Conditions: Recurrent Glioblastoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 24
Healthy volunteers: no

Brief summary:
This phase II trial studies how well HIF-2 alpha inhibitor PT2385 works in treating patients with recurrent glioblastoma. HIF-2 alpha inhibitor PT2385 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the efficacy of hypoxia inducible factor (HIF)-2 alpha inhibitor PT2385 (PT2385) as measured by radiographic response rate (by Response Assessment in Neuro-Oncology, RANO, criteria) in patients with recurrent glioblastoma.

SECONDARY OBJECTIVES:

I. To estimate the efficacy of PT2385 as measured by progression free and overall survival in patients with recurrent glioblastoma.

II. To determine the safety of oral PT2385 in patients with recurrent glioblastoma.

TERTIARY OBJECTIVES:

I. To describe the pharmacokinetic and pharmacodynamic properties of PT2385 in patients with recurrent glioblastoma.

II. To describe baseline intratumoral hypoxia using novel, advanced magnetic resonance (MR)-based neuroimaging sequences in patients with recurrent glioblastoma.

III. To explore genetic polymorphisms involved in the metabolism of PT2385.

OUTLINE:

Patients receive HIF-2 alpha inhibitor PT2385 orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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

Arms:
arm 1: Patients receive HIF-2 alpha inhibitor PT2385 PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Pharmacological Study

Laboratory Biomarker Analysis

Pharmacogenomic Study

Interventions: intervention 1: HIF-2alpha Inhibitor PT2385 intervention 2: Pharmacological Study intervention 3: Laboratory Biomarker Analysis intervention 4: Pharmacogenomic Study
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Correlative studies intervention 4: Correlative studies

Protocol document:
Prot_SAP_000.pdf: 
Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
ABTC # 1602  
NCI # ABTC-1602  
PI: R. Strowd  
  
1  
 
  
03/07/18  
NCT03216499    
  
  
  
  
                                           ABTC #: 1602  
 
  
  
  
  
  
  
  
  
  
NCI #: ABTC-1602  
   
  
  
  
  
  
  
  
  
              
  
   
Version Date – 03/07/18  
Previous Version Date: 02/03/17, 05/24/17  
  
Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha 
Inhibitor, PT2385, for Patients with Recurrent Glioblastoma  
  
A Protocol of the Adult Brain Tumor Consortium (ABTC)   
  
Coordinating Center: ABTC Central Operations Office,  
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins   
  
Study Chair  
Roy E. Strowd, III, MD  
Wake Forest University  
  
Department of Neurology  
Medical Center Boulevard  
Wake Forest Baptist Medical Center    
Winston Salem, NC, 27157  
Phone: 336-716-7548   
Fax: 336-716-7794  
Email: rstrowd@wakehealth.edu  
Biostatistician  
Xiaobu Ye, MD, MS  
Johns Hopkins University  
600 N. Wolfe Street/ Meyer 8-181D  
Baltimore, MD 21287  
Phone: 410-614-6261  
Email: xye3@jhmi.edu  
 
  
  
Imaging Chair  
Benjamin M. Ellingson, PhD  
University of California Los Angeles  
924 Westwood Blvd,  Suite 615  
Los Angeles, CA 90024  
Phone: 310-481-7572  
Email: bellingson@mednet.ucla.edu  
  
  
  
  
Investigational Agents: PT2385,   
NSC #: 790866; IND #: 135032; NCT#: 03216499   
IND Protocol Sponsor: Roy E. Strowd, III, MD, Adult Brain Tumor Consortium, Wake Forest 
University  
Other Sponsors: Peloton Therapeutics, CTEP/DCTD/NCI  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
ABTC # 1602  
NCI # ABTC-1602  
PI: R. Strowd  
  
2  
 
  
03/07/18  
  
 
  
Version  
  
  
  
PARTICIPATING INVESTIGATORS:   
Adult Brain Tumor Consortium participating members  
  
Nursing Contact  
Ashley Renee Carroll, RN, BSN  
  
Wake Forest University  
  
Phone: 336-713-3539  
Fax: 336-713-5445  
  
  
  
Email: arcarrol@wakehealth.edu  
  
Pharmacy Contact  
Anne Delisa, PharmD, BCOP  
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins  
Phone: 410-502-1036  
Email: adelisa@jhmi.edu  
  
  
ABTC Manager  
  
Joy Fisher  
Johns Hopkins University  
Phone: 410-955-3657  
Email: jfisher@jhmi.edu  
  
ABTC Data Coordinator Serena 
Desideri, MD  
Johns Hopkins University  
Phone: 410-614-4400  
Email: sdeside1@jhmi.edu  
  
Protocol Development  
Coordinator  
Megan Sims  
Johns Hopkins University  
Phone: 410-614-3086  
Email: msims3@jhmi.edu  
  
ABTC Database  
Coordinator  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
ABTC # 1602  
NCI # ABTC-1602  
PI: R. Strowd  
  
3  
 
  
  
Version 03/07/18  
  
Jason Zhao  
Johns Hopkins University  
Phone: 410-502-9997  
Email: jzhao8@jhmi.edu  
  
  
  
 
  
Version  
  
TABLE OF CONTENTS  
TABLE OF CONTENTS .............................................................................................................................................. 3 
1.0  OBJECTIVES ......................................................................................................................................................... 5 
2.0  BACKGROUND AND RATIONALE .................................................................................................................. 5 
2.1  GLIOBLASTOMA ........................................................................................................................................................ 5 
2.2   PT2385 .................................................................................................................................................................... 6 
2.3  RATIONALE ............................................................................................................................................................... 9 
2.4  CORRELATIVE STUDIES BACKGROUND ................................................................................................................... 10 
3.0  PATIENT ELIGIBILITY CRITERIA ............................................................................................................... 13 
3.1  PATIENT SAMPLE .................................................................................................................................................... 13 
3.2  ELIGIBILITY CRITERIA ............................................................................................................................................. 14 
3.3  INELIGIBILITY CRITERIA ......................................................................................................................................... 16 
4.0  TREATMENT PLAN .......................................................................................................................................... 17 
4.1  TREATMENT SCHEMA .............................................................................................................................................. 17 
4.2  TREATMENT REQUIREMENTS .................................................................................................................................. 18 
4.3  DRUG ADMINISTRATION ......................................................................................................................................... 18 
4.4  GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ........................................................ 19 
5.0  DOSING DELAYS/DOSE MODIFICATION FOR TOXICITY ..................................................................... 20 
5.1  DOSE MODIFICATION FOR PT2385 .......................................................................................................................... 21 
5.2 MAJOR EVENTS ........................................................................................................................................................ 22 
5.3 USE OF HEMATOLOGIC GROWTH FACTORS .............................................................................................................. 22 
5.4  TOXICITY CRITERIA ................................................................................................................................................ 22 
6.0  PHARMACEUTICAL INFORMATION .......................................................................................................... 22 
6.1   AGENT ORDERING .................................................................................................................................................. 23 
6.2   AGENT ACCOUNTABILITY ...................................................................................................................................... 24 
7.0  PROCEDURES FOR PATIENT ENTRY ON STUDY .................................................................................... 24 
8.0  RESPONSE ASSESSMENT / SAFETY AND QUALITY ASSURANCE ...................................................... 26 


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
ABTC # 1602  
NCI # ABTC-1602  
PI: R. Strowd  
  
4  
 
  
03/07/18  
8.1 CRITERIA FOR RESPONSE ASSESSMENT .................................................................................................................... 26 
8.2 ASSESSMENT OF RESPONSE ...................................................................................................................................... 28 
8.3 SAFETY ASSESSMENTS ............................................................................................................................................. 28 
8.4  QUALITY ASSURANCE ............................................................................................................................................. 28 
9.0  MONITORING OF PATIENTS ......................................................................................................................... 29 
9.1  TABLE OF REQUIRED OBSERVATIONS ..................................................................................................................... 29 
9.2  ADVERSE EVENTS: LISTS AND REPORTING REQUIREMENTS .................................................................................... 30 
9.2.1  Adverse Events and Potential Risks ............................................................................................................. 31 
9.2.2  Adverse Event Characteristics..................................................................................................................... 35 
9.3  SERIOUS ADVERSE EVENTS AND EXPEDITED ADVERSE EVENT REPORTING ........................................................... 36 
9.3.1  Definition – Serious Adverse Event (SAE) ................................................................................................... 36 
9.3.2  Expedited Adverse Event Reporting ............................................................................................................ 36 
9.3.3  Other SAE Reporting ................................................................................................................................... 37 
9.4  ROUTINE ADVERSE EVENT REPORTING .................................................................................................................. 38 
9.5  CORRELATIVE STUDIES ........................................................................................................................................... 39 
9.5.1 Pharmacokinetic Assessment (All Patients) ................................................................................................. 39 
9.5.2 Pharmacodynamics and Laboratory Biomarkers (All Patients) .................................................................. 39 
9.5.3 Pharmacogenomic Assessment (All Patients) .............................................................................................. 40 
9.5.4  Exploratory pH and Hypoxia MRI (All Patients at Select Sites) ................................................................. 40 
9.5.5  Archival Tumor Tissue for IDH1 Mutational Status and HIF Expression (All Patients) ............................ 41 
10.0    OFF TREATMENT/OFF STUDY CRITERIA ............................................................................................. 42 
10.1  OFF TREATMENT CRITERIA ................................................................................................................................... 42 
10.2  OFF STUDY CRITERIA ............................................................................................................................................ 43 
11.0   STATISTICAL CONSIDERATIONS ............................................................................................................. 43 
12.0   STUDY ADMINISTRATION .......................................................................................................................... 47 
12.1  INVESTIGATOR’S STUDY FILE ............................................................................................................................... 47 
12.2  SOURCE DATA/DOCUMENTS ................................................................................................................................. 47 
12.3  DOCUMENT RETENTION AND ARCHIVING ............................................................................................................. 47 
12.4   DATA COLLECTION/REPORTING ........................................................................................................................... 47 
12.5  STUDY MONITORING ............................................................................................................................................. 48 
12.6  AUDITS AND INSPECTIONS..................................................................................................................................... 49 
13.0  REFERENCES ................................................................................................................................................... 49 
14.0  ETHICAL AND LEGAL CONSIDERATIONS .............................................................................................. 51 
APPENDIX I – PATIENT MEDICATION DIARY ................................................................................................ 52 
APPENDIX II – PARTIAL LIST OF STRONG CYP2C19 AND CYP3A4 INHIBITORS ................................. 54 
APPENDIX III – PARTIAL LIST OF SUBSTRATES OF CYP3A4, CYP2B6, CYP2C9, AND CYP2C19 ....... 55 
APPENDIX IV – PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD .............................. 56 
 


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
ABTC # 1602  
NCI # ABTC-1602  
PI: R. Strowd  
  
5  
 
  
  
Version 03/07/18  
  
  
  
    
 
1.0  
OBJECTIVES   
  
Primary Objective  
  
To estimate the efficacy of PT2385 as measured by radiographic response rate (by 
Response Assessment in Neuro-Oncology, RANO, criteria) in patients with recurrent 
glioblastoma  
    
  
Secondary Objectives  
  
1. To estimate the efficacy of PT2385 as measured by progression free and overall 
survival in patients with recurrent glioblastoma  
   
2. To determine the safety of oral PT2385 in patients with recurrent glioblastoma  
   
Exploratory Objectives  
  
1. To describe the pharmacokinetic and pharmacodynamic properties of PT2385 in 
patients with recurrent glioblastoma  
  
2. To describe baseline intratumoral hypoxia using novel, advanced MR-based 
neuroimaging sequences in patients with recurrent glioblastoma  
  
3. To explore genetic polymorphisms involved in the metabolism of PT2385  
  
    
 
2.0  
BACKGROUND AND RATIONALE  
  
 
2.1  
Glioblastoma  
  
Although the recent addition of temozolomide (TMZ) to radiation therapy for the 
treatment of glioblastoma (GBM) has resulted in improved outcomes, the estimated 2year 
survival with maximal therapy remains only 27% (Stupp, et al., 2005; Stupp, et al., 2009). 
Almost all GBMs progress, with a median time to progression of approximately 7 
months. The prognosis is very poor for patients who have progressive/recurrent GBM. 
There is currently no standard therapy for recurrence. Salvage chemotherapies are largely 
ineffective, with progression-free survival at 6 months (PFS6) rates of 10-15%.  
Bevacizumab therapy at recurrence is associated with a high response rate, but not 


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
ABTC # 1602  
NCI # ABTC-1602  
PI: R. Strowd  
  
6  
 
  
  
Version 03/07/18  
  
significantly increased survival. Survival after failure of bevacizumab administered for 
GBM recurrence is very poor with a median survival of 4-6 months and PFS 6 of 0 
(Reardon, et al., 2012). Hence, new therapies for recurrent GBM are urgently needed.  
  
