Phase I Study of TRC102 in Combination With Cisplatin and Pemetrexed in Patients With Advanced Solid Tumors / Phase II Study of TRC102 With Pemetrexed in Patients Refractory to Pemetrexed and Cisplatin or Carboplatin
Phase: PHASE1
Conditions: Advanced Malignant Solid Neoplasm, Advanced Peritoneal Malignant Mesothelioma, Advanced Pleural Malignant Mesothelioma, Recurrent Peritoneal Malignant Mesothelioma, Recurrent Pleural Malignant Mesothelioma, Refractory Malignant Solid Neoplasm, Unresectable Solid Neoplasm
Sponsor: National Cancer Institute (NCI)

NCI Protocol #: 9837; PhI-76 
Version Date: March 7, 2019 
 
i 
SUMMARY OF CHANGES 
 
Date: 
March 7, 2019 
Document: 
NCI Protocol #9837, PhI-76: “Phase I Study of TRC102 in Combination 
with Cisplatin and Pemetrexed in Patients with Advanced Solid Tumors / 
Phase II Study of TRC102 with Pemetrexed in Patients Refractory to 
Pemetrexed and Cisplatin or Carboplatin.” 
Note: 
The following is a Summary of Changes between the 11.13.18 and 3.7.19 
versions of the protocol 
 
Section 
Description of Change (v. 11.13.18 and v. 3.7.19) 
Face page 
Updated protocol version in header and added new version date March 7, 2019 to 
protocol history. 
TOC 
Updated page numbers. 
5.5 
Clarified that patients who have clinical benefit may continue on treatment (even if 
meeting the protocol definition of progression) at the discretion of the treating MD.   
8.1.2.1 
Replace section with the following: 
NCI-supplied agents may be requested by the Principal Investigator (or their 
authorized designee) at each participating institution.  Pharmaceutical Management 
Branch (PMB) policy requires that 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), Biosketch, Agent Shipment Form, 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. 
In general, sites may order initial agent supplies when a subject is being screened 
for enrollment onto the study. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application.  Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account 
status, a “current” password, and active person registration status.  For questions 
about drug orders, transfers, returns, or accountability, call or email PMB any time.  
Refer to the PMB’s website for specific policies and guidelines related to agent 
management.   
 
PI Response:  Done. 

NCI Protocol #: 9837; PhI-76 
Version Date: March 7, 2019 
 
ii 
Section 
Description of Change (v. 11.13.18 and v. 3.7.19) 
8.1.2.2 
Replace section with the following: 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this 
protocol. 
PI Response:  Done. 
8.1.2.3 
Insert as a new subsection 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• IB Coordinator:  IBCoordinator@mail.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
 
PI Response: Done 
8.1.2.4 
Insert this as a new subsection 
Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators 
and research staff through the PMB Online Agent Order Processing (OAOP) 
application.  Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account 
status and a “current” password.  Questions about IB access may be directed to the 
PMB IB coordinator via email. 
PI Response: Done. 
12.2 
Please revise the following paragraph as indicated. 
Data collection for this study will be done exclusively through Medidata Rave.  
Access to the trial in Rave is granted through the iMedidata application to all persons 
with the appropriate roles assigned in the Regulatory Support System (RSS).  To 

NCI Protocol #: 9837; PhI-76 
Version Date: March 7, 2019 
 
iii 
Section 
Description of Change (v. 11.13.18 and v. 3.7.19) 
access Rave via iMedidata, the site user must have an active CTEP IAM account 
(check at < https://ctepcore.nci.nih.gov/iam  >) and the appropriate Rave role (Rave 
CRA, Rave Read-Only, Rave CRA (Lab Admin), Rave SLA, or Rave Investigator) 
(Rave CRA, Read-Only, CRA, Lab Admin, SLA, or Site Investigator) on either the 
LPO or participating organization roster at the enrolling site. To the hold Rave CRA 
role or Rave CRA (Lab Admin) Rave CRA role or CRA Lab Admin role, the user 
must hold a minimum of an AP registration type.  To hold the Rave Site Investigator 
role, the individual must be registered as an NPIVR or IVR.  Associates can hold 
read-only roles in Rave.  If the study has a DTL, individuals requiring write access to 
Rave must also be assigned the appropriate Rave tasks on the DTL.  (Note: A DTL is 
NOT required for this study.).   
PI Response: Done. 

NCI Protocol #: 9837; PhI-76 
Version Date: March 7, 2019 
 
1 
 
NCI Protocol #: 
9837 
 
Local Protocol #: 
PhI-76 
 
ClinicalTrials.gov Identifier:  NCT02535312 
 
TITLE:  Phase I Study of TRC102 in Combination with Cisplatin and Pemetrexed in Patients 
with Advanced Solid Tumors / Phase II Study of TRC102 with Pemetrexed in Patients 
Refractory to Pemetrexed and Cisplatin or Carboplatin 
 
 
Corresponding Organization: LAO-CA043 / City of Hope Comprehensive Cancer Center 
LAO 
 
1500 E. Duarte Road 
 
Duarte, CA 91010 
 
Phone:  (626) 256-4673 x 65928 
 
Fax:  (626) 423-5365 
 
Email:  ccc@coh.org  
 
Principal Investigator: 
Marianna Koczywas, MD 
City of Hope 
1500 E. Duarte Road 
 
Duarte, CA 91010 
 
Phone:  (626) 256-4673 
 
Fax:  626-301-8233 
 
Email:  mkoczywas@coh.org  
 
NOTE: 
As of March 13, 2018, Arm A (3-drug combination) is open to all ETCTN sites.   
  
Arm B (2-drug combination) is open to all ETCTN sites. 
 
Participating Organizations  
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 

NCI Protocol #: 9837; PhI-76 
Version Date: March 7, 2019 
 
2 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
 
 
Statistician: 
Jeff Longmate, PhD  
 
City of Hope Comprehensive Cancer Center 
 
1500 E. Duarte Road 
 
Duarte, CA 91010 
 
Phone:  (626) 256-4673  
 
Email:  jlongmate@coh.org   
 
 
 
NCI-Supplied Agent:  
 TRC102 (Methoxyamine hydrochloride, NSC 3801) 
Other Agent(s):  
 Cisplatin (Platinol) – commercial supply 
                             
 Pemetrexed (Alimta) – commercial supply 
IND #:   
 
IND Sponsor:   
DCTD, NCI 
 
 
Protocol Type / Version # / Version Date: 
December 17, 2014 
Initial Protocol 
 
 
 
 
February 17, 2015  
Response to Consensus 
Review 
 
 
 
 
February 26, 2015  
Response to Follow Up 
Review 
 
 
 
 
May 11, 2015  
 
Amendment (cIRB 
stipulations) 
 
 
 
 
June 18, 2015  
 
Amendment (cIRB 
stipulations) 
 
 
 
 
August 4, 2015 
 
Amendment 
 
 
 
 
November 10, 2015 Amendment 
 
 
 
 
January 4, 2016 
 
Amendment 
 
 
 
 
February 25, 2016  
Amendment 
 
 
 
 
October 24, 2016  
Amendment 
 
 
 
 
January 13, 2017  
Amendment 
 
 
 
 
July 26, 2017  
 
Amendment  
 
 
 
 
September 28, 2017 Amendment 
 
 
 
 
March 13, 2018 
 
Amendment 
 
 
 
 
November 13, 2018 Amendment 
 
 
 
 
March 7, 2019  
 
Amendment 

NCI Protocol #: 9837; PhI-76 
Version Date: March 7, 2019 
 
3 
SCHEMA 
 
NOTE: 
As of March 13, 2018, Arm A (3-drug combination) is open to all ETCTN sites.  
  
Arm B (2-drug combination) is open to all ETCTN sites.   
 
Arm A: 
This arm is a Phase I trial to select a Recommended Phase 2 Dose (RP2D) of TRC102 in 
combination with Cisplatin and Pemetrexed in patients with advanced solid tumors. During the 
initial dose escalation, patients will be accrued in cohorts of 3, with dose escalation based on 
toxicities experienced during the first cycle (see sections 5.3 and 13.1). Escalation is planned to 
proceed through 4 dose levels (Table 1), unless the escalation rules require stopping at a lower 
maximum tolerated dose level (tentative MTD). In that case, Dose Level 4 will be re-defined to 
combine the TRC102 dose from the tentative MTD with Cisplatin at 75 mg/m2 (per Table1) and 
escalation will proceed to the re-defined Dose Level 4. Six patients will be treated at the final 
RP2D before expanding that dose level   
 
Cohorts of patients will receive escalating doses of TRC102, orally, daily (days 1-4) in 
combination with cisplatin and pemetrexed on day 1, as shown in Table 1.  
 
Table 1 
Dose Level 
TRC102 
(days 1-4, q 21 days) 
Pemetrexed 
(day 1, q 21 days) 
Cisplatin 
(day 1, q 21 days) 
– 1 
25 mg/day, PO 
500 mg/m2, IV 
60 mg/m2, IV 
1 
50 mg/day, PO 
500 mg/m2, IV 
60 mg/m2, IV 
2 
75 mg/day, PO 
500 mg/m2, IV 
60 mg/m2, IV 
3 
100 mg/day, PO 
500 mg/m2, IV 
60 mg/m2, IV 
4 
{chemotherapy-
naïve patients} 
100 mg/day, or MTD w/ 60 
mg/m2 cisplatin, whichever is 
lower, PO 
500 mg/m2, IV 
75 mg/m2, IV 
 
 
Arm B: 
This arm is designed as the first stage of a two stage (Gehan) design trial of patients with 
mesothelioma who had progressed while being treated with or had recurred within 6 months of 
being treated with pemetrexed + cisplatin frontline.  Patients will be treated at dose level 1 without 
cisplatin (Table 1). Given the low probability of responses in this population being retreated with 
pemetrexed, one response out of 14 would be of interest. 
 

NCI Protocol #: 9837; PhI-76 
Version Date: March 7, 2019 
 
4 
TABLE OF CONTENTS 
SCHEMA .........................................................................................................................................3 
1. 
OBJECTIVES ......................................................................................................................6 
1.1 
Primary Objectives ...................................................................................................6 
1.2 
Secondary Objectives: .............................................................................................6 
2.0 
BACKGROUND .................................................................................................................6 
2.1 
Malignant Mesothelioma .........................................................................................6 
2.2 
TRC102 ....................................................................................................................7 
2.3 
BER Inhibition by TRC102 .....................................................................................7 
2.4 
Nonclinical Studies ..................................................................................................8 
2.5 
Clinical Studies ......................................................................................................10 
2.6 
Potential  Risks ......................................................................................................11 
2.7 
Drug Interactions ...................................................................................................12 
2.8 
Pemetrexed, Cisplatin and TRC102 .......................................................................12 
2.9 
Rationale ................................................................................................................14 
2.10 
Correlative Studies Background ............................................................................14 
3 
PATIENT SELECTION ....................................................................................................15 
3.1 
Eligibility Criteria ..................................................................................................15 
3.2 
Exclusion Criteria ..................................................................................................17 
3.3 
Inclusion of Women and Minorities ......................................................................18 
4 
REGISTRATION PROCEDURES (Rostered Protocol Model) ........................................18 
4.1 
Investigator and Research Associate Registration with CTEP ..............................18 
4.2 
Site Registration .....................................................................................................19 
4.3 
Patient Registration ................................................................................................21 
4.4 
General Guidelines .................................................................................................23 
5 
TREATMENT PLAN ........................................................................................................23 
5.1 
Screening and Pretreatment Assessments ..............................................................23 
5.2 
Agent Administration .............................................................................................23 
5.3 
Definition of Dose-Limiting Toxicity ....................................................................26 
5.4 
General Concomitant Medication and Supportive Care Guidelines ......................27 
5.5 
Duration of Therapy ...............................................................................................28 
5.6 
Duration of Follow Up ...........................................................................................28 
5.7 
Criteria for Removal from Study ...........................................................................29 
6 
DOSING DELAYS/DOSE MODIFICATIONS................................................................29 
6.1 
Arm A: TRC102 in combination with Cisplatin and Pemetrexed .........................29 
6.2 
Arm B: TRC102 in combination with Pemetrexed ................................................31 
6.3 
Management of Specific Adverse Events – Chemotherapy ..................................32 
6.4 
Maximum Treatment Delay ...................................................................................32 
7 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................32 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) .....................32 

NCI Protocol #: 9837; PhI-76 
Version Date: March 7, 2019 
 
5 
7.2 
Adverse Event Characteristics ...............................................................................37 
7.3 
Expedited Adverse Event Reporting ......................................................................37 
7.4 
Routine Adverse Event Reporting .........................................................................39 
7.5 
Secondary Malignancy ...........................................................................................39 
7.6 
Second Malignancy ................................................................................................40 
8 
PHARMACEUTICAL INFORMATION ..........................................................................40 
8.1 
CTEP IND Agent ...................................................................................................40 
9 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................43 
9.1 
Pharmacokinetics of TRC102 ................................................................................43 
9.2 
Correlative Studies .................................................................................................43 
10. 
STUDY CALENDAR .......................................................................................................48 
11 
MEASUREMENT OF EFFECT........................................................................................49 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................49 
11.2 
Response Criteria ...................................................................................................53 
12 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................55 
12.1 
Data Reporting .......................................................................................................55 
12.2 
CTEP Multicenter Guidelines ................................................................................58 
12.3 
Collaborative Agreements Language .....................................................................58 
13 
STATISTICAL CONSIDERATIONS...............................................................................60 
13.1 
Study Design/Endpoints.........................................................................................60 
13.2 
Sample Size/Accrual Rate ......................................................................................61 
13.3 
Stratification Factors ..............................................................................................61 
13.4 
Analysis of Secondary Endpoints ..........................................................................61 
13.5 
Reporting and Exclusions ......................................................................................62 
13.6 
Study Status Updates and Study Closure ...............................................................62 
14 
CCC POLICIES FOR MONITORING CONSORTIUM TRIALS ...................................64 
14.1 
Oversight ................................................................................................................65 
15 
REFERENCES ..................................................................................................................67 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................72 
APPENDIX B 
INFORMATION ON POSSIBLE DRUG INTERACTIONS ...................73 
APPENDIX C        NOT APPLICABLE .......................................................................................74 
APPENDIX D        PATIENT MEDICATION DIARY ...............................................................75 
APPENDIX E        SPECIMEN COLLECTION FORM FOR PHARMACODYNAMIC 
STUDIES NCI PROTOCOL #9837, PHI-76 ....................................................................76 
 
 

NCI Protocol #: 9837; PhI-76 
Version Date: March 7, 2019 
 
6 
1. OBJECTIVES 
 
We hypothesize: (1) TRC102 combined with pemetrexed and cisplatin can be administered safely 
in patients with advanced solid tumors;(2) the combination may be effective in patients with 
advanced unresectable malignant mesothelioma; (3) TRC102 combined with pemetrexed will 
produce responses in patients with advanced malignant mesothelioma who progressed on or had a 
recurrence with 3 months of treatment with pemetrexed and cisplatin. 
 
1.1 
Primary Objectives 
 
Arm A: 
1. To determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose 
(RP2D) for the combination of TRC102  with pemetrexed and cisplatin in patients with 
advanced solid tumors 
2. To describe the toxicities of TRC102 combined with pemetrexed and cisplatin at each dose 
studied 
3. To describe responses to the drug combination at each dose level 
 
Arm B: 
 
1. To  detect activity of the combination of TRC 102 and pemetrexed, as evidenced by tumor 
response in patients with advanced malignant mesothelioma previously treated with 
pemetrexed and cisplatin 
 
1.2 
Secondary Objectives: 
 
1. To describe pharmacokinetic parameters of TRC102 given concurrent with pemetrexed 
and cisplatin 
2. To evaluate the pharmacodynamic parameters of TRC102 given concurrently with 
pemetrexed and cisplatin 
3. To explore the feasibility of establishing pleural and peritoneal effluent-derived cell lines 
and to evaluate the response of cultured pleural and peritoneal mesothelioma cells to 
cisplatin, pemetrexed, and TRC102 
4. To document all objective clinical responses to TRC102 in combination with pemetrexed 
and cisplatin 
 
 
2.0 BACKGROUND 
 
2.1  Malignant Mesothelioma 
 
Malignant pleural mesothelioma (MPM) is a life-threatening malignancy with an incidence that is 
increasing worldwide. Projections from Europe indicate a doubling of the number of new cases, 
from 5,000 in 1998 to an estimated 9,000 in 2018. Mesothelioma is estimated to occur in 
approximately 2,500 people in the United States every year (1, 2). Malignant peritoneal 
mesothelioma (MPeM) accounts for approximately 10% of all mesotheliomas, with the vast 
majority of the remaining cases arising from the pleura (3, 4).The disease is difficult to treat, 

NCI Protocol #: 9837; PhI-76 
Version Date: March 7, 2019 
 
7 
because most patients have advanced disease at presentation. Median overall survival is 
approximately 1 year and the cure with even triple modality (cytoreductive surgery, chemotherapy 
and radiation) is rare. MPM occurs mainly in older men (median age of 72 years) who have been 
exposed to asbestos, although it occurs decades after exposure years later) (5).  Treatment options 
for patients with malignant pleural and peritoneal mesothelioma are limited, with only one 
approved chemotherapy regimen, pemetrexed and cisplatin, which results in modest survival 
improvement (6, 7). Therefore, the limited responses to treat MPM suggest that new therapeutic 
avenues should be explored. 
 
In a phase I clinical and pharmacokinetic study, the combination of pemetrexed and cisplatin 
showed antitumor activity in different tumor types, including patients with MPM, and the 
recommended dose was 500 mg/m2 plus cisplatin 75 mg/m2. In a large, phase III, randomized trial 
using the same dose, pemetrexed yielded a response rate of 41.3% in combination with cisplatin 
and a prolonged survival time when compared with single-agent cisplatin (12.1 versus 9.3 
months)(37). The combination of pemetrexed and cisplatin, which has emerged as the most 
effective chemotherapeutic regimen in MPM, is associated with higher response rates and 
improved survival and quality of life. This combination has been approved by the United States 
Food and Drug Administration and the European regulatory agency [The European Medicines 
Agency/Committee for Medicinal Products for Human Use] as a first-line chemotherapy regimen 
in MPM. 
 
