Arm B cohort is currently dosed at 150mg/m2 of TMZ and 120mg/ m2 of 
TRC102. Of note, these studies employ the intravenous formulation of TRC102, not the 
oral formulation as proposed in this protocol.  
Early results of this trial were presented at AACR in 2012 (Savvides (b) abstract). In Arm 
A, grade 3 psychoses at 15mg/m2 TRC102 occurred in a patient with Parkinson disease 
on increasing opioid doses. A grade 3 allergic reaction classified as an idiosyncratic event 


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resulted in further expansion to 10 evaluable patients, with no additional DLTs observed. 
No DLTs have been observed in Arm B. The best response in Arm B is partial response 
in one patient with GBM and stable disease in head/neck squamous cell brain metastasis, 
off treatment for 24 months.  
     
2.3 
Rationale  
 
TRC102 reverses TMZ resistance in preclinical models at doses that are well tolerated.   
When administered with TMZ, TRC102 covalently binds to apurinic/apyrimidinic (AP) 
sites which are generated by DNA glycosylase in an attempt to replace DNA bases 
damaged by TMZ.  TRC102-bound AP sites are refractory to the catalytic activity of the 
apurinic/apyrimidinic endonuclease (APE), leading to the interruption of BER.  
Moreover, TRC102-bound DNA causes topoisomerase II dependent DNA strand breaks 
that induce apoptosis. TRC102 is selective for rapidly dividing cancer cells as these cells 
express higher levels of topoisomerase II compared with normal cells.  Therefore we 
propose a trial of TMZ and TRC102 in patients with recurrent GBM who have failed 
prior TMZ. 
 
 
 
 


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3.0 
PATIENT ELIGIBILITY CRITERIA 
 
 
3.1  
Patient Sample 
 
Sample Size:  
 
 
 
Arm 1: 31 bevacizumab-naïve patients 
 
Arm 2: 35 bevacizumab-refractory patients  
 
 
 
Accrual Rate: 
 
4-5 patients per month  
 
 
 
 
Gender: 
 
Male and female 
 
Age: 
 
Patients must be at least 18 years of age.  
 
Race: 
 
Minorities will be actively recruited.  No exclusion to this study will be based on race or 
ethnicity.  
 
 
3.2 
Eligibility Criteria 
 
1. Patients must have histologically confirmed glioblastoma that is progressive or 
recurrent following radiation therapy and temozolomide. 
 
2. Tumor MGMT methylation status must be available. Results of routinely used 
methods for MGMT methylation testing (e.g. MSPCR or quantitative PCR) are 
acceptable. 
 
3. Arm 1 patients must have measurable (defined by at least 1 cm x 1 cm) contrast-
enhancing disease by MRI imaging within 21 days of starting treatment.  
 
4. Patients must be able to undergo MRI of the brain with gadolinium. Patients must be 
maintained on a stable or decreasing dose of corticosteroid regimen (no increase for 5 
days) prior to this baseline MRI. 
 


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5. Arm 1 patients must be in first recurrence of glioblastoma following radiation therapy 
and temozolomide.  
Arm 2 patients may have an unlimited number of prior therapy regimens but may not 
have received prior antiangiogenesis therapy except for bevacizumab (patients may 
not have received aflibercept, ramucirumab, cediranib, cabozantinib, or XL184). 
 
6. Arm 1 patients must have not received bevacizumab previously.  
Arm 2 patients must have progressed/recurred on bevacizumab as the most recent 
regimen. Patients on Arm 2 should continue on bevacizumab as clinically necessary 
to control brain edema. 
 
7. Patients must have a tumor tissue form indicating availability of archived tissue from 
initial resection at diagnosis of glioblastoma completed and signed by a pathologist. 
See Section 9.5.1. Availability of tissue is not a requirement for study participation. 
 
8. Patients must have recovered from severe toxicity of prior therapy. The following 
intervals from previous treatments are required to be eligible: 
 
• 
12 weeks from the completion of radiation  
• 
6 weeks from a nitrosourea chemotherapy 
• 
3 weeks from a non-nitrosourea chemotherapy 
• 
4 weeks from any investigational (not FDA-approved) agents  
• 
2 weeks from administration of a non-cytotoxic, FDA-approved agent 
(e.g., erlotinib, hydroxychloroquine, etc.) 
 
9. Patients must be 18 years of age or older.  
 
10. Patients must have a Karnofsky Performance Status ≥ 60% (i.e. the patient must be 
able to care for himself/herself with occasional help from others). 
 
11. Patients must have the following organ and marrow function: 
 
Absolute neutrophil count 
>1,500/mcL 
Platelets 
>100,000/mcL 
Hemoglobin 
> 9 g/dL 
Total bilirubin                          ≤ institutional upper limit of normal 
AST (SGOT)/ALT (SGPT) 
≤ 4 × institutional upper limit of normal 
Creatinine  
 
≤ institutional upper limit of normal 
 
                    OR 
Creatinine clearance   
 
>60 ml/min/1.73m2 for patients with creatinine 
levels above institutional normal 
APTT or PTT 
 
≤ 1.5 x institutional upper limit of normal 
 
12. Patients must be able to provide written informed consent. 
 


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13. Women of childbearing potential must have a negative serum pregnancy test prior to 
study start. Women of childbearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to 
study entry, for the duration of study participation, and through 30 days after the last 
dose of study drug.  Should a woman become pregnant or suspect she is pregnant 
while participating in this study, she should inform her treating physician 
immediately. Men treated or enrolled on this protocol must also agree to use 
adequate contraception prior to the study, for the duration of study participation, and 
through 30 days after the last dose of study drug.   
 
14. Patients must have no concurrent malignancy except curatively treated basal or 
squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or 
bladder.  Patients with prior malignancies must be disease-free for ≥ five years. 
 
15. Patients must be able to swallow capsules. 
 
 
3.3 
Ineligibility Criteria 
 
1. 
Patients receiving any other investigational agents are ineligible. 
 
2. 
Patient must not have known sensitivity to TRC102 or any formulation excipients. 
 
3. 
Patients on enzyme-inducing anti-epileptic drugs (EIAED) are not eligible for 
treatment on this protocol. Patients may be on non-enzyme inducing anti-epileptic 
drugs or not be taking any anti-epileptic drugs. Patients previously treated with 
EIAED may be enrolled if they have been off the EIAED for 10 days or more prior 
to the first dose of TRC102. 
 
4. 
Patients must not be on any anticoagulation. 
 
5. 
Patient must not have prior gastrointestinal (GI) surgery or GI disease that might 
interfere with the absorption of TRC102. 
 
6. 
Patients who have not recovered to <CTCAE grade 2 toxicities related to prior 
therapy are ineligible. 
 
7. 
Patients must not have active brain metastases from a systemic solid tumor. 
 
8. 
Patients with uncontrolled intercurrent illness including, but not limited to, ongoing 
or active infection, symptomatic congestive heart failure, clinically significant 
cardiac disease, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements, are 
ineligible.  
 


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9. 
Pregnant women are excluded from this study because TRC102 has potential for 
teratogenic or abortifacients effects.  Because there is an unknown but potential risk 
for adverse events in nursing infants secondary to treatment of the mother with 
TRC102, breastfeeding should be discontinued if the mother is treated with 
TRC102. 
 
10. HIV-positive patients on combination antiretroviral therapy are ineligible because of 
the potential for pharmacokinetic interactions with TRC102. In addition, these 
patients are at increased risk of lethal infections when treated with marrow-
suppressive therapy.  
 


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4.0 
TREATMENT PLAN 
 
This is a Phase II, open-label, multicenter study of TRC102 in patients with recurrent 
glioblastoma. All subjects must have had histological confirmation of glioblastoma by 
either biopsy or resection that is progressive or recurrent following radiation therapy + 
temozolomide. 
 
This phase II trial will be performed in 2 sequential arms: the first arm of bevacizumab-
naïve patients and the second arm of bevacizumab-failure patients. 
 
 
       
 
 
 
 
 
* Arm 2 (bevacizumab refractory cohort) will only activate if Arm 1 (bevacizumab-
naïve cohort) meets the statistical criteria of efficacy. See Section 11.0, Statistical 
Considerations. 
 
4.1 
Treatment Schema  
 
Arm 1: Bevacizumab-naïve patients 
Arm 1 will estimate the efficacy of TRC102 and temozolomide (TMZ), as measured by 
response rate, in bevacizumab-naïve glioblastoma (patients may not have received prior 
treatment with bevacizumab). 
 
Arm 2: bevacizumab-refractory patients 
(This arm will only activate if Arm 1 meets the statistical criteria of efficacy as defined 
in Section 11.0) 
Arm 2 will estimate the efficacy of TRC102 and TMZ, as measured by response rate, in 
bevacizumab-refractory glioblastoma (patients must have progressed/recurred following 
prior treatment with bevacizumab but should continue receiving bevacizumab as 
clinically indicated). 
 
All patients will receive the maximum tolerated dose of oral TRC102 as determined in 
the NCI phase I trial, 150mg flat dose, combined with temozolomide 150mg/m2 on days 
1-5 every 28 days. The dose of temozolomide will remain at 150 mg/m2 throughout the 
study. 
 