Hypoxia is a prominent feature of the tumor microenvironment in GBM.  
Pseudopallisading necrosis, one of the defining histologic characteristics of GBM, 
represents hypoxic tumor cells migrating away from dysfunctional vasculature (Rong, 
Durden, Van Meir, & Brat, 2006). This hypoxic environment promotes the self-renewal 
properties of glioma stem cells (GSCs) and may even drive non-stem cells toward a 
stemlike phenotype (Heddleston, Li, Hjelmeland, & Rich, 2009). Furthermore, hypoxia 
has been implicated as a potential mechanism of resistance to radiation therapy, a critical 
aspect of GBM treatment. However, to date few therapeutic agents have been developed 
which successfully modulate hypoxia pathways and improve outcomes in GBM.  
  
 
2.2   
PT2385  
  
Rationale for the Therapeutic Target and Pathway  
Several biochemical pathways mediate the cellular effects of hypoxia. Most importantly 
are the roles of the hypoxia inducible factors (HIFs). While HIF1-alpha (HIF1a) has been 
perhaps most widely studied in a variety of cancer models, HIF2a is potentially a more 
appealing target in GBM. HIF2a drives expression of numerous genes involved in 
angiogenesis (i.e. VEGFA), proliferation (i.e. cyclin D1), cell survival (e.g. class III 
betatubulin), and immune evasion (i.e. CD73). In contrast to HIF1a which is expressed in 
both GSCs and normal neural progenitors, HIF2a is specific and selective for GSCs (Li et 
al., 2009). In fact, the effects of hypoxia on the GSC phenotype has been shown to be 
directly mediated by HIF2a (Seidel et al., 2010). Dual labeling immunofluorescence studies 
show that HIF2a is co-expressed in cells expressing stem-cell markers (i.e. CD133) in 
perivascular locations and around areas of necrosis (Li et al., 2009). Furthermore, HIF2a 
and not HIF1a has been shown to regulate genes involved in mediating hypoxia-induced 
stemness (i.e. MAML3, NFATc2), promoting CD133 expression, and increasing 
neurosphere formation (Seidel et al., 2010). HIF2a is associated with CDH5-mediated 
neovasculogenesis in stem cell populations (Mao, Xue, Wang, Zhang, & Yan, 2013). 
HIF2a has been linked to over-expression of class III beta-tubulin, a survival factor that 
rescues cells from programmed cell death and has been linked to chemoresistance (Bordji, 
Grandval, Cuhna-Alves, Lechapt-Zalcman, & Bernaudin, 2014), aggressiveness (Katsetos, 
Dráberová, Legido, Dumontet, & Dráber, 2009), and poor prognosis (Ferrandina et al., 
2006; Zhang et al., 2012). In conclusion, targeting HIF2a represents an opportunity to focus 
on a fundamental component of GBM (e.g. hypoxia) and potentially target the stem-like 
cell population which is purported to contribute to glioma heterogeneity, resistance to 
current therapies, and disease recurrence.  
   


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
ABTC # 1602  
NCI # ABTC-1602  
PI: R. Strowd  
  
7  
 
  
  
Version 03/07/18  
  
Preclinical Data in GBM  
PT2385 is a first-in-class, orally administered 
potent and selective small molecule (383.34 
Da) inhibitor of HIF2a. PT2385 has been 
shown to inhibit HIF2a-mediated signaling by 
disrupting the formation of the HIF2a:ARNT 
heterodimer in cells. Thus, in tumors where 
HIF2a is activated, PT2385 blocks the 
transcription of several genes involved in 
oncogenesis, including angiogenesis (e.g. 
VEGFA), proliferation (e.g. cyclin D1), 
immune evasion (e.g. CD73), metabolism 
(e.g. glucose transporter 1), and cell survival 
(e.g. class III beta-tubulin) (Chen et al., 2016; 
Wallace et al., 2016).  
  
PT2385 is a first-of-its-kind agent and is unlike anti-VEGF or other existing targeted 
agents. Its mechanism of action is well upstream of existing anti-VEGF agents with more 
widespread cellular actions. Unlike anti-VEGF agents, PT2385 has no effect on rat blood 
pressure or heart rate at 5-times maximal efficacious exposure supporting its unique 
cellular action at the level of HIF2a. This activity translates to anti-tumor efficacy in mouse 
xenograft models of GBM (Table 1).   
  
 


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
ABTC # 1602  
NCI # ABTC-1602  
PI: R. Strowd  
  
8  
 
  
  
Version 03/07/18  
  
PT2399, a close structural analog of PT2385 with comparable brain uptake and the tool 
molecule used by external collaborators for preclinical testing, was evaluated in 4 
orthotopic patient-derived xenograft 
(PDX) models of GBM. Survival 
benefit was observed in 3 of 4 
models tested (Table 1, Figure 1a & 
1b) 
with 
an 
average 
survival 
advantage ranging 12-45%  
(all 
 
p<0.001).  
Growth inhibition 
has also been observed in an 
orthotopic renal cell carcinoma brain 
metastasis 
model 
(personal 
correspondence: Maher and Bachoo, 
University of Texas at Southwestern 
Medical Center).  
  
Blood Brain Barrier Penetration  
An important component of the development of novel drugs for treatment of GBM is the 
ability to cross the blood brain barrier (BBB). PT2385 has favorable characteristics for 
blood brain penetration in humans including low molecular weight (383 Da), low water 
solubility (log D value in octanol/water pH 7.4 is 2.19; <3 being favorable), and high 
brain/plasma ratio in rats (ratio 0.9, Fig 2).   
  
Studies in animals demonstrated the oral bioavailability to be 40% in rats and ~90% in 
dogs. The volume of distribution is greater than the total body water in mice, rats, dogs, 
and monkeys with a tmax between 0.5-2 hours and terminal half-life of 9 and 12 hours in rat 
plasma and brain, respectively. Plasma protein binding of PT2385 was 82% for human 
plasma protein with half-life of approximately 14 hours. The drug undergoes oxidative  
 
metabolism  
via  
CYP2C19  
and  
CYP3A4  
and  
O-glucuronidation  
(UDP- 
glucuronosyltransferase-2B7 isoenzyme) to form an inactive glucuronide conjugate 
(PT2639). PT2385 induced concentration-dependent increases in CYP2B6 and CYP3A4 
mRNA cultured human hepatocytes with half-maximal effective concentrations (EC50 
values) ranging from 10.3 to 33.5μM (4-13μg/mL) for CYP2B6 and from 9.3-41.2μM 
(3.616μg/mL) for CYP3A4.  
  
Prior and Ongoing Clinical Trials with PT2385  
As of August 15, 2016, PT2385 had been studied in 70 subjects, 16 healthy volunteers 
and 54 patients with ccRCC. Fifty-one patients have been enrolled in Part 1 of Study 
PT2385-101, the first-in-human study of PT2385; 26 patients were enrolled in the 
doseescalation portion of Part 1, which has now completed enrollment and all dose-
limiting toxicity evaluation periods. The dosages evaluated in the dose-escalation portion 
ranged from 100 to 1800 mg b.i.d. No dose-limiting toxicities were observed; no patients 
died during the study and no patients were discontinued from the study because of 
adverse events (AEs). The 800 mg b.i.d. dosage was selected as the recommended phase 


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
ABTC # 1602  
NCI # ABTC-1602  
PI: R. Strowd  
  
9  
 
  
  
Version 03/07/18  
  
2 dose based on an assessment of safety, pharmacokinetic, and pharmacodynamic data 
(Courtney et al., 2016). Twenty-five patients were enrolled in the dose expansion portion 
of Part 1 at a dosage of 800 mg b.i.d.  
  
The most commonly reported AEs among the 51 patients enrolled in Part 1 were anemia, 
fatigue, peripheral edema, nausea and lymphocyte count decreased. Most AEs have been 
mild to moderate in severity and were reported as National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) Grade 1 to 2. The most common Grade 
3/4 toxicities included anemia (5), decreased lymphocyte counts (5), hypoxia (5), and 
hypophosphatemia (3). One patient had a complete response (CR), four patients had a 
partial response (PR), and 17 patients had stable disease for more than 16 weeks. The 
longest duration of treatment has been 537 days for a patient in the 200 mg b.i.d. dosage 
group and 468 days for a patient treated at the 800 mg b.i.d dose.  
  
In Part 2 of the study, PT2385 (800 mg b.i.d. orally) is being evaluated in combination 
with nivolumab (Opdivo®) (3 mg/kg intravenously once every two weeks). Three patients 
with ccRCC have been treated with the combination of PT2385 and nivolumab. There 
were 10 reported AE’s; photophobia was the only event reported in more than one patient 
(2). All AE’s in Part 2 were reported as Grade 1, with the exception of one Grade 3 AE of 
pleural effusion, which also met SAE criteria. The event of pleural effusion was 
considered not related to PT2385, but related to progressive disease.   
  
Study PT2385-102 evaluated the effect of food on the pharmacokinetics of PT2385 in 16 
healthy female volunteers in a crossover study. The presence of food had a mild effect 
(19% to 37% increase) on the exposure to PT2385 in this study; little to no effect was 
observed in exposure to PT2639 (the primary metabolite of PT2385) in the presence of 
food. The most common adverse events were headache, venipuncture site bruising, and 
nausea.  
  
 
2.3  
Rationale   
  
Based on preclinical efficacy as a single-agent, favorable blood brain barrier penetrating 
properties, and acceptable safety profile with an established recommended phase II dose, 
we propose a phase II efficacy study of PT2385 in recurrent GBM. This study will provide 
the first-ever experience of PT2385 in GBM and provide the initial clinical experience of 
targeting this novel therapeutic pathway.  
  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
ABTC # 1602  
NCI # ABTC-1602  
PI: R. Strowd  
  
10  
 
  
  
Version 03/07/18  
  
Bevacizumab-naïve patients have been specifically selected for this study. PT2385 is unlike 
other agents currently approved for the treatment of recurrent GBM. Though PT2385 
potently inhibits tumor production of VEGF, its action is well upstream of VEGF with 
widespread cellular action on cyclin 
D1, CD73, GLUT1, and others. 
Clinically, VEGF tyrosine kinase 
inhibitors 
are 
associated 
with 
hypertension; however, such findings 
could not be recapitulated in preclinical 
models of PT2385 treated rats (Fig 3). 
To avoid any potential impact of 
bevacizumab on tumor associated 
hypoxia, in this first experience of 
PT2385 in GBM, we propose to study 
this 
agent 
in 
bevacizumab-naïve 
patients at first recurrence.  
  
Radiographic response has been specifically selected as the primary endpoint in this study 
and is supported by recent Cancer Treatment and Evaluation Program (CTEP)-approved 
trials ongoing within the Adult Brain Tumor Consortium (ABTC) including ABTC 1402. 
Overall and progression-free survival data will be gathered as secondary endpoints to 
inform subsequent drug development in this population.  
  
Overall, this study will provide an initial experience of the clinical activity of PT2385 in 
GBM as a single agent. If positive, subsequent studies will determine the safe and effective 
dose of PT2385 which can be combined with radiation and/or temozolomide as a new 
therapeutic approach in the newly diagnosed setting.  
  
In a condition with a dismal prognosis and limited therapeutic options, PT2385 is an 
extremely attractive agent for study. It targets a signaling pathway that is highly relevant 
for GBM and for which no similar agents are currently undergoing testing.  
Pharmacologic properties (i.e. molecular weight <400 Da, low water solubility) support 
ideal properties for blood brain penetration which is supported in preclinical studies. This 
agent shows promising activity in preclinical orthotopic PDX models of GBM and is an 
ideal first-in-class agent to investigate. In this study, we propose the first-ever experience 
with this agent in patients with recurrent GBM.  
  
 
2.4  
Correlative Studies Background  
   
Pharmacokinetic Assessment  
Pharmacokinetics:  
In the existing experience in the single-arm phase I study of PT2385 in patients with renal 
cell carcinoma (RCC), pharmacokinetic data suggests that a small subset of patients may 
rapidly metabolize PT2385 into its inactive metabolite, thus limiting exposure to drug. To 


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
ABTC # 1602  
NCI # ABTC-1602  
PI: R. Strowd  
  
11  
 
  
  
Version 03/07/18  
  
further explore this variability, pharmacokinetic data will be assessed. Plasma 
concentrations of PT2385 and PT2639 will be determined by validated liquid 
chromatography/mass spectrometry methods. All PK studies and analyses will be funded 
by Peloton Therapeutics and contracted by Peloton Therapeutics through an external 
vendor which has been feasible in the ongoing phase 1 study in RCC. All PK studies and 
analyses will be performed by Peloton Therapeutics.  
  