The resistance of MPM to conventional treatment and poor clinical outcome has prompted basic 
research to identify possible new molecular targets. However multiple randomized phase II trials, 
with and without new drugs in combination with platinum doublet failed to give a better signal 
activity than single arm phase II trials (38-40). Given the modest improvement in survival with the 
standard of care combination of pemetrexed and cisplatin, new treatment options are needed to 
improve patients’ outcomes. The addition of a drug like TRC102 with the potential to enhance 
efficacy of this combination may provide a new therapeutic option for patients with malignant 
mesothelioma.   
 
Despite the initial responses to systemic chemotherapy, recurrence or progression of disease occurs 
in almost all patients. There are currently no effective treatment options for either patients who 
relapse following first-line chemotherapy or do not respond to cisplatin-pemetrexed combination. 
Second-line options include pemetrexed (if not administered first line), vinorelbine, or 
gemcitabine. Data suggest that rechallenging with pemetrexed is effective if patients had a good 
response to first-line pemetrexed. Limited data is available to guide second-line therapy. There is 
unmet need to develop novel agents for second-line treatment of patients with advanced 
mesothelioma. 
 
2.2 TRC102 
 
2.3 BER Inhibition by TRC102 
 
TRC102 (methoxyamine hydrochloride, TRACON Pharmaceuticals Inc.) is a novel inhibitor 
of base excision repair (BER) with a unique mechanism of action. The active molecule is a 
small organic amine that is highly water soluble and nearly completely bioavailable after oral 

NCI Protocol #: 9837; PhI-76 
Version Date: March 7, 2019 
 
8 
administration. TRC102 acts through a novel mechanism to inhibit BER and has demonstrated 
the ability to potentiate the activity of the alkylating agents temozolomide and carmustine, and 
the antimetabolite agents fludarabine and pemetrexed, in murine models of human cancer. 
  
Among the various mechanisms by which resistance to chemotherapy can develop, the base 
excision repair (BER) pathway has been shown to promote resistance to both alkylating and 
antimetabolite chemotherapy. TRC102 is a biochemical inhibitor of the BER pathway. 
Pharmacology studies have demonstrated its ability to inhibit BER induced by treatment with 
alkylating agents, including temozolomide, and anti-metabolite chemotherapy, including 
pemetrexed. TRC102 binds to apurinic or apyrimidinic DNA that is produced in cells actively 
engaged in the process 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 temozolomide and pemetrexed (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-cancerous cells (i.e., bone marrow cells) that express low 
levels of topo II.  
 
2.4 Nonclinical Studies 
 
In vitro and xenograft studies indicate that low doses of TRC102 are able to potentiate the 
activity of temozolomide and pemetrexed on human cancer cell lines. TRC102 interrupts BER 
by binding AP sites induced by chemotherapy treatment and thereby increases DNA strand 
breaks. Notably, doses of 2 to 4 mg/kg given by intraperitoneal injection reversed resistance 
of human cancer cell lines grown in mice to concurrently administered temozolomide or 
pemetrexed. 
 
In vitro and in vivo TRC102 safety pharmacology studies were conducted in compliance with 
Good Laboratory Practice regulations. These included an in vitro hERG assay and in vivo 
studies to assess respiratory and central nervous system function in rats and cardiovascular 
safety in dogs. TRC102 had no effect on hERG channel current at the highest concentration 
tested of 3000 ng/mL and also had no effect on QT intervals in dogs at the highest dose tested 
of 25 mg/kg (approximately 489 mg/m2), which was associated with high plasma 
concentrations of TRC102 (Cmax of > 470 ng/mL). The dose of 25 mg/kg produced non-
cardiac adverse events, including emesis, tremors or convulsions, and a modest increase in 
heart rate that may have been secondary to stress at this dose level, but other parameters, such 
a blood pressure and body temperature, were unaffected. Respiratory and CNS safety 
pharmacology studies in Sprague-Dawley rats indicated no effect at the highest dose tested of 
100 mg/kg (approximately 600 mg/m2), which resulted in high plasma concentrations of 
TRC102 (Cmax of > 7000 ng/mL)). Taken together, the safety pharmacology studies indicate 
that single doses well in excess of those shown to potentiate the efficacy of chemotherapy in 
pre-clinical models (2 to 4 mg/kg resulting in a Cmax of approximately 50 to 100 ng/mL) had 
little or no effect on cardiovascular parameters in dogs and no effect on respiratory or 
neurologic function in rats. 
 

NCI Protocol #: 9837; PhI-76 
Version Date: March 7, 2019 
 
9 
The collective PK/TK studies of TRC102 indicated high oral availability and systemic 
exposure proportional to dose. TRC102 was rapidly absorbed in rats and dogs following oral 
gavage and cleared with a half-life of approximately 3 hours in the rat and 7 hours in the dog. 
Twice daily administration for 5 days of a 14-day cycle resulted in expected increases in trough 
concentrations within a dosing cycle, but did not lead to accumulation across cycles of dosing. 
Importantly, TRC102 pharmacokinetics were not affected by concurrent administration of 
pemetrexed, and, similarly, pemetrexed pharmacokinetics were not affected by concurrent 
administration of TRC102. Protein binding studies indicate minimal binding of TRC102 to 
plasma proteins. 
 
TRC102 was not mutagenic at concentrations up to 1250 μg/mL in the bacterial mutagenicity 
assay and 2200 μg/mL in the mouse lymphoma assay. Thus, there is no indication based on 
the available data that TRC102 would pose a potential genotoxic risk to humans.  
A primary manifestation of toxicity was anemia in both rats and dogs. This effect was 
consistent between the single-cycle and three-cycle studies, and resulted in secondary 
alterations in related hematology parameters and changes in the histomorphology of bone 
marrow, spleen and liver consistent with a red blood cell regenerative response. However, there 
was no evidence of a cumulative effect over multiple (3) repeated dose cycles in either species 
and the effect was reversible. In addition to this effect, mortality occurred in dogs that received 
TRC102 doses more than four times higher than those that caused anemia. The cause of death 
was not elucidated. 
 
In the rat, extravascular removal of red blood cells by the spleen appeared to be the primary 
cause of the peripheral anemia, which was evident from the microscopic observation of 
hemosiderin deposition in the spleen (within macrophages) and from the increase in spleen 
weight, as well as from the sporadic detection of increased serum levels of bilirubin, a 
breakdown product of hemoglobin. There may also have been some RBC removal by the liver, 
as reflected by the microscopic finding of green pigment in the liver, but there was no increase 
in liver weight. There was clearly not an underproduction of erythrocytes in the bone marrow, 
as the marrow was hypercellular and there were several alterations in hematology parameters 
that were hallmarks of an ongoing regenerative response (i.e., increased reticulocyte counts 
and MCV and MCH, with a decrease in MCHC). The absence of hemoglobinuria and other 
hallmarks of intravascular hemolysis, coupled with the findings noted above, indicated 
extravascular red cell lysis in the spleen was the most likely explanation for anemia. 
 
Similarly, in the dog, RBC counts, hemoglobin, hematocrit and MCHC were decreased, while 
MCV, MCH and reticulocyte counts were increased, with the microscopic finding of bone 
marrow hypercellularity. However, microscopic changes in the spleen were not observed. 
There were slight, isolated increases in serum bilirubin. The hypercellularity of the bone 
marrow and reticulocytosis were indicative of an erythrocytic regenerative response to the 
peripheral anemia. In addition, bone marrow cytology on the dose range-finding study was 
also consistent with a compensatory response to anemia. Given the absence of clinical signs of 
significant blood loss and the slight elevation of bilirubin (a hemoglobin catabolism product) 
in some dogs, red cell lysis was felt to be the most likely explanation for anemia. The absence 
of hemoglobinuria and other hallmarks of intravascular hemolysis, coupled with the findings 
noted above, indicated anemia was due to extravascular red cell lysis. Therefore, as in the rat, 

NCI Protocol #: 9837; PhI-76 
Version Date: March 7, 2019 
 
10 
microscopic changes in the bone marrow coupled with alterations in hematology and serum 
chemistry parameters represented accelerated erythropoiesis in response to red cell loss. 
 
Other TRC102-related effects in the repeat dose studies in dogs consisted of abnormal excreta 
and emesis. While these findings are consistent with the known effects of pemetrexed, and in 
fact were present in all groups that received pemetrexed, their incidence was similar in dogs 
that received only TRC102 at the high dose of 12 mg/kg/day, and thus a relationship to 
TRC102 could not be discounted. Body weight and food consumption were unaffected in this 
group, and the abnormal excreta and emesis subsided upon cessation of treatment. 
   
One additional study was conducted to support clinical administration of TRC102 as part of a 
standard pemetrexed regimen. Leucovorin is an approved rescue agent for pemetrexed 
overdosage or toxicity. A rescue study was conducted in eight dogs that were given an 
exaggerated dose of pemetrexed alone (50 mg/kg twice within four days) and concurrently 
with five days of oral TRC102 at the HNSTD of 12 mg/kg/day, as determined in the three-
cycle GLP toxicology study in dogs. The dogs were divided into two groups, one of which 
received leucovorin treatment and one that did not. The effectiveness of the leucovorin 
treatment was evident. The survival rate of dogs that received leucovorin was 100% versus 
25% in those that did not. Leucovorin treated dogs also had improved clinical condition, the 
reversal of pemetrexed-induced inappetence and corresponding body weight loss, and 
reduction of pemetrexed-induced leukopenia within one to four days after starting the 
leucovorin treatment. Therefore, leucovorin’s effectiveness as a rescue treatment in dogs was 
not compromised by the presence of TRC102 (12 mg/kg/day for five consecutive days) at an 
exaggerated pemetrexed dose. 
 
Given the high degree of similarity in the major toxicologic effect in both species and in all 
studies, the NOAELs and HNSTDs served as the basis for determining the more sensitive 
toxicology species, and therefore the more appropriate species upon which to base the clinical 
starting dose. In the single-cycle toxicity studies, the rat NOEL and HNSTD were both 
approximately 1.6-fold higher than the dog NOAEL and HNSTD. A similar trend held true for 
the three-cycle studies, where the rat NOAEL and HNSTD were approximately 2.7- and 2.2-
fold higher than the dog NOAEL and HNSTD. Thus, across the range of doses tested and in 
both single and multiple cycle studies, the dog was more sensitive to the effects of TRC102 
and was judged to be the more conservative toxicology model upon which to base the clinical 
starting dose. 
 
2.5 Clinical Studies 
 
TRC102 was studied in 28 patients in a completed multicenter, open label, phase 1 clinical 
study (102ST101) that evaluated the maximum tolerated dose (MTD), safety profile, 
pharmacokinetics, and pharmacodynamics of TRC102 alone and in combination with 
standard-dose pemetrexed in patients with advanced cancer. The TRC102 dose was escalated 
in serial cohorts of patients using a standard 3 + 3 design. TRC102 doses studied were 15, 30, 
60, and 100 mg/m2/d given p.o. for four days of repeating two or three week cycles.  
 
The MTD of TRC102 was exceeded at 100 mg/m2/d due to the dose limiting toxicity (DLT) 

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of grade 3 anemia in three of six patients. Anemia was the only DLT reported and was 
consistent with preclinical toxicology studies in dogs and rats showing that anemia from 
extravascular hemolysis (in the spleen) was dose limiting. The frequency and severity of 
anemia did not increase as the number of treatment cycles accumulated. Hematologic toxicity 
other than anemia was not observed after treatment with TRC102 alone, and treatment with 
TRC102 and pemetrexed resulted in myelosuppression similar to that reported for pemetrexed 
alone. Treatment-related nonhematologic adverse events were generally mild to moderate. The 
only exceptions were one patient with grade 3 fatigue and another with grade 3 diarrhea. Both 
grade 3 nonhematologic adverse events occurred at 100 mg/m2/d. 
TRC102 given by intravenous administration is being studied in two ongoing trials sponsored 
by Case Comprehensive Cancer Center. Case 1Y05 is evaluating TRC102 in combination with 
temozolomide and Case 2Y10 is evaluating TRC102 in combination with fludarabine. Fifty-
nine patients have been treated at doses ranging from 15 mg/m2/day to 150 mg/m2/day in Case 
1Y05 and nineteen patients have been treated at doses ranging from 15 mg/m2/day to 30 
mg/m2/day in Case 2Y10 to date. Dose limiting toxicities occurring in Case-sponsored trials 
included psychosis and allergic reaction; which were observed in study Case 1Y05 in 
combination with temozolomide. Of note, the single episodes of psychosis and allergic reaction 
were seen at the 15 mg/m2/day dose level and were not observed following escalation to the 
150 mg/m2/day dose level in study Case 1Y05. Currently patients are being dosed at the 150 
mg/m2/day dose level in study Case 1Y05 and at 30 mg/m2/day in study Case 2Y10. 
Correlative studies demonstrate that TRC102 interrupts base excision repair in treated patients, 
even at the lowest level. Several patients have demonstrated stable disease [14]. 
 
TRC102 is also being studied in an ongoing clinical trial sponsored by NCI CTEP. Study 9483 
is evaluating TRC102 in combination with temozolomide in patients with relapsed solid 
tumors and lymphomas. As of this update, fifteen patients have been treated in study 9483. 
One unexpected serious suspected adverse reaction was reported, of grade 4 platelet count 
decrease and grade 4 neutrophil count decrease in a patient with colorectal cancer treated with 
TRC102 (75 mg p.o. qD) in combination with temozolomide (150 mg/m2 p.o. qD) for the 
initial five days of recurring 28 day cycles. 
 
2.6 Potential  Risks 
 
TRC102 has been studied in three clinical studies evaluating doses from 15 mg/m2/day to 100 
mg/m2/day in combination with pemetrexed, temozolomide or fludarabine. The most common 
adverse event (and dose limiting toxicity) observed in patients treated to date has been anemia. 
Anemia is characterized by a reactive reticulocytosis, increased bilirubin and decreased 
haptoglobin in the absence of hemoglobinuria. These clinical findings are consistent with 
extravascular hemolysis, which was observed in preclinical studies in dog and rat. The anemia 
is reversible and treatable with transfusion, growth factors and dose reduction. 
  
Toxicology studies have been conducted using TRC102 in two relevant animal models, rats 
and dogs. Studies in both species involved the administration of 15 doses over 32 days and 
studies in dogs assessed the toxicity of TRC102 when administered with the approved dose of 
pemetrexed. These studies indicated that TRC102 caused anemia in both species that was 
consistent with splenic sequestration and lysis of erythrocytes that resulted in physiologically 

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12 
responsive hematologic changes (e.g., reticulocytosis), slight isolated increases in serum 
bilirubin and bone marrow hypercellularity. Importantly, these adverse effects were reversible 
and not influenced by the concurrent administration of the approved dose of pemetrexed. 
 
Convulsions or tremors, impaired muscle coordination and hyperactivity were noted in dogs 
treated with repeated doses of TRC102 more than 4-fold higher than those that resulted in 
anemia. This potential toxicity has not been observed in clinical trials of TRC102 [14] Patients 
with a history of seizures or central nervous system tumors, who may be at increased risk for 
convulsions were excluded from initial clinical study. 
 
Myelosuppression was not worse in preclinical models administered pemetrexed with 
TRC102. Patients treated with TRC102 at the maximum tolerated dose in combination with 
standard dose pemetrexed also did not appear to exhibit an increased frequency of 
myelosuppression compared with historical controls. However, an increased frequency of 
temozolomide-induced neutropenia was observed following dosing of intravenous TRC102 in 
rats and a serious adverse event of grade 4 neutropenia and thrombocytopenia was observed in 
one patient who received TRC102 with temozolomide. An increased frequency of 
myelosuppression is possible in patients receiving myelosuppressive chemotherapeutics with 
TRC102. 
 
Other adverse events observed in the Phase 1 study considered possible related to TRC102 
included fatigue, anorexia, nausea, vomiting, diarrhea, pyrexia, mucosal inflammation and 
rash. Two unexpected serious events (one event of psychosis and one of idiosyncratic allergic 
reaction) were observed at a dose of intravenous TRC102 (15 mg/m2/d) below the maximum 
tolerated dose and were considered possible related to the drug. These events have not recurred 
at higher doses as of August 21, 2014. 
 
2.7 Drug Interactions 
 
Drug interaction studies of oral TRC102 and intravenous pemetrexed in dogs and rats indicate 
that TRC102 pharmacokinetics are not influenced by concurrent administration of intravenous 
pemetrexed and pemetrexed pharmacokinetics are not influenced by concurrent administration 
of TRC102. Studies also indicated no pharmacokinetic interaction between intravenous 
TRC102 and temozolomide. Studies with other anti-cancer agents have not been conducted. 
There is no information available on the potential of drug interaction via the P450 enzyme 
system. 
 
2.8 Pemetrexed, Cisplatin and TRC102 
 
At present MPM and MPeM protocols use both cisplatin and pemetrexed. Platinum-based 
compounds are among the most commonly prescribed drugs used to treat solid tumors(8, 9). 
Cisplatin binds to DNA hindering both DNA replication and RNA translation, eventually 
triggering apoptosis. Pemetrexed inhibits enzymes used in purine and pyrimidine biosynthesis 
that can lead to incorporation of uracil into DNA that can lead to strand breaks(10-14). Both 
drugs lead to cell death if the damage generated is not repaired. To counteract those effects, 
cells have evolved DNA repair mechanisms that preserve genomic integrity and eliminate 

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13 
damage. Cisplatin damage to DNA is removed by nucleotide excision repair (NER) and other 
mechanisms repairing DNA cross links(11, 15-19). Uracil in DNA is eliminated by uracil-
DNA glycosylase (UNG) in base excision repair (BER). In normal cells, DNA repair functions 
to limit mutations and prevent cell death. However, in tumor cells, DNA repair pathways can 
counteract therapeutic effects of drug treatments and can assist in the development of 
resistance. Thus, both NER and BER can present obstacles to effective treatment (20, 21) using 
the presently accepted therapeutic protocol.  
 
One method to enhance the cytotoxic effects of chemotherapeutic drug attack on tumor cells 
is by limiting a tumor’s capacity to repair DNA damage. Excision repair, including NER and 
BER, is a major repair pathway and both parts of excision repair have multiple proteins 
contributing to re-establishing genetic information and protecting against cell death. NER 
generally removes bulky DNA adducts in a 29nt-long oligonucleotide leaving a gap that must 
be filled in by a DNA polymerase. The other excision repair pathway, BER, acts on individual 
DNA bases that have been damaged directly through alkylation, abnormal bases incorporated 
into DNA by the action of antimetabolite agents, as well as some mispaired bases. The initial 
step in BER leaves an abasic (AP or apurinic/apyrimidinic) site. If there is a failure to complete 
repair and the repair intermediates remain, cell death can occur. Thus, if constrained to tumor 
cells, the residual repair intermediates have the potential to improve the therapeutic index of 
alkylating agents and antimetabolites (11, 15, 16). 
 