 
 
 
Arm 1: 31 patients   
Bevacizumab-naïve cohort 
Primary endpoint: response rate 
Arm 2*: 35 patients  
Bevacizumab-refractory cohort 
Primary endpoint: response rate 
 


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TRC102 and TMZ are being given together as a combined treatment.  If for any reason a 
patient is permanently taken off TRC102  or TMZ the patient will be off treatment.   
 
An MRI will be performed prior to every odd-numbered cycle (every 8 weeks). 
 
Patients will continue receiving TRC102 and TMZ until they meet the criteria for disease 
progression or other criteria for going off treatment (Section 10.0). All patients will be 
followed for survival. 
 
4.2 
Treatment Requirements 
  
All eligible patients who consent to this study must have a baseline (post-operative, if 
surgery is applicable) pre-treatment MRI. This baseline scan must be done within 21 days 
prior to the initiation of treatment.    
 
Prior to every cycle patients must have: 
 
1) ANC ≥ 1500/µl and platelets  ≥ 100,000 /µl. 
 
    AND 
2) All toxicities recovered to ≤ grade 1 [or tolerable grade 2 for non-hematologic 
toxicity] or ≤ baseline. 
 
4.3 
Drug Administration 
 
No investigational or commercial agents or therapies other than those described below 
may be administered with the intent to treat the patient's malignancy.  
 
Treatment will be administered on an outpatient basis. Patients will be provided with 
medication diaries and instructed in their use. Patients will be instructed to bring all 
unused medication and their diaries to each study visit for assessment of compliance. 
 
4.3.1 TRC102 Administration 
 
TMZ (150mg/m2) and TRC102 at 150mg flat dose given 
Days 1-5 every 28 days 
MRI performed every 8 weeks 
RANO criteria used for response evaluation 
TMZ and TRC102 continued until disease progression or 
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TRC102 will be administered on an outpatient basis once daily as an oral dose of 150mg 
flat dose given for 5 consecutive days every 4 weeks. Patients should take the dose 
approximately the same time each day, in the morning, at the same time as the 
temozolomide dose.  
 
Drug should be taken on an empty stomach, 1 hour before a meal or 2 hours after a meal. 
Take with 8 ounces of water. Capsules should be swallowed whole, do not chew or crush. 
 
 If a patient misses or vomits a dose, he or she should be instructed not to take or make up 
that dose and to resume dosing with the next scheduled dose.  Missed or vomited doses 
should not be made up. A dose will be considered missed, and should not be made up, if 
more than 6 hours have passed from the time the dose is normally taken. 
 
4.3.2 Temozolomide Administration 
 
Temozolomide will be administered orally once a day for 5 consecutive days and 
repeated every 28 days. The dose will be 150 mg/m2/day.  
 
The dose administered will be determined using the body surface area (BSA) calculated 
at the beginning of each cycle. The BSA will be calculated from the height obtained at 
the baseline evaluation and from the weight obtained at the most recent pre-odd-
numbered cycle evaluation before each 5-day TMZ treatment.  Prior to each 5-day 
treatment with temozolomide a complete blood count (CBC) has to be obtained (within  
-5 days prior to dosing). The start of all 5-day TMZ treatments will be scheduled every 4 
weeks (28 days, +3 days) after the first daily dose of temozolomide of the preceding 5-
day treatment. 
 
If liver function tests (alkaline phosphatase, total bilirubin, SGOT, SGPT) are abnormal, 
the decision to initiate temozolomide treatment should carefully consider the benefits and 
risks for the individual patient. For patients with significant liver function abnormalities, 
the benefits and risks of continuing treatment should be carefully considered. 
 
Blood counts will be evaluated weekly.  Within -5 days prior to the first dose of each 5-
day TMZ treatment, the patient must have an ANC ≥ 1500/ul and platelet count ≥ 
100,000/ul.  On Day 1 of each cycle (within -5 days) all non-hematological toxicity 
grades 3 or 4 (except for alopecia, nausea and vomiting), related at least possibly to TMZ 
must have resolved (CTCAE grade ≤ 1 [or tolerable grade 2]).  If toxicity persists, 
treatment should be delayed by one week for up to 3 consecutive weeks and directions 
for dose reduction should be followed (see Section 5.2). If after 3 weeks of delay all 
toxicity has still not resolved then any further adjuvant treatment with temozolomide 
should be stopped (patient is off treatment). 
 
For this study of the combination treatment of temozolomide and TRC102, the dose of 
temozolomide will remain at 150mg/m2 for the duration of the study and not escalate to 
200 mg/m2.  If during the first cycle the patient experiences platelets < 50,000/ul and/or 


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ANC < 1000/ul and/or a non-hematologic toxicity ≥ grade 3 then patient should follow 
directions for dose reduction in Section 5.2.   
 
Capsules of temozolomide are available in 5, 20, 100, 140, 180, 250 mg strengths. The 
daily dose will be rounded to the nearest 10 mg. The exact dose administered should be 
recorded in the CRF. Each daily dose should be given with the least number of capsules. 
 
Temozolomide should be taken at the same time as TRC102 capsules on an empty 
stomach, 1 hour before a meal or 2 hours after a meal. Take with 8 ounces of water.   
Patients should be told to swallow the whole capsules in rapid succession without 
chewing them. If vomiting occurs during the course of treatment, no re-dosing of the 
patient is allowed before the next scheduled dose. Missed doses should not be made up. 
A dose will be considered missed, and should not be made up, if more than 6 hours have 
passed from the time the dose is normally taken. 
 
Antiemetic prophylaxis with a 5-HT3-antagonist is strongly recommended.  
 
4.4 
General Concomitant Medication and Supportive Care Guidelines 
 
  
Prohibited Concomitant Medication During Study 
 
   
Patients may receive other medications that the investigator deems to be medically 
necessary, with the specific exception of non-protocol specified chemotherapy, 
radiotherapy, anti-neoplastic biological therapy or other investigational agents.  Patients 
who require the use of any of the aforementioned treatments for clinical management 
should be removed from the study. 
 
Anticoagulants 
 
Patients may not be on anticoagulation at study start but may be treated with 
anticoagulation therapy for medical reasons that occur on study. 
 
Corticosteroids 
 
Postoperatively, corticosteroids should be tapered to a stable dose as determined by the 
clinical status of the patient.  The lowest required steroid dose should be maintained 
throughout the duration of the study in order to eliminate steroid effects as a confounding 
variable in the interpretation of serial brain imaging studies. Corticosteroid doses can be 
tapered as clinically indicated if the patient appears to be responding to therapy as judged 
by serial scans. Corticosteroid dose may, of course, be increased in the event of clinical 
deterioration or at the discretion of the attending physician. In the event of suspected 
clinical deterioration, repeat brain imaging is recommended. 
 
Anticonvulsants 
 


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No data exist regarding the interaction of TRC102 with enzyme-inducing anti-epileptic 
drugs (EIAEDs). For this study, patients may not be on EIAEDs; patients who require 
anti-epileptic drugs (AED) may be on non-enzyme inducing anti-epileptic drugs 
(NEIAED). If a patient on this study protocol needs to have an AED started or needs to 
have a second AED added then only NEIAED should be used.  There must be a ≥ 10 day 
period from discontinuation of an EIAED and initiation of therapy.  In the event that an 
enzyme-inducing anti-epileptic drug must be used for a patient on study the patient will 
be removed from the protocol. 
  
Herbal and Non-Traditional Medications 
  
  
  
No data exist regarding the interaction of TRC102 with commonly used herbal or non-
traditional medications. Patients should be instructed not to use such medications while 
receiving TRC102 therapy. 
 
 
 
 
  
 
5.0 
DOSING DELAYS/DOSE MODIFICATION FOR TOXICITY 
 
Clinically significant adverse events or abnormal laboratory values assessed as unrelated 
to disease progression, intercurrent illness, or concomitant medications require dose delay 
and dose modification. Such toxicities must have an attribution of possible, probable, or 
definite to TRC102 or temozolomide (see Section 9.2.2). 
 
In general, if toxicity occurs that is attributed to only one of the agents, only that agent 
should be dose-reduced/modified. The dose of the other agent can be maintained at the 
same level. If multiple toxicities occur, dose modification decisions should be based on 
the most severe toxicity. 
 
Because the protocol is designed to look at the effects of a combination treatment of 
TRC102 with TMZ, if either TRC102 or TMZ is permanently discontinued, the 
patient will be off treatment. 
 
For patients experiencing toxicity meeting the criteria below, the attributed drug(s) will 
be stopped.  If the patient recovers (≤ grade 1 [or tolerable grade 2 for non-hematologic 
toxicity] or ≤ baseline) a dose reduction is required for subsequent doses. Skipped doses 
will not be made up. If there is any question or confusion concerning a toxicity, the 
treating site should contact the ABTC Central Office to determine patient’s toxicity 
status.  The ABTC Central Office, with the Study Chair, will make the final decision. 
 
 Hematological toxicities will require dose modification if any of the following 
occur and complete blood counts and differentials were obtained according to the 
mandated schedule (CBC, differential, and platelets drawn twice a week until the 
ANC ≥ 1500/mm3 and platelets ≥100,000/mm3): grade 3 or 4 lymphopenia will not 
be considered a toxicity requiring dose modification. 
   