Pharmacogenomic Assessment:   
PT2385 is metabolized by the polymorphic CYP2C19 (PMID 10971203) and CYP3A4 
(PMID 16509759), suggesting the potential for CYP2C19 and CYP3A4 polymorphisms to 
influence the metabolism of PT2385 and potentially contribute to patient-to-patient 
variability in drug metabolism. Data from the phase 1 study in ccRCC are being gathered 
to explore potential explanations but a genomic target and validated assay do not currently 
exist. The primary objective of the study proposed is to determine the radiographic 
response rate and the study is designed to achieve this objective. Whole blood samples will 
be collected for sequencing of genes that may be involved in regulating PT2385 
metabolism. Samples will be stored by Peloton Therapeutics for future pharmacogenomics 
analysis.  
  
Pharmacodynamic Assessment  
Pharmacodynamic markers to be assessed may include, but are not limited to, levels of 
erythropoietin (EPO) and vascular endothelial growth factors (e.g. VEGF, soluble VEGF). 
These markers have demonstrated the most promise based on data from the phase I study 
in ccRCC. Plasma concentrations of EPO and VEGF will be determined by commercially 
available ELISA contracted through an external vendor and funded by Peloton 
Therapeutics. This process has been feasible in the phase 1 study in ccRCC. All PD studies 
and analyses will be performed by Peloton Therapeutics.  
  
Hypoxia Imaging  
Patient selection is a critical component of the therapeutic development of targeted agents. 
While hypoxia is central to the pathogenesis of GBM, biologic response to agents that 
target hypoxia pathways may vary based on the degree of hypoxia present, the reliance on 
hypoxic pathways, and other factors. As such, critical to the development of the proposed 
agent is the exploration of imaging and other methods to inform patient selection. While 
several modalities hold promise in imaging hypoxia, no clinically available gold standard 
currently exists. Two innovative hypoxia and pH-weighted MR-based imaging sequences 
have been recently developed by a collaborator through the ABTC (Ellingson/UCLA).  
These sequences and associated endpoints are an exploratory component of this study. The 
sequences will not be used to evaluate radiographic response or progression (i.e. PFS) and 
are not designed as companion or integral biomarkers in this study. Importantly, tumor 
hypoxia and acidity are hypothesized to be potential drivers of HIF2a expression and may 
not change as a result of HIF2a inhibition; however, pre-treatment levels of hypoxia and 
acidity may predict patients that respond from inhibition of HIF2a. The proposed advanced 
imaging will be performed at baseline to explore the degree of hypoxia present at treatment 


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
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initiation. The objective for this correlative imaging component of the study is to describe 
the hypoxia signature of these tumors at baseline and explore possible correlations with 
clinical outcomes.  
  
Fast pH-weighted Molecular Magnetic Resonance Imaging (MRI) using Amine CESTEPI: 
The chemical exchange between amine and amide protons in bulk water has been shown 
to be pH dependent using an imaging method called chemical exchange saturation transfer 
(CEST) imaging. In a recently set of published studies by Dr. Ellingson and colleagues, 
pH-weighted imaging was shown to have high spatial correspondence between regions of 
tumor acidity, elevated choline on MRS, elevated lactate on MRS, and elevated 18F-
FDOPA uptake (Figure 4, Harris et al., 2015; Harris et al., 2016. Results also suggested 
patients with acidic lesions (Figure 4D) were more likely to progress earlier after starting 
radiochemotherapy (Figure 4F), while patients with non-acidic lesions (Figure 4E) were 
more likely to respond favorably to therapy. Further, if tumors became less acidic during 
treatment they were also more likely to have a favorable PFS (Harris et al., 2015). Together, 
these results suggest characterization of intratumoral pH may be an important biologic 
feature that should be quantified in GBM patients, particularly for therapies that focus on 
manipulating the microenvironment, metabolism, or oxygenation.  
  
  
  
Figure 4: Amine CEST-EPI Imaging  
  
  
  
  
  
  
  
  
Fast Hypoxia-Weighted MRI using Multi-Echo Spin-and-Gradient Echo (ME-SAGE)- 
EPI:   
Recently, investigators have demonstrated the ability to estimate simultaneous T2 and T2* 
maps using multi-echo spin-and-gradient echo planar imaging (ME-SAGE)-EPI.  Using a 
combination of T2, T2* and relative cerebral blood volume (rCBV), Magnetic Resonance 
(MR) estimates of relative oxygen extraction fraction (rOEF) can be acquired (Hirsch et 
al., 2014; He et al., 2007; Toth et al., 2013). Pilot results suggest these rOEF maps show 
measurable changes as a result of radiotherapy (Figure 5) (Toth et al., 2013). Thus, we will 


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
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PI: R. Strowd  
  
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acquire rOEF maps prior to HIF2a inhibition in order to explore whether patients with 
relatively hypoxic tumors respond favorably to PT2385. Using a combined multi-echo 
CEST-SAGE-EPI acquisition we will simultaneously estimate both pH and rOEF in the 
current study.  
  
Figure 5: Hypoxia Weighted CEST-EPI-MTR Imaging showing (K) post-contrast T1-weighted image of a centrally 
ringenhancing recurrent GBM, (L) fluid attenuated inversion recovery (FLAIR) image of this lesion with surrounding 
edema, (M) FDOPA-PET demonstrating central regions of increase dopamine uptake, and (N) hypoxia-weighted CEST-
EPIMTR sequences showing regions of hypoxia extending beyond the centrally enhancing necrotic focus into region of 
FLAIR abnormality.  
  
  
  
 
3.0  
PATIENT ELIGIBILITY CRITERIA  
    
 
3.1  
Patient Sample  
  
Sample Size:   
    
  
Minimum: 24 patients / Maximum: 35 patients  
    
Accrual Rate:   
  
3-5 patients per month   
    
  
Gender:  
  
Male and female  
  
Age:  
  
Patients must be at least 18 years of age.   
  
Race:  
  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
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Minorities will be actively recruited.  No exclusion to this study will be based on race or 
ethnicity.   
  
PLANNED ENROLLMENT REPORT  
Racial Categories  
Ethnic Categories  
Total  
 
 
 
Not Hispanic or Latino  
Hispanic or Latino  
 
  
Female  
Male  
Female  
Male  
  
American Indian/ Alaska  
Native  
0  
0  
0  
0  
0  
Asian  
1  
2  
0  
0  
3  
Native Hawaiian or Other  
Pacific Islander  
0  
0  
0  
0  
0  
Black or African  
American  
2  
3  
0  
0  
5  
White  
7  
15  
2  
3  
27  
More Than One Race  
0  
0  
0  
0  
0  
Total  
10  
20  
2  
3  
35  
  
 
3.2  
Eligibility Criteria  
  
1. 
Patients must have histologically confirmed glioblastoma that is progressive or 
recurrent following radiation therapy and temozolomide according to the Response 
Assessment in Neuro-Oncology (RANO) criteria with:  
a) 
New contrast-enhancing lesion outside of radiation field on decreasing, stable, 
or increasing doses of corticosteroids.  
b) Increase by ≥ 25% in the sum of the products of perpendicular diameters 
between the postradiotherapy scan with the smallest tumor measurement and a 
scan at least 12 weeks from completion of RT+TMZ, on stable or increasing 
doses of corticosteroids.  
Note: clinical deterioration not attributable to concurrent medication or comorbid 
conditions is sufficient to declare progression on current treatment but not for entry 
onto a clinical trial for recurrence.  
  
2. 
Tumor O(6)-methylguanine-DNA-methyltransferase (MGMT) methylation status 
must be available. Results of routinely used methods for MGMT methylation testing 
(e.g. methylation-specific polymerase chain reaction, MSPCR, or quantitative PCR) 
are acceptable.  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
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3. 
Patients must have a tumor tissue form indicating availability of archived tissue 
from a previous surgery for glioblastoma, completed and signed by a pathologist. 
See Section 9.5.5.  
  
4. 
Patients must have measurable (defined by at least 1 cm x 1 cm) contrast-enhancing 
disease by MRI imaging within 21 days of starting treatment.   
  
5. 
Patients must be able to undergo MRI of the brain with gadolinium. Patients must 
be maintained on a stable or decreasing dose of corticosteroid regimen (no increase 
for 5 days) prior to this baseline MRI.   
  
6. 
Patients must be in first recurrence of glioblastoma following radiation therapy and 
temozolomide.   
  
7. 
Patients must have recovered from severe toxicity of prior therapy. The following 
intervals from previous treatments are required to be eligible:  
  
• 
12 weeks from the completion of radiation.   
• 
6 weeks from a nitrosourea chemotherapy  
• 
3 weeks from a non-nitrosourea chemotherapy  
• 
4 weeks from any investigational (not FDA-approved) agents   
• 
2 weeks from administration of a non-cytotoxic, FDA-approved agent 
(e.g., erlotinib, hydroxychloroquine, etc.)  
  
8. 
Patients must be 18 years of age or older.   
  
9. 
Patients must have a Karnofsky Performance (KPS) Status  60% (i.e. the patient 
must be able to care for himself/herself with occasional help from others).  
  
10. Patients must have the following organ and marrow function:  
  
 
Absolute neutrophil count  
>1,500/mcL  
 
Platelets  
>100,000/mcL  
 
Hemoglobin  
> 9 g/dL  
Total bilirubin                           institutional upper limit of normal 
AST (SGOT)/ALT (SGPT)  4 × institutional upper limit of normal  
 
Creatinine   
  
≤ institutional upper limit of normal  
 
   
                    OR  
Creatinine clearance    >60 ml/min/1.73m2 for patients with creatinine levels 
above institutional normal  
 
APTT or PTT  
  
≤ 1.5 x institutional upper limit of normal  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
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11. Patients must be able to provide written informed consent.  
  
12. Women of childbearing potential must have a negative serum pregnancy test prior to 
study start. Women of childbearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to 
study entry, for the duration of study participation, and through 30 days after the last 
dose of study drug.  Should a woman become pregnant or suspect she is pregnant 
while participating in this study, she should inform her treating physician 
immediately. Men treated or enrolled on this protocol must also agree to use 
adequate contraception prior to the study, for the duration of study participation, and 
through 30 days after the last dose of study drug.    
  
13. Patients must have no concurrent malignancy except curatively treated basal or 
squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or 
bladder.  Patients with prior malignancies must be disease-free for  five years.  
  
14. Patients must be able to swallow tablets.  
  
  
 
3.3  
Ineligibility Criteria  
  
1. 
Patients receiving any other investigational agents are ineligible.  
  
2. 
Patients must not have received prior anti-VEGF therapy including bevacizumab 
(i.e.  
patients must be bevacizumab naïve)  
  
3. 
Patients with a history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to PT2385 are ineligible.  
  
4. 
Patients on enzyme-inducing anti-epileptic drugs (EIAED) are not eligible for 
treatment on this protocol. Patients may be on non-enzyme inducing anti-epileptic 
drugs or not be taking any anti-epileptic drugs. Patients previously treated with 
EIAED may be enrolled if they have been off the EIAED for 10 days or more prior 
to the first dose of PT2385.  
  
5. 
Patients with a history of bleeding diathesis are ineligible.  
  
6. 
Patients who have not recovered to <CTCAE grade 2 toxicities related to prior 
therapy are ineligible.  
  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
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PI: R. Strowd  
  
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7. 
Patients with uncontrolled intercurrent illness including, but not limited to, ongoing 
or active infection, symptomatic congestive heart failure, clinically significant 
cardiac disease, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements, are 
ineligible.   
  
8. 
Pregnant women are excluded from this study because the effects of PT2385 on a 
fetus are unknown.  Because there is an unknown but potential risk for adverse 
events in nursing infants secondary to treatment of the mother with PT2385, 
breastfeeding should be discontinued if the mother is treated with PT2385.  
  
9. 
HIV-positive patients on combination antiretroviral therapy are ineligible due to 
potential drug-drug interactions with PT2385.   
  
  
 
4.0  
TREATMENT PLAN  
  
This is a Phase II, open-label, multicenter efficacy study of PT2385 as monotherapy in 
patients with recurrent glioblastoma. All subjects must have had histological confirmation 
of glioblastoma by either biopsy or resection that is progressive or recurrent following 
radiation therapy + temozolomide.   
  
 
4.1  
Treatment Schema   
  
The goal of this study is to estimate the efficacy of PT2385 as measured by radiographic 
response in recurrent GBM.   
  
Following enrollment, patients will receive PT2385 at the recommended phase II dose of 
800 mg twice daily, continuously in 28-day cycles until progression or unacceptable 
toxicity. Patients will be followed by routine blood work, and general and neurological 
examination. A brain MRI will be performed prior to every odd-numbered cycle (every 8 
weeks). Response will be assessed by RANO criteria (Section 8.1).   
  