Most drugs inhibiting cellular pathways are directed toward blocking the activity of specific 
enzymes. In contrast, targeting abasic sites in DNA using TRC102 (methoxyamine 
hydrochloride, TRACON Pharmaceuticals Inc.) impairs growth and potentiates the antitumor 
effect of cisplatin and methotrexate in osteosarcoma cells, and could work in concert with other 
alkylating agents and antimetabolites(10, 11, 22-28). TRC102 modifies a central DNA 
substrate in BER, the AP site aldehyde (29). Although known to modify AP sites for over 30 
years, TRC102 has only been pursued as a therapeutic agent since ~1999(30-33). TRC102 
rapidly and covalently binds to AP sites generated during BER, and TRC102-bound DNA 
causes topoisomerase II-dependent irreversible strand breaks and apoptosis(27) The induction 
of apoptosis by TRC102 is more selective for cancer cells, due to the overexpression of 
topoisomerase II in many tumors. In nonmalignant cells with low topoisomerase II expression, 
TRC102-bound DNA is excised and replaced by the long patch DNA repair system(34). The 
TRC102 activity is independent of O6-methylguanine-DNA methyltransferase (MGMT) 
expression in tumors, DNA mismatch repair status, or p53 status. TRC102 potentiates the 
activity of other DNA repair inhibitors, including PARP inhibitors(11, 24, 27, 29). Pemetrexed 
induces BER in response to uracil incorporation into DNA, which is removed by uracil-DNA 
glycosylase (13, 26). TRC102 modifies the resulting AP sites and acts as a topoisomerase II 
poison, causing DNA strand breaks, and ultimately apoptosis. In vivo, using a mouse model 
with a human non-small cell lung cancer xenograft, TRC102 extended median tumor growth 
delay from 2 days with pemetrexed alone to 9 days with the combination without added 
toxicity(35). In repeat-dose toxicity studies, TRC102 caused anemia by extravascular red cell 
lysis (i.e., through splenic sequestration of erythrocytes) at a dose 10-fold higher than that 
required for activity positive response to treatment. The anemia was reversible, not cumulative 
or severe and was unaffected by coadministration of pemetrexed. (TRACON Pharmaceuticals, 
unpublished data). 

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14 
 
Clinical investigations have evaluated criteria for pemetrexed use.  The standard approved 
single dose for pemetrexed in humans is 500 mg/m2. The first study to assess the 
pharmacological effects of TRC102 in combination with the pemetrexed in humans established 
a maximum tolerated (MTD) daily oral dose(36). The MTD was 60 mg/m2/d for 4 days in 
combination with standard dose pemetrexed every 3 weeks. Consistent with preclinical testing 
data, at 100 mg/m2/d, the MTD TRC102 dose was exceeded due to extravascular hemolytic 
anemia requiring transfusion and dose-reduction. Anemia was the only dose-limiting toxicity 
(DLT) and was predicted by animal studies where extravascular hemolysis occurred at doses 
20-fold higher than required for efficacy. TRC102 accumulated with daily dosing in a manner 
consistent with its half-life >24 hours, but did not accumulate between cycles. 
Pharmacodynamic data confirmed the capacity of TRC102 to modify AP sites generated 
following pemetrexed treatment (36). 
 
2.9 Rationale 
 
Chemotherapy represents the largest class of treatment used for patients with metastatic or 
advanced solid tumors. However, for majority of patients, disease progression occurs despite 
treatment with various combinations of chemotherapeutics, and most eventually succumb to 
their cancer. Resistance to chemotherapy is a primary reason that patients fail treatment. 
Among the various mechanisms by which resistance to chemotherapy can develop, the base 
excision repair (BER) pathway has been shown to promote resistance to both alkylating and 
antimetabolite chemotherapy. TRC102 acts through a novel mechanism to inhibit BER and 
can potentially enhance the activity of cisplatin and pemetrexed and reverse resistance to 
pemetrexed. We hypothesize: 
 
1. TRC102 combined with pemetrexed and cisplatin can be administered safely in 
patients with advanced solid tumors; 
2. The combination may be effective in patients with advanced unresectable malignant 
mesothelioma;  
3. TRC102 combined with pemetrexed will produce responses in patients with 
advanced malignant mesothelioma who progressed on or had a recurrence with 3 
months of treatment with pemetrexed and cisplatin. 
 
 
2.10 
Correlative Studies Background 
2.10.1 Pharmacokinetics of TRC102 and cisplatin  
 
Previous Phase I clinical investigation demonstrated no significant effect of pemetrexed 
on the PK of TRC102 and vice versa (36). Similarly, no PK interaction has been 
identified when pemetrexed and cisplatin are given together (41). Therefore, we will 
focus on the PK of TRC102 and cisplatin in this 3 drug combination regimen.  
 
2.10.2 Establishment of pleural and peritoneal effluent-derived cell lines 
 
The pleural and peritoneal effluent are often collected from mesothelioma patients. These 

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15 
cells potentially have tumor associated cells that can be evaluated for response to 
therapies. Moreover, the mesotheliomas are classified as epithelial, fibrous, or mixed. 
Depending on the type, there may also be differential response to treatments and these 
cells will provide a valuable resource for evaluation of different therapies and to also 
provide a molecular basis for the classification of the histopathological assignments. 
 
2.10.3 Response of cultured pleural and peritoneal cells to cisplatin, pemetrexed, and 
TRC102 
 
The cell lines developed above could present a possible advance in treatment of 
mesothelioma. We will test the response of the cells to TRC102 in conjunction with 
cisplatin and pemetrexed. The results that we obtain will be compared to the patient 
responses in the study. We will vary the amounts of cisplatin, pemetrexed, and TRC102 
to evaluate the cell death for each drug individually, as pairs, and finally all together. We 
have used these techniques in the past (50) and will apply them to this work.  
 
2.10.4  Determination of abasic site modification in patient samples 
 
TRC102 reacts with the C1’ aldehyde of the deoxyribose at the AP site and leads to a 
modification of DNA that is not easily repaired. The TRC102 modification of the AP site 
blocks the reaction with a reagent that is designated as an aldehyde reactive probe 
(ARP)(52). We will use the ARP to determine the effect of the TRC102 on AP sites. 
 
2.10.5 Determination of cisplatin modification levels using ELISA methods 
Use of a cisplatin specific antibody will permit at least the examination of the relative 
levels of cisplatin adducts formed in DNA to provide an evaluation of the level found in 
cells. We will use an ELISA method that detects low levels of cisplatin (53-55). 
 
2.10.6 Circulating tumor cells isolated from patient blood samples 
 
Prior to treatment, patient blood samples will be processed to obtain CD146-positive 
circulating tumor cells (CTC) and those cells will be used for culture because it is 
anticipated that the CTCs have a high potential to be involved in metastasis. The cultured 
CTCs could yield provide a resource for the study of therapeutic response. 
 
3 PATIENT SELECTION 
 
NOTE: 
As of March, 13, 2018, Arm A (3-drug combination) is open to all ETCTN sites. 
  
Arm B (2-drug combination) is open to all ETCTN sites.   
 
3.1 Eligibility Criteria  
 

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16 
3.1.1 Arm A Dose Escalation: Patients with histologically or cytologically proven advanced 
solid tumors for which standard treatments are not available, or for whom the current 
dose level of cisplatin in combination with pemetrexed is appropriate; ≤ 2 prior cytotoxic 
chemotherapy regimen. 
3.1.2 Arm A Dose Level 4 (75 mg/m2 Cisplatin): Patients with histologically proven 
chemotherapy-naïve advanced unresectable solid tumors for which pemetrexed combined 
with cisplatin is an indicated regimen  
3.1.3 Arm B (First stage of Phase II of TRC102 and pemetrexed): Patients with malignant 
pleural or peritoneal mesothelioma who had progressed while being treated with or had 
recurred within 6 months of being treated with pemetrexed and cisplatin or carboplatin 
frontline.  Intervening treatment is allowed. 
  
3.1.4 Prior pemetrexed is allowed except Arm A Dose Level 4 (Cisplatin 75 mg/m2). 
 
3.1.5 Male or female Age ≥18 years.   
Because no dosing or adverse event data are currently available on the use of TRC102 in 
combination with Pemetrexed and Cisplatin in patients <18 years of age, children are 
excluded from this study, but will be eligible for future pediatric trials. 
 
3.1.6 ECOG performance status 0 -1 (Karnofsky ≥70%, see Appendix A). 
 
3.1.7 Life expectancy of greater than 3 months. 
 
3.1.8 Patients must have normal organ and marrow function as defined below: 
− 
absolute neutrophil count 
≥1,500/µL 
− 
platelets 
≥100,000/µL 
− 
hemoglobin 
 > 10.0 g/dl 
− 
prothrombin time or INR  
< 1.5 x ULN 
− 
total bilirubin 
< 1.5 x ULN  
- 
AST(SGOT)/ALT(SGPT)      ≤2.5 × institutional ULN or < 5 x ULN if metastatic     
                                                disease involves liver 
- 
Serum creatinine         
< 1.5 x ULN or a calculated creatinine clearance 
≥60 ml/min/1.73 m2 (Cockcroft-Gault method) for 
patients receiving combination of cisplatin and 
pemetrexed and >45 ml/min/1.73 m2 for patients 
receiving pemetrexed; 24 hour urine for creatinine 
clearance is acceptable if the calculated creatinine 
clearance is insufficient;  
 
3.1.9 For patients enrolled in Arm B (First stage of Phase II of TRC102 and pemetrexed) 
measurable disease is required according to the RECIST criteria for patients with solid 
tumors and modified RECIST criteria as described by Byrne and Novak for patients with 
malignant pleural mesothelioma. Pleural effusion and ascites are not considered 
measurable disease.  
 

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17 
3.1.10 Patients must be able to swallow whole capsules; nasogastric or G-tube administration is 
not allowed.  
 
3.1.11 The effects of TRC102 on the developing human fetus are unknown.  For this reason and 
because TRC102 as well as other therapeutic agents used in this trial are known to be 
teratogenic, women of child-bearing 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 4 months after completion of the study drugs.  
Should a woman become pregnant or suspect she is pregnant while she or her partner is 
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 4 months after completion of 
TRC102, pemetrexed and cisplatin administration. 
 
Non-childbearing potential is defined as (by other then medical reasons): ≥ 45 years of age 
and has not had menses for ≥ 2 years, amenorrheic for < 2 years without hysterectomy and 
oophorectomy and a follicle-stimulating hormone value in the postmenopausal range upon 
pretrial (screening) evaluation, or post hysterectomy, oophorectomy or tubal ligation. 
Documented hysterectomy or oophorectomy must be confirmed with medical records of 
the actual procedure or confirmed by ultrasound. Tubal ligation must be confirmed with 
medical records of the actual procedure otherwise the patient must be willing to use 2 
adequate barrier methods throughout the study, starting with the screening visit though 4 
months after the last dose of study drugs. 
 
3.1.12 Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 Exclusion Criteria 
 
3.2.1 Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered 
from adverse events due to agents administered more than 4 weeks earlier. Patients who 
have had targeted therapy will be required to wait 2 weeks due to short half-life of the 
drugs. Treatment with bisphosphonates is permitted. 
 
3.2.2 Patients who are receiving any other investigational agents.  
3.2.3 Patients with active brain metastases or carcinomatous meningitis are excluded from this 
clinical trial. Patients with treated brain metastases, whose brain metastatic disease has 
remained stable for greater than or equal to 4 weeks without requiring steroid and anti-
seizure medications are eligible to participate. 
3.2.4 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to TRC102 or pemetrexed and cisplatin 
3.2.5 http://medicine.iupui.edu/clinpharm/ddis/No studies have been performed to assess 
potential metabolic and transport interactions of TRC102.  As part of the 
enrollment/informed consent procedures, the patient will be counseled on the risk of 

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18 
interactions with other agents, and what to do if new medications need to be prescribed or 
if the patient is considering a new over-the-counter medicine or herbal product.  The case 
report form must capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies. [See Section 5.4.] 
3.2.6 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
3.2.7 Pregnant women are excluded from this study because TRC102 is agent with the 
potential for teratogenic or abortifacient 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.  These potential risks may also apply to other agents used in this study. 
 
3.2.8 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.  
Appropriate studies will be undertaken in patients receiving combination antiretroviral 
therapy when indicated. 
 
3.2.9 Patients with known disorders associated with hemolysis. 
 
3.2.10 Patients with thromboembolic disease and on anticoagulation. 
 
3.2.11 Patients with a prior cumulative cisplatin dose > 300 mg/m2 (pertains to Arm A only). 
 
3.3 Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
4 REGISTRATION PROCEDURES (ROSTERED PROTOCOL MODEL) 
 
4.1 Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to OPEN or RAVE or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration type are outlined 
in the table below. 

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19 
 
Documentation Required 
IVR 
NPIVR AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
• Added to a site roster 
• Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• Act as the site-protocol PI on the IRB approval 
• Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
Additional information can be found on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact the RCR 
Help Desk by email at < RCRHelpDesk@nih.gov >. 
 
4.2 Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
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 be approved to enroll patients.  Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a determination of whether 
a site has fulfilled all regulatory criteria including but not limited to the following:  
 
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the Lead Network or a participating organization 
• A valid IRB approval 

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20 
• Compliance with all protocol specific requirements 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• Active registration status 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site. 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process.  Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally.  
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
 
4.2.1 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the NCI protocol # 9837 protocol page 
located on the CTSU Web site.  Permission to view and download this protocol is 
restricted and is based on person and site roster data housed in the CTSU RSS.  To 
participate, Investigators and Associates must be associated with the Corresponding or 
Participating protocol organization in the RSS.  
 
• Go to https://www.ctsu.org and log in using your CTEP IAM username and 
password 
• Click on the Protocols tab in the upper left of your screen 
• Either enter the protocol # in the search field at the top of the protocol tree, or 
• Click on the By Lead Organization folder to expand, then select LAO – CA043, 
and protocol #9837 
• Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.  (Note: For sites under the CIRB 
initiative, IRB data will load to RSS as described above  
 
4.2.2 Submitting Regulatory Documents 
 
Requirements For 9837 Site Registration: 
 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption Form, or 
combination is accepted ) 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS. 

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21 
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab 
→Regulatory Submission  
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support.   
4.2.3 Checking Site Registration Status 
 
You can verify your site registration status on the members’ section of the CTSU 
website.  
• Go to https://www.ctsu.org and log in using your CTEP IAM username and 
password. 
• Click on the Regulatory tab at the top of your screen. 
• Click on the Site Registration subtab. 
• Enter your 5-character CTEP Institution Code and click on Go. 
Note: If possible, please allow three working days for site registration approval before 
attempting to enroll your first patient.  The status given only reflects compliance with 
IRB documentation and institutional compliance with protocol-specific requirements as 
outlined by the Lead Network. It does not reflect compliance with protocol requirements 
for individuals participating on the protocol or the enrolling investigator’s status with the 
NCI or their affiliated networks. 
 
4.3 Patient Registration 
4.3.1 OPEN / IWRS 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available to users on a 24/7 basis.  It 
is integrated with the CTSU Enterprise System for regulatory and roster data interchange 
and with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. 
 
For trials with slot reservation requirements, OPEN will connect to IWRS at enrollment 
initiation to check slot availability.  Registration staff should ensure that a slot is 
available and secured for the patient before completing an enrollment. 
 
• Site staff with the appropriate roles will reserve slots using IWRS (https://open.ctsu.org/).  
 

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22 
• City of Hope Cancer Center will receive notification via the IWRS when a slot has been 
reserved. An email will be sent from the City of Hope Cancer Center to the site requesting 
further information such as: the patient initials, tumor type and potential start date. The 
spot will show as ‘pending approval’ in the system until the site sends a REGISTRATION 
FORM/ELIGIBILITY CHECKLIST accompanied with the signed consent, baseline labs, 
pathology report, CT/x-ray reports to the City of Hope Cancer Center at ccc@coh.org for 
review and confirmation of eligibility.  
 
• Once the Registration has been reviewed, the City of Hope Cancer Center will either 
approve or disapprove the request depending on confirmation of patient eligibility. If 
approved, the City of Hope Cancer Centre will update the spot to ‘reserved’ in IWRS.  
 
• The site can now enroll the patient into the study in OPEN 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
4.3.2 OPEN/IWRS User Requirements 
 
OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 
• To enroll patients or request slot reservations:  Be on an ETCTN Corresponding or 
Participating Organization roster with the role of Registrar.  Registrars must hold a 
minimum of an AP registration type.  If a DTL is required for the study, the 
registrar(s) must also be assigned the OPEN Registrar task on the DTL.  (Note: A 
DTL is NOT required for this study.) 
• To approve slot reservations or access cohort management:  Be identified to 
Theradex as the “Client Admin” for the study.  
• Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, 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 CTSU web site as a tool to 
verify eligibility. 
• If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
 
4.3.3 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which 
is available on the Theradex website:  

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23 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11. This 
link to the Theradex website is also on the CTSU website OPEN tab. For questions about 
the use of IWRS for slot reservations, contact the Theradex Helpdesk: 609-619-7862 or 
Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
4.4 General Guidelines 
 
Following registration, patients should begin protocol treatment within 5 days.*  Issues that 
would cause treatment delays should be discussed with the Principal Investigator.  If a patient 
does not receive protocol therapy following registration, the patient’s registration on the study 
may be canceled.  The Study Coordinator (ccc@coh.org) should be notified of cancellations as 
soon as possible. 
 
5 TREATMENT PLAN 
 
5.1 Screening and Pretreatment Assessments 
 
 
Written informed consent for participation in the study must be obtained before performing any 
study-specific screening tests or evaluations. Informed Consent Forms for enrolled patients and 
for patients who are not subsequently enrolled will be maintained at the study site.  
Screening tests and evaluations will be performed within 7 days prior to study treatment initiation, 
unless otherwise specified. Screening tumor assessments must be obtained within 28 days of study 
treatment and Informed Consent must be obtained within 28 days. All screening evaluations must 
be completed and reviewed to confirm that patients meet all eligibility criteria.  
Eligible patients will be treated either on Arm B or Arm A as specified in the Eligibility 
Criteria. 
 