• ANC of < 500/mm3. 


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• Platelets < 25,000/mm3.  
• Febrile neutropenia 
• Any hematological toxicity that prevents administration of > 80% of 
the planned TRC102 and temozolomide doses 
 
 Non-hematological toxicities will require dose modification if any of the following 
occur: 
 
• Grades 3-4 severity (except nausea, vomiting, and diarrhea without 
sufficient prophylaxis; except alopecia; except grade 3 hyperglycemia; 
except grade 3 electrolyte disturbances that are asymptomatic and that 
respond to replacement therapy; and except grade 3 neurologic toxicity 
responding within two weeks to steroids, anticonvulsants, or 
electrolyte correction. A subject’s first episode of deep venous 
thrombosis (DVT) or pulmonary embolism (PE) will not require dose 
modification.) 
  
ANY TOXICITY (AS DEFINED ABOVE) CAUSING DELAY IN TREATMENT OF OVER 
21 DAYS IN THE START OF A CYCLE WOULD RESULT IN TAKING THE PATIENT 
OFF TREATMENT. 
 
5.1 
Dose Modification for TRC102 
 
The dose levels and the general approach to TRC102 dose modification on this trial are 
shown below. Adverse events (AEs) should be treated with the appropriate maximum 
supportive care, and dose reductions should be clearly recorded on the case report form. 
 
Dose reductions are required for any clinically significant toxicity as defined above. 
Dosing will stop until the toxicity has resolved to ≤ grade 1 (or tolerable grade 2 for non-
hematologic toxicity) or ≤ baseline. The maximum length of time that TRC102 can be 
held is 21 days. If treatment-related toxicity is not resolved in ≤ 21 days, the patient will 
be removed from treatment. After resolution, when dose reduction is permitted, the dose 
of TRC102 will be modified as stipulated below, with a maximum of 2 dose reductions.  
If there is any question, the ABTC Central Office and the Study Chair should be 
contacted. 
 
Dose Reduction Table for TRC102 
Dose Level 
TRC102  
Starting dose 
150mg flat dose 
First dose reduction 
125mg flat dose 
Second dose reduction 
100mg flat dose  
 
 
5.2 
Dose Modification for Temozolomide 
 


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Clinically significant toxicities having an attribution to TMZ of possible, probable or 
definite will result in the following TMZ dose modifications.   Dosing is based on 
toxicity during the prior treatment cycle. If multiple toxicities are seen, the dose 
administered should be based on the dose reduction required for the most severe grade of 
any single toxicity.  
 
Blood counts will be evaluated weekly.  Within -5 days prior to first dose of each 5-day 
TMZ treatment the patient must have an ANC ≥ 1500/ul and platelet count ≥ 100,000/ul.  
On Day 1 of each cycle (within -5 days) all non-hematological toxicity grade 3 or 4 
(except for alopecia, nausea and vomiting) must have resolved (CTCAE grade ≤ 1 [or 
tolerable grade 2]).  If toxicity persists, treatment should be delayed by one week for up 
to 3 consecutive weeks. If after 3 weeks of delay all toxicity has still not resolved then 
any further treatment with temozolomide should be stopped (patient is off treatment). 
 
Dose reductions: If any non-hematological toxicity observed during the most recent pre-
cycle evaluation was CTCAE Grade > 2 (except for alopecia, nausea and vomiting) 
and/or if platelets < 50,000/ul and/or ANC < 1000/ul, then the dose should be reduced 
by one dose level (see table below). For patients who would require dose reductions to a 
dose level < 100mg/m2/day, temozolomide will be stopped. Also, if any of the same non-
hematological Grade 3 toxicity recurs (except for alopecia, nausea and vomiting) after 
reduction for that toxicity, then temozolomide will be stopped (patient is off treatment). 
 
Temozolomide Dose Reduction Table 
Dose Level 
TMZ Dose mg/m2 
starting dose 
150 
first dose reduction 
100 
second dose reduction 
off treatment 
 
• If any non-hematological toxicity observed was CTCAE Grade 4 (except for alopecia, 
nausea and vomiting) then adjuvant temozolomide treatment should be stopped (patient 
is off treatment). 
 
Subsequent 5-day TMZ treatments: Any dose reductions of temozolomide will be 
determined according to (1) non-hematological toxicity during the preceding treatment 
cycle, as well as (2) the worst ANC and platelets toxicity. No dose escalation should be 
attempted. The same dose reductions as for the second 5-day TMZ treatment should be 
applied. 
 
5.3 
Major Events 
 
Major Events are non-treatment-related grade 3 and 4 hematologic and non-hematologic 
toxicities. Treatment should be delayed for major events if TRC102 may further 
complicate the non-treatment-related event.  If a major event requires a delay of treatment, 
treatment must be delayed until toxicity is resolved (≤ grade 1 [or tolerable grade 2 for 
non-hematologic toxicity] or ≤ baseline). If toxicity is not resolved in ≤ 28 days, the 


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patient will be removed from treatment.  The ABTC Central Office should be consulted if 
you are not clear on whether to continue or delay treatment. 
 
5.4 
Use of Hematologic Growth Factors 
 
No growth factors (G-CSF or GM-CSF) are to be used prophylactically in this protocol.  
Clinicians caring for patients on this protocol are permitted to use these growth factors to 
provide optimal care for patients with severe neutropenia in accordance with the ASCO 
guidelines, (JCO, 12, 1994: pp2471-2508).  If these growth factors are used in the acute 
setting of neutropenia and infection (documented or suspected), they will not be utilized 
prophylactically in subsequent cycles and they will not subsequently be used in lieu of 
dose reduction of (study agent). 
 
5.5 
Toxicity Criteria 
 
All toxicities will be described and graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0.  All appropriate treatment areas should 
have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can 
be downloaded from the CTEP web site (http://ctep.cancer.gov). See also Section 9.2.2, 
Recording of Adverse Events. 
 
 


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6.0 
PHARMACEUTICAL INFORMATION 
 
6.1 
TRC102 
 
Chemical Name:  Methoxyamine hydrochloride 
 
Other Names:  Methoxyamine HCl 
 
Classification:  Biochemical inhibitor of the BER pathway  
 
Molecular Formula: CH3ONH2•HCl 
 
M.W.:  
83.52 Daltons 
 
Approximate Solubility:   At ambient temperature, TRC102 is freely soluble in water, 
sparingly in ethanol (70mg/mL), and slightly in DMSO (140mg/mL).  
 
Mode of Action: TRC102 has the ability to interrupt the process of base excision repair 
(BER) by binding to apurinic/apyrimidinic sites produced during the initial step of the 
BER pathway. These sites are substrates for topoisomerase II (topo II); an enzyme that 
cleaves damaged DNA.  TRC102 has demonstrated the ability to potentiate the activity of 
the alkylating agents temozolomide and carmustine, and antimetabolite agents 
fludarabine and pemetrexed, in murine models of human cancer. Therefore, TRC102 may 
be able to potentiate the activity of alkylating and antimetabolite chemotherapy in 
patients. 
 
Description:  TRC102, a white, crystalline solid, is the hydrochloride salt of 
methoxyamine. 
 
How Supplied: TRC102 is supplied by IriSys, Inc. and distributed by the Pharmaceutical 
Management Branch, CTEP/DCTD/NCI.  The white, opaque, size 2, hard gelatin 
capsules contain 25 mg of Methoxyamine HCl powder, microcrystalline cellulose, 
crosspovidone, sodium starch glycolate, colloidal silicon dioxide, and talc.  Each HDPE 
bottle with child-resistant screw cap contains 30 capsules. 
 
Storage: Store bottles of TRC102 at refrigerated temperature (2-8°C).  
 
Stability:  Shelf life surveillance of the intact bottles is ongoing. 
 
Route of Administration:  Oral 
 
Method of Administration:  Capsules are taken in the morning after patients have fasted 
for at least two hours.  Take with 8 ounces of water.  Capsules should be swallowed whole, 
do not chew or crush.  Patients should refrain from eating or drinking for one hour following 
TRC102 dosing. 
 
Availability 
 


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TRC102 is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI.  
 
TRC102 is provided to the NCI under a Collaborative Agreement between the 
pharmaceutical collaborator and the DCTD, NCI (see Section 14.0). 
 
6.1.1  Agent Ordering and Agent Accountability 
 
TRC102 may be requested by the Principal Investigator (or their authorized designees) at 
each participating institution.  Pharmaceutical Management Branch (PMB) policy 
requires that the agent be shipped directly to the institution where the patient is to be 
treated.  PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained).  The CTEP-assigned protocol number must be used for 
ordering all CTEP-supplied investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF).  If 
there are several participating investigators at one institution, CTEP-supplied 
investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx).  
Access to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account (https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” 
account status and a “current” password.  For questions about drug orders, transfers, 
returns, or accountability, call (240) 276-6575 Monday through Friday between 8:30 am 
and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
6.1.2  Agent Inventory Records 
 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all agents 
received from DCTD using the NCI Oral Drug Accountability Record Form (Oral 
DARF).  (See the NCI Investigator’s Handbook for Procedures for Drug Accountability 
and Storage.) 
 