  
  
Blood samples to characterize the plasma pharmacokinetics and pharmacodynamics of 
PT2385 will be obtained from all patients at baseline and in Weeks 1, 2, and 4 of the first 
All Cycles (28 - day cycles)   
  
PT2385: 800 mg b.i.d. continuously   
MRI  performed  every 8 weeks   
until progression   


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
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NCI # ABTC-1602  
PI: R. Strowd  
  
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cycle (see Sections 9.5.1 and 9.5.2). A blood sample for pharmacogenomic assessment will 
also be obtained at baseline (Section 9.5.3).  
  
Patients at qualified sites will have simultaneous pH- and hypoxia-weighted MRI performed 
at baseline (Section 9.5.4).  
  
Patients will continue receiving PT2385 until they meet the criteria for disease progression 
or other criteria for going off treatment (Section 10.0). Standard of care treatment options 
will exist for patients who suffer tumor progression or recurrence on treatment. All patients 
will be followed for progression-free and overall survival. Overall survival will be assessed 
as the date from treatment start to death from any cause.  
  
 
4.2  
Treatment Requirements  
   
All eligible patients who consent to this study must have a baseline (post-operative, if  
surgery is applicable) pre-treatment MRI showing measurable disease (i.e. 1 cm x 1 cm 
enhancement). This baseline scan must be done within 21 days prior to the initiation of 
treatment.     
  
Prior to every cycle patients must have:  
  
1) ANC  1500/µl and platelets   100,000 /µl.  
 
  
    AND  
2) All toxicities recovered to ≤ grade 1 (or tolerable grade 2 for non-hematologic 
toxicity) or ≤ baseline.  
  
 
4.3  
Drug Administration  
  
No investigational or commercial agents or therapies other than those described below 
may be administered with the intent to treat the patient's malignancy.   
  
Treatment will be administered on an outpatient basis. Patients will be provided with 
medication diaries (Appendix I) and instructed in their use. Patients will be instructed to 
bring all unused medication and their diaries to each study visit for assessment of 
compliance.  
  
 
4.3.1  PT2385 Administration  
  
PT2385 will be administered on an outpatient basis as an oral dose of 800 mg twice daily. 
Patients should take the doses approximately the same time each day. Each dose should 
be taken 12 hours apart (±2 hours). Tablets should be taken with 8 ounces of water and 


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
ABTC # 1602  
NCI # ABTC-1602  
PI: R. Strowd  
  
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may be taken with or without food. Tablets should be swallowed whole, not chewed or 
crushed.  
  
Missed doses may be made up if taken within 4 hours after the scheduled administration 
time. Study drug may not be taken within 8 hours before the scheduled time for 
administration of the next dose. Patients who vomit after study drug administration 
should not retake that study drug dose but should resume taking study drug with the next 
scheduled dose.  
  
Patients will be requested to record each dose of PT2385 on the Patient Medication Diary 
in Appendix I.  
  
 
4.4  
General Concomitant Medication and Supportive Care Guidelines  
  
   
Prohibited Concomitant Medications During Study  
      
Patients may receive other medications that the investigator deems to be medically 
necessary, with the specific exception of non-protocol specified chemotherapy, 
radiotherapy, anti-neoplastic biological therapy or other investigational agents.  Patients 
who require the use of any of the aforementioned treatments for clinical management 
should be removed from the study.  
  
PT2385 is primarily metabolized by UGT2B17, UGT2B7, UGT2B15, CYP2C19 and 
CYP3A4. Strong inhibitors of CYP2C19 and CYP3A4 should be avoided in patients 
receiving PT2385 (Appendix II).   
  
PT2385 has been shown to induce the enzymes CYP3A4 and CYP2B6 in cultured human 
hepatocytes.  Simcyp PBPK model simulations indicate weak-to-moderate CYP3A4 
substrate midazolam DDIs (~50% reduction in midazolam AUC) at the clinically relevant 
PT2385 doses. Simulations also indicate that PT2385 is a weak CYP2B6 inducer (< 11% 
AUC reduction for CYP2B6 substrate bupropion at the clinically relevant PT2385 doses).  
PT2385 is not a potent inhibitor for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19,  
CYP2D6 and CYP3A4 (IC50 > 8.8 μg/mL).  It is unlikely to significantly inhibit these 
CYPs at the clinically relevant PT2385 concentrations (Cmax ~ 3.14 μg/mL). A partial list 
of CYP3A4, CYP2B6, CYP2C9, and CYP2C19 substrates is provided in Appendix III.  
  
Patients taking medications metabolized by CYP3A4 and CYP2B6 should be monitored 
carefully for decreases in drug effect.  Patients taking medications metabolized by  
CYP2C9 and CYP2C19 should be monitored for potential increases in drug effect.    
  
Corticosteroids  
  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
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NCI # ABTC-1602  
PI: R. Strowd  
  
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Postoperatively, corticosteroids should be tapered to a stable dose as determined by the 
clinical status of the patient.  The lowest required steroid dose should be maintained 
throughout the duration of the study in order to eliminate steroid effects as a confounding 
variable in the interpretation of serial brain imaging studies. Corticosteroid doses can be 
tapered as clinically indicated if the patient appears to be responding to therapy as judged 
by serial scans. Corticosteroid dose may, of course, be increased in the event of clinical 
deterioration or at the discretion of the attending physician. In the event of suspected 
clinical deterioration, repeat brain imaging is recommended.  
  
Anticonvulsants  
  
No data exist regarding the interaction of PT2385 with enzyme-inducing anti-epileptic 
drugs (EIAEDs). For this study, patients may not be on EIAEDs; patients who require 
antiepileptic drugs (AED) may be on non-enzyme inducing anti-epileptic drugs (NEIAED). 
If a patient on this study protocol needs to have an AED started or needs to have a second 
AED added then only NEIAED should be used.  There must be a ≥ 10 day period from 
discontinuation of an EIAED and initiation of therapy.  In the event that an EIAED drug 
must be used for a patient on study the patient will be removed from the protocol.  
   
Herbal and Non-Traditional Medications  
      
   
No data exist regarding the interaction of PT2385 with commonly used herbal or 
nontraditional medications. Patients should be instructed not to use such medications while 
receiving PT2385 therapy.  
    
  
  
     
 
5.0  
DOSING DELAYS/DOSE MODIFICATION FOR TOXICITY  
  
Clinically significant adverse events or abnormal laboratory values assessed as unrelated 
to disease progression, intercurrent illness, or concomitant medications may require dose 
delay and/or dose modification. Such toxicities must have an attribution of possible, 
probable, or definite to PT2385 (see Section 9.2.2). If multiple toxicities occur, dose 
modification decisions should be based on the most severe toxicity.  
  
For patients experiencing toxicity meeting the criteria below, PT2385 will be stopped.  If 
the patient recovers (≤ grade 1 [or tolerable grade 2 for non-hematologic toxicity] or ≤ 
baseline) a dose reduction is required for subsequent doses. Skipped doses will not be made 
up. If there is any question or clarification required concerning a toxicity, the treating site 
should contact the ABTC Central Office to determine patient’s toxicity status.  The ABTC 
Central Office, with the Study Chair (who may consult with Peloton Medical), will make 
the final decision.  
  
➢ Hematological toxicities will require dose modification if any of the following 
occur and complete blood counts and differentials were obtained according to the 


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
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mandated schedule (CBC, differential, and platelets drawn twice a week until the 
ANC  1500/ mcL and platelets 100,000/ mcL): grade 3 or 4 lymphopenia will 
not be considered a toxicity requiring dose modification.  
    
• 
ANC of < 500/ mcL  
• 
Platelets < 25,000/ mcL    
• 
Febrile neutropenia  
• 
Any hematological toxicity that prevents administration of ≥ 80% of 
the planned PT2385 doses for that cycle  
  
➢ Non-hematological toxicities will require dose modification if any of the following 
occur:  
  
• 
Grades 3-4 severity (except nausea, vomiting, and diarrhea without 
sufficient prophylaxis; except alopecia; except grade 3 hyperglycemia; 
except grade 3 electrolyte disturbances that are asymptomatic and that 
respond to replacement therapy; and except grade 3 neurologic toxicity 
responding within two weeks to steroids, anticonvulsants, or 
electrolyte correction; and except Grade 3 asymptomatic hypoxia. A 
subject’s first episode of deep venous thrombosis [DVT] or pulmonary 
embolism [PE] will not require dose modification)  
   
ANY TREATMENT RELATED TOXICITY (AS DEFINED ABOVE) CAUSING DELAY IN  
TREATMENT OF OVER 21 DAYS IN THE START OF A CYCLE WOULD RESULT IN  
TAKING THE PATIENT OFF TREATMENT.  
  
 
5.1  
Dose Modification for PT2385  
  
The dose levels and the general approach to PT2385 dose modification on this trial are 
shown below. Adverse events (AEs) should be treated with the appropriate maximum 
supportive care, and dose reductions should be clearly recorded on the case report form.  
  
Dose reductions are required for any clinically significant toxicity as defined above. Dosing 
will stop until the toxicity has resolved to ≤ grade 1 (or tolerable grade 2 for 
nonhematologic toxicity) or ≤ baseline. After resolution, when dose reduction is permitted, 
the dose of PT2385 will be modified as stipulated below, with a maximum of 2 dose 
reductions. The maximum length of time that PT2385 can be held is 21 days. If 
treatmentrelated toxicity is not resolved in  21 days, the patient will be removed from 
treatment.  If there is any question, the ABTC Central Office and the Study Chair should 
be contacted. The ABTC Study Chair may consult with Peloton Medical as needed for any 
issues.  
  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
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NCI # ABTC-1602  
PI: R. Strowd  
  
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Dose Reduction Table for PT2385  
Dose Level  
PT2385  
Starting dose  
800 mg b.i.d.  
First dose reduction  
600 mg b.i.d.  
Second dose reduction  
400 mg b.i.d.  
  
  
 
5.2  
Major Events  
  
Major Events are non-treatment-related grade 3 and 4 hematologic and non-hematologic 
toxicities. Treatment should be delayed for major events if PT2385 may further complicate 
the non-treatment-related event.  If a major event requires a delay of treatment, treatment 
must be delayed until toxicity is resolved (≤ grade 1 [or tolerable grade 2 for nonhematologic 
toxicity] or ≤ baseline). If toxicity is not resolved in  28 days, the patient will be removed 
from treatment.  The ABTC Central Office should be consulted if you are not clear on 
whether to continue or delay treatment.  
  
 
5.3  
Use of Hematologic Growth Factors  
  
During the first 28 days of treatment, granulocyte colony stimulating factor (G-CSF) should 
be administered only for severe or prolonged neutropenia or for neutropenic sepsis.  There 
will be no constraint on the use of growth factors during subsequent treatment; however, 
prophylactic use is discouraged and adherence to the American Society of Clinical 
Oncology (ASCO) guidelines is recommended (JCO, 12, 1994: pp 2471-2508).  Patients 
should receive all necessary supportive care, including blood products, transfusions, 
antibiotics, pain medications, bisphosphonates, and replacement hormonal therapies 
(insulin, thyroid hormones, estrogen/progesterone).  
  
 
5.4  
Toxicity Criteria  
  
All toxicities will be described and graded according to the NCI Common Terminology  
Criteria for Adverse Events (CTCAE) version 4.0 until March 31, 2018; CTCAE version 
5.0 will be utilized 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). See also 
Section 9.2.2, Recording of Adverse Events.  
  
  
 
6.0  
PHARMACEUTICAL INFORMATION  
  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
ABTC # 1602  
NCI # ABTC-1602  
PI: R. Strowd  
  
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PT2385  
  
Chemical Name:  3-(((1S)-2,2-difluoro-1-hydroxy-7-methanesulfonyl-2,3-dihydro-
1Hinden-4-yl)oxy)-5-fluorobenzonitrile  
  
Other Names:  PT2385, PT-2385, PT0002385 and CK 1558  
  
Chemical Structure:    
  
  
 
Molecular Formula: C17H12F3NO4S.  
M.W.: 383.34 g/mol   
  
Chemical Properties: PT2385 has low solubility in water.  The Log D value for PT2385 
in octanol/water pH 7.4 is 2.19.   
  
Pharmaceutical Properties: PT2385 is an anticancer agent that inhibits the function of 
HIF-2α by disrupting the formation of the HIF-2α:ARNT heterodimer with consequent 
impairment of hypoxic signaling in cancer cells.   
  
Formulations: PT2385 is formulated as an immediate release tablet in a 200 mg strength.  
The excipients used in the formulation include United States Pharmacopeia or National 
Formulary grade lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, 
hydroxypropyl cellulose, polysorbate 80 and magnesium stearate.    
  