Arm A – TRC102 in combination with Cisplatin and Pemetrexed. 
 
Arm B – TRC 102 in combination with Pemetrexed 
 
5.2 Agent Administration 
 
5.2.1 
Arm A: TRC102 in combination with Cisplatin and Pemetrexed 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential risks 
are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
5.2.1.1 
Premedication  
Folic acid 350-1000µg, PO, daily beginning approximately 7 days prior to the first infusion of 
pemetrexed and continuing until 3 weeks after discontinuation of pemetrexed; Vitamin B12 
1000µg IM or subcutaneous every 9 weeks beginning approximately 1-2 weeks before the first 
infusion of pemetrexed and continuing until 3 weeks after discontinuation of pemetrexed; 
Dexamethasone 4 mg twice daily the day prior to, the day of and the day after each infusion of 

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24 
pemetrexed (may be discontinued if toxicities of steroids develop and cutaneous side effects do 
not occur). Anti-emetics will be given per standard institutional practice guidelines. An 
aprepitant in combination with a 5-HT3 antagonist is recommended. 
   
5.2.1.2 
TRC102 
Patients will receive escalating doses of TRC102, orally, daily (days 1-4) in combination with 
cisplatin and pemetrexed on day 1, as shown in Table 1. The study drug TRC102 will be self-
administered (by the patients themselves).  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.  The investigator will instruct the patient to take the study drug exactly as specified in the 
protocol. For TRC102 the patient will be requested to maintain a medication diary of each dose of 
medication.  The medication diary will be returned to clinic staff at the end of each course 
(Appendix D). For TRC102 the patient will be requested to maintain a medication diary of each 
dose of medication. The medication diary will be returned to clinic staff at the end of each course. 
 
Patients will receive 4 doses of oral TRC102 day 1-4 of each cycle.  On day 1 of each cycle, 
TRC102 will be administered prior to pemetrexed and cisplatin; pemetrexed 500 mg/m2 will be 
administered as an IV infusion over 10 minutes; and cisplatin 60 mg/m2 (75 mg/m2 for dose level 
4) will be administered as an IV  infusion over 30-60 minutes after the end of the pemetrexed. 
Pemetrexed will be administered prior to cisplatin. 
 
The Pemetrexed and Cisplatin will be administered as an IV infusion on Day 1 of each 21-day 
cycle until disease progression, unacceptable toxicity, withdrawal from study or for maximum of 
6 cycles as outlined in section 5.5.  
Table 1 
Dose Level 
TRC102 
(days 1-4, q 21 days) 
Pemetrexed 
(day 1, q 21 days) 
Cisplatin 
(day 1, q 21 days) 
– 1 
25 mg/day, PO 
500 mg/m2, IV 
60 mg/m2, IV 
1 
50 mg/day, PO 
500 mg/m2, IV 
60 mg/m2, IV 
2 
75 mg/day, PO 
500 mg/m2, IV 
60 mg/m2, IV 
3 
100 mg/day, PO 
500 mg/m2, IV 
60 mg/m2, IV 
4 
{chemotherapy-
naïve patients} 
100 mg/day, or MTD w/ 60 
mg/m2 cisplatin, whichever is 
lower, PO 
500 mg/m2, IV 
75 mg/m2, IV 
 
At the RP2D, the cohort will be expanded to treat a total of 14 mesothelioma patients to obtain 
additional safety data, PK data, and a preliminary indication if the combination might be effective. 
 
5.2.1.3 
Pemetrexed  
 
Pemetrexed for injection will is commercially available and will not be supplied.  Pemetrexed is 
administered by intravenous infusion over 10 minutes per local practice guidelines. Refer to 
package insert for more information. 
 

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25 
5.2.1.4 
Cisplatin 
 
On day 1 of each cycle, cisplatin 60 mg/m2 (75 mg/m2 for dose level 4) will be administered as 30 
-60 minutes infusion after the end of the pemetrexed. Cisplatin will be administered to patients in 
Arm A on Day 1 of each 21-day cycle until disease progression, unacceptable toxicity, withdrawal 
from study or for maximum of 6 cycles as outlined in section 5.5. 
 
Cisplatin for infusion is commercially available and will not be supplied.  Cisplatin is 
administered by intravenous infusion over 30 - 60 minutes per local practice guidelines. Refer to 
package insert for more information. The starting dose (60 mg/m2) and all appropriate subsequent 
doses must be diluted in a chloride-containing vehicle (preferably NS or D5NS) to achieve a final 
concentration < 1 mg/ml less than 8 hours prior to administration and administered intravenously 
over 30 – 60 minutes. Cisplatin is a renally excreted and potentially nephrotoxic agent and requires 
careful attention to patient hydration for safe administration to avoid nephrotoxicity.  Cisplatin 
must be given with at least 1 liter of NS intravenous hydration (total pre-and post-hydration), of 
which at least 500 ml must be administered as pre-hydration immediately prior to administering 
the cisplatin. Patient should be also encouraged to drink fluids generously on the day of cisplatin 
treatment.  It is left to the discretion of the treating investigator whether furosemide or mannitol-
forced diuresis should be given immediately following cisplatin infusion or whether potassium or 
magnesium should be included in the NS hydration solution. Anti-emetics will be given per 
standard institutional practice guidelines. An aprepitant in combination with a 5-HT3 antagonist 
is recommended.  To prevent delayed emesis, on Days 2, 3, and 4 after each cisplatin 
administration, dexamethasone 4 – 8 mg PO BID and a dopamine receptor antagonist 
(prochlorperazine/compazine) 10 – 15 mg PO, BID, or metoclopramide (Reglan) 10 mg PO every 
6 hours is recommended.  Ondansetron 8 mg PO TID may be substituted for the dopamine 
antagonist. Other supportive treatment such as antidiarrheals, (eg, loperamide, rehydration), 
analgesics, blood products, etc, are permitted at any time and should be administered according to 
the institutional standard practice of care. 
 
5.2.2 
Arm B: TRC102 in combination with Pemetrexed 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
 5.2.2.1 
Premedication 
Folic acid 350-1000µg, PO, daily beginning approximately 7days prior to the first infusion of 
pemetrexed and continuing until 3 weeks after discontinuation of pemetrexed; Vitamin B12 
1000µg IM or subcutaneous every 9 weeks beginning approximately 1-2 weeks before the first 
infusion of pemetrexed and continuing until 3 weeks after discontinuation of pemetrexed. 
 
Dexamethasone 4 mg twice daily the day prior to, the day of, and the day after each infusion of 
pemetrexed (may be discontinued if toxicities of steroids develop and cutaneous side effects do 
not occur). 
 

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26 
5.2.2.2 
TRC102 
Patients will receive TRC102 dose level 1, 50 mg/day (Table 1, Section 4.2), orally, daily (days 1-
4) in combination with pemetrexed 500 mg/m2 on day 1. The study drug TRC102 will be self-
administered (by the patients themselves).  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. The investigator will instruct the patient to take the study drug exactly as specified 
in the protocol. For TRC102 the patient will be requested to maintain a medication diary of each 
dose of medication.  The medication diary will be returned to clinic staff at the end of each course. 
On day 1 of each cycle, TRC102 will be administered prior to pemetrexed.  
 
5.2.2.3 
Pemetrexed  
Pemetrexed for injection will is commercially available and will not be supplied.  Pemetrexed is 
administered by intravenous infusion over 10 minutes per local practice guidelines. Refer to 
package insert for more information. The Pemetrexed will be administered as an IV infusion on 
Day 1 of each 21-day cycle until disease progression, unacceptable toxicity or withdrawal from 
study as outlined in section 5.5. 
 
5.3 Definition of Dose-Limiting Toxicity 
 
DLT Dose Limiting Toxicity is defined as an adverse event that occurs in during cycle 1 that is 
related (possibly, probably, or definitely) to administration of study drug and fulfills one of the 
following criteria: 
 
Grade ≥ 3 non-hematological toxicity will be considered dose limiting with the following 
clarifications:  
• Grade 3 diarrhea will only be considered dose limiting if it is refractory to 
maximal supportive care measures. Bloody or grade 4 diarrhea will be dose 
limiting.  
• ≥ Grade 3 nausea and vomiting will only be considered dose limiting if it is 
refractory to maximal anti-emetic therapy.  
• ≥ Grade 3 rise in creatinine, not able to be corrected to grade 1 or less with IV 
fluids will be considered dose limiting. All grade 4 rises in creatinine will be dose 
limiting.  
• ≥ Grade 3 electrolyte toxicities unable to be corrected to grade 1 or baseline with 
maximal electrolyte repletion will be considered dose limiting.  
• Tumor pain will not be considered dose limiting.  
Grade 4 thrombocytopenia or grade 3 thrombocytopenia with bleeding 
 Grade 3 anemia 
Grade 4 neutropenia lasting ≥ 7 days or febrile neutropenia.  
Treatment delay > 2 weeks as a result of unresolved toxicity. 
Inability to administer 3 of the 4 doses of TRC102 in the 1st week (7 days) of a cycle as a result 
of unresolved toxicity. 
 
 
The trial will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE), as 

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27 
defined in section 6.  Management and dose modifications associated with the above adverse 
events are outlined in Section 6. 
 
Dose escalation will proceed within each cohort according to the following scheme.  Dose-
limiting toxicity (DLT) is defined above.   
 
 
Number of Patients with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
≥2 
Dose escalation will be stopped.  This dose level will be 
declared the non-tolerated dose. Three (3) additional 
patients will be entered at the next lowest dose level if 
only 3 patients were treated previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed to 
the next dose level. 
• If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
non-tolerated dose.  Three (3) additional patients will 
be entered at the next lowest dose level if only 3 
patients were treated previously at that dose. 
≤1 out of 6 at highest dose level 
below any non-tolerated dose 
This is generally the recommended phase 2 dose 
(RP2D). At least 6 patients must be entered at the 
RP2D. In this study, if dose level 3 is non-tolerated, and 
a lower dose level is the RP2D by these rules, dose level 
4 will be re-defined per Table 1, and tried as the next 
dose level. 
 
5.4 General Concomitant Medication and Supportive Care Guidelines 
 
No studies have been performed to assess potential metabolic and transport interactions of 
TRC102.  Because there is a potential for interaction of TRC102 with other concomitantly 
administered drugs, the case report form must capture the concurrent use of all other drugs, over-
the-counter medications, or alternative therapies.  The Principal Investigator should be alerted if a 
drug-drug interaction is a suspected component of an adverse event. 
 
Colony Stimulating Factors (CSFs) should not be used during the first course of treatment.  The 
prophylactic use of CSFs is not recommended as long as the subject remains on study. In the event 
of neutropenia without fever following subsequent courses of treatment, current ASCO guidelines 
recommend that CSFs should not be routinely used. 
In the event of febrile neutropenia following subsequent courses of treatment, CSFs may be 
administered according to current ASCO guidelines. 

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28 
 
For subsequent courses, it is recommended that CSF be initiated no earlier than 24 hours after the 
administration of chemotherapy. 
 
If administered, CSFs must be discontinued at least 24 hours before receiving the next course of 
treatment with study drug. 
 
The use of recombinant erythropoietin for the treatment of chemotherapy-induced anemia is 
permitted in Arm B and following cycle 2 in Arm A at the discretion of the treating physicians. 
Blood transfusion is allowed. 
 
5.5 Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for 6 cycles* 
or until one of the following criteria applies: 
 
• 
Disease progression, 
 
• 
Intercurrent illness that prevents further administration of treatment, 
 
• 
Unacceptable adverse event(s), 
 
• 
Patient decides to withdraw from the study, or 
 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
*For patients on Arm A, patients must discontinue cisplatin, but may continue treatment with 
TRC102 and pemetrexed beyond cycle 6 if the patient continues to benefit (even if meeting the 
protocol definition of progression) from treatment at the discretion of the treating physician.  For 
patients on Arm B, patients may continue treatment with TRC102 and pemetrexed beyond cycle 
6 if the patient continues to benefit (even if meeting the protocol definition of progression) from 
treatment at the discretion of the treating physician. 
 
At the time of withdrawal, all study procedures outlined for the End of Study visit should be 
completed. 
   
The primary reason for a patient’s withdrawal from the study is to be recorded in the source 
documents. 
 
5.6 Duration of Follow Up 
 
Patients will be followed for 8 weeks after removal from study or until death, whichever occurs 
first.  Patients removed from study for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event. 
 

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29 
5.7 Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.5 applies.  The 
reason for study removal and the date the patient was removed must be documented in the Case 
Report Form. 
 
6 DOSING DELAYS/DOSE MODIFICATIONS 
 
The trial will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 for toxicity and Adverse Event Reporting until March 31, 2018.  CTCAE version 5.0 will be 
utilized for AE reporting beginning April 1, 2018.  A copy of the CTCAE version 5.0 can be 
downloaded 
from 
the 
CTEP 
home 
page 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. . 
 
6.1  Arm A: TRC102 in combination with Cisplatin and Pemetrexed 
 
On day 1 Cycle 1, administration of  TRC102, pemetrexed and cisplatin requires an absolute 
neutrophil count (ANC) of > 1500 and platelets count of > 100,000, and calculated creatinine 
clearance > 60 ml/min/1.73 m2 (Cockcroft-Gault method); 24 hour urine for creatinine clearance 
is acceptable if the calculated creatinine clearance is insufficient. In the subsequent cycles that 
include cisplatin, patients can receive a reduced dose of cisplatin (See table in 6.1.3.2.) if creatinine 
clearance > 50 ml/min/1.73 m2 and < 60 ml/min/1.73 m2 (Cockcroft- Gault method) on day 1.  In 
the subsequent cycles that do NOT include cisplatin, administration of  TRC102 and pemetrexed 
requires an absolute neutrophil count (ANC) of > 1500 and platelets count of > 100,000, and 
calculated creatinine clearance > 45 ml/min/1.73 m2 (Cockcroft-Gault method) on day 1; 24 hour 
urine for creatinine clearance is acceptable if the calculated creatinine clearance is insufficient. 
 
The start of the next cycle may be delayed a maximum of 14 days. 
 
6.1.1 TRC102 
 
TRC102 can be held for up to two weeks for resolution toxicity per the guidelines below.  If 
TRC102 is held on day 1 of a cycle, pemetrexate and cisplatin will be held as well, i.e. the entire 
cycle will be held for up to two weeks.  If TRC102 is held on days 2-4, the remaining TRC102 
doses for the cycle will be administered when the re-treatment criteria are met provided that they 
can be administered in the 1st week (7 days) of the cycle.  No TRC102 doses will be administered 
on day 8 or following of a cycle.  The next cycle will begin as scheduled provided that re-treatment 
criteria are met. 
 
6.1.1.1 Hematologic Toxicity 
Subjects with grade > 2 anemia and requiring blood transfusion will have work up with laboratory 
tests: CBC with red cell indices, platelet count, and examination of the peripheral smear; 
reticulocyte count; routine hepatic function, including direct and indirect bilirubin; LDH; 
autoimmune studies (eg, Coombs testing) as appropriate; serum/urine free hemoglobin and urinary 
hemosiderin if intravascular hemolysis is suspected; Hematology consultation may be requested. 
 

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30 
Anemia 
Management/Next Dose for TRC102 
≤ Grade 1 
No change in dose 
Grade 2 
Hold* until ≤ Grade 1.  Resume at same dose 
level. 
Grade 3 
Hold* until < Grade 1.  Resume at one dose level 
lower**. 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Patients can receive blood transfusion. 
 
6.1.1.2 Non-hematologic Toxicity 
If a patient experiences  grade 3 drug related toxicity at any time in a cycle, treatment will be 
held.  If TRC102 is held for transient, correctable, non-DLT toxicity (See Section 5.3), the 
remaining TRC102 doses for the cycle will be administered at the same dose level when the re-
treatment criteria are met, provided that they can be administered in the 1st week (7 days) of the 
cycle.  No TRC102 doses will be administered on day 8 or following of a cycle and TRC102 will 
be administered at the same dose level in the next cycle.  If TRC102 is held for toxicity qualifying 
as DLT, no more TRC102 doses will be administered for the remaining of the cycle and TRC102 
will be reduced by one dose level for the next cycle. Patient should not be retreated until all 
toxicities resolve to  grade 1.  Start of a new cycle of therapy may be held up to two weeks for 
toxicities to resolve.  If the patient experiences another  3 toxicity, treatment will be held for up 
to two weeks.  Patient can be retreated if all toxicities resolve to  grade 1. TRC102 will be reduced 
by one dose level. Maximum two dose reductions are permitted. If the toxicities don’t resolve, 
patient should be removed from study. 
  
6.1.2 Pemetrexed 
There is no dose reduction for hematologic or nonhematologic toxicity.  If pemetrexed is held, 
TRC102 and cisplatin will be held as well, i.e. the entire course will be held for up to two weeks. 
 
6.1.3 Cisplatin 
Day 1 Cycle 1 cisplatin administration, of each cycle, requires an absolute neutrophil count (ANC) 
of > 1500 and platelets count of > 100,000, and calculated creatinine clearance > 60 m/min 
(Cockcroft-Gault method); 24 hour urine for creatinine clearance is acceptable if the calculated 
creatinine clearance is insufficient.  In the subsequent cycles patients can receive a reduced dose 
of cisplatin (See table in 6.1.3.2.) if creatinine clearance > 50 ml/min/1.73 m2 and < 60 ml/min/1.73 
m2 (Cockcroft- Gault method).  If cisplatin is held, TRC102 and pemetrexed will be held as well, 
i.e. the entire course will be held for up to two weeks. 
 
6.1.3.1 
Hematologic Toxicity 
There is no cisplatin dose reduction for hematologic toxicity in this regimen. 
 
6.1.3.2 
Renal Toxicity- Cisplatin Modification for Renal Function 
 
 
   Calculated 
 
 
 
 
 
Creatinine Clearance 
 
 
Treatment  
 

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31 
 
> 60 ml/min/1.73 m2  
 
 
 
Full dose of cisplatin 
 
< 60 ml/min/1.73 m2 but  
> 50 ml/min/1.73 m2  
 
 
 
Reduce dose (See table below.)  
 