6.2 
Temozolomide 
 
Generic name:  
Temozolomide 
 
Commercial name:  
Temodar® 
 
Chemical name:  
3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-as-
tetrazine-8 carboxamide 


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Classification 
Antineoplastic agent, alkylating 
 
Molecular Formula:  
C6H6N6O2 
 
Molecular Weight:  
194.15 
 
Mechanism of Action: 
Temozolomide is not directly active but undergoes 
rapid non-enzymatic conversion at physiologic pH 
to the reactive compound 5-(3-methyltriazen-1-yl)-
imidazole-4-carboxamide (MTIC). The cytotoxicity 
of MTIC is thought to be primarily due to alkylation 
of DNA. Alkylation (methylation) occurs mainly at 
the O6 and N7 positions of guanine. 
 
Appearance:  
White to light tan/light pink powder 
 
Melting point:  
Decomposes at 206ºC 
 
How Supplied: 
Commercially available 
 
Stability:  
The molecule is stable at acidic pH (<5), and labile 
at pH >7, hence TEMODAR can be administered 
orally. The prodrug, temozolomide, is rapidly 
hydrolyzed to the active 5-(3-methyltriazen-1-
yl)imidazole-4-carboxamide (MTIC) at neutral and 
alkaline pH values, with hydrolysis taking place 
even faster at alkaline pH. The product label 
recommends Storage at 25°C (77°F); excursions 
permitted to 15°-30°C (59°-86°F).  
 
Half life:  
Temozolomide is rapidly eliminated with a mean 
elimination half-life of 1.8 hours 
 
Packaging, Dispensing and Storage 
 
TEMODAR Capsules are available in 5-mg, 20-mg, 100-mg, 140-mg, 180-mg, and 250-
mg strengths. The capsules contain a white capsule body with a color cap and the colors 
vary based on the dosage strength. The 5-mg, 20-mg, 100-mg, 140-mg, and 180-mg 
capsule strengths are available in 5-count and 14-count packages. The 250-mg capsule 
strength is available in a 5-count package. The product label recommends Storage at 
25°C (77°F); excursions permitted to 15°-30°C (59°-86°F).  Labeling of the packages 
containing the capsules will be done in accordance with the local procedures (as required 
by law).  According to the dosing the hospital pharmacist delivers the temozolomide 
dosage for a complete cycle to the subject.  
 


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7.0 
PROCEDURES FOR PATIENT ENTRY ON STUDY 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU) Regulatory 
Office and uses the Oncology Patient Enrollment Network (OPEN). 
 
Site Registration Requirements – IRB Approval 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can enroll patients. Study centers can check the status of 
their registration packets by querying the Regulatory Support System (RSS) site 
registration status page of the CTSU member web site by entering credentials at 
https://www.ctsu.org and clicking on the RSS tab. 
 
Site registration documents and a CTSU Transmittal Sheet (on CTSU website) must be 
submitted to the CTSU Regulatory Office at the following address: 
 
CTSU Regulatory Office 
Coalition of National Cancer Cooperative Groups 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
CTSURegulatory@ctsu.coccg.org (for submission of regulatory materials only) 
 
Patient Registration: 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). All site staff will use OPEN. OPEN is a web-based registration system available 
to users 9 a.m. to 4:30 p.m. Eastern Time. The system can be accessed by entering 
credentials at https://www.ctsu.org and clicking on the OPEN tab, or by entering 
credentials at the OPEN portal URL https://open.ctsu.org. 
 
Prior to discussing protocol entry with the patient, site staff must check the ABTC 
website (abtconsortium.org) for protocol status and slot availability.  
 
Prior to accessing OPEN, site staff should verify the following: 
  
• All eligibility criteria have been met within the protocol stated timeframes. Site staff 
should use the registration forms provided on the group web site as a tool to verify 
eligibility. 
• All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).  
  
Access requirements for OPEN: 


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• Site staff will need to be registered with CTEP and have a valid and active CTEP-
IAM account. This is the same account (user id and password) used for credentialing 
in the CTSU members' web site.  
• To perform registrations, the site user must have been assigned the 'Registrar' role (or 
equivalent) on the relevant Group or CTSU roster.  
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. Upon completion of the registration process in OPEN, sites should 
contact the ABTC Central Office to confirm the patient’s registration.  
  
Further instructional information is provided on the CTSU members' web site OPEN tab 
or within the OPEN URL (https://open.ctsu.org). For any additional questions contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.   
 
 
8.0 
RESPONSE ASSESSMENT / SAFETY AND QUALITY ASSURANCE 
 
8.1 
Criteria for Response Assessment 
 
Subjects with measurable disease will be assessed by the RANO (radiographic 
assessment in neuro-oncology) criteria (Wen 2010).  For the purposes of this study, 
subjects should be re-evaluated at the end of every 2 cycles (approximately every 8 
weeks) with a contrast-enhanced cranial MRI scan. The response will be determined as 
outlined in the RANO criteria below. 
 
Measurable disease. Bidimensionally, contrast-enhancing, measurable lesions with 
clearly defined margins by MRI scan, with a minimal diameter of 1 cm, and visible on 2 
axial slices which are at least 5 mm apart with 0 mm skip. Measurement of tumor around 
a cyst or surgical cavity, if necessary, requires a minimum thickness of 3 mm. If there are 
too many measurable lesions to measure at each evaluation, the investigator must choose 
the largest two to be followed before a participant is entered on study. The remaining 
lesions will be considered non-measureable for the purpose of objective response 
determination. Unless progression is observed, objective response can only be determined 
when all measurable and non-measurable lesions are assessed.  
 
Complete Response (requires all of the following): 
 
a)   Complete disappearance of all enhancing measurable and non-measurable disease 
sustained for at least 4 weeks. In the absence of a confirming scan 4 weeks later, this 
scan will be considered only stable disease. 
b)   No new lesions. 
c)   All measurable and non-measurable lesions must be assessed using the same 
techniques as baseline. 
d)   Subjects must be off corticosteroids (or on physiologic replacement doses only). 
e)   Stable or improved non-enhancing (T2/FLAIR) lesions. 
f)   Stable or improved clinically. 


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Note: Subjects with non-measurable disease cannot have a complete response. The best 
response possible is stable disease. 
 
Partial Response (requires all of the following): 
 
a)   Greater than or equal to 50% decrease compared to baseline in the sum of products of 
perpendicular diameters of all measurable enhancing lesions sustained for at least 4 
weeks. In the absence of a confirming scan 4 weeks later, this scan will be considered 
only stable disease. 
b)   No progression of non-measurable disease. 
c)   No new lesions. 
d)   All measurable and non-measurable lesions must be assessed using the same 
techniques as baseline. 
e)   The corticosteroid dose at the time of the scan evaluation should be no greater than 
the dose at time of baseline scan. 
f)   Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared to baseline scan. 
g)   Stable or improved clinically. 
 
Note: Subjects with non-measurable disease cannot have a partial response. The best 
response possible is stable disease. 
 
Stable Disease (requires all of the following): 
 
a)   Does not qualify for CR, PR, or progression. 
b)   The designation of stable disease requires a minimum of 4-week duration. 
c)   All measurable and non-measurable sites must be assessed using the same techniques 
as baseline. 
d)   Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared to baseline scan. In the event that the corticosteroid dose was increased for 
new symptoms and signs without confirmation of disease progression on 
neuroimaging, and subsequent follow-up imaging shows that this increase in 
corticosteroids was required because of disease progression, the last scan considered 
to show stable disease will be the scan obtained when the corticosteroid dose was 
equivalent to the baseline dose. 
e)   Stable clinically. 
 
Progressive Disease (defined by any of the following): 
 
a) ≥25% increase in sum of the products of perpendicular diameters of enhancing 
lesions compared to the smallest tumor measurement obtained either at baseline (if no 
decrease) or best response, on stable or increasing doses of corticosteroids.*  
b)  Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses 
of corticosteroids compared to baseline scan or best response following initiation of 


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therapy,* not due to co-morbid events (radiation therapy, demyelination, ischemic 
injury, infection, seizures, postoperative changes, or other treatment effects). 
c)   Any new lesion. 
d)  Clear clinical deterioration not attributable to other causes apart from the tumor (e.g., 
seizures, medication adverse effects, complications of therapy, cerebrovascular 
events, infection, etc.) or changes in corticosteroid dose. The definition of clinical 
deterioration is left to the discretion of the treating physician, but it is recommended 
that a decrease in 20% of KPS or from any baseline to 50% or less be considered, 
unless attributable to comorbid events. 
e)   Failure to return for evaluation due to death or deteriorating condition. 
f)   Clear progression of non-measurable disease. 
 
* Stable doses of corticosteroids include patients not on corticosteroids. 
 
8.2 
Assessment of Response 
 
Assessment of response will begin with the MRI performed just prior to every odd-
numbered treatment cycle.   If during any scheduled MRI, the subject has a Complete 
Response or Partial Response, the MRI should be repeated prior to the next cycle.  All 
scans are to be compared to the smallest measurement scan to date.  The subject will then 
return to the every odd-numbered cycle schedule.  This is required to confirm the 
duration of response.  Subjects will be classified as responders if they have a minimum 
duration of response for 4 weeks at any time after the first cycle of TRC102. MRI scans 
of subjects showing tumor response will be centrally reviewed by a neuroradiologist who 
will independently assess tumor size and compute percent tumor regression. 
 