Storage: PT2385 tablets are to be stored at room-temperature conditions, 15°C to 30°C 
(59°F to 86°F).  
  
Stability:  Studies are ongoing to monitor the stability of PT2385 tablets.  
  
Route of Administration:  Oral, given with or without food. Each dose should be taken 
with 8 ounces (240 mL) of water.  
  
 
6.1   
Agent Ordering   
  
The investigator or those named as sub-investigators on the Statement of Investigator Form 
1572 agree to supply study drugs only to those patients enrolled in the study.  The 


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
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NCI # ABTC-1602  
PI: R. Strowd  
  
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investigator or designee will keep a current and accurate inventory of all clinical drug 
supplies provided by Peloton Therapeutics.  The study site will maintain a dispensing log.    
  
Once a site has submitted all required regulatory documents to ABTC and Peloton (Forms 
1572, CVs, licenses, IRB protocol approval) an initial supply of drug can be ordered. An 
ABTC drug order form, which can be found on the ABTC website (ABTConsortium.org), 
should be emailed to the ABTC Central Office to initiate sending drug.    The ABTC Central 
Office will forward the drug order form to Peloton.  Please allow a minimum of 7 days 
from the receipt of the drug order at Peloton for drug shipment.  
  
 
6.2   
Agent Accountability  
  
Each institutional investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the inventory and disposition of all drugs received from 
Peloton, using the NCI Oral Drug Accountability Record Form (Oral DARF).   
   
Upon termination of the study the investigator or designee must complete a final 
inventory of supplies.  
  
  
 
7.0  
PROCEDURES FOR PATIENT ENTRY ON STUDY  
  
This study is supported by the NCI Cancer Trials Support Unit (CTSU) Regulatory 
Office and uses the Oncology Patient Enrollment Network (OPEN).  
  
CTEP Registration Procedures  
  
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) and 
ABTC policy require all investigators participating in any NCI-sponsored clinical trial to 
register and to renew their registration annually.  
  
Registration requires the submission of:  
• 
a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature  
• 
a current Curriculum Vitae (CV)  
• 
a completed and signed Supplemental Investigator Data Form (IDF)  
• 
a completed Financial Disclosure Form (FDF) with an original signature  
  
Fillable PDF forms and additional information can be found on the CTEP website at 
http://ctep.cancer.gov/investigatorResources/investigator_registration.htm.  
  
For questions about Investigator Registration, please contact the CTEP Investigator 
Registration Help Desk by email at pmbregpend@ctep.nci.nih.gov.  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
ABTC # 1602  
NCI # ABTC-1602  
PI: R. Strowd  
  
25  
 
  
  
Version 03/07/18  
  
  
Site Registration Requirements – IRB Approval  
  
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can enroll patients. Study centers can check the status of 
their registration packets by querying the Regulatory Support System (RSS) site 
registration status page of the CTSU member web site by entering credentials at 
https://www.ctsu.org and clicking on the RSS tab.  
  
Site registration documents must be submitted to the Regulatory Submission Portal of the 
CTSU Member Web site (login is required).  To access the Regulatory Submission Portal, 
the site staff must have an Active CTEP IAM account.  Site staff can utilize the Regulatory 
Submission Portal at any time by clicking the “Regulatory submission” subtab under the  
“Regulatory” Tab, located at the top of all pages on the CTSU members’ website.  (See 
Regulatory Submission Portal User Guide 12.6.16 on CTSU website (www.ctsu.org) for 
detailed instructions on how to use portal).   
  
Patient Registration:  
  
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). All site staff will use OPEN. OPEN is a web-based registration system available 
to users 9 a.m. to 4:30 p.m. Eastern Time. The system can be accessed by entering 
credentials at https://www.ctsu.org and clicking on the OPEN tab, or by entering 
credentials at the OPEN portal URL https://open.ctsu.org.  
  
Prior to discussing protocol entry with the patient, site staff must check the ABTC 
website (ABTConsortium.org) for protocol status and slot availability.   
  
Prior to accessing OPEN, site staff should verify the following:  
   
• 
All eligibility criteria have been met within the protocol stated timeframes. Site staff 
should use the registration forms provided on the group web site as a tool to verify 
eligibility.  
• 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable).   
   
Access requirements for OPEN:  
   
• 
Site staff will need to be registered with CTEP and have a valid and active CTEP-
IAM account. This is the same account (user id and password) used for credentialing 
in the CTSU members' web site.   
• 
To perform registrations, the site user must have been assigned the 'Registrar' role (or 
equivalent) on the relevant Group or CTSU roster.   


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
ABTC # 1602  
NCI # ABTC-1602  
PI: R. Strowd  
  
26  
 
  
  
Version 03/07/18  
  
  
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. Upon completion of the registration process in OPEN, sites should 
contact the ABTC Central Office to confirm the patient’s registration.   
   
Further instructional information is provided on the CTSU members' web site OPEN tab 
or within the OPEN URL (https://open.ctsu.org). For any additional questions contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.    
  
  
 
8.0  
RESPONSE ASSESSMENT / SAFETY AND QUALITY ASSURANCE  
  
 
8.1  
Criteria for Response Assessment  
  
Subjects with measurable disease will be assessed by the RANO (radiographic assessment 
in neuro-oncology) criteria (Wen et al., 2010).  For the purposes of this study, subjects 
should be re-evaluated at the end of every 2 cycles (approximately every 8 weeks) with a 
contrast-enhanced cranial MRI scan. The response will be determined as outlined in the 
RANO criteria below.  
  
Measurable disease. Bidimensionally, contrast-enhancing, measurable lesions with clearly 
defined margins by MRI scan, with a minimal size of 1 cm x 1 cm, and visible on 2 axial 
slices which are at least 5 mm apart with 0 mm skip. Measurement of tumor around a cyst 
or surgical cavity, if necessary, requires a minimum thickness of 3 mm. If there are >2 
lesions (multifocal) at baseline, the investigator must choose the largest two to be followed 
before a participant is entered on study. The remaining lesions will be considered 
nonmeasureable for the purpose of objective response determination. Unless progression 
is observed, objective response can only be determined when all measurable and 
nonmeasurable lesions are assessed.   
  
Complete Response – CR (requires all of the following):  
  
a) Complete disappearance of all enhancing measurable and non-measurable disease 
sustained for at least 4 weeks. In the absence of a confirming scan 4 weeks later, this 
scan will be considered only stable disease. b) No new lesions.  
c) All measurable and non-measurable lesions must be assessed using the same 
techniques as baseline.  
d) Subjects must be off corticosteroids (or on physiologic replacement doses only).  
e) Stable or improved non-enhancing (T2/FLAIR) lesions.  
f) Stable or improved clinically.  
  
Note: Subjects with non-measurable disease cannot have a complete response. The 
best response possible is stable disease.  
  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
ABTC # 1602  
NCI # ABTC-1602  
PI: R. Strowd  
  
27  
 
  
  
Version 03/07/18  
  
Partial Response – PR (requires all of the following):  
  
a) Greater than or equal to 50% decrease compared to baseline in the sum of 
products of perpendicular diameters of all measurable enhancing lesions sustained 
for at least 4 weeks. In the absence of a confirming scan 4 weeks later, this scan 
will be considered only stable disease.  
b) No progression of non-measurable disease.  
c) No new lesions.  
d) All measurable and non-measurable lesions must be assessed using the same 
techniques as baseline.  
e) The corticosteroid dose at the time of the scan evaluation should be no greater 
than the dose at time of baseline scan.  
f) Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared to baseline scan. g) Stable or improved clinically.  
  
Note: Subjects with non-measurable disease cannot have a partial response. The best 
response possible is stable disease.  
  
Stable Disease – SD (requires all of the following):  
  
a) Does not qualify for CR, PR, or progressive disease (PD).  
b) The designation of stable disease requires a minimum of 4-week duration.  
c) All measurable and non-measurable sites must be assessed using the same 
techniques as baseline.  
d) Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared to baseline scan. In the event that the corticosteroid dose 
was increased for new symptoms and signs without confirmation of disease 
progression on neuroimaging, and subsequent follow-up imaging shows that this 
increase in corticosteroids was required because of disease progression, the last 
scan considered to show stable disease will be the scan obtained when the 
corticosteroid dose was equivalent to the baseline dose. e) Stable clinically.  
  
Progressive Disease – PD (defined by any of the following):  
  
a) 
≥25% increase in sum of the products of perpendicular diameters of enhancing 
lesions compared to the smallest tumor measurement obtained either at baseline (if no 
decrease) or best response, on stable or increasing doses of corticosteroids.*   
b) 
Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing 
doses of corticosteroids compared to baseline scan or best response following initiation 
of therapy,* not due to co-morbid events (radiation therapy, demyelination, ischemic 
injury, infection, seizures, postoperative changes, or other treatment effects). c) Any 
new lesion.  
d) Clear clinical deterioration not attributable to other causes apart from the tumor 
(e.g., seizures, medication adverse effects, complications of therapy, 


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
ABTC # 1602  
NCI # ABTC-1602  
PI: R. Strowd  
  
28  
 
  
  
Version 03/07/18  
  
cerebrovascular events, infection, etc.) or changes in corticosteroid dose. The 
definition of clinical deterioration is left to the discretion of the treating physician, 
but it is recommended that a decrease in 20% of KPS or from any baseline to 50% 
or less be considered, unless attributable to comorbid events.  
e) Failure to return for evaluation due to death or deteriorating condition.  
f) Clear progression of non-measurable disease.  
  
* Stable doses of corticosteroids include patients not on corticosteroids.  
  
 
8.2  
Assessment of Response  
  
Assessment of response will begin with the MRI performed just prior to every 
oddnumbered treatment cycle. If during any scheduled MRI, the subject has a Complete 
Response or Partial Response, the MRI should be repeated prior to the next cycle.  All 
scans are to be compared to the smallest measurement scan to date.  The subject will then 
return to the every odd-numbered cycle schedule. This is required to confirm the duration 
of response.  Subjects will be classified as responders if they have a minimum duration of 
response for 4 weeks at any time after the first cycle of PT2385. MRI scans of subjects 
showing tumor response will be centrally reviewed by a neuroradiologist who will 
independently assess tumor size and compute percent tumor regression.  
  
 
8.3  
Safety assessments  
  
Safety assessments will consist of monitoring and recording all adverse events and serious 
adverse events, the regular monitoring of hematology and blood chemistry, pregnancy 
testing (in women of childbearing potential), regular measurement of vital signs, and the 
performance of physical/neurological examinations; ECGs and other cardiac monitoring 
may be performed as necessary.  
  
 
8.4  
Quality Assurance  
  
Neuropathology:  The neuropathologic diagnosis of glioblastoma will be made at the 
respective institution. If any question arises regarding the accuracy of the neuropathologic 
diagnosis, slides (and pathological blocks, if necessary) will be reviewed by the central 
review pathologist. For protocols with “response” as an outcome, all patients with a 
documented complete response or partial response may have representative pathology 
slides undergo central review.  
  
Neuroradiology:  MRI scans of patients showing tumor response as assessed locally will 
be centrally reviewed by the ABTC Imaging Core at the UCLA Brain Tumor Imaging 
Laboratory by board-certified neuroradiologists who will independently assess tumor size 
and assess radiographic response.  
  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
ABTC # 1602  
NCI # ABTC-1602  
PI: R. Strowd  
  
29  
 
  
  
Version 03/07/18  
  
Adherence to protocol therapy:  Screening/baseline source documentation will be 
submitted/uploaded into CTEP’s iMedidata Rave system and will be reviewed by the 
ABTC Central Office. As a quality assurance measure for the treatment delivered on this 
protocol, primary patient records may be reviewed. The records to be examined will be 
selected retrospectively and at random; complete records must therefore be maintained on 
each patient treated on the protocol.  These records should include primary documentation 
(e.g., laboratory report slips, X-ray reports, scan reports, pathology reports, physician notes, 
etc.), which confirm that:  
  
• 
The patient met each eligibility criterion.  
• 
Signed informed consent was obtained prior to treatment.  
• 
Treatment was given according to protocol (dated notes about doses given; any 
reasons for any dose modifications).  
• 
Toxicity was assessed according to protocol (laboratory report slips,  etc.).  
• 
Response was assessed according to protocol (MRI scan, lab reports, dated notes 
on measurements and clinical assessment, as appropriate).  
• 
NCI Drug Accountability Records were maintained for this protocol.  
 