 
 
 
 
 
 
< 50 ml/min/1.73 m2  
 
 
 
Hold 
cisplatin 
until 
recovery;* 
monitor weekly retreat with cisplatin 
dose decreased by 1 dose level. 
 
*If treatment is held for > 2 weeks, the patient should be removed from the 
protocol treatment (per Section 5.5).  Recovery is defined as > 50 ml/min/1.73 
m2. 
 
 
Cisplatin starting dose 
1st dose reduction 
2nd dose reduction 
60 mg/m2 
45 mg/m2 
Off study 
75 mg/m2 
60 mg/m2 
45 mg/m2 
 
6.2 Arm B: TRC102 in combination with Pemetrexed 
 
On day 1, administration of  TRC102 and pemetrexed requires an absolute neutrophil count 
(ANC) of > 1500 and platelets count of > 100,000, and calculated creatinine clearance > 45 
ml/min/1.73 m2 (Cockcroft-Gault method); 24 hour urine for creatinine clearance is acceptable if 
the calculated creatinine clearance is insufficient.  
 
The start of the next cycle may be delayed a maximum of 14 days. 
 
6.2.1 TRC102 
 
TRC102 can be held for up to two weeks for resolution toxicity per the guidelines below.  If 
TRC102 is held on day 1 of a cycle, pemetrexate will be held as well, i.e. the entire cycle will be 
held for up to two weeks.  If TRC102 is held on days 2-4, the remaining TRC102 doses for the 
cycle will be administered when the re-treatment criteria are met provided that they can be 
administered in the 1st week (7 days) of the cycle.  No TRC102 doses will be administered on 
day 8 or following of a cycle.  The next cycle will begin as scheduled provided that re-treatment 
criteria are met. 
 
6.2.1.1 Hematologic Toxicity 
Subjects with grade > 2 anemia and requiring blood transfusion will have work up with laboratory 
tests: CBC along with red cell indices, platelets count, and examination of the peripheral smear; 
reticulocyte count; routine hepatic function, including direct and indirect bilirubin; LDH; 
autoimmune studies (eg, Coombs testing) as appropriate; serum/urine free hemoglobin and urinary 
hemosiderin if intravascular hemolysis is suspected; Hematology consultation may be requested. 
 
 

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32 
Anemia 
Management/Next Dose for TRC102 
≤ Grade 1 
No change in dose 
Grade 2 
Hold* until ≤ Grade 1.  Resume at same dose 
level. 
Grade 3 
Hold* until < Grade 1.  Resume at one dose level 
lower**. 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Patients can receive blood transfusion. 
 
6.2.1.2  Non-hematologic Toxicity 
If a patient experiences  grade 3 drug related toxicity at any time in a cycle, treatment will be 
held.  If TRC102 is held for transient, correctable, non-DLT toxicity (See Section 5.3), the 
remaining TRC102 doses for the cycle will be administered at the same dose level when the re-
treatment criteria are met, provided that they can be administered in the 1st week (7 days) of the 
cycle.  No TRC102 doses will be administered on day 8 or following of a cycle and TRC102 will 
be administered at the same dose level in the next cycle.  If TRC102 is held for toxicity 
qualifying as DLT, no more TRC102 doses will be administered for the remaining of the cycle 
and TRC102 will be reduced by one dose level for the next cycle. Patient should not be retreated 
until all toxicities resolve to  grade 1.  Start of a new cycle of therapy may be held up to two 
weeks for toxicities to resolve.  If the patient experiences another  3 toxicity, treatment will be 
held for up to two weeks.  Patient can be retreated if all toxicities resolve to  grade 1. TRC102 
will be reduced by one dose level. Maximum two dose reductions are permitted. If the toxicities 
don’t resolve, patient should be removed from study. 
 
6.2.2 Pemetrexed 
There is no dose reduction for hematologic or nonhematologic toxicity. If pemetrexed is held, 
TRC102 will be held as well, i.e. the entire course will be held for up to two weeks. 
 
6.3 Management of Specific Adverse Events – Chemotherapy  
Please refer to each drug's package insert for further detail Pemetrexed [package insert] 2012; 
Cisplatin [package insert] 2012 
 
6.4  Maximum Treatment Delay 
If the treatment delay is >2 weeks the patient will be taken off study. 
 
7 ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting via the CTEP Adverse Event Reporting 
System (CTEP-AERS) in addition to routine reporting. 
 
7.1 Comprehensive Adverse Events and Potential Risks List (CAEPR) 
 

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The Comprehensive Adverse Event 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 of AEs, 
the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column 
and is identified with bold and italicized text.  The 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/adverse_effects.htm for further clarification.  
 
The CAEPR may not provide frequency data; if not, refer to the Investigator’s Brochure for this 
information. 
 
NOTE:  The highest grade currently reported is noted in parentheses next to the AE in the 
SPEER.  Report ONLY AEs higher than this grade expeditiously.  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. 
 
7.1.1 CAEPRs for CTEP IND Agent 
 
7.1.1.1 CAEPR for Methoxyamine hydrochloride (TRC102, NSC 3801) 
 
                                                                                                       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) 

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34 
 
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: 
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. 
 
 
7.1.2 Adverse Event List(s) for Cisplatin 
Cisplatin injection produces cumulative nephrotoxicity which is potentiated by aminoglycoside 
antibiotics. The serum creatinine, blood urea nitrogen (BUN), creatinine clearance, and 

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35 
magnesium, sodium, potassium, and calcium levels should be measured prior to initiating therapy, 
and prior to each subsequent course. At the recommended dosage, cisplatin injection should not 
be given more frequently than once every 3 to 4 weeks. Elderly patients may be more susceptible 
to nephrotoxicity. 
 
There are reports of severe neuropathies in patients in whom regimens are employed using higher 
doses of cisplatin injection or greater dose frequencies than those recommended. These 
neuropathies may be irreversible and are seen as paresthesias in a stocking-glove distribution, 
areflexia, and loss of proprioception and vibratory sensation. Elderly patients may be more 
susceptible to peripheral neuropathy. 
 
Loss of motor function has also been reported. Anaphylactic-like reactions to cisplatin injection 
have been reported. These reactions have occurred within minutes of administration to patients 
with prior exposure to cisplatin injection, and have been alleviated by administration of 
epinephrine, corticosteroids, and antihistamines. 
 
Cisplatin injection can commonly cause ototoxicity which is cumulative and may be severe. 
Audiometric testing should be performed prior to initiating therapy and prior to each subsequent 
dose of drug. 
 
Cisplatin injection can cause fetal harm when administered to a pregnant woman. Cisplatin 
injection is mutagenic in bacteria and produces chromosome aberrations in animal cells in tissue 
culture. In mice cisplatin injection is teratogenic and embryotoxic. If this drug is used during 
pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised 
of the potential hazard to the fetus. Patients should be advised to avoid becoming pregnant. 
 
The carcinogenic effect of cisplatin injection was studied in BD IX rats. Cisplatin injection was 
administered intraperitoneally to 50 BD IX rats for 3 weeks, 3 X 1 mg/kg body weight per week. 
Four hundred and fifty-five days after the first application, 33 animals died, 13 of them related to 
malignancies: 12 leukemias and 1 renal fibrosarcoma. 
 
The development of acute leukemia coincident with the use of cisplatin injection has been reported. 
In these reports, cisplatin injection was generally given in combination with other leukemogenic 
agents. 
 
Injection site reactions may occur during the administration of cisplatin injection. Given the 
possibility of extravasation, it is recommended to closely monitor the infusion site for possible 
infiltration during drug administration. A specific treatment for extravasation reactions is unknown 
at this time. 
Please refer to the package insert for the comprehensive list of adverse events. 
 
7.1.3 Adverse Event List(s) for Pemetrexed 
Patients treated with Pemetrexed must be instructed to take folic acid and vitamin B12 as a 
prophylactic measure to reduce treatment-related hematologic and GI toxicity. In clinical studies, 
less overall toxicity and reductions in Grade 3/4 hematologic and nonhematologic toxicities such 

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36 
as neutropenia, febrile neutropenia, and infection with Grade 3/4 neutropenia were reported when 
pretreatment with folic acid and vitamin B12 was administered. 
 
Skin rash has been reported more frequently in patients not pretreated with a corticosteroid in 
clinical trials. Pretreatment with dexamethasone (or equivalent) reduces the incidence and 
severity of cutaneous reaction. 
 
Pemetrexed can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, 
and anemia (or pancytopenia); myelosuppression is usually the dose-limiting toxicity. Dose 
reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum 
nonhematologic toxicity seen in the previous cycle. 
 
Pemetrexed is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed 
in patients with creatinine clearance < 45 ml/min/1.73 m2. Insufficient numbers of patients have 
been studied with creatinine clearance < 45 ml/min/1.73 m2 to give a dose recommendation. 
Therefore, pemetrexed should not be administered to patients whose creatinine clearance is < 45 
ml/min/1.73 m2. One patient with severe renal impairment (creatinine clearance 19 ml/min/1.73 
m2) who did not receive folic acid and vitamin B12 died of drug-related toxicity following 
administration of pemetrexed alone. 
 
Caution should be used when administering NSAIDs concurrently with pemetrexed to patients 
with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 ml/min/1.73 m2). 
 
Patients should not begin a new cycle of treatment unless the ANC is > 1500 cells/mm3, the 
platelet count is > 100,000 cells/mm3, and creatinine clearance is > 45 ml/min/1.73 m2. 
 
Based on its mechanism of action, pemetrexed can cause fetal harm when administered to a 
pregnant woman. Pemetrexed administered intraperitoneally to mice during organogenesis was 
embryotoxic, fetotoxic, and teratogenic in mice at greater than 1/833rd the recommended human 
dose. If pemetrexed is used during pregnancy, or if the patient becomes pregnant while taking this 
drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing 
potential should be advised to avoid becoming pregnant. Women should be advised to use effective 
contraceptive measures to prevent pregnancy during treatment with pemetrexed. 
 
Please refer to the package insert for the comprehensive list of adverse events. 
 
7.1.4 Other Agent(s) 
To reduce toxicity, patients treated with pemetrexed must be instructed to take a low-dose oral 
folic acid preparation or multivitamin with folic acid on a daily basis (Alimta [package insert] 
2012). At least 5 daily doses of folic acid must be taken during the 7-day period preceding the first 
dose of pemetrexed; and dosing should continue during the full course of therapy and for 21 days 
after the last dose of pemetrexed. Patients must also receive one intramuscular or subcutaneous 
injection of vitamin B12 during the week preceding the first dose of pemetrexed and every 3 cycles 
thereafter. Subsequent vitamin B12 injections may be given the same day as pemetrexed. In 
clinical trials, the dose of folic acid studied ranged from 350 to 1000 μg, and the dose of vitamin 
B12 was 1000 μg. The most commonly used dose of oral folic acid in clinical trials was 400 μg. 

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37 
 
Patients should receive appropriate hydration prior to and/or after receiving platinum therapy. 
 
7.2 Adverse Event Characteristics  
 
• 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 until March 31, 2018 for AE reporting.  CTCAE version 5.0 will be 
utilized for AE reporting beginning April 1, 2018.  All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can 
be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
section 7.3.4. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 Expedited Adverse Event Reporting 
 
7.3.1 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 for DCTD 
(CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP 
Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
).  These requirements are briefly outlined in the tables below (Section 7.3.3). 
 
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. 
 

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7.3.2 CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization, the local treating physician, and the 
Reporter and Submitter.  CTEP-AERS provides a copy feature for other e-mail recipients.  
 
The Coordinating Center of the Corresponding Organization 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. 
 
7.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned 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. 
 
Death due to progressive disease should be reported as Grade 5 “Disease Progression” 
under the system organ class (SOC) “General disorders and administration site 
conditions.”.  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 

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39 
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 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.4 Routine Adverse Event 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. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.   
 
7.5 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 expeditiously 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 

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40 
reported via the routine reporting mechanisms outlined in each protocol.  
 
7.6 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 AE 
reporting unless otherwise specified. 
 
8 PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 7.1. 
 
8.1 CTEP IND Agent 
 
8.1.1 CTEP IND Agent TRC102 (NSC 3801)) 
 
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 Tracon Pharmaceuticals 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).  
 

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41 
Stability:  Shelf life surveillance of the intact bottles in 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 
 
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 12.3). 
 
8.1.2 Agent Ordering and Agent Accountability 
 
8.1.2.1 NCI-supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) 
policy requires that 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), Biosketch, Agent Shipment 
Form, 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. 
 
In general, sites may order initial agent supplies when a subject is being screened for 
enrollment onto the study. 
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application.  Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account and the maintenance of an “active” account status, a 
“current” password, and active person registration status.  For questions about drug 
orders, transfers, returns, or accountability, call or email PMB any time.  Refer to the 
PMB’s website for specific policies and guidelines related to agent management.   
 
8.1.2.2 Agent Inventory Records  
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, dispensing and final disposition of all agents received from 
the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record 
(DARF) available on the CTEP forms page.  Store and maintain separate NCI 

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42 
Investigational Agent Accountability Records for each agent, strength, formulation and 
ordering investigator on this protocol. 
 
8.1.2.3 Useful Links and Contacts 
• 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• 
NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• 
PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP 
• 
CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
• 
CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• 
IB Coordinator:  IBCoordinator@mail.nih.gov  
• 
PMB email:  PMBAfterHours@mail.nih.gov 
• 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) 
 
8.1.2.4 Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and 
research staff through the PMB Online Agent Order Processing (OAOP) application.  
Access to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account and the maintenance of an “active” account status and a “current” 
password.  Questions about IB access may be directed to the PMB IB coordinator via 
email. 
 
8.1.3 Cisplatin Commercial Agent  
Description:  Cis-diamminedichloroplatinum (Platinol or cisplatin) is a heavy metal 
complex and is water soluble. It is a white lyphilized powder with a molecular weight 
of 300.1. 
 
Formulation:  Cisplatin is available as 50mg/50ml and 100mg/100ml multi-dose 
vials. Each ml also contains 9mg sodium chloride. Hydrochloric acid and/or sodium 
hydroxide is added to adjust the pH. 
 
Storage and Stability:  The intact vials may be stored at room temperature (15 -
25%), protected from light, for the lot life indicated on the package.  Do not 
refrigerate. The solution may be further diluted in a chloride-containing vehicle such 
as D5NS, NS, or D5-1/2NS (precipitate occurs in D5W) and stored at room 
temperature for up to 24 hours. 
 
Administration:  Cisplatin should be given immediately after preparation as slow 
intravenous infusion over 30 - 60 minutes.  Needles or intravenous sets containing 
aluminum parts that may come in contact with cisplatin (Platinol) should not be used 
for preparation or administration, as a black precipitate is formed within 30 minutes.  
Please refer to the approved package labeling for complete prescribing and toxicity 

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43 
information. 
 
Supplier:  Cisplatin is commercially available.  This drug will not be supplied by the 
NCI. 
 
8.1.4 Pemetrexed Commercial Agent  
Description:  Pemetrexed (Alimta) is a folate analog metabolic inhibitor; it is a white 
to either light-yellow or green-yellow lyophilized powder 
Formulation:  Pemetrexed for injection is commercially supplied as a sterile, 
lyophilized powder for intravenous infusion packaged in a single-use glass vials 
containing 100 mg or 500 mg pemetrexed. The freeze-dried drug product is pemetrexed 
disodium and mannitol in a 1:1 ration. Sodium hydroxide and/or hydrochloric acid 
solution maybe added during processing to adjust the pH. Each vial contains an excess 
of pemetrexed to facilitate the withdrawal of the label amount.  
 
Storage and Stability:  The drug product is stable when stored at controlled room 
temperature and normal lightning conditions.  
 
Administration: Each vial must be reconstituted with sodium chloride (0.9%) 
solution for injection, without preservative, resulting in a solution containing 
10mg/mL to 50 mg/mL. Pemetrexed infusion solutions prepared in this manner are 
compatible with polyvinyl chloride and polyolefin line administration sets and 
infusion bags. Pemetrexed is physically incompatible with diluents containing 
calcium, including Lactated Ringer’s injection.  
 
Supplier:  Pemetrexed is commercially available.  This drug will not be supplied by 
the NCI. 
 
9 BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1       Pharmacokinetics of TRC102 – Not Applicable  
 
9.2 Correlative Studies 
 
9.2.1 Establishment of pleural and peritoneal effluent-derived cell lines 
The pleural and peritoneal effluent are often collected from mesothelioma patients. These 
cells potentially have tumor associated cells that can be evaluated for response to 
therapies. Moreover, the mesotheliomas are classified as epithelial, fibrous, or mixed. 
Depending on the type, there may also be differential response to treatments and these 
cells will provide a valuable resource for evaluation of different therapies and to also 
provide a molecular basis for the classification of the histopathological assignments.  
 
Only patient samples from City of Hope will be used for the establishment of mesothelial 
cells from pleural or peritoneal effluents. For City of Hope patients only, samples will 
be transported to Dr. O’Connor’s laboratory in the Gonda Bldg, Rm 4131A (see 
Appendix E for specimen collection form). The day prior to the procedure, please 

NCI Protocol #: 9837; PhI-76 
Version Date: March 7, 2019 
 
44 
contact Dr. O’Connor at x68220 and/or Ms. Yesenia Thompson at x63696. 
 
Methods: We will centrifuge the pleural or peritoneal effluent at 300Xg for 10 minutes to 
pellet cells. Cells remaining after centrifugation will be resuspended in RPMI, 10% fetal 
calf serum with Glutamax, and supplemented with penicillin, streptomycin. Cells will be 
plated onto 6 cm culture dishes and cultured at 5% CO2 and 37oC and allowed to develop 
into colonies. Different cell types will be isolated based on morphology as clones 
assigned generally as epithelial or fibrous. Following isolation, next-generation RNA 
sequencing (RNA-seq) will be performed to identify expression levels of the ensemble of 
genes in the mesothelioma cell lines. Those will be analyzed using data mining 
techniques to establish differences in the cell types. Differences in cell types will be 
assigned and compared to a recent publication that used microarray analysis (44).  We 
will examine topoisomerase II levels in these cell lines, because that has been directly 
linked to response to TRC102 (27). 
 
Expected Results: We anticipate that a majority of pleural and peritoneal effluents will 
produce viable cell lines based on the literature. Furthermore, we will possibly identify 
more diagnostic biomarkers that have prognostic or therapeutic value. We will 
particularly focus on CDKN21, CDKN2B, BAP1, NF2, and TP53 expression levels, 
which were recently presented as important in diagnosis (44). 
 