8.3 
Safety assessments 
 
Safety assessments will consist of monitoring and recording all adverse events and 
serious adverse events, the regular monitoring of hematology and blood chemistry, 
regular measurement of vital signs, and the performance of physical/neurological 
examinations. 
 
8.4 
Quality Assurance 
 
Neuropathology:  The neuropathologic diagnosis of glioblastoma will be made at the 
respective institution.  If any question arises regarding the accuracy of the 
neuropathologic diagnosis, slides (and pathological blocks, if necessary) will be reviewed 
by the central review pathologist.  For protocols with “response” as an outcome, all 
patients with a documented complete response or partial response will have 
representative pathology slides undergo central review. 
 
Neuroradiology:  MRI scans of patients showing tumor response will be centrally 
reviewed by a neuroradiologist who will independently assess tumor size and compute 
percent tumor regression. 
 


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Neuro-oncology:  The local investigator at the participating institution will communicate 
to the ABTC Central Office any unexpected neurological effects such as change in 
seizure frequency, alteration in neuromuscular function, alteration in cognitive function, 
or fluctuations in serum anticonvulsant drug levels. 
 
Adherence to protocol therapy:  Screening/baseline source documentation will be 
submitted/uploaded into CTEP’s iMedidata Rave system and will be reviewed by the 
ABTC Central Office. As a quality assurance measure for the treatment delivered on this 
protocol, primary patient records may be reviewed.  The records to be examined will be 
selected retrospectively and at random; complete records must therefore be maintained on 
each patient treated on the protocol.  These records should include primary 
documentation (e.g., laboratory report slips, X-ray reports, scan reports, pathology 
reports, physician notes, etc.), which confirm that: 
 
•  
The patient met each eligibility criterion. 
•  
Signed informed consent was obtained prior to treatment. 
• 
Treatment was given according to protocol (dated notes about doses given; any 
reasons for any dose modifications). 
•  
Toxicity was assessed according to protocol (laboratory report slips,  etc.). 
• 
Response was assessed according to protocol (MRI scan, lab reports, dated notes 
on measurements and clinical assessment, as appropriate). 
•  
NCI Drug Accountability Records were maintained for this protocol. 


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9.0 
MONITORING OF PATIENTS 
 
9.1       Table of Required Observations   
 
Arms 1 & 2 (28-Day Cycles) 
 
Baseline 
 
Days 1-5 
of every 
cycle 
Weekly 
During 
Cycle 1  
Weekly 
During 
All 
Cycles 
Pre-Odd 
Cycles 
(cycles 3+) 
Pre- Even 
Cycles 
Off 
Treatment 
 
30 Days 
post-last 
dose  
TRC102 
 
6 
 
 
 
 
 
 
Temozolomide 
 
7 
 
 
 
 
 
 
Glucocorticoids Dose 
Evaluation 
1 
 
 
 
5 
 
8 
 
AE Evaluation 
1 
 
12 
 
5 
5 
8,10 
11 
MRI 
1 
 
 
 
5 
 
8 
 
H&P/Neuro Exam 
1 
 
 
 
5 
5 
8 
 
KPS 
1 
 
 
 
5 
5 
8 
 
Vital Signs 
1,2 
 
12 
 
2,5 
2,5 
2,8 
 
CBC, Diff, Platelets 
1 
 
 
9,12 
5,9 
5,9 
8,9 
 
Serum Chemistry 
1,3 
 
12 
 
3,5 
3,5 
3,8 
 
APTT or PTT 
1 
 
 
 
 
 
 
 
Serum Pregnancy Test 
1,4 
 
 
 
 
 
 
 
Archived Tumor Tissue 
13 
 
 
 
 
 
 
 
  1– All baseline measurements must be done within minus 21 calendar days of  treatment administration unless   
        otherwise specified. 
  2– Including blood pressure, respiratory rate, heart rate, temperature, weight, height: height is required at baseline 
only; weight is required at pre-odd cycle evaluations only. 
  3– Including albumin, alkaline phosphatase, total bilirubin, calcium, creatinine, magnesium, phosphorus, potassium, 
SGOT, SGPT, sodium. 
  4– For women of child-bearing potential. 
  
  5– Within minus 5 calendar days of cycle start. 
  6– TRC102 is administered orally on Days 1-5 of each 28-day cycle (see Section 4.3.1). Patients are required to keep 
a medication diary. 
7– Temozolomide is administered orally on Days 1-5 of each 28-day cycle (see Section 4.3.2). Patients are required 
to keep a medication diary. 
  8– Evaluations done within +7 days of off treatment date unless indicated: do not repeat: if MRI within minus 14 
days of off-treatment date; if  H&P/neuro, KPS, labs within minus 5 days of off-treatment date.  
  9– If ANC < 1500 or plts < 100,000, CBCs/differentials will be repeated twice a week until counts are recovered 
(ANC ≥1500 or plts ≥100,000) per protocol.  If counts are recovered (ANC ≥1500 or plts ≥100,000) on day of 
scheduled drawing do not repeat until next protocol schedule day 
10 – Adverse Events must be followed for at least 30 days from last dose of TRC102. 
11– Perform within +14 days of the 30-day post-last dose date. 
12– ± 1 day 
13– Unstained slides from initial resection at diagnosis of glioblastoma, if available (see Section 9.5.1) 
 


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9.2 
Adverse Events: Lists and Reporting Requirements  
 
Patients will be evaluated for toxicity if they have received at least one dose of TRC102 
or temozolomide.  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 9.2.1, below) and the characteristics of an observed AE 
(Section 9.2.2) will determine whether the event requires expedited reporting via the 
CTEP Adverse Event Reporting System (CTEP-AERS) in addition to routine reporting. 
    
Adverse Events will be collected for at least 30 days following the last dose of study 
drug.  
 
All adverse events must be reported to the ABTC Central Office and the NCI in the 
manner described and per the requirements of the investigative site’s Institutional Review 
Board.  
 
Adverse events will be entered into CTEP’s Medidata Rave database by the investigative 
site in a timely manner.  See Section 12.0 – Records to be Kept. 
 
9.2.1 Comprehensive Adverse Events and Potential Risks Lists (CAEPR) 
 
9.2.1.1 Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Methoxyamine hydrochloride (TRC102, NSC 3801) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single 
list of reported and/or potential adverse events (AE) associated with an agent using a 
uniform presentation of events by body system. In addition to the comprehensive list, a 
subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a 
separate column and is identified with bold and italicized text. This subset of AEs 
(SPEER) is a list of events that are protocol specific exceptions to expedited reporting to 
NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event 
Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pd
f for further clarification.  The CAEPR does not provide frequency data; refer to the 
Investigator's Brochure for this information.  Below is the CAEPR for Methoxyamine 
hydrochloride (TRC102).  
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using 
multiple investigational agents and has an AE listed on different SPEERs, use the lower 
of the grades to determine if expedited reporting is required. 
 
 
 


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Version 1.0, February 8, 20131 
Adverse Events with Possible 
Relationship to Methoxyamine hydrochloride (TRC102) 
(CTCAE 4.0 Term) 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
  Anemia (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Diarrhea 
  Diarrhea (Gr 1) 
 
Mucositis oral 
  Mucositis oral (Gr 1) 
 
Nausea 
  Nausea (Gr 2) 
 
Vomiting 
  Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Fatigue 
  Fatigue (Gr 2) 
 
Fever 
  Fever (Gr 1) 
INVESTIGATIONS 
  
 
Blood bilirubin increased 
  Blood bilirubin increased Gr 1) 
 
Haptoglobin decreased 
  Haptoglobin decreased (Gr 1) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
  Anorexia (Gr 1) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Pruritus 
  Pruritus (Gr 1) 
 
Rash maculo-papular 
  Rash maculo-papular (Gr 1) 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
Also reported on methoxyamine hydrochloride (TRC102) trials but with the relationship to 
methoxyamine hydrochloride (TRC102) still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Hemolysis 
GASTROINTESTINAL DISORDERS - Constipation  
IMMUNE SYSTEM DISORDERS – Allergic reaction 
INVESTIGATIONS - Alanine aminotransferase increased; Aspartate aminotransferase increased; 
Creatinine increased; Lymphocyte count decreased; Neutrophil count decreased; Platelet count decreased; 
White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hypocalcemia 
NERVOUS SYSTEM DISORDERS - Dysgeusia 
PSYCHIATRIC DISORDERS – Psychosis 
RESPIRATORY, THORACIC, & MEDIASTINAL DISORDERS - Dyspnea 
VASCULAR DISORDERS - Thromboembolic event 
 
Animal Data: The following toxicities have been observed in animal studies with methoxyamine 
hydrochloride (TRC102): 
Dogs: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - bone marrow hypercellularity; epididymal 
cellular debris; small thymus 
GASTROINTESTINAL DISORDERS - abnormal excreta 
INVESTIGATIONS – increased reticulocytes, lymphocytes increased 
NERVOUS SYSTEM DISORDERS - convulsions; tremors 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - seminiferous tubule degeneration 
Rats: 


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BLOOD AND LYMPHATIC SYSTEM DISORDERS - enlarged or swollen spleens; increased spleen 
weight 
INVESTIGATIONS - increased monocytes; increased reticulocytes; lymphocytes increased  
 
Note: Methoxyamine hydrochloride (TRC102) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, or the combination may 
result in events never previously associated with either agent. 
 