9.0  
MONITORING OF PATIENTS  
  
 
9.1  
Table of Required Observations    
  
PT2385 (28-Day Cycles)  
  
Baseline  
  
Days 1-28 
of every 
cycle  
Cycle 1  
Weekly  
During  
Cycle 1  
Weekly  
During 
All  
Cycles  
Pre-Odd  
Cycles  
(cycles 3+)  
Pre-Even  
Cycles  
Off   
Treatment  
30 Days 
post-last 
dose   
PT2385  
  
6  
  
  
  
  
  
  
  
Glucocorticoids Dose 
Evaluation  
1  
  
  
  
  
5  
  
8  
  
AE Evaluation  
1  
  
  
7  
  
5  
5  
8,10  
11  
MRI  
1,15  
  
  
  
  
5  
  
8  
  
H&P/Neuro Exam  
1  
  
  
  
  
5  
5  
8  
  
KPS  
1  
  
  
  
  
5  
5  
8  
  
Vital Signs with pulse 
oximetry  
1,2  
  
  
2,7  
  
2,5  
2,5  
2,8  
  
CBC, Diff, Platelets  
1  
  
  
  
9,7  
5,9  
5,9  
8  
  
Serum Chemistry  
1,3  
  
  
3,7  
  
3,5  
3,5  
3,8  
  
APTT or PTT  
1  
  
  
  
  
  
  
  
  
Serum Pregnancy Test  
1,4  
  
  
  
  
  
  
  
  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
ABTC # 1602  
NCI # ABTC-1602  
PI: R. Strowd  
  
30  
 
  
  
Version 03/07/18  
  
Plasma Samples for 
Pharmacokinetics   
  
  
12  
  
  
  
  
  
  
Plasma Samples for 
Pharmacodynamics   
  
  
13  
  
  
  
  
  
  
Plasma Sample for 
Pharmacogenomics  
14  
  
  
  
  
  
  
  
  
Archived Tumor Tissue 
16  
  
  
  
  
  
  
  
  
  1– All baseline measurements must be done within minus 21 calendar days of  treatment administration unless           
otherwise specified.  
  2– Including blood pressure, respiratory rate, heart rate, temperature, weight, height: height is required at baseline 
only; weight is required at pre-odd cycle evaluations only. Patients with dyspnea or asymptomatic desaturation 
(oxygen saturation <92%), will be further evaluated as clinically indicated: evaluation may include chest x-ray, 
arterial blood gas analysis, pulmonary function testing including diffusion capacity, co-oximetry, as well as 
evaluation for specific causes of hypoxia/dyspnea.  
  3– Including albumin, alkaline phosphatase, total bilirubin, calcium, creatinine, magnesium, phosphorus, potassium, 
SGOT, SGPT, sodium.  
 
  4– For women of child-bearing potential.  
   
  5– Within minus 5 calendar days of cycle start.  
  6– PT2385 is administered orally twice daily on Days 1-28 of each 28-day cycle (see Section 4.3.1). Patients are 
required to keep a medication diary. 7– ± 1 day  
  8– Evaluations done within +7 days of off treatment date unless indicated: do not repeat: if MRI within minus 14 
days of off-treatment date; if  H&P/neuro, KPS, labs within minus 5 days of off-treatment date.   
  9– If ANC < 1500 or plts < 100,000, CBCs/differentials will be repeated twice a week until counts are recovered  
(ANC 1500 or plts 100,000) per protocol.  If counts are recovered (ANC 1500 or plts 100,000) on day of 
scheduled drawing do not repeat until next protocol schedule day  
10 – Adverse Events must be followed for at least 30 days from last dose of PT2385.  
11– Perform within +14 days of the 30-day post-last dose date.  
12– Plasma samples will be obtained for pharmacokinetics in Cycle 1 at Weeks 1, 2, and 4; see Section 9.5.1 for 
details.  
13– Plasma samples will be obtained for pharmacodynamics in Cycle 1 at Weeks 1 and 4; see Section 9.5.2 for details.  
14– A single whole blood sample will be collected at baseline for pharmacogenomics. See Section 9.5.3.  
15– Baseline MRI at qualified sites will also include advanced MR imaging measurements in addition to standard 
anatomic sequences. See Section 9.5.4.  
16– Archived tumor tissue from the most recent resection for glioblastoma will be collected from patients when 
sufficient tissue is available. See Section 9.5.5.  
  
  
 
9.2  
Adverse Events: Lists and Reporting Requirements   
  
Patients will be evaluated for toxicity if they have received at least one dose of PT2385.   
  
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 9.2.1, below) and the characteristics of an observed AE 
(Section 9.2.2) will determine whether the event requires expedited reporting via the CTEP 
Adverse Event Reporting System (CTEP-AERS) in addition to routine reporting.      
Adverse Events will be collected for at least 30 days following the last dose of study 
drug.   
  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
ABTC # 1602  
NCI # ABTC-1602  
PI: R. Strowd  
  
31  
 
  
  
Version 03/07/18  
  
All adverse events must be reported to the ABTC Central Office and the NCI in the 
manner described and per the requirements of the investigative site’s Institutional Review 
Board.   
  
Adverse events will be entered into CTEP’s Medidata Rave database by the investigative 
site in a timely manner.  See Section 12.0 – Records to be Kept.  
  
9.2.1 Adverse Events and Potential Risks   
A total of 110 patients have received PT2385 in Study PT2385-101. In Part 1, 26 patients 
were enrolled in the dose-escalation phase and 25 in the dose-expansion phase. Fifty 
patients have been enrolled in Part 2, and 9 patients in Part 3. As of October 22, 2017, 
the longest duration of treatment of any patient in PT2385-101 is 969 days for a patient 
in the 200 mg b.i.d. dose group. The longest duration of treatment of a patient at the 800 
mg b.i.d. dose (the recommended phase 2 dose) is 859 days.   
  
Part 1: No dose-limiting toxicities were observed during the dose-escalation portion of 
Part 1 of the study. As of October 22, 2017, no patients in Part 1 have died during the study 
and no patients were discontinued from the study because of adverse events. The most 
commonly reported AEs in 51 patients enrolled in the dose-escalation and expansion 
cohorts were anemia, fatigue, peripheral edema, nausea and back pain.  Most AEs were 
mild to moderate in severity and were reported as Grade 1 to 2. The most common Grade 
3/4 toxicities included anemia (5), decreased lymphocyte counts (4), hypoxia (5), and 
hypophosphatemia (4).  
  
Part 2: In Part 2 of the study, ccRCC patients were enrolled at a dose of 800 mg b.i.d. 
orally and 3 mg/kg of nivolumab intravenously once every two weeks. As of October 22, 
2017, 50 patients have been treated with the combination of PT2385 and nivolumab.  The 
most commonly reported AEs were fatigue, anemia, nausea, arthralgia and back pain. Most 
AEs were reported as Grade 1 or Grade 2 in severity. The only Grade 3 or 4 toxicities 
reported in more than one patient included anemia (3), back pain (3), fatigue (2), hypoxia 
(2), pleural effusion (2), and lymphocyte count decreased (2).  
  
Part 3: In Part 3 of the study, ccRCC patients were enrolled at a dosage of 800 mg b.i.d. 
orally in combination with cabozantinib (dose levels: 40 mg q.d. and 60 mg q.d.). The most 
commonly reported AEs were anemia, alanine aminotransferase increased, hypertension, 
and proteinuria. Most AE’s were reported as Grade 1 or Grade 2 in severity. The only Grade 
3 toxicity reported in more than one patient was hypophosphatemia.  
  
Serious Adverse Events in Study PT2385-101: The serious adverse events reported in 
Part 1, Part 2, and Part 3 of the study, as of October 22, 2017, are listed in Table 2, Table 
3, and Table 4 respectively. Fifty-eight of the AEs reported for 33 patients met SAE criteria, 
of which only four were considered to be possibly related to PT2385 by Peloton.  
  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
ABTC # 1602  
NCI # ABTC-1602  
PI: R. Strowd  
  
32  
 
  
  
Version 03/07/18  
  
Central Nervous System: No adverse CNS effects were observed in toxicity studies of 
PT2385 and the results of neurologic safety pharmacology testing (FOB) were negative for 
any effects. However, PT2385 is known to cross the blood-brain barrier and significant 
concentrations have been found in the brain. Three cases of Grade 2 aphasia with 
VHLassociated ccRCC in clinical study PT2385-202 after the data-cutoff date of October 
22, 2017. These three case reports met “serious” criteria of important medical events, and 
SUSAR criteria. In the absence of confounding factors, Peloton assessed all three case 
reports as possibly related to PT2385. Prior to the above cases, there have been no previous 
reports of aphasia across the PT2385 clinical development program. The only other AEs in 
the Nervous system disorder SOC that have been reported in >10% of patients include 
dizziness and headache, all Grade 1 or Grade 2 in severity. Patients participating in clinical 
studies of PT2385 will be observed carefully for any potential CNS toxicities.  
 
Table 2:  
Serious Adverse Events Reported in Part 1 of Study PT2385-101  
System Organ Class/ Preferred  
Term  
No. of 
Events  
Dosage  
(mg b.i.d.)  
Relationship  
Treatment  
Discontinued  
Because of 
AE  
Cardiac Disorders Atrial 
Fibrillation  
1  
1  
 
800  
  
Unrelated  
 
No  
Gastrointestinal Disorders  
Constipation  
Small Intestinal Obstruction  
Varices esophageal  
3  
1  
1  
1  
 
800  
800  
800  
  
Unrelated  
Unlikely  
Unrelated  
 
No 
No  
No  
  
General Disorders 
Chest Pain  
Non-Cardiac chest pain  
2  
1  
1  
 
800  
800  
  
Unrelated  
Unrelated  
 
No  
No  
Infections and Infestations  
Pneumonia  
Septic Shock  
Urinary tract infection  
5  
2  
1  
2  
 
400/400 800  
800/800  
  
Unrelated/Unlikely  
Unlikely  
Unrelated/Unrelated  
 
No/No 
No  
No/No  
Metabolism and Nutrition Disorders  
Dehydration  
Hypercalcemia  
2  
1  
1  
 
800  
800  
  
Unrelated  
Unrelated  
 
No  
No  
Musculoskeletal 
and 
Connective 
Tissue Disorders  
Arthralgia  
Back pain  
Osteoarthritis  
Pain  
Pain in extremity  
 
6  
1  
1  
1  
1  
2  
 
 
800  
200  
800  
400  
800/800  
  
  
Unrelated  
Unrelated  
Unrelated  
Unrelated  
Unrelated/Unrelated  
 
 
No  
No  
No  
No  
No/No  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
ABTC # 1602  
NCI # ABTC-1602  
PI: R. Strowd  
  
33  
 
  
  
Version 03/07/18  
  
Nervous System Disorders 
Dysarthria  
Transient ischemic attack  
2  
1  
1  
 
800  
800  
  
Unlikely  
Unlikely  
 
No  
No  
Renal and Urinary Disorders 
Acute kidney injury  
Hematuria  
2  
1  
1  
 
800  
800  
  
Unrelated  
Unrelated  
 
No  
No  
Respiratory, Thoracic and  
Mediastinal Disorders 
Hypoxia  
Pulmonary embolism  
 
3  
2  
1  
 
 
1200/1200  
800  
  
  
Possibly/Unlikely 
Possibly  
 
 
No/No  
No  
Surgical and Medical Procedures  
Nephrostomy  
1  
1  
 
800  
  
Unrelated  
 
No  
Vascular Disorders  
Hypotension  
Bleeding varicose vein  
2  
1  
1  
 
800  
800  
  
Unrelated  
Unrelated  
 
No  
No  
  
Table 3:       Serious Adverse Events Reported in Part 2 of Study PT2385-101  
System Organ Class/ Preferred  
Term  
No. of 
Events  
Dose of 
PT2385 
(mg 
b.i.d.)  
Relationship (PT2385 
/ nivolumab)  
Treatment  
Discontinued  
Because of AE  
Gastrointestinal Disorders  
Gastrointestinal hemorrhage  
Constipation 
Pancreatitis  
3  
1  
1  
1  
 
800  
800  
800  
  
Unrelated/Unrelated 
Unrelated/Unrelated  
Unrelated/Unrelated  
 
No  
No  
No  
General Disorders  
Death 
Pain  
3  
1  
2  
 
800  
800  
  
Possibly/Possibly  
Unrelated/Unrelated  
 
Yes 
No  
Infections and Infestations  
Localized infection  
1  
1  
 
800  
  
Unrelated/Unrelated  
 
No  
Injury, poisoning and procedural 
complications  
Administration related reaction  
1  
 
1  
 
  
800  
  
  
Unrelated/Possibly  
 
  
Yes  
Investigations  
Blood creatinine increased  
Blood bilirubin increased  
Troponin T increased  
3  
1  
1  
1  
 