Alternative methods/results: If no cells arise using the initial culturing techniques, we 
will change the conditions, based on rational evaluation of the culture media from 
different laboratories and based on the experience in our group to culture from tissue 
explants. However, based on literature reports, we do not anticipate that culturing the 
effluents will be overwhelming. If we identify different markers, those are potentially 
important and could be publishable (44-49). 
 
9.2.2 Response of cultured pleural and peritoneal cells to cisplatin, pemetrexed, and 
TRC102.  
 
The cell lines developed above could present a possible advance in treatment of 
mesothelioma. We will test the response of the cells to TRC102 in conjunction with 
cisplatin and pemetrexed. The results that we obtain will be compared to the patient 
responses in the study. We will vary the amounts of cisplatin, pemetrexed, and TRC102 
to evaluate the cell death for each drug individually, as pairs, and finally all together. We 
have used these techniques in the past (50) and will apply them to this work. 
 
Methods: The cell culture parameters will be established in the previous aim. The cells 
will be cultured and the conditions to establish clonality will be empirically determined. 
Cells will be exposed to cisplatin, pemetrexed, or TRC102 or the different combinations 
(51).  From the clonal survival data, we will determine the LD50 values for each of the 
drugs and the combinations, along with the level of synergy or antagonism. These data 
will be compared to the responses obtained in the Phase I patients. 
 
Expected Results: We expect that the results we obtain in vitro will provide information 

NCI Protocol #: 9837; PhI-76 
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45 
that can be used to alter drug treatment in subsequent studies. The results are expected to 
parallel the response of patients to the combination therapy. 
 
Alternative methods/results: It is possible that the pleural and peritoneal effluents will not 
be clonal. If that is the case another viability assay will be used (e.g., Trypan blue 
permeability). The drug treatment regime in vitro could be different from what is 
observed in patients. If that is the case, we will consider a mouse xenograft model using a 
treatment with drug ratios similar to that found in cell culture. If that revised combination 
ratio shows more promise, it would be considered for future patient trials. 
 
9.2.3 Determination of abasic site modification in patient samples 
 
TRC102 reacts with the C1’ aldehyde of the deoxyribose at the AP site and leads to a 
modification of DNA that is not easily repaired. The TRC102 modification of the AP site 
blocks the reaction with a reagent that is designated as an aldehyde reactive probe (ARP) 
(52). We will use the ARP to determine the effect of the TRC102 on AP sites. 
 
Methods: Based on previous work (36), we will collect peripheral blood mononuclear 
cells (PBMCs) (buffy coat from 12 ml heparinized whole blood) on day 1 cycle 2 before 
cisplatin/pemetrexed treatment and then following treatment at 4 ± 1 hour and 24 ± 4 
hours. The AP sites will be determined using the ARP (Dojindo Molecular Technologies, 
Gaithersburg, MD) and will be normalized to the pre-treatment levels for each patient. 
 
Expected Results: The level of ARP reacted with the cisplatin/pemetrexed/TRC102 
treated patient PBMCs should be lower than for the cisplatin/pemetrexed treated patient 
samples. This indicates that the TRC102 has limited the number of AP sites because the 
sites are already modified by TRC102. Therefore, blocking of the ARP modification will 
indicate functionality of the TRC102. 
 
Alternative methods/results: If the ARP reactivity is low, there is a possibility that the 
TRC102 is not reacting with the AP sites in the PBMCs. It is still possible that the 
TRC102 has modified the mesothelioma cells and will have a therapeutic effect. If there 
is a positive effect on patient responses to mesothelioma in the 
cisplatin/pemetrexed/TRC102 arm even though not shown to modify the AP sites in this 
assay, the PBMCs could be a poor indicator of pharmacological response. 
 
9.2.3.1 
Processing of Buffy Coat for PBMCs 
 
Equipment 
• 12 mL of blood collected in Sodium Heparin or Lithium Heparin green-top tubes 
(3 4-ml vacutainer tubes, BD Cat. # 367884 or equivalent; OR 2 6-ml vacutainer 
tubes, BD Cat. #367886  or equivalent) 
• One 15 ml size plastic conical centrifuge tube with screw cap 
• Transfer pipettes 
• Two polypropylene 2.0 mL screw-top cryovials (Corning Cat #430659 or 
equivalent; available 50/pk from Cole-Parmer Item # EW-44351-02) 

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46 
 
Reagents 
• Phosphate Buffered Saline (PBS) without Ca++ or Mg++ (Sigma Aldrich catalog 
#D8537 or  equivalent) 
Procedure 
• Samples will be collected into green-top tubes with sodium heparin or lithium 
heparin on day 1 of cycle 2 just prior to treatment and then at 4 and 24 hours post 
treatment. Blood samples will be kept at room temperature (18-26oC) and properly 
labeled with patient information and study number. 
• Once each blood sample is collected, the tube should be inverted approximately 8-
10 times to ensure that the whole blood is mixed thoroughly with the anticoagulant. 
• The green-top tubes should be transported to the local processing laboratory and 
centrifuged as soon as possible to preserve the abasic sites (no longer than 30 
minutes after blood collection).  The tubes will be centrifuged at room temperature 
for 10 min at 1000 RCF (relative centrifugal force). 
• The plasma layer will be removed, taking care not to disturb the off-white buffy 
coat layer, and discarded. 
• The buffy coat will be transferred to a 15 ml conical centrifuge tube using a transfer 
pipette and add 10 mL of ice-cold PBS to the tube. Cap the tube and invert several 
times to mix.  
• The cells suspension should be centrifuged at 300RCF for 10 min at 4◦C. When the 
centrifugation is finished, the supernatant will be taken off and discarded. 
• Resuspend cells in 2 ml PBS and transfer to 2 x 2.0 mL screw-top cryovial that 
have been labeled with the study name (PHI-76), patient’s study accession number, 
the sample date, and nominal time (i.e. pre, 4 hour, or 24 hour).   
• The freezer vials should be centrifuged at 300RCF for 5 min at 4oC (if feasible) and 
the supernatant removed using a transfer pipette so that only the dry pellet remains.  
• Cell pellets should be stored at -80°C until batch shipping. 
• The complete set of PBMC samples should be shipped overnight on dry ice to the 
following address with specimen collection form (Appendix E): 
 
 
 
Dr. Timothy Synold 
 
 
 
Shapiro Building Room 1042 
 
 
 
City of Hope National Medical Center 
 
 
 
1500 E. Duarte Rd. 
 
 
 
Duarte, CA  91010 
 
 
 
Phone (626) 256-4673, ext. 62110 
 
 
 
Fax – (626) 471-9376 
 
 
 
Email – tsynold@coh.org 
 
 
9.2.4 Determination of cisplatin modification levels using ELISA methods 
 
Use of a cisplatin specific antibody will permit at least the examination of the relative 
levels of cisplatin adducts formed in DNA to provide an evaluation of the level found in 
cells. We will use an ELISA method that detects low levels of cisplatin (53-55).  

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47 
 
Methods: We will perform staining for the cisplatin adducts as described. PBMCs from 
the samples described above will be used to determine the level of modification by 
cisplatin using an ELISA assay with a commercial antibody (Anti-Cisplatin modified 
DNA antibody [CP9/19])(55). Extracts from the PBMCs will be isolated and compared to 
cisplatin modified standards. The same patient samples used from the previous aim will 
be used to determine the cisplatin levels. 
 
Expected results: We anticipate that the level of cisplatin modification will not change 
based on treatment using TRC102. 
 
Alternative methods/results: If there is not enough PBMC sample to obtain a reproducible 
cisplatin determination, we will only determine the level for AP sites, because that is 
anticipated to be the major factor.    
 
 
 

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48 
10. STUDY CALENDAR 
Baseline evaluations are to be conducted within 7 days prior to start of protocol therapy.  Scans 
and x-rays must be done <4 weeks prior to the start of therapy.  In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy. Arm B patients will receive TRC102 and pemetrexed 
without cisplatin. 
 
Pre- 
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wke 
12 
Off Studyf 
TRC102 dosing: Day 1-4, q 
21 days 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Cisplatin dosing 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Pemetrexed dosing 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X---------------------------------------------------------------------------------------------X 
 
Physical examg 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Vital signsg 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weightg 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Performance statusg 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
CBC w/diff, pltsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistrya,g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prothrombin time or INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG (as indicated) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
X---------------------------------------------------------------------------------------------X 
X 
Tumor measurements 
X 
Tumor measurements are repeated every 2 cycles (6 weeks).  Documentation 
(radiologic) must be provided for patients removed from study for progressive 
disease. 
X 
Radiologic tumor 
assessment/response 
evaluation (CT scans)b 
X 
Radiologic measurements should be performed every 2 cycles (6 weeks).  After 6 
cycles of therapy, scans can be performed every 3 cycles (9 weeks). 
X 
B-HCGc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Correlative studies as defined 
in section 9.2 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
a: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, 
total protein, SGOT [AST], SGPT [ALT], sodium. 
b:  
Radiological assessment should be performed within 28 days  before start of treatment and subsequently every 2 cycles (6 weeks), until 
disease progression, or end of treatment. All assessment should be performed within +/- 7 days of the scheduled day of assessment. 
c:  
Serum pregnancy test (women of childbearing potential). 
e:  
Patients may receive up to 6 cycles of therapy; For patients on Arm A, Dose level 4 (chemotherapy-naïve), patients may discontinue 
cisplatin and continue treatment with TRC102 and pemetrexed at the discretion of the treating physician.  
f.  
Off-study evaluation.  Follow-up per Section 5.6.  
g.      Laboratory evaluations and clinic visits at specified timepoints +/- 2 days. 
 
 

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49 
 
11 MEASUREMENT OF EFFECT 
 
11.1 Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 2 cycles (6 
weeks). Once a patient completes 6 cycles of therapy, scans can be performed every 3 cycles (9 
weeks).  In addition to a baseline scan, confirmatory scans should also be obtained at least 4 
weeks following initial documentation of objective response.  
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
In the current study, tumor thickness perpendicular to the chest wall or mediastinum will be 
assessed according to modified RECIST criteria for Malignant Pleural Mesothelioma [57]. 
Accordingly, at least 6 measurable lesions ( 2 measurements per CT section, taken 
perpendicularly to a bony structure, in 3 different sections) should be identified as target lesions 
and recorded and measured at baseline. A sum of the longest diameter for all target lesions will 
be calculated and reported at the baseline sum longest diameter. It will be used as the reference 
by which to characterize the objective tumor response. Transverse cuts at least 1 cm apart and 
related to anatomical landmarks in the thorax will be chosen to allow reproducible assessment at 
later time points. At reassessment, pleural thickness will be measured at the same position at the 
same level. The minimum size of a measurable lesion should be no less than double the slice 
thickness and also have a minimum size of 10 mm. 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with TRC102.  
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 

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50 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) 
by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable.  If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the 
protocol. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm [0.5 cm]).  At baseline and in 
follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 
to <1.5 cm] short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 

NCI Protocol #: 9837; PhI-76 
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51 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter 
as assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is 
recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less.  If CT 
scans have slice thickness greater than 5 mm (0.5 cm), the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable in certain 
situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 

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52 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008].  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 

NCI Protocol #: 9837; PhI-76 
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53 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
11.2 Response Criteria 
 
11.2.1 Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm (<1 cm). 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm (0.5 cm).  
(Note:  the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.2.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
[<1 cm] short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 

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54 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
11.2.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may 
beaccepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 

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55 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
11.2.4 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
12 STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 Study Oversight 
 
See also Section 14 ‘CCC POLICIES FOR MONITORING CONSORTIUM TRIALS,’ 
Subsection 14.1 ‘Oversight. 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and serious 
adverse events; reporting of expedited adverse events; and accumulation of reported adverse 
events from other trials testing the same drug(s).  The Protocol Principal Investigator and 

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statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
For the Phase 1 portion of this study, all decisions regarding dose escalation/expansion/de-
escalation require sign-off by the Protocol Principal Investigator through the CTMS/IWRS.  In 
addition, for the Phase 1 portion, the Protocol Principal Investigator will have at least monthly, or 
more frequently, conference calls with the Study Investigators and the CTEP Medical Officer(s) 
to review accrual, progress, and adverse events and unanticipated problems.   
 
During the Phase 2 portion of the study, the Protocol Principal Investigator will have, at a 
minimum, quarterly conference calls with the Study Investigators and the CTEP Medical 
Officer(s) to review accrual, progress, and pharmacovigilance.  Decisions to proceed to the second 
stage of a Phase 2 trial will require sign-off by the Protocol Principal Investigator and the Protocol 
Statistician through IWRS and Medidata Rave. 
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
12.2 Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the site 
user must have an active CTEP IAM account (check at < https://ctepcore.nci.nih.gov/iam  >) and 
the appropriate Rave role (Rave CRA, Rave Read-Only, Rave CRA (Lab Admin), Rave SLA, or 
Rave Investigator) on either the LPO or participating organization roster at the enrolling site. To 
the hold Rave CRA role or Rave CRA (Lab Admin) role, the user must hold a minimum of an 
AP registration type.  To hold the Rave Investigator role, the individual must be registered as an 
NPIVR or IVR.  Associates can hold read-only roles in Rave.  If the study has a DTL, 
individuals requiring write access to Rave must also be assigned the appropriate Rave tasks on 
the DTL.  (Note: A DTL is NOT required for this study.).   
 
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.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  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 in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen.   
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 

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57 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
 
12.2.1 Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data 
will submitted to CTMS at least once every two weeks via Medidata Rave (or other 
modality if approved by CTEP).  Information on CTMS reporting is available at 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-
site audits will be conducted on an 18-36 month basis as part of routine cancer center site 
visits. More frequent audits may be conducted if warranted by accrual or due to concerns 
regarding data quality or timely submission.  For CTMS monitored studies, after users 
have activated their accounts, please contact the Theradex Help Desk at (609) 799-7580 
or by email at CTMSSupport@theradex.com for additional support with Rave and 
completion of CRFs. 
 
12.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all 
investigators at the ETCTN Sites understand the procedures for data submission for each 
ETCTN protocol and that protocol specified data are submitted accurately and in a timely 
manner to the CTMS via the electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less 
than once every 2 weeks.  The timeliness of data submissions and timeliness in resolving 
data queries will be tracked by CTMS.  Metrics for timeliness will be followed and 
assessed on a quarterly basis.  For the purpose of Institutional Performance Monitoring, 
data will be considered delinquent if it is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing 
basis as data is received.  Queries will be issued by CTMS directly within Rave.  The 
queries will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to 
resolve.  Monthly web-based reports are posted for review by the Drug Monitors in the 
IDB, CTEP.  Onsite audits will be conducted by the CTMS to ensure compliance with 
regulatory requirements, GCP, and NCI policies and procedures with the overarching 
goal of ensuring the integrity of data generated from NCI-sponsored clinical trials, as 
described in the ETCTN Program Guidelines, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
)  and CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the 

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recommended phase 2 dose (RP2D), and a description of any dose-limiting toxicities 
(DLTs).  CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry 
and Repository (caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models).  Customized eCRFs will 
be included when appropriate to meet unique study requirements.  The PI is encouraged 
to review the eCRFs, working closely with CTMS to ensure prospectively that all 
required items are appropriately captured in the eCRFs prior to study activation.  CTMS 
will prepare the eCRFs with built-in edit checks to the extent possible to promote data 
integrity. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
). 
12.3 CTEP Multicenter Guidelines 
 
N/A 
 
12.4 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 

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59 
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).  
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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12.5 Genomic Data Sharing Plan 
 
 
 
N/A 
 
13 STATISTICAL CONSIDERATIONS 
 
13.1 Study Design/Endpoints 
 
The primary objectives in Arm A are to select a Recommended Phase 2 Dose (RP2D) for 
TRC102 in combination with cisplatin and pemetrexed for use in patients with malignant solid 
tumors.  In Arm B the primary objective is look for preliminary evidence of activity of the 
starting dose level in patients with advanced malignant mesothelioma previously treated with 
pemetrexed and cisplatin.   
 
Arm A:  The RP2D will be established using escalation rules in section 5.3, design to escalate, 
in cohorts of 3, through four planned dose levels, with an additional de-escalation dose if needed 
(Table 1).  The primary endpoint is dose-limiting toxicity (DLT), which is defined in section 5.3, 
along with dose escalation rules.  Toxicity is graded NCI Common Terminology Criteria for 
Adverse Events (CTCAE), as specified in section 6.   
 
For the first 3 dose levels, TRC102 dose will be escalated with Cisplatin held constant at 60 
mg/m2.  The fourth dose level holds TRC 102 constant, and escalates Cisplatin.    An important 
detail is that dose level 4 has an alternate definition in the event that dose escalation stops short 
of dose level 3 (where TRC 102 is at its maximum planned dose).  Assuming that the escalation 
rules establish a lower dose as the RP2D, we will regard that as tentative, and use the TRC102 
dose from that level (with 75 mg/m2 Cisplatin and 500 mg/m2  Pemetrexed) in a re-defined dose 
level 4.  Six patients will be treated at the tentative RP2D before escalating to the re-defined dose 
level 4 as the final dose level.  If, however, the dose escalation does not stop short of dose level 
3, then dose escalation may proceed to level 4 directly, as originally defined, in accordance with 
the escalation rules.  This does not necessarily require more than 3 subjects at dose level 3. 
 
Patients will be enrolled in cohorts of three until a final RP2D is established.  Definitions of 
“evaluable for toxicity” and “evaluable for response” are given in section 10.5.1.  Dose 
escalation decisions will be based on patients who are fully treated (patients must receive the 
prescribed doses of pemetrexed and cisplatin, and ≥ 75% of the prescribed dose of TRC102 in 
the cycle) without DLT, or who experience DLT after any amount of treatment. 
 
Arm B will enroll 14 patients with advanced malignant mesothelioma previously treated with 
pemetrexed and cisplatin who are evaluable for response.  Patients will be treated with 50 
mg/day of TRC102, orally, days 1-4, every 21 days and 500 mg/m2 of pemetrexed, 
intravenously, day 1, every 21 days.  This is the first stage of a two stage Gehan design looking 
for RECIST responses.  Because the expectation of response to any agent is very low for this 
group, any responses will be of interest.  If no responses are seen among 14 subjects, the upper 
95% confidence limit for response rate would be below 20%.  If any responses are seen among 
the 14 subjects, demonstrating that responses are possible, additional study will be needed to 

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better obtain an estimate of the response rate with an acceptable confidence interval (the second 
stage of the Gehan design). 
 