9.2.1.2 Adverse Event List for Temozolomide 
 
Known potential toxicities of temozolomide are hematological toxicities (leucopenia, 
lymphopenia, thrombocytopenia, and anemia), renal insufficiency, nausea and vomiting, 
liver enzyme abnormalities, lethargy, rash, headache, alopecia, constipation, 
fatigue/malaise, anorexia, hyperglycemia and diarrhea are known toxicities. Recently, 
cases of hepatic injury, including fatal hepatic failure, have been observed in patients 
enrolled in clinical studies utilizing the agent temozolomide. In addition, it was noted that 
liver toxicity may occur several weeks or more after initiation of treatment or after 
temozolomide discontinuation. Refer to the package insert for additional information on 
adverse events observed to date.  
 
Rats given temozolomide in recent multidose toxicity studies have developed 
adenocarcinoma of the breast, fibrosarcomas, malignant Schwannomas (a variant of 
fibrosarcoma), keratoacanthomas and basal cell adenomas. Similar studies conducted in 
dogs did not reveal any similar findings. The significance of this finding for humans is 
not known presently. 
 
Temozolomide is potentially mutagenic and should be handled with appropriate 
precautions by both staff and subjects. Subjects with known or suspected hypersensitivity 
to temozolomide should not be treated with temozolomide. There are no data available on 
the effect or management of temozolomide overdose. 
 
Additional information is available in the temozolomide package insert 
(www.temodar.com). 
 
9.2.2 Adverse Event Characteristics 
 
Definition - Adverse Event (AE) 
 
Adverse event is defined as any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of a medical 
treatment or procedure regardless of whether it is considered related to the medical 
treatment or procedure (attribution of unrelated, unlikely, possible, probable, or definite). 
 
Recording of Adverse Events - ABTC AE Form  
 


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• The investigator will monitor each patient closely for the development of adverse 
events and record all such events on the ABTC AE Case Report Form.  Each single 
sign or symptom must be reported separately.  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting.  All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE 
version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). You 
must use one of the CTCAE criteria to define your event. 
 
Adverse events not included in the CTCAE should be reported under “Other” within 
the appropriate category and graded 1 to 5 according to the general grade definitions - 
mild, moderate, severe, life-threatening, fatal or disabling - as provided in the 
CTCAE or the CTCAE Manual.  New adverse events may be submitted to the CTEP 
Help Desk at ncictcaehelp@mail.nih.gov for annual evaluation by the CTCAE 
Change Management Committee. 
   
• For expedited reporting purposes only: AEs for TRC102 that are bold and 
italicized in the CAEPR (i.e., those listed in the SPEER column, Section 9.2.1.1) 
should be reported through CTEP-AERS only if the grade is above the grade 
provided in the SPEER. 
 
• Attribution of the AE: The investigator will be asked to document his/her opinion of 
the relationship of the event to study medication as follows: 
 
 
- Unrelated – The AE is clearly not related to the investigational agent(s). 
- Unlikely – The AE is doubtfully related to the investigational agent(s). 
- Possible – The AE may be related to the investigational agent(s). 
- Probable – The AE is most likely related to the investigational agent(s). 
- Definite – The AE is clearly related to the investigational agent(s). 
 
• All adverse events should be followed up in accordance with good medical practice.  
Abnormalities of laboratory events which, in the opinion of the investigator, 
constitute adverse events (even if not serious) should be followed. 
 
9.3 
Serious Adverse Events and Expedited Adverse Event Reporting 
 
9.3.1 Definition – Serious Adverse Event (SAE) 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours 


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4) A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
5) A congenital anomaly/birth defect 
6) Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
 
9.3.2 Expedited Adverse Event Reporting 
 
 
Use CTEP-AERS Web Application and Document on ABTC AE Form  
 
• All SAEs must be documented on both the ABTC AE form and using the CTEP-
AERS Web Application within 24 hours of learning of the event. 
 
• Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse 
Event Reporting System), accessed via the CTEP web site (https://eapps-
ctep.nci.nih.gov/ctepaers).  The reporting procedures to be followed are presented 
in the “NCI Guidelines for Investigators: Adverse Event Reporting 
Requirements” which can be downloaded from the CTEP web site 
((http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_ev
ents.htm). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is 
to be made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is 
restored, the 24-hour notification phoned in must be entered electronically into 
CTEP-AERS by the original submitter at the site.  
 
• CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) 
of the Adult Brain Tumor Consortium (ABTC), the local treating physician, and 
the Reporter and Submitter.  CTEP-AERS provides a copy feature for other e-
mail recipients. 
 
• The ABTC Central Office is responsible for submitting to the CTSU 
documentation of AEs that they deem reportable for posting on the CTSU 
protocol web page and inclusion on the CTSU bi-monthly broadcast. 
 
• Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID provided 
during trial registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below.  Attribution to treatment or 
other cause must be provided. 


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Death due to progressive disease should be reported as Grade 5 “Neoplasms 
benign, malignant and unspecified (including cysts and polyps) - Other 
(Progressive Disease)” under the system organ class (SOC) of the same name.  
Evidence that the death was a manifestation of underlying disease (e.g., 
radiological changes suggesting tumor growth or progression: clinical 
deterioration associated with a disease process) should be submitted. 
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 


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applies after this reporting period. 
Effective Date:  May 5, 2011 
 
9.3.3 Other Reporting 
 
Any Serious Adverse Event, as described in Section 9.3.1, including death due to any 
cause, which occurs during this study must be reported immediately (within 24 hours) 
to the ABTC Central Office.   
 
 
 A phone call must be made to: 
 
SERENA DESIDERI 
ABTC DATA COORDINATOR 
OFFICE: 410-614-4400 
FAX: 410-614-9335 
OR JOY FISHER, ABTC MANAGER: 410-955-3657 / 410-599-4610 
 
  
 
These events also must be reported by the investigator to the appropriate Institutional 
Review Board (IRB). 
 
Patients who are removed from study due to adverse events should be followed until the 
adverse event has resolved or stabilized.  Copies of relevant documentation, such as 
laboratory reports, should be kept with the patient's study records. 
 
Secondary Malignancy  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to 
describe the event: 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML]) 
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol. 
 
Second Malignancy: 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT 
a metastasis from the initial malignancy).  Second malignancies require ONLY routine 
reporting via CDUS unless otherwise specified. 
 
Second Malignancy 


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A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT 
a metastasis from the initial malignancy).  Second malignancies require ONLY routine 
reporting via CDUS unless otherwise specified. 
 
9.4       Routine Adverse Event and Data Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions.  
 
This study will be monitored by the Clinical Data Update System (CDUS).  The ABTC 
Central Office is responsible for compiling and submitting CDUS data to CTEP for all 
participants and for providing the data to the principal investigator for review. 
 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  
Reports are due January 31, April 30, July 31 and October 31. 
 


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9.5  
Exploratory Correlative Studies  
 
9.5.1 Immunohistochemical Detection of Topoisomerase IIα and MPG on Archived 
Tumor Samples  
 
Formalin fixed, paraffin embedded pretreatment tumor specimens will be stained with 
antibodies to methylpurine DNA-glycosylase (MPG) and topoisomerase IIα (Topo IIα) 
in the IHC lab of the Tissue Resources Core of the Case Comprehensive Cancer Center, 
under the direction of Dr. Dawn Dawson. The IHC Core has extensive experience in 
method development and validation of IHC for use as correlative markers in clinical 
trials. The relevant antibodies have been identified and methods developed for the targets.  
 
IHC results will be determined by a combination of the percentage of tumor cell staining 
and the intensity of tumor cell staining. These results will be correlated between the 
responders and non-responders in the trial. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Methyl Purine DNA-Glycosylase  
 
Topoisomerase IIα  
 
 
(Abcam#ab55461) 
 
 
 
(BioCare#API3045AA) 
 
Figure 1: Immunohistochemical staining of clinical GBM specimens. Archived GBM specimens were 
identified, slides were cut, antigen retrieval was performed and slides stained with the indicated primary 
antibodies and HRP conjugated anti-mouse secondary antibodies and DAB detection performed in a 
Nemesis IHC Autostainer. 
 
Sample Packaging and Shipping 
 
Archived tumor tissue from the initial resection at diagnosis of glioblastoma (pre-
treatment) will be collected from patients when sufficient tissue is available.  At the time 
of registration, prior to beginning treatment, a tumor tissue form indicating availability 


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will need to be completed and signed by a pathologist.  This form provides written 
documentation of the availability of tissue for this study and the pathologist’s agreement 
to send it as described below. A  minimum of 10 unstained slides will be requested. The 
associated pathology report from the institution of collection should be shipped with the 
slides.  
 