800  
800  
800  
  
Unrelated/Unrelated  
Unrelated/Unrelated  
Unrelated/Unrelated  
 
No  
No  
No  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
ABTC # 1602  
NCI # ABTC-1602  
PI: R. Strowd  
  
34  
 
  
  
Version 03/07/18  
  
Metabolism and Nutrition Disorders  
Hyperkalemia  
1  
1  
 
800  
  
Unrelated/Unrelated  
 
No  
Musculoskeletal and Connective  
Tissue Disorders  
Musculoskeletal chest pain  
Back pain  
Musculoskeletal disorder  
 
3  
1  
1  
1  
 
  
800  
800  
800  
  
  
Unrelated/Unrelated  
Unrelated/Unrelated  
Unrelated/Unrelated  
 
  
No  
No  
No  
Nervous System Disorders Spinal 
cord compression  
1  
1  
 
800  
  
Unrelated/Unrelated  
 
No  
Renal and Urinary Disorders  
Acute kidney injury  
1  
1  
 
800  
  
Unrelated/Unrelated  
 
No  
Respiratory, Thoracic and  
Mediastinal Disorders 
Hypoxia  
Pleural effusion  
 
5  
1  
4  
 
  
800  
800  
  
  
Possibly/Unrelated  
Unrelated/Possibly  
 
No  
No  
Surgical and Medical Procedures  
Craniotomy  
1  
1  
  
800  
   
Unrelated/Related  
   
No  
  
  
  
  
 
Table 4:  
Serious Adverse Events Reported in Part 3 of Study PT2385-101  
System Organ Class/ Preferred  
Term  
No. of 
Events  
Dose of 
PT2385 
(mg 
b.i.d.)  
Relationship (PT2385 
/ cabozantinib)  
Treatment  
Discontinued  
Because of AE  
Cardiac 
Disorders 
Atrial Fibrillation  
1  
1  
800  
Unrelated/Unrelated  
No  
General Disorders 
Disease progression  
1  
1  
800  
Unrelated/Unrelated  
No  
Musculoskeletal and Connective 
Tissue Disorders  
Back pain  
 
2  
2  
 
800  
  
Unrelated/Unrelated  
 
No  
Respiratory, Thoracic and  
Mediastinal Disorders  
Dyspnea  
Epistaxis  
 
2  
1  
1  
 
800  
800  
  
Unrelated/Unrelated  
Unrelated/Related  
 
No  
No  
  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
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9.2.2 Adverse Event Characteristics  
  
Definition - Adverse Event (AE)  
  
Adverse event is defined as any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of a medical 
treatment or procedure regardless of whether it is considered related to the medical 
treatment or procedure (attribution of unrelated, unlikely, possible, probable, or definite).  
  
Recording of Adverse Events - ABTC AE Form   
  
• 
The investigator will monitor each patient closely for the development of adverse 
events and record all such events on the ABTC AE Case Report Form.  Each single 
sign or symptom must be reported separately.   
  
• 
CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting until March 31, 2018. 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). You 
must use one of the CTCAE criteria to define your event.  
  
Adverse events not included in the CTCAE should be reported under “Other” within 
the appropriate category and graded 1 to 5 according to the general grade definitions - 
mild, moderate, severe, life-threatening, fatal or disabling - as provided in the 
CTCAE or the CTCAE Manual.  New adverse events may be submitted to the CTEP 
Help Desk at ncictcaehelp@mail.nih.gov for annual evaluation by the CTCAE 
Change Management Committee.  
    
• 
Attribution of the AE: The investigator will be asked to document his/her opinion of 
the relationship of the event to study medication as follows:  
  
  
- Unrelated – The AE is clearly not related to the investigational agent(s).  
- Unlikely – The AE is doubtfully related to the investigational agent(s).  
- Possible – The AE may be related to the investigational agent(s).  
- Probable – The AE is most likely related to the investigational agent(s).  
- Definite – The AE is clearly related to the investigational agent(s).  
  
• 
All adverse events should be followed up in accordance with good medical practice.  
Abnormalities of laboratory events which, in the opinion of the investigator, 
constitute adverse events (even if not serious) should be followed.  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
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9.3  
Serious Adverse Events and Expedited Adverse Event Reporting  
  
9.3.1 Definition – Serious Adverse Event (SAE)  
  
An adverse event is considered serious if it results in ANY of the following outcomes:  
1) Death  
2) A life-threatening adverse event   
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions   
5) A congenital anomaly/birth defect  
6) Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  
  
9.3.2 Expedited Adverse Event Reporting  
  
➢ Use CTEP-AERS Web Application and Document on ABTC AE Form   
  
• 
All SAEs must be documented on both the ABTC AE form and using the 
CTEPAERS Web Application within 24 hours of learning of the event.  
  
• 
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse 
Event Reporting System), accessed via the CTEP web site 
(https://eappsctep.nci.nih.gov/ctepaers). In the rare occurrence when Internet 
connectivity is lost, a 24-hour notification is to be made to the ABTC Central 
Office by telephone at  410-614-4400 or 410-955-3657 or 410-599-4610.  Once 
Internet connectivity is restored, the 24-hour notification must be entered 
electronically into CTEP-AERS by the original submitter at the site.  
  
• 
ABTC will be notified automatically when an SAE is reported through 
CTEPAERS (within 24 hours). All SAEs will be documented and tracked by the 
ABTC Central Office. Queries and follow up required for completing all SAEs 
will be conducted through the ABTC Central Office in a timely fashion. When an 
expedited report is required (7 or 15 days), a speedy resolution of queries will be 
expected in order to allow for on-time reporting to the FDA. ABTC is responsible 
for reporting all applicable SAEs to the FDA.   
  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
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37  
 
  
  
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• 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) 
of the Adult Brain Tumor Consortium (ABTC), the local treating physician, and 
the Reporter and Submitter.  CTEP-AERS provides a copy feature for other e-
mail recipients.  
  
• 
The ABTC Central Office is responsible for submitting to the CTSU 
documentation of AEs that they deem reportable for posting on the CTSU 
protocol web page and inclusion on the CTSU bi-monthly broadcast.  
  
• 
Expedited Reporting Guidelines  
  
Use the NCI protocol number and the protocol-specific patient ID provided 
during trial registration on all reports.  
  
Note:  A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below.  Attribution to treatment or 
other cause must be provided.  
  
Death due to progressive disease should be reported as Grade 5 “ Disease 
progression” in 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.  
  
9.3.3 Other SAE Reporting  
  
Any Serious Adverse Event, as described in Section 9.3.1, including death due to any cause, 
which occurs during this study must be reported immediately (within 24 hours) to the 
ABTC Central Office.    
  
  
 A phone call must be made to:  
  
SERENA DESIDERI  
ABTC DATA COORDINATOR  
OFFICE: 410-614-4400  
FAX: 410-614-9335  
OR JOY FISHER, ABTC MANAGER: 410-955-3657 / 410-599-4610  
    
  
These events also must be reported by the investigator to the appropriate Institutional 
Review Board (IRB).  
  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
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Patients who are removed from study due to adverse events should be followed until the 
adverse event has resolved or stabilized.  Copies of relevant documentation, such as 
laboratory reports, should be kept with the patient's study records.  
  
Secondary Malignancy   
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm.   
Any secondary malignancies that occur following treatment with PT2385should be 
reported via CTEP-AERS. Three options are available to describe the event:  
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)   
• Treatment-related secondary malignancy   
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in Section 12.0.  
  
Second Malignancy  
  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT 
a metastasis from the initial malignancy).  Second malignancies require ONLY routine 
reporting via CDUS unless otherwise specified.  
  
 
9.4  
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 (Section 12.4).   
  
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.  For this trial the Adverse Event 
CRF is used for routine AE reporting in Rave.  
 


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
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PI: R. Strowd  
  
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9.5   
Correlative Studies   
  
9.5.1 Pharmacokinetic Assessment (All Patients)  
  
  
This correlative study is mandatory for all patients.  
  
Blood samples will be collected for the determination of PT2385 and its direct 
glucuronide metabolite (PT2639) plasma concentrations at the following time points:  
  
• 
Cycle 1, Week 1, Day 1, Pre-dose 1: within 15 minutes prior to dose  
• 
Cycle 1, Week 1, Day 1, 6 Hours Post-dose 1: 6 hours +/- 15 minutes post-dose  
• 
Cycle 1, Week 3, Day 15, Pre-dose 1: within 30 minutes prior to dose  
• 
Cycle 2, Week 1, Day 1, Pre-dose 1: within 30 minutes prior to dose  
  
Details for the collection, processing, storage, and shipment of samples for the 
determination of PK effects are provided in the lab manual.  
  
These times points have been selected based on experience from the ongoing phase 1 
study in RCC where the pretreatment and 6 hour post-dose time points provide optimal 
assessment of trough and maximum observed plasma concentration (Cmax). Week 2 and 
week 4 will provide data on steady state. Plasma concentrations of PT2385 and PT2639 
will be determined by validated liquid chromatography/mass spectrometry methods 
contracted by Peloton Therapeutics through an external vendor.   
  
9.5.2 Pharmacodynamics and Laboratory Biomarkers (All Patients)  
  
This correlative study is mandatory for all patients.  
  
In the phase I study in RCC, target engagement as measured by diminution of EPO 
expression is rapid, pronounced, and sustained starting at 6 hours post-dose #1. Based on 
this experience, plasma samples for analysis of PD effects (biomarkers) in this study will 
be collected at the following time points:  
  
• 
Cycle 1, Week 1, Day 1, Pre-dose 1: Within 15 minutes prior to dose  
• 
Cycle 1, Week 1, Day 1, 6 Hours Post-dose 1: 6 hours +/- 15 minutes post-dose  
Cycle 2, Week 1, Day 1, Pre-dose 1: Within 30 minutes prior to dose  
    
Details for the collection, processing, storage, and shipment of samples for the 
determination of PD effects are provided in the lab manual.  
  
Plasma concentrations of EPO and VEGF will be determined by commercially available 
ELISA and contracted through an external vendor by Peloton Therapeutics.   


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
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9.5.3 Pharmacogenomic Assessment (All Patients)   
  
This correlative study is mandatory for all patients.  
  
A single whole blood sample will be collected at baseline for sequencing of genes that 
may be involved in regulating PT2385 metabolism. Details for the collection, processing, 
storage, and shipment of samples for the determination of PG effects are provided in the 
lab manual. Samples will be stored by an external vendor contracted by Peloton 
Therapeutics for pharmacogenomics analysis.  
  
PT2385 is metabolized by the polymorphic CYP2C19 (PMID 10971203) and CYP3A4 
(PMID 16509759), suggesting the potential for CYP2C19 and CYP3A4 polymorphisms 
to influence the metabolism of PT2385 and potentially contribute to patient-to-patient 
variability in drug metabolism. Data from the phase 1 study in RCC are being gathered to 
explore potential explanations but a genomic target and validated assay do not currently 
exist.   
  
9.5.4 Exploratory pH and Hypoxia MRI (All Patients at Select Sites)  
  
The following correlative imaging will be performed at baseline on all patients at sites 
with advanced imaging capabilities as defined below.  
  
Simultaneous pH- and hypoxia-weighted MRI using multi-echo amine chemical exchange 
saturation transfer spin-and-gradient echo echo planar imaging (ME-aCESTSAGE-EPI):   
  
The correlative imaging components of the study are purely exploratory. The purpose is 
to investigate whether baseline imaging phenotypes derived from pH- and 
hypoxiaweighted imaging predict patients that will respond from inhibition of HIF2a. We 
hypothesize that patients with acidic or hypoxic tumors will likely express high levels of 
HIF2a, making these patients particularly amenable to HIF2a inhibitor treatment.  
  
In this study we will perform a single image acquisition to simultaneously quantify pH 
and hypoxia using a custom multi-echo amine chemical exchange saturation transfer 
spin-and-gradient echo echo planar imaging (ME-aCEST-SAGE-EPI) technique. We will 
quantify (1) the magnetization transfer ratio asymmetry at the amine proton off-resonance 
frequency (MTRasym @ 3ppm) as a measure of tumor acidity and (2) R2’ or rOEF 
estimates (rOEF = R2’/(c*rCBV) as a measure of tissue hypoxia. These studies will be 
performed only at baseline, prior to treatment initiation, to explore whether baseline 
acidity or hypoxia predict patients that will respond to HIF2a inhibition.  
  