13.2 Sample Size/Accrual Rate 
 
Arm A is expected to require between 12 and 19 subjects, who are treated until DLT or 
completion of their first course.  Arm B will require 14 subjects evaluable for response.  
Mesothelioma occurs predominantly in older men, although adult men and women of all races 
and ethnic groups are eligible for this trial.  The total sample size target is between 26 and 33 
subjects, with 30 expected. 
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ 
Alaska Native 
 
 
 
 
 
Asian 
1 
4 
0 
0 
5 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
0 
2 
0 
0 
2 
White 
3 
14 
1 
5 
23 
More Than One Race 
0 
0 
0 
0 
0 
Total 
4 
20 
1 
5 
30 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015)  
OMB No. 0925-0001/0002 
 
13.3   Stratification Factors 
 
Not applicable in this study. 
 
13.4  Analysis of Secondary Endpoints 
 
Evaluation and analysis of pharmacokinetic parameters is described in section 8.  Briefly, 
individual PK parameter estimates (e.g., Cmax, Vss, CLsys, t1/2, and area under the curve 
[AUC]) will be determined for TRC102 and cisplatin for each patient and tabulated using 

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62 
summary statistics (means and coefficients of variation). 
 
Feasibility of establishing pleural and peritoneal effluent-derived cell lines will be reflected in the 
number successfully established.  Response of cultured pleural and peritoneal mesothelioma cells 
to cisplatin, pemetrexed, and TRC102 will be studied using standard experimental design 
approaches and generalized linear model analyses. 
 
RECIST-defined responses will be summarized as a fraction of all subjects, and as a fraction of all 
subjects in Arm B, using exact binomial 9 percent confidence intervals. 
 
13.5    Reporting and Exclusions 
 
13.5.1 Evaluation of Toxicity 
 
As noted above, all patients will be evaluable for toxicity from the time of their first 
treatment with TRC102, but subjects must be fully treated or experience DLT to be 
included in escalation decisions. 
 
13.5.2 Evaluation of Response 
 
All patients included in the Arm B must be assessed for response to treatment, even if 
there are major protocol treatment deviations or if they are ineligible.  Each patient with 
measurable disease will be assigned one of the following categories:  1) complete 
response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death from 
malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 
9) unknown (not assessable, insufficient data).  
 
All of the patients who met the eligibility criteria (with the possible exception of those 
who received no study medication) should be included in the main analysis of the 
response rate.  Patients in response categories 4-9 should be considered to have a 
treatment failure (disease progression).  Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate.  Precise 
definitions for categories 4-9 will be protocol specific.  
 
Conclusions about response rates in  Arm B will be based on all patients treated in that 
arm.  Supplementary analyses may then be performed including dose-escalation subjects 
and correlative information.  Any subset analyses will only serve to supplement main 
conclusion about responses in Arm B, which will include all subjects enrolled in those 
arm, and to describe responses to the drug combination at each dose level in Arm A. 
 
13.6 Study Status Updates and Study Closure 
 
13.6.1 Definitions of Study Status Changes 
 
13.6.1.1 
Temporarily Closed to Accrual 
 

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The study status is Temporarily Closed to Accrual when no patient slots are currently 
available, but there is the possibility that the trial will re-open for accrual (patient slots 
become available).  Sites are not permitted to accrue additional patients until CTEP is 
notified of Re-Activation. 
 
Study status will need to be changed to Temporarily Closed to Accrual when any of the 
following criteria are met: 
 
• Sites are notified by CTEP (via Request for Rapid Amendment [RRA]) of 
changes in the risk/benefit ratio that necessitate changes to the patient Informed 
Consent document.  Requested changes will be specified in the RRA and must be 
reviewed by the study’s IRB. 
• CTEP and the lead investigator agree that unacceptable toxicities necessitate a 
discussion to change the dosing/regimen. 
• A protocol-defined benchmark has been achieved (such as an interim analysis 
before proceeding to the next stage).  
• Investigators encounter any of the stopping criteria described in Section 13.1. 
 
13.6.1.2 
Closed to Accrual 
 
The study status is (permanently) Closed to Accrual when no more patient enrollment 
slots are available, and at least one patient is still actively receiving the study treatment.  
Sites are no longer permitted to enroll additional patients. 
 
Patient slots are no longer available when the following criteria are met: 
 
• The pre-specified number of evaluable patients has been successfully enrolled, 
treated, and evaluated. 
• The study treatment has failed to meet the pre-specified efficacy goal at the stage 
1 interim analysis. 
• CTEP and the investigators agree that unacceptable toxicities preclude further 
enrollment. 
• Investigators encounter any of the stopping criteria described in Section 13.1. 
 
13.6.1.3 
Closed to Accrual and Treatment 
 
The study status is Closed to Accrual and Treatment when no more patient enrollment 
slots are available and no patients are currently receiving the study treatment.  Patients 
may still be enrolled on the protocol only for the purposes of follow-up. 
 
Patient accrual and treatment will be permanently halted when any of the following 
criteria are met: 
 
• Enrollment was previously closed (study status of “Closed to Accrual”), and no 
patients are receiving the study treatment. 
• CTEP and the investigators agree that unacceptable toxicities preclude further 

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64 
enrollment.  In this case, CTEP and the investigators must collaborate to alter the 
regimen or to halt the study treatment altogether as soon as it can be safely done 
for patients currently receiving treatment.  
 
CTEP and Theradex must be notified when patients are no longer receiving treatment 
[i.e., when the last patient(s) to be receiving treatment is/are no longer receiving the study 
regimen for any reason]. 
 
13.6.1.4 
Closed to Follow-Up 
 
The study is considered Closed to Follow-Up when all protocol-defined follow-up 
procedures have been completed for all patients who have not been removed from the 
study for other reasons.  That is, there are no outstanding follow-up procedures to be 
performed as mandated by the protocol. 
 
CTEP does not need to be notified of a status change to “Closed to Follow Up.” 
 
13.6.1.5 
Complete 
 
Study is considered Complete if it has been at least thirty (30) days since the last patient 
follow-up evaluation.   
 
A citation to a final study report (manuscript, meeting abstract, etc.) is required with the 
submission of the Protocol Status Update Form to CTEP PIO.   
 
13.6.2 Responsibility for Filing Protocol Status Update Forms 
 
CTEP must be notified of all study status changes in Section 14.1 (except for Closed to Follow-
Up) by the Corresponding Organization via Protocol Status Update Form, available from the 
CTEP website at http://ctep.cancer.gov/protocolDevelopment/default.htm#amendments.    
 
Theradex must be notified as soon as all patients are off treatment (i.e., when study status 
changes to Closed to Accrual and Treatment).  Theradex will produce a report within 90 days of 
this notification. 
 
14 CCC POLICIES FOR MONITORING CONSORTIUM TRIALS 
 
This protocol is monitored at several levels, as described in this section.  To summarize:  The trial 
PI has access to the data at all times.  The CCC Data Coordinating Center reviews accrual and 
toxicities monthly.  An external, independent DSMC reviews the study progress twice yearly.  In 
addition, for the Phase I portion, the study PI will have monthly - and as needed - conference calls 
with study investigators to review accrual, progress, and any unforeseen issues.  Dose 
escalation/expansion/de-escalation decisions require sign-off by the study PI (or his or her 
designee) and study statistician (or his or her designee).  During the Phase II portion, the study PI 
will have quarterly - and as needed - conference calls with study investigators to review accrual, 
progress, and any unforeseen issues.  Decisions to proceed to the second stage of the Phase II 

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65 
trial will require sign-off by the study PI and (the trial statistician). 
 
The protocol principal investigator (PI) is responsible for monitoring the conduct and progress of 
this Phase II trial, including the ongoing review of accrual, data and toxicities, as well as the 
accumulation of reported adverse events from other trials testing the same drug(s).  The 
participating clinicians and their designees are responsible for timely submission of adverse event 
reports (see Section 7.0) and case report forms.  The Data Coordinating Center for the CCC 
Consortium is responsible for providing the PI with access to the submitted case report form data 
in summary and detail in a timely fashion.   Although the PI is responsible for evaluating the 
cumulative reported adverse events and the impact that these have on the continued conduct of the 
trial, it is the Data Coordinating Center of the CCC that distributes all submitted SAE reports to 
the appropriate individuals, including the local protocol principal investigators, at each of the 
participating institutions.   
 
The Data Coordinating Center posts a summary (accrual, toxicities, and responses) of each CCC 
initiated trial on the CCC website.  In this way, each PI has access to up-to-date information on 
the status of his or her trial.  In consultation with the collaborating statistician, the PI is responsible 
for review of: 
 
(a) 
for Phase I trials, all dose limiting toxicities and decisions regarding dose escalation, 
expansion, as well as decisions to terminate escalation, and  
(b) 
for Phase II trials, the toxicities and therapeutic endpoints referred to in the statistical plan. 
 
The Data Coordinating Committee meets monthly to review data management and data quality 
issues – completeness of data submissions as well as accuracy in terms of built-in, computerized 
logic checks.  Any issues identified and the corrective plans are presented to the Internal 
Committee and at the next CCC teleconference meeting for review and approval. 
 
14.1 Oversight 
 
Oversight of the conduct of CCC trials occurs at several levels: 
 
1. 
The Data Coordinating Center for the CCC flags all trials that are approaching a decision 
in terms of toxicity (for both Phase I and Phase II trials) or responses (for Phase II trials).  
Decisions are made by the PI with input from the statistician and discussion with the 
principal investigator of the funding mechanism or his or her designee, and are 
communicated to the participating centers by the CCC Data Coordinating Center. At the 
monthly teleconferences, the accrual of each open protocol is reviewed. 
 
2. 
For CTEP sponsored Phase I trials, data are reported to the NCI-designated clinical trials 
monitoring service (CTMS) which will audit patients’ records on each protocol – at each 
CCC institution; this audit is initiated by CTEP.   
 
3. 
An independent CCC DSMC will review CCC trials every 6 months. This DSMC will 
consist of 6 voting members (3 medical oncologists or hematologists involved in Phase I/II 

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66 
cancer clinical trials but not participating in CCC studies, a patient representative and a 
statistician) and a non-voting CCC statistician.   
 
a. 
DSMC meetings will take place twice a year.  Additional meetings will be convened if 
necessary.  
b. 
This DSMC will review each CCC trial in terms of accrual, toxicity/safety, and adherence 
to trial design, audit results, and likelihood of successful completion.   
c. 
The DSMC will report to the CCC leadership. 
 
 

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15 REFERENCES 
 
1. 
Tsao AS, Wistuba I, Roth JA, Kindler HL. Malignant pleural mesothelioma. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology. 
2009;27(12):2081-90. Epub 2009/03/04 09:00. doi: 10.1200/JCO.2008.19.8523. PubMed PMID: 
19255316. 
2. 
Price B, Ware A. Time trend of mesothelioma incidence in the United States and 
projection of future cases: an update based on SEER data for 1973 through 2005. Critical reviews 
in toxicology. 2009;39(7):576-88. Epub 2009/08/05 09:00. doi: 10.1080/10408440903044928. 
PubMed PMID: 19650718. 
3. 
Carteni G, Manegold C, Garcia GM, Siena S, Zielinski CC, Amadori D, et al. 
Malignant peritoneal mesothelioma-Results from the International Expanded Access Program 
using pemetrexed alone or in combination with a platinum agent. Lung cancer (Amsterdam, 
Netherlands). 2009;64(2):211-8. Epub 2008/12/02 09:00. doi: 10.1016/j.lungcan.2008.08.013. 
PubMed PMID: 19042053. 
4. 
Mirarabshahii P, Pillai K, Chua TC, Pourgholami MH, Morris DL. Diffuse malignant 
peritoneal mesothelioma--an update on treatment. Cancer treatment reviews. 2012;38(6):605-12. 
Epub 2011/11/23 06:00. doi: 10.1016/j.ctrv.2011.10.006. PubMed PMID: 22104079. 
5. 
Lanphear BP, Buncher CR. Latent period for malignant mesothelioma of occupational 
origin. Journal of occupational medicine : official publication of the Industrial Medical 
Association. 1992;34(7):718-21. Epub 1992/07/01. PubMed PMID: 1494965. 
6. 
Remon J, Lianes P, Martinez S, Velasco M, Querol R, Zanui M. Malignant 
mesothelioma: new insights into a rare disease. Cancer treatment reviews. 2013;39(6):584-91. 
Epub 2013/01/02 06:00. doi: 10.1016/j.ctrv.2012.12.005. PubMed PMID: 23276688. 
7. 
van Meerbeeck JP, Scherpereel A, Surmont VF, Baas P. Malignant pleural 
mesothelioma: the standard of care and challenges for future management. Critical reviews in 
oncology/hematology. 
2011;78(2):92-111. 
Epub 
2010/05/15 
06:00. 
doi: 
10.1016/j.critrevonc.2010.04.004. PubMed PMID: 20466560. 
8. 
de Castria TB, da Silva EM, Gois AF, Riera R. Cisplatin versus carboplatin in 
combination with third-generation drugs for advanced non-small cell lung cancer. The Cochrane 
database 
of 
systematic 
reviews. 
2013;8:CD009256. 
Epub 
2013/08/21 
06:00. 
doi: 
10.1002/14651858.CD009256.pub2. PubMed PMID: 23949842. 
9. 
Rosenberg B, VanCamp L, Trosko JE, Mansour VH. Platinum compounds: a new class 
of potent antitumour agents. Nature. 1969;222(5191):385-6. Epub 1969/04/26. PubMed PMID: 
5782119. 
10. 
Bulgar A, Miao Y, Borden E, Gerson S, Liu L. Enhancement of decitabine cytotoxicity 
by methoxyamine via inhibition of base excision repair.  Proc Am Assoc Cancer Res; April 18, 
2009; Denver, CO. Philadelphia (PA): AACR; 2009. p. Abstract #5547. 
11. 
Liu L, Gerson SL. Therapeutic impact of methoxyamine: blocking repair of abasic sites 
in the base excision repair pathway. Current opinion in investigational drugs (London, England : 
2000). 2004;5(6):623-7. Epub 2004/07/10 05:00. PubMed PMID: 15242251. 
12. 
Weeks LD, Fu P, Gerson SL. Uracil-DNA glycosylase expression determines human 
lung cancer cell sensitivity to pemetrexed. Molecular cancer therapeutics. 2013;12(10):2248-60. 
Epub 2013/07/23 06:00. doi: 10.1158/1535-7163.MCT-13-0172. PubMed PMID: 23873851. 
13. 
Bulgar AD, Weeks LD, Miao Y, Yang S, Xu Y, Guo C, et al. Removal of uracil by 
uracil DNA glycosylase limits pemetrexed cytotoxicity: overriding the limit with methoxyamine 
to inhibit base excision repair. Cell death & disease. 2012;3:e252. Epub 2012/01/13 06:00. doi: 

NCI Protocol #: 9837; PhI-76 
Version Date: March 7, 2019 
 
68 
10.1038/cddis.2011.135. PubMed PMID: 22237209; PubMed Central PMCID: PMC3270269. 
14. 
Weeks LD, Zentner GE, Scacheri PC, Gerson SL. Uracil DNA glycosylase (UNG) loss 
enhances DNA double strand break formation in human cancer cells exposed to pemetrexed. Cell 
death & disease. 2014;5:e1045. Epub 2014/02/08 06:00. doi: 10.1038/cddis.2013.477. PubMed 
PMID: 24503537; PubMed Central PMCID: PMC3944228. 
15. 
Damia G, D'Incalci M. Targeting DNA repair as a promising approach in cancer 
therapy. European journal of cancer (Oxford, England : 1990). 2007;43(12):1791-801. Epub 
2007/06/26 09:00. doi: 10.1016/j.ejca.2007.05.003. PubMed PMID: 17588740. 
16. 
Madhusudan S, Hickson ID. DNA repair inhibition: a selective tumour targeting 
strategy. Trends in molecular medicine. 2005;11(11):503-11. Epub 2005/10/11 09:00. doi: 
10.1016/j.molmed.2005.09.004. PubMed PMID: 16214418. 
17. 
De Silva IU, McHugh PJ, Clingen PH, Hartley JA. Defects in interstrand cross-link 
uncoupling do not account for the extreme sensitivity of ERCC1 and XPF cells to cisplatin. Nucleic 
Acids Res. 2002;30(17):3848-56. Epub 2002/08/31 10:00. PubMed PMID: 12202770; PubMed 
Central PMCID: PMC137407. 
18. 
Wood RD. Mammalian nucleotide excision repair proteins and interstrand crosslink 
repair. Environ Mol Mutagen. 2010;51(6):520-6. Epub 2010/07/27 06:00. doi: 10.1002/em.20569. 
PubMed PMID: 20658645; PubMed Central PMCID: PMC3017513. 
19. 
Enoiu M, Jiricny J, Scharer OD. Repair of cisplatin-induced DNA interstrand 
crosslinks by a replication-independent pathway involving transcription-coupled repair and 
translesion synthesis. Nucleic Acids Res. 2012;40(18):8953-64. Epub 2012/07/20 06:00. doi: 
10.1093/nar/gks670. PubMed PMID: 22810206; PubMed Central PMCID: PMC3467066. 
20. 
Bonanno L, Favaretto A, Rosell R. Platinum drugs and DNA repair mechanisms in 
lung cancer. Anticancer research. 2014;34(1):493-501. Epub 2014/01/10 06:00. PubMed PMID: 
24403507. 
21. 
Rodrigues AS, Gomes BC, Martins C, Gromicho M, Oliveira NG, Guerreiro PS, et al. 
DNA repair and resistance to cancer therapy.  New Research Directions in DNA Repair. Rijeka: 
InTech; 2013. p. 489-528. 
22. 
Bulgar A, Miao Y, Gerson S, Liu L. Dual inhibition of BER by TRC102 and PARP 
inhibitor (ABT 888) synergistically enhances cytotoxicity of TMZ in human melanoma Proc Am 
Assoc Cancer Res; Apr 17-21; Washington, DC. Philadelphia (PA): AACR; 2010. p. Abstract 
#682. 
23. 
Bulgar AD, Snell M, Donze JR, Kirkland EB, Li L, Yang S, et al. Targeting base 
excision repair suggests a new therapeutic strategy of fludarabine for the treatment of chronic 
lymphocytic leukemia. Leukemia. 2010;24(10):1795-9. Epub 2010/09/03 06:00. doi: 
10.1038/leu.2010.166. PubMed PMID: 20811400. 
24. 
Liu L, Yan L, Donze JR, Gerson SL. Blockage of abasic site repair enhances antitumor 
efficacy of 1,3-bis-(2-chloroethyl)-1-nitrosourea in colon tumor xenografts. Molecular cancer 
therapeutics. 2003;2(10):1061-6. Epub 2003/10/28 05:00. PubMed PMID: 14578471. 
25. 
Montaldi AP, Pezuk JA, Sakamoto-Hojo ET, Tone LG, Brassesco MS. Base Excision 
Repair Inhibition by Methoxyamine Impairs Growth and Sensitizes Osteosarcoma Cells to 
Conventional Treatments. Journal of Cancer Therapy. 2014;2014. 
26. 
Weeks L, Bulgar A, Donze J, Miao Y, Liu L, Gerson S. Induction of uracil DNA 
glycosylase (UDG) in human cancer cells in response to antimetabolites combined with 
methoxyamine.  Proc Am Assoc Cancer Res; April 18 Denver, CO. Philadelphia (PA): AACR; 
2009. p. Abstract #3765:. 