Ship slides and associated pathology report to: 
 
John Pink, PhD 
Scientific Director, Translational Research Core Facility 
Case Comprehensive Cancer Center 
2103 Cornell Road 
Wolstein Research Building 3529 
Cleveland, OH 44106-7285 
Office: 216-368-5420 
Lab: 216-368-1141 
Email: jrp16@case.edu 
 
 
10.0    OFF TREATMENT/OFF STUDY CRITERIA 
 
Each subject has the right to withdraw from the study at any time without prejudice.  The 
investigator may discontinue any subject’s participation for any reason, including adverse 
event or failure to comply with the protocol (as judged by the investigator such as 
compliance below 80%, failure to maintain appointments, etc.). 
Should a subject withdraw from the study, the reason must be stated on the case report 
form, and a final evaluation of the subject should be performed.  
 
Patients who go off treatment must be followed for adverse events (AEs) for at least 30 
days from the last dose of TRC102. 
 
 
10.1 
 Off Treatment Criteria 
 
1. Disease Progression:  Remove patient from protocol therapy at the time progressive 
disease is documented. Disease progression is defined as:  Progressive neurologic 
abnormalities not explained by causes unrelated to tumor progression (e.g. anticonvulsant 
or  corticosteroid toxicity, electrolyte abnormalities, hyperglycemia, etc.) or a greater 
than 25% increase in the measurement of the tumor by MRI scan.  If neurologic status 
deteriorates, on a stable or increasing dose of steroids, or if new lesions appear on serial 
MRI, further study treatment will be discontinued. 
 
2. Adverse Event: 
• Intercurrent illness that prevents further administration of treatment 
• Patients who experience unacceptable toxicity. Patients removed from study for 
unacceptable adverse events will be followed until resolution or stabilization of 


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the adverse event. 
 
3. Patient Withdrawal: Patient’s refusal to continue treatment: in this event, document the 
reason for withdrawal. 
 
4. Non Compliance: Failure to comply with protocol (as judged by the investigator such as 
compliance below 80%, failure to maintain appointments, etc.) 
 
5. Physician Decision: If at any time the treating physician feels constraints of this protocol 
are detrimental to the patient’s health remove the patient from protocol therapy. 
 
6. Protocol Defined Delay:  
• 
Patients who experience a treatment-related toxicity causing a delay in treatment 
>21 days 
• 
Delay in protocol >28 days for major events or other non-treatment related delays 
• 
Patients who require >2 dose reductions 
• 
If either TRC102 or temozolomide is permanently discontinued, patient will be 
off treatment. 
• 
Patients who must be put on an enzyme-inducing anti-epileptic drug (EIAED) 
during the study  
 
7. Death 
 
10.2 
Off Study Criteria 
 
Patients will only be off study at the time of death. All patients will be followed for 
survival every 2 months for the first two years from the off treatment date; after 2 years, 
patients will be followed every 6 months until death. Survival status may be obtained by 
phone call, clinic visit, or medical records (e.g. physician notes/laboratory results of 
clinic or hospital visit). Please note that additional survival status reports will be required 
twice yearly for ABTC Central Office reporting. 
 
 


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11.0   STATISTICAL CONSIDERATIONS 
 
 
Primary Objectives 
           
Arm 1 
 
Objective response 
 
Arm 2  
 
Objective response 
 
Secondary Objectives 
 
1. Toxicity and safety of the combination TMZ and TRC102 
2. Progression-free survival, progression-free survival at 6 months, and overall survival  
 
Exploratory Objective 
       
Correlation of MPG, topo IIα, and MGMT with response, PFS, and overall survival  
 
Sample size justification for primary endpoints: 
 
Arm1:  The Arm 1 study is to test the hypothesis that the combination treatment of TMZ 
and TRC102 will achieve 30% radiographic response rate (PR+CR) in patients with first 
recurrence of glioblastoma. A 2-stage design (minimax design) would discriminate 
between true response rates of no more than 13% and at least 30%.  Maximum trial size 
would be set at 31 evaluable patients.  If at least 7 responses (at least 22.5%) were 
observed among the 31 evaluable patients, this regimen would be considered worthy of 
further testing in this disease.  If no more than 2 responses (no more than 10.5%) were 
observed among the initial 19 patients, the study would be terminated early and declared 
negative.  This design yields at least 85% power to detect a true response rate of at least 
30%.  It yields at least .90 probability of a negative result if the true response rate is no 
more than 13%, with at least .54 probability of early negative stopping.   
 
The Arm 2 study for bevacizumab-refractory patients is warranted only if the Arm 1 
study meets its efficacy criteria. Arm 2 will not open without prior discussion between 
ABTC and CTEP. 
 
Arm2: Arm 2 is a single arm study to test the hypothesis of clinical benefit of 30% 
radiographic response rate (PR+CR) for patients who had multiple numbers of prior 
therapies and are bevacizumab refractory, who are treated with TMZ and TRC102, and 
who continue bevacizumab. A safety run with 6 patients will be conducted prior to 
hypothesis testing in Arm 2. The expected DLT rate is ≤ 33%. If more than 2 patients 
experience dose limiting toxicity (DLT) associated with this regimen, Arm 2 will not be 
pursued further for safety reasons.  If 2 or fewer patients experience DLT, Arm 2 will be 


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conducted using Simon’s two-stage design. The 6 patients who were treated in the initial 
safe run will be counted as part of the first stage patients in the two-stage design. 
 
Using Simon’s two-stage design, if at least 7 responses (at least 20%) were observed 
among the 35 evaluable patients, this regimen could be considered worthy of further 
testing in this disease. If no more than 2 responses (no more than 11%) were observed 
among the initial 18 patients, the study would be terminated early and declared negative. 
This design yields at least 90% power to detect a true response rate of at least 30% from a 
null of 10% at an alpha level of 0.05 (one-sided). It yields 73% probability of early 
stopping if the true response rate is 10%.  
 
All secondary and exploratory objective outcomes will be analyzed using standard 
descriptive statistical methods. Potential statistical comparisons are considered 
exploratory.      
 
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
2 
2 
0 
0 
4 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
2 
3 
0 
0 
5 
White 
15 
22 
2 
3 
42 
More Than One Race 
0 
0 
0 
0 
0 
Total 
19 
27 
2 
3 
51 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015) 
 
OMB No. 0925-0001/0002 
 


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12.0   RECORDS TO BE KEPT   
  
  
  
 
 
Data collection for this study will be done exclusively through CTEP’s Medidata 
Rave.   
 
Access to the trial in Rave is granted through the iMedidata application to all persons 
with the appropriate roles in the Regulatory Support System (RSS).  To access 
iMedidata/Rave the site user must have an active CTEP IAM account (https://eapps-
ctep.nci.nih.gov/iam).  In addition, site users that are a member of the ABTC must have 
the Rave CRA role in RSS at the enrolling site. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles 
assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata.   
Please note, site users will not be able to access the study in Rave until all required 
Medidata and study specific trainings are completed.  Trainings will be listed in the upper 
right pane of the iMedidata screen.   
 
Users that have not previously activated their iMedidata/Rave accounts will also receive an 
invitation from iMedidata to activate their account.  If you have any questions please contact 
the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
• All data are due within 14 days of evaluation time point.  Please see Section 
9.1 for evaluation time points. 
• Serious Adverse Events, PHONE IMMEDIATELY, SEE SECTION 9.3 
 
 
13.0  REFERENCES 
 
Ang C, Guiot MC, Ramanakumar AV, Roberge D, Kavan P. Clinical significance of 
molecular biomarkers in glioblastoma. Can J Neurol Sci 2010;37:625-30. 
Batchelor TT, Mulholland P, Neyns B, et al. Phase III randomized trial comparing the 
efficacy of cediranib as monotherapy, and in combination with lomustine, versus 
lomustine alone in patients with recurrent glioblastoma. J Clin Oncol 2013;31:3212-8. 
Gordon MS, Rosen LS, Mendelson D, et al. A phase 1 study of TRC102, an inhibitor of 
base excision repair, and pemetrexed in patients with advanced solid tumors. Invest New 
Drugs 2013;31:714-23. 
Liu L, Taverna P, Whitacre CM, Chatterjee S, Gerson SL. Pharmacologic disruption of 
base excision repair sensitizes mismatch repair-deficient and -proficient colon cancer 
cells to methylating agents. Clin Cancer Res 1999;5:2908-17. 
Liu L, Nakatsuru Y, Gerson SL. Base excision repair as a therapeutic target in colon 
cancer. Clin Cancer Res 2002;8:2985-91. 
Montaldi AP, Sakamoto-Hojo ET. Methoxyamine sensitizes the resistant glioblastoma 
T98G cell line to the alkylating agent temozolomide. Clin Exp Med 2013;13:279-88. 


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Savvides PS, Xu Y, Liu L, et al. Phase 1 clinical trial of the base-excision repair inhibitor 
Methoxyamine-HCl (TRC102; MX) in combination with Temozolomide (TMZ) in 
patients with solid tumors Cancer Research 2012;72  
Reardon DA, Herndon JE, 2nd, Peters KB, et al. Bevacizumab continuation beyond 
initial bevacizumab progression among recurrent glioblastoma patients. Br J Cancer 
2012;107:1481-7. 
Sawides P, Xu Y, Liu L, et al. Pharmacokinetic profile of the base-excision repair 
inhibitor methoxyamine-HCl (TRC102; MX) given as an one-hour intravenous infusion 
with temozolomide (TMZ) in the first-in-human phase I clinical trial. ASCO Meeting 
Abstracts 2010;28:e13662. 
Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and 
adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-96. 
Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and 
adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a 
randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 
2009;10:459-66. 
Tang JB, Svilar D, Trivedi RN, et al. N-methylpurine DNA glycosylase and DNA 
polymerase beta modulate BER inhibitor potentiation of glioma cells to temozolomide. 
Neuro Oncol 2011;13:471-86. 
Taverna P, Liu L, Hwang HS, Hanson AJ, Kinsella TJ, Gerson SL. Methoxyamine 
potentiates DNA single strand breaks and double strand breaks induced by temozolomide 
in colon cancer cells. Mutat Res 2001;485:269-81. 
Weeks LD, Fu P, Gerson SL. Uracil-DNA glycosylase expression determines human 
lung cancer cell sensitivity to pemetrexed. Mol Cancer Ther 2013;12:2248-60. 
Weller M, Cloughesy T, Perry JR, Wick W. Standards of care for treatment of recurrent 
glioblastoma--are we there yet? Neuro Oncol 2013;15:4-27. 
Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for 
high-grade gliomas: response assessment in neuro-oncology working group. J Clin 
Oncol. Apr 10 2010;28(11):1963-1972. 
Wick W, Puduvalli VK, Chamberlain MC, et al. Phase III study of enzastaurin compared 
with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol 
2010;28:1168-74. 
Yan L, Bulgar A, Miao Y, et al. Combined treatment with temozolomide and 
methoxyamine: blocking apurininc/pyrimidinic site repair coupled with targeting 
topoisomerase IIalpha. Clin Cancer Res  
Yang S, Savvides P, Liu L, Gerson SL, Xu Y. Development and validation of an LC-
MS/MS method for pharmacokinetic study of methoxyamine in phase I clinical trial. J 
Chromatogr B Analyt Technol Biomed Life Sci 2012;901:25-33. 
 


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14.0 
COLLABORATIVE AGREEMENTS LANGUAGE 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the 
Pharmaceutical Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI 
Division of Cancer Treatment and Diagnosis.  Therefore, the following 
obligations/guidelines, in addition to the provisions in the “Intellectual Property Option to 
Collaborator” (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) 
contained within the terms of award, apply to the use of the Agent(s) in this study: 
 
1.   Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) 
and shall be maintained as such by the investigators. The protocol documents for 
studies utilizing Agents contain confidential information and should not be shared or 
distributed without the permission of the NCI.  If a copy of this protocol is requested 
by a patient or patient’s family member participating on the study, the individual 
should sign a confidentiality agreement. A suitable model agreement can be 
downloaded from: http://ctep.cancer.gov. 
 
2.   For a clinical protocol where there is an investigational Agent used in combination 
with (an)other Agent(s), each the subject of different Collaborative Agreements, the 
access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data”): 
 
a.   NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with NCI, 
the design of the proposed combination protocol, and the existence of any 
obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 
 
b.   Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow said 
other Collaborator to develop, obtain regulatory approval or commercialize its 
own Agent. 
 
c.   Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own Agent. 
 
3.   Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 
described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 


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Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy of 
Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4.   When a Collaborator wishes to initiate a data request, the request should first be sent 
to the NCI, who will then notify the appropriate investigators (Group Chair for 
Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact 
them. 
 
5.   Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if 
there is a DMC for this clinical trial. 
 
6.   Any manuscripts reporting the results of this clinical trial must be provided to CTEP 
by the Group office for Cooperative Group studies or by the principal investigator for 
non-Cooperative Group studies for immediate delivery to Collaborator(s) for advisory 
review and comment prior to submission for publication.  Collaborator(s) will have 
30 days from the date of receipt for review.  Collaborator shall have the right to 
request that publication be delayed for up to an additional 30 days in order to ensure 
that Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected.  Copies of abstracts must be provided to 
CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and 
preferably at least three (3) days prior to submission, but in any case, prior to 
presentation at the meeting or publication in the proceedings. Press releases and other 
media presentations must also be forwarded to CTEP prior to release. Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 


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15.0  ETHICAL AND LEGAL CONSIDERATIONS 
 
 
This study will be conducted in accordance with the Declaration of Helsinki and in 
compliance with all applicable laws and regulations of the locale where the study is 
conducted. 
 
It is the responsibility of the investigator that the patient is made aware and consent is 
given that personal information may be scrutinized during audits by competent authorities 
and properly authorized persons, but that personal information will be treated as strictly 
confidential and not be publicly available.  The investigator is responsible for the retention 
of the patient log and patient records. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX I – PATIENT MEDICATION DIARIES 
 
TRC102 DIARY (TRC102 on Days 1- 5 every 28 days) 
 
Patient Name____________________________ (initials acceptable)   Patient Study ID ___________________   
 
Cycle # _______ 
 
INSTRUCTIONS TO THE PATIENT: 
1. 
You will take TRC102______ mg on Days 1- 5 of every 28-day cycle.  
Take TRC102 in the morning at the same time as your temozolomide capsules, on an empty 
stomach, 1 hour before a meal or 2 hours after. Take with 8 ounces of water. Capsules should 
be swallowed whole, do not chew or crush. 
2. Record the date and the time you took the TRC102 dose.   
Record missed or skipped dose(s). 
3. Bring this form and any remaining TRC102 when you return for each appointment. 
 
 
Week Day 
 
Date 
 
Time of 
dose  
# of 25 mg 
capsules 
 
 
 
Week 
 
 
Day 
 
 
Date 
 
1 
1 
 
 
3 
15 
(no dose) 
– 
 
2 
 
 
 
 
16 
(no dose) 
– 
 
3 
 
 
 
17 
(no dose) 
– 
 
4 
 
 
 
 
18 
(no dose) 
– 
 
5 
 
 
 
 
19 
(no dose) 
– 
 
6 
(no dose) 
– 
– 
 
20 
(no dose) 
– 
 
7 
(no dose) 
– 
– 
 
21 
(no dose) 
– 
2 
8 
(no dose) 
– 
– 
4 
22 
(no dose) 
– 
 
9 
(no dose) 
– 
– 
 
23 
(no dose) 
– 
 
10 
(no dose) 
– 
– 
 
24 
(no dose) 
– 
 
11 
(no dose) 
– 
– 
 
25 
(no dose) 
– 
 
12 
(no dose) 
– 
– 
 
26 
(no dose) 
– 
 
13 
(no dose) 
– 
– 
 
27 
(no dose) 
– 
 
14 
(no dose) 
– 
– 
 
28 
(no dose) 
– 
 
 
Patient’s Signature _________________________________________________________________________ 
 
Date ____________________ 
 
Nurse’s Signature ________________________________________________________________________ 
 
Date ____________________  
 
 
 
 
 
 
 


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TEMOZOLOMIDE DIARY (Temozolomide on Days 1- 5 every 28 days) 
 
Patient Name____________________________ (initials acceptable)   Patient Study ID ___________________   
 
Cycle # _______ 
 
INSTRUCTIONS TO THE PATIENT: 
1. 
You will take Temozolomide (TMZ) ______ mg on Days 1- 5 of every 28-day cycle.  
Take the TMZ capsules in the morning at the same time as your TRC102 capsules, on an empty stomach, 
1 hour before a meal or 2 hours after.  
Take with 8 ounces of water. Capsules should be swallowed whole, do not chew or crush. 
Dose:  take ___ 5 mg capsules, ___ 20 mg capsules, ___ 100 mg capsules, ___ 140 mg capsules, ___ 
180 mg capsules, and ___ 250 mg capsules. 
2. Record the date, the time you took the capsules, and the number of capsules of each size that you took.   
Record missed or skipped dose(s). 
3. 
Bring this form and your bottles of TMZ capsules when you return for each appointment. 
 
Week Day 
 
Date 
 
Time of 
dose  
# of TMZ capsules 
 
 
 
Week 
 
 
Day 
 
 
Date 
 
5  
mg 
20 
mg 
100 
mg 
140 
mg 
180 
mg 
250 
mg 
1 
1 
 
 
 
 
 
 
 
3 
15 (no dose) 
– 
 
2 
 
 
 
 
 
 
 
 
 
16 (no dose) 
– 
 
3 
 
 
 
 
 
 
 
 
17 (no dose) 
– 
 
4 
 
 
 
 
 
 
 
 
 
18 (no dose) 
– 
 
5 
 
 
 
 
 
 
 
 
 
19 (no dose) 
– 
 
6 
(no dose) 
– 
– 
 
20 (no dose) 
– 
 
7 
(no dose) 
– 
– 
 
21 (no dose) 
– 
2 
8 
(no dose) 
– 
– 
4 
22 (no dose) 
– 
 
9 
(no dose) 
– 
– 
 
23 (no dose) 
– 
 
10 (no dose) 
– 
– 
 
24 (no dose) 
– 
 
11 (no dose) 
– 
– 
 
25 (no dose) 
– 
 
12 (no dose) 
– 
– 
 
26 (no dose) 
– 
 
13 (no dose) 
– 
– 
 
27 (no dose) 
– 
 
14 (no dose) 
– 
– 
 
28 (no dose) 
– 
 
 
Patient’s Signature _________________________________________________________________________ 
 
Date ____________________ 
 
Nurse’s Signature ________________________________________________________________________ 
 
Date ____________________