NCI Protocol #: 9837; PhI-76 
Version Date: March 7, 2019 
 
69 
27. 
Yan L, Bulgar A, Miao Y, Mahajan V, Donze JR, Gerson SL, et al. Combined treatment 
with temozolomide and methoxyamine: blocking apurininc/pyrimidinic site repair coupled with 
targeting topoisomerase IIalpha. Clinical cancer research : an official journal of the American 
Association for Cancer Research. 2007;13(5):1532-9. Epub 2007/03/03 09:00. doi: 10.1158/1078-
0432.CCR-06-1595. PubMed PMID: 17332299. 
28. 
Liu L, Bulgar A, Adams B, Theuer C, Leigh B, Gerson S. Combining pemetrexed with 
temozolomide and TRC102 (methoxyamine) causes synergistic cytotoxicity in melanoma cells. 
EJC 
Suppl. 
2010;8(7):165-. 
doi: 
10.1016/s1359-6349(10)72224-2. 
PubMed 
PMID: 
WOS:000288460100509. 
29. 
Liu L, Nakatsuru Y, Gerson SL. Base excision repair as a therapeutic target in colon 
cancer. Clinical cancer research : an official journal of the American Association for Cancer 
Research. 2002;8(9):2985-91. Epub 2002/09/17 10:00. PubMed PMID: 12231545. 
30. 
Liuzzi M, Talpaert-Borle M. A new approach to the study of the base-excision repair 
pathway using methoxyamine. The Journal of biological chemistry. 1985;260(9):5252-8. Epub 
1985/05/10. PubMed PMID: 2580833. 
31. 
Talpaert-Borle M, Liuzzi M. Reaction of apurinic/apyrimidinic sites with 
[14C]methoxyamine. A method for the quantitative assay of AP sites in DNA. Biochimica et 
biophysica acta. 1983;740(4):410-6. Epub 1983/09/09. PubMed PMID: 6349690. 
32. 
Rosa S, Fortini P, Karran P, Bignami M, Dogliotti E. Processing in vitro of an abasic 
site reacted with methoxyamine: a new assay for the detection of abasic sites formed in vivo. 
Nucleic Acids Res. 1991;19(20):5569-74. Epub 1991/10/25. PubMed PMID: 1719478; PubMed 
Central PMCID: PMC328958. 
33. 
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. Clinical cancer research : an official journal of the American Association for 
Cancer Research. 1999;5(10):2908-17. Epub 1999/10/28. PubMed PMID: 10537360. 
34. 
Horton JK, Prasad R, Hou E, Wilson SH. Protection against methylation-induced 
cytotoxicity by DNA polymerase beta-dependent long patch base excision repair. The Journal of 
biological chemistry. 2000;275(3):2211-8. Epub 2000/01/15 09:00. PubMed PMID: 10636928. 
35. 
Liu L, Bulgar A, Donze J, Adams B, Theuer C, Gerson S. Prevention of base excision 
repair by TRC102 (methoxyamine) potentiates the antitumor activity of pemetrexed in vitro and 
in vivo.  AACR-NCI-EORTC International Conference: Molecular Targets and Cancer 
Therapeutics; October 22-26; San Francisco, CA: AACR; 2007. p. Abstract #292. 
36. 
Gordon MS, Rosen LS, Mendelson D, Ramanathan RK, Goldman J, Liu L, 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(3):714-23. Epub 2012/10/12 06:00. doi: 
10.1007/s10637-012-9876-9. PubMed PMID: 23054206. 
37. 
Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. 
Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with 
malignant pleural mesothelioma. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology. 2003;21(14):2636-44. Epub 2003/07/16 05:00. doi: 
10.1200/JCO.2003.11.136. PubMed PMID: 12860938. 
38. 
Hassan R, Jahan TM, Kindler HL, Bazhenova L, Reck M, Pastan I, et al. Amatuximab, 
a chimeric monoclonal antibody to mesothelin, in combination with pemetrexed and cisplatin in 
patients with unresectable pleural mesothelioma: Results of a multicenter phase II clinical trial.  
2012 ASCO Annual Meeting2012. p. Abstract #7030. 

NCI Protocol #: 9837; PhI-76 
Version Date: March 7, 2019 
 
70 
39. 
Kindler HL, Karrison TG, Gandara DR, Lu C, Krug LM, Stevenson JP, et al. 
Multicenter, double-blind, placebo-controlled, randomized phase II trial of gemcitabine/cisplatin 
plus bevacizumab or placebo in patients with malignant mesothelioma. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology. 2012;30(20):2509-15. 
Epub 2012/06/06 06:00. doi: 10.1200/JCO.2011.41.5869. PubMed PMID: 22665541; PubMed 
Central PMCID: PMC3397785. 
40. 
Krug LM, Wozniak AJ, Kindler HL, Feld R, Koczywas MN, Morero JL, et al. 
Randomized phase II trial of pemetrexed/cisplatin with or without CBP501 in patients with 
advanced malignant pleural mesothelioma (MPM).  2012 ASCO Annual Meeting2012. p. Abstract  
#7029. 
41. 
Dickgreber NJ, Fink TH, Latz JE, Hossain AM, Musib LC, Thomas M. Phase I and 
pharmacokinetic study of pemetrexed plus cisplatin in chemonaive patients with locally advanced 
or metastatic malignant pleural mesothelioma or non-small cell lung cancer. Clinical cancer 
research : an official journal of the American Association for Cancer Research. 2009;15(1):382-9. 
Epub 2009/01/02 09:00. doi: 10.1158/1078-0432.CCR-08-0128. PubMed PMID: 19118069. 
42. 
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. Journal of 
chromatography B, Analytical technologies in the biomedical and life sciences. 2012;901:25-33. 
Epub 2012/06/30 06:00. doi: 10.1016/j.jchromb.2012.05.036. PubMed PMID: 22743337. 
43. 
Synold TW, Takimoto CH, Doroshow JH, Gandara D, Mani S, Remick SC, et al. Dose-
escalating and pharmacologic study of oxaliplatin in adult cancer patients with impaired hepatic 
function: a National Cancer Institute Organ Dysfunction Working Group study. Clinical cancer 
research : an official journal of the American Association for Cancer Research. 2007;13(12):3660-
6. Epub 2007/06/19 09:00. doi: 10.1158/1078-0432.CCR-06-2385. PubMed PMID: 17575231. 
44. 
de Reynies A, Jaurand MC, Renier A, Couchy G, Hysi I, Elarouci N, et al. Molecular 
classification of malignant pleural mesothelioma: identification of a poor prognosis subgroup 
linked to the epithelial-to-mesenchymal transition. Clinical cancer research : an official journal of 
the American Association for Cancer Research. 2014;20(5):1323-34. Epub 2014/01/21 06:00. doi: 
10.1158/1078-0432.CCR-13-2429. PubMed PMID: 24443521. 
45. 
Daubriac J, Fleury-Feith J, Kheuang L, Galipon J, Saint-Albin A, Renier A, et al. 
Malignant pleural mesothelioma cells resist anoikis as quiescent pluricellular aggregates. Cell 
death and differentiation. 2009;16(8):1146-55. Epub 2009/04/04 09:00. doi: 10.1038/cdd.2009.32. 
PubMed PMID: 19343038. 
46. 
Ishiwata I, Ishiwata E, Hirano T. Establishment of a human malignant fibrous 
mesothelioma cell line and the biological characteristics compared with malignant epithelial 
mesothelioma cell line. Human cell. 2008;21(3):79-87. Epub 2008/08/01 09:00. doi: 
10.1111/j.1749-0774.2008.00053.x. PubMed PMID: 18667024. 
47. 
Zhang J, Qiu S, Zhang Y, Merino M, Fetsch P, Avital I, et al. Loss of mesothelin 
expression by mesothelioma cells grown in vitro determines sensitivity to anti-mesothelin 
immunotoxin SS1P. Anticancer research. 2012;32(12):5151-8. Epub 2012/12/12 06:00. PubMed 
PMID: 23225411. 
48. 
Klominek J, Robert KH, Hjerpe A, Wickstrom B, Gahrton G. Serum-dependent growth 
patterns of two, newly established human mesothelioma cell lines. Cancer Res. 1989;49(21):6118-
22. Epub 1989/11/01. PubMed PMID: 2790824. 
49. 
Zeng L, Fleury-Feith J, Monnet I, Boutin C, Bignon J, Jaurand MC. 
Immunocytochemical characterization of cell lines from human malignant mesothelioma: 

NCI Protocol #: 9837; PhI-76 
Version Date: March 7, 2019 
 
71 
characterization of human mesothelioma cell lines by immunocytochemistry with a panel of 
monoclonal antibodies. Hum Pathol. 1994;25(3):227-34. Epub 1994/03/01. PubMed PMID: 
7512071. 
50. 
Clark CC, Weitzel JN, O'Connor TR. Enhancement of synthetic lethality via 
combinations of ABT-888, a PARP inhibitor, and carboplatin in vitro and in vivo using BRCA1 
and BRCA2 isogenic models. Molecular cancer therapeutics. 2012;11(9):1948-58. Epub 
2012/07/11 06:00. doi: 10.1158/1535-7163.MCT-11-0597. PubMed PMID: 22778154; PubMed 
Central PMCID: PMC3551628. 
51. 
Chou TC. Theoretical basis, experimental design, and computerized simulation of 
synergism and antagonism in drug combination studies. Pharmacological reviews. 
2006;58(3):621-81. Epub 2006/09/14 09:00. doi: 10.1124/pr.58.3.10. PubMed PMID: 16968952. 
52. 
Nakamura J, Walker VE, Upton PB, Chiang SY, Kow YW, Swenberg JA. Highly 
sensitive apurinic/apyrimidinic site assay can detect spontaneous and chemically induced 
depurination under physiological conditions. Cancer Res. 1998;58(2):222-5. Epub 1998/01/27. 
PubMed PMID: 9443396. 
53. 
Liedert B, Pluim D, Schellens J, Thomale J. Adduct-specific monoclonal antibodies for 
the measurement of cisplatin-induced DNA lesions in individual cell nuclei. Nucleic Acids Res. 
2006;34(6):e47. Epub 2006/03/31 09:00. doi: 10.1093/nar/gkl051. PubMed PMID: 16571898; 
PubMed Central PMCID: PMC1420801. 
54. 
Olaussen KA, Adam J, Vanhecke E, Vielh P, Pirker R, Friboulet L, et al. PARP1 impact 
on DNA repair of platinum adducts: preclinical and clinical read-outs. Lung cancer (Amsterdam, 
Netherlands). 2013;80(2):216-22. Epub 2013/02/16 06:00. doi: 10.1016/j.lungcan.2013.01.014. 
PubMed PMID: 23410825. 
55. 
Tilby MJ, Johnson C, Knox RJ, Cordell J, Roberts JJ, Dean CJ. Sensitive detection of 
DNA modifications induced by cisplatin and carboplatin in vitro and in vivo using a monoclonal 
antibody. Cancer Res. 1991;51(1):123-9. Epub 1991/01/01. PubMed PMID: 1703029. 
56.   
 
Sato, A., I. Torii, et al. (2010). "Immunocytochemistry of CD146 is useful to 
discriminate between malignant pleural mesothelioma and reactive mesothelium." Mod Pathol 
23(11): 1458-1466. 
57.  
 
Byrne, M. J. and A. K. Nowak (2004). "Modified RECIST criteria for assessment of 
response in malignant pleural mesothelioma." Ann Oncol 15(2): 257-260. 
 
 

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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 

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APPENDIX B 
INFORMATION ON POSSIBLE DRUG INTERACTIONS 
 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team 
 
Not Applicable: No studies have been performed to assess potential metabolic and transport 
interactions of TRC102.  Because there is a potential for interaction of TRC102 with other 
concomitantly administered drugs, the case report form must capture the concurrent use of all 
other drugs, over-the-counter medications, or alternative therapies.  The Principal Investigator 
should be alerted if a drug-drug interaction is a suspected component of an adverse event. 
 
 
 
INFORMATION ON POSSIBLE DRUG 
INTERACTIONS  
You are enrolled on a clinical trial using the experimental agent 
TRC102 (NSC 3801).  This clinical trial is sponsored by the 
NCI.  There is no information on how TRC102 interacts with drugs 
that are processed by your liver.  Because of this, it is very important 
to: 
 
➢ 
Tell your doctors if you stop taking regular medicine or if 
you start taking a new medicine. 
➢ 
Tell all of your prescribers (doctor, physicians’ assistant, 
nurse practitioner, pharmacist) that you are taking part in a 
clinical trial
 
➢ Your study doctor’s name is _____________________________ 
and can be contacted at_________________________________.  

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APPENDIX C        NOT APPLICABLE  
 
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APPENDIX D        PATIENT MEDICATION DIARY 
 
 
 
Today’s date _____________________        Cycle Number: __________        Agent:  TRC102 
 
Patient Name_____________________(initials acceptable)  
             
 
Patient Study ID ________________________ 
 
 
INSTRUCTIONS TO THE PATIENT: 
 
1. Complete one form for each cycle of treatment. 
2. You will take TRC102 capsules by mouth for the first four days of each cycle.  Capsules 
are taken in the morning after you have fasted for at least two hours.  Take with 8 ounces of 
water.  Capsules should be swallowed whole, do not chew or crush.  You should refrain from 
eating or drinking for one hour following TRC102 dosing.  Dose:  take ________ 25 mg 
capsules.  If you miss a dose (do not take it within 6 hours of scheduled time), skip the dose 
and resume taking TRC 102 at the next scheduled time. 
4. Record the date, the number of capsules that you took, and when you took them.   
5. If you have any comments or notice any side effects, please record them in the Comments 
column.   
6. Please bring this form and your bottles of TRC102 capsules when you return for each 
appointment. 
7.    Please store TRC 102 capsules in the refrigerator. 
 
 
Day 
 
Date 
 
Time of 
dose  
TRC102 
 # of capsules 
taken 
Comments 
25 mg 
 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
 
 
 
Patient’s signature _____________________________________________________________ 
 
 
   Physician’s Office will complete this section: 
1. Date patient started protocol treatment______________      
2. Date patient was removed from study_______________ 
3. Patient’s planned total daily dose
 ___________________________________________________________________________  
3. Total number of capsules taken this month of TRC102_________________   
 
CTEP-assigned Protocol # 9837 
Consortium Protocol PhI-76 
Local Protocol # ___________________ 

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76 
4. Physician/Nurse/Data Manager’s Signature 
 ___________________________________________________________________________  
 
 
 
APPENDIX E        SPECIMEN COLLECTION FORM FOR PHARMACODYNAMIC 
STUDIES NCI PROTOCOL #9837, PHI-76 
 
 
Title:  Phase I Study of TRC102 in Combination with Cisplatin and Pemetrexed in Patients with 
Advanced Solid Tumors / Phase II Study of TRC102 with Pemetrexed in Patients Refractory to Cisplatin 
and Pemetrexed  
 
Patient's Name_______________  __________________Patient Accession #  ______ ______ ______ 
 
                       (first)                          (last) 
Study Site  ___________________ 
 
 
TRC102 Dose   __________ mg/dose 
Start Date/time 
________________________ 
 
Sample Type (Check one) 
 
 
Plural Effusion (City of Hope Only – See Section 9.2.1) 
[  ] 
 
 
Peritoneal Effusion (City of Hope Only – See Section 9.2.1) 
[  ] 
 
 
Peripheral Blood for Buffy Coat/PBMCs (All Sites – See Section 9.2.3.1) 
[  ] 
[12 mL of blood collected in Sodium Heparin or Lithium Heparin green-top tubes (3 4-ml 
vacutainer tubes, BD Cat. # 367884 or equivalent; OR 2 6-ml vacutainer tubes, BD Cat. #367886  
or equivalent)] 
 
 
 
 
Sample Acquisition 
Date and Time 
________________________ 
 
Sample Processing Started 
Start Date and Time 
________________________ 
 
Shipping Date Date 
________________________ 
 
 
-SHIPPING INFORMATION ON APPENDIX E PAGE 2- 

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77 
APPENDIX E – Page 2 
SPECIMEN COLLECTION FORM FOR PHARMACODYNAMIC STUDIES 
NCI Protocol #9837, PHI-76  
 
Shipping information: 
 
Plural Effusion or Peritoneal Effusion (City of Hope Only): 
 
Samples will be transported to Dr. O’Connor’s laboratory in the Gonda Bldg, Rm 4131A. The 
day prior to the procedure, please contact Dr. O’Connor at x68220 and/or Ms. Yesenia Thompson 
at x63696. 
 
Peripheral Blood for Buffy Coat/PBMCs (All Sites): 
 
Dr. Timothy Synold 
Shapiro Building Room 1042 
City of Hope National Medical Center 
1500 E. Duarte Rd. 
Duarte, CA  91010 
Phone (626) 256-4673, ext. 62110 
Fax – (626) 471-9376 
Email – tsynold@coh.org