Simultaneous pH- and hypoxia-weighted MRI will be performed at baseline only with 
Siemens 3T MR systems, which are available at 7 of the 11 ABTC sites. Thus, correlative 


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
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PI: R. Strowd  
  
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imaging data will be restricted to those patients enrolled at these sites. Based on prior 
enrollment data and experience within the ABTC, we anticipate that at least 25 patients 
(if the study proceeds to full enrollment) or 16 patients (i.e. if early stoppage criteria are 
met) to be analyzable for this exploratory objective. Of note, this study is not designed to 
validate these imaging sequences, as all correlative imaging is strictly exploratory and 
optional. Acidity and hypoxia imaging scans are purely investigational and will NOT be 
used for efficacy measurements. Efficacy will be determined by radiographic response 
and PFS using RANO criteria alone.   
  
Prior to patient enrollment, all sites able to perform simultaneous pH- and 
hypoxiaweighted MRI will receive this sequence from Dr. Ellingson at UCLA through 
communications with Siemens Healthcare. This sequence is approximately 10-15 minutes 
long and will be placed into the imaging protocol prior to contrast agent administration.  
Raw imaging data will be transmitted electronically via the standing protocol of the Adult 
Brain Tumor Consortium to Dr. Ellingson at UCLA for data processing and imaging 
analysis.  
  
9.5.5 Archival Tumor Tissue for IDH1 Mutational Status and HIF Expression (All Patients)  
  
Archived tumor tissue from the most recent resection for glioblastoma will be collected 
from patients, when sufficient tissue is available. If sufficient tissue is not available from 
the most recent surgery, then tissue from an earlier surgery is acceptable, if available, 
including from the initial resection at diagnosis.  
  
At the time of registration, prior to beginning treatment, a tumor tissue form indicating 
availability must be completed and signed by a pathologist.  This form provides written 
documentation of the availability of tissue for this study and the pathologist’s agreement 
to send it as described below.  
  
10 unstained slides, preferentially from the most recent tumor resection, will be 
requested.  The associated pathology report from the institution of collection should be 
shipped with the slides.   
  
Details for the collection and shipment of tissue samples are provided in the lab manual.  
  
9.5.5.1 IDH Mutational Status  
  
If IDH1 mutational status testing was performed and reported previously, testing will not 
need to be repeated. For patients with reported IDH1 test results, the previous IDH1 test 
report should be submitted. Results of routinely used methods for IDH1 testing are 
acceptable (i.e. immunohistochemistry, DNA-based methods). Results should include at 
least IDH1-R132 status; results of less common IDH gene mutation is not required.  
  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
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PI: R. Strowd  
  
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Immunostaining for IDH1-R132H will be performed on all available tumor tissue using 
established methods. Briefly, tumor slides will be evaluated by the neuro-pathologist. 
Sections will be stained and scored according to previously described methods using an 
anti-human IDH1-R132H antibody (Capper et al., 2010) and reported as IDH1-R132H 
mutant positive or negative.  
  
9.5.5.2 HIF Expression  
  
Tumor tissue samples will be analyzed for HIF-2α and HIF-1α expression, and for the 
presence of other elements of the HIF pathway.    
  
  
10.0    OFF TREATMENT/OFF STUDY CRITERIA  
  
Each subject has the right to withdraw from the study at any time without prejudice.  The 
investigator may discontinue any subject’s participation for any reason, including adverse 
event or failure to comply with the protocol (as judged by the investigator such as 
compliance below 80%, failure to maintain appointments, etc.).  
Should a subject withdraw from the study, the reason must be stated on the case report 
form, and a final evaluation of the subject should be performed.   
  
Patients who go off treatment must be followed for adverse events (AEs) for at least 30 
days from the last dose of PT2385.  
    
 
10.1  Off Treatment Criteria  
  
1. Disease Progression:  Remove patient from protocol therapy at the time progressive 
disease is documented. Disease progression is defined as:  Progressive neurologic 
abnormalities not explained by causes unrelated to tumor progression (e.g. 
anticonvulsant or  corticosteroid toxicity, electrolyte abnormalities, hyperglycemia, 
etc.) or a greater than 25% increase in the measurement of the tumor by MRI scan.  
If neurologic status deteriorates, on a stable or increasing dose of steroids, or if new 
lesions appear on serial MRI, further study treatment will be discontinued.  
  
2. Adverse Event:  
• Intercurrent illness that prevents further administration of treatment  
• Patients who experience unacceptable toxicity. Patients removed from study for 
unacceptable adverse events will be followed until resolution or stabilization of 
the adverse event.  
  
3. Patient Withdrawal: Patient’s refusal to continue treatment: in this event, document 
the reason for withdrawal.  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
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PI: R. Strowd  
  
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4. Non-Compliance: Failure to comply with protocol (as judged by the investigator 
such as compliance below 80%, failure to maintain appointments, etc.)  
  
5. Physician Decision: If at any time the treating physician feels constraints of this 
protocol are detrimental to the patient’s health remove the patient from protocol 
therapy.  
  
6. Protocol Defined Delay:   
• Patients who experience a treatment-related toxicity causing a delay in treatment 
>21 days  
• Delay in protocol >28 days for major events or other non-treatment related delays  
• Patients who require >2 dose reductions  
• Patients who must be put on an enzyme-inducing anti-epileptic drug (EIAED) 
during the study   
  
7. Death  
  
 
10.2  Off Study Criteria  
  
Patients will only be off study at the time of death. All patients will be followed for survival 
every 2 months for the first two years from the off treatment date; after 2 years, patients 
will be followed every 6 months until death. Survival status may be obtained by phone call, 
clinic visit, or medical records (e.g. physician notes/laboratory results of clinic or hospital 
visit). Please note that additional survival status reports will be required twice yearly for 
ABTC Central Office reporting.  
  
  
11.0   STATISTICAL CONSIDERATIONS  
  
 
  
Primary Objectives  
            
To estimate tumor objective response rate. The tumor response includes complete 
response (CR) and partial response (PR) per RANO criteria.    
  
Secondary Objectives  
  
1. To determine the safety of oral PT2385 800 mg twice daily in patients with 
recurrent glioblastoma  
2. To estimate overall survival   
3. To estimate progression-free survival  
  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
ABTC # 1602  
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PI: R. Strowd  
  
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Exploratory Objectives  
        
1. To describe the pharmacokinetic and pharmacodynamic properties of PT2385 in 
patients received PT2385 800 mg twice daily, continuously in 28-day per cycle.    
2. To describe baseline intratumoral hypoxia using MR-based neuroimaging 
sequences.   
  
Sample size justification  
  
This is a single-arm, open label, multi-institutional, non-randomized safety and efficacy 
study in patients with first recurrence of GBM. The primary endpoint is tumor 
radiographic response (PR+CR).  The study hypothesizes the single agent of PT2385 will 
achieve at least 20% radiographic response rate. The 20% response rate is considered 
clinically meaningful compared to a null hypothesis of 5% response rate (Taal et al., 
2014).   
  
The sample size estimation is based on a 2-stage design (minimax) with 85% statistical 
power and a false positive rate at 5%. At the first stage, 24 patients will be enrolled onto 
the study. The trial will be stopped and accept the null hypothesis if the response rate is 
less than or equal to 1/24.  Otherwise, the study will continue to stage 2. The probability 
of early stopping for futility is 0.661 when the null is true and 0.033 when a true response 
is 20%. Eleven additional patients will be enrolled on the second stage of the trial. If 5 
out 35 patients have an objective response, the study will reject the null hypothesis to 
conclude PT2385 is effective to treat patients with first recurrence of glioblastoma.     
  
Analysis Plan   
  
General considerations:   
The primary efficacy analysis will be performed on the Intent-to-Treat (ITT) population 
which is defined as all subjects who were enrolled onto the study. The primary safety 
analysis will be performed on the safety population who received at least one dose of 
study drug.  
  
Objective response rate  
  
To estimate tumor objective response rate, the proportion of patients who had objective 
partial response (PR) or complete response (CR) during the course of the treatment will 
be estimated along with 95% confidence intervals using the exact binomial method.   
  
Overall Survival  
  
To estimate overall survival, survival time is defined as the time from the date of 
treatment start to the date of death occurrence /or censored at the time of last known 


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
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PI: R. Strowd  
  
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alive. Survival probability and median time survival will be estimated using KaplanMeier 
method along with 95% confidence interval.  
  
Progression-free Survival  
  
To estimate progression-free survival (PFS), progression-free survival time is defined as 
the date of treatment start to the date progression was deemed. Probability of PFS and 
median of PFS will be estimated using Kaplan-Meier method along with 95% confidence 
interval.  
  
Date of progression will not be imputed for patients with missing tumor assessment(s) 
during planned tumor assessment. Patients who died without a reported progression, with 
complete scheduled imaging scans will be considered to have progressive disease on the 
date of death. Patients who did not have disease progression or died with more than two 
missing planned MRI scans will be censored at the date of last tumor assessment.  
  
Safety/Toxicity  
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
used for scoring toxicity and adverse events until March 31, 2018; CTCAE version 5.0 
will be utilized beginning April 1, 2018. The severity and frequency of toxicity will be 
tabulated using descriptive statistics. The proportions of subjects who experienced grade 
3 or above toxicities will be estimated, along with 95% confidence intervals by each type 
of toxicity.  
  
Pharmacokinetics  
  
Pharmacokinetic analyses are generally in descriptive nature and they will be performed 
with Phoenix® WinNonlin® software. PK parameters, including area under the curve  
(AUC), and maximum concentration (Cmax) at 6 hours post-dose, will be determined for 
PT2385 and PT2639 (i.e. primary inactive metabolite). Each PK parameter will be 
summarized descriptively (n, arithmetic mean, standard deviation, minimum, median, 
maximum, and coefficient of variation). Geometric means will be reported for AUC and 
Cmax parameters. For PK analysis, PT2385 and PT2639 plasma concentrations that are 
below the limit of quantitation of the assay will be censored during analysis. Standard 
clinical trial monitoring and data management practices will be used to ensure the 
integrity of study data.  
  
Pharmacodynamics  
  
The plasma concentration level of each exploratory Pharmacodynamic marker (i.e. EPO, 
VEGF) will be summarized descriptively (arithmetic mean, standard deviation) at each 
sample collection time point (pretreatment, 6-hours post-dose, steady state, progression). 
Their changes from baseline will be presented using standard descriptive statistics and 


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
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PI: R. Strowd  
  
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graphic summaries. Possible association between changes of concentration and clinical 
outcomes could be explored suing statistical modeling technics.      
  
Hypoxia Imaging  
Hypoxia imaging is strictly exploratory. The objective is to describe tumoral hypoxia 
using advanced MR-based sequences prior to treatment initiation in patients with 
recurrent GBM. Advanced MRI imaging including CEST and rOEF will be 
postprocessed as per standard protocols including motion and inhomogeneity correction 
prior to analysis. Post-processing will be performed by Dr. Ben Ellingson (UCLA, ABTC 
Imaging Core).  
  
Measurements of Acidic Tumor Volume: Relative pH assessed using MTRasym at 3ppm 
will be calculated by first performing B0 homogeneity correction, then calculating the 
difference in signal intensity between positive and negative offset frequencies divided by 
the signal intensity with no saturation, (S+3ppm – S-3ppm)/S0, for each image voxel. Acidic 
tumor will be defined as having MTRasym @ 3ppm > 5% as determined empirically 
(Harris et al., 2015). Both mean MTRasym @ 3ppm and volume of acidic tumor within 
contrast enhancing and/or T2 hyperintense tumor regions will be used as exploratory 
measures of tumor acidity.  
  
Measurements of Hypoxic Tumor Volume: The blood oxygenation-based reversible 
transverse relaxation rate, R2’, has been shown to be directly proportional to relative 
oxygen extraction fraction (rOEF), scaled by the relative cerebral blood volume (rCBV) 
(Hirsch et al., 2014; Toth et al., 2013). In the current study we will estimate R2’ using T2 
and T2* measurements obtained from the ME-SAGE component of the acquisition [R2’ =  
(1/T2*) – (1/T2)]. If available, we will use rCBV measurements from dynamic 
susceptibility contrast (DSC) perfusion MRI to estimates rOEF (rOEF = R2’/(c*rCBV), 
where c is a constant relating to the specific static magnetic field strength). Both mean 
R2’ and estimates of rOEF within contrast enhancing and/or T2 hyperintense tumor 
regions will be used as exploratory measures of tumor hypoxia.  
  
Baseline tumor acidity and hypoxia will be defined both as continuous (e.g. mean 
MTRasym @ 3ppm, mean R2’, etc.) as well as categorical variables (i.e. acidic/hypoxic vs 
non-acidic/hypoxic) based on >50% of tumor having an acidic signature (>3% MTRasym 
@ 3ppm) or hypoxic signature (R2’ > 5 s-1).   
  
Descriptive statistics including the proportion of acidic/hypoxic and non-acidic/hypoxic 
lesions will be estimated with 95% confidence intervals. Fisher’s exact test or other 
nonparametric analysis methods will be used to explore potential correlations between 
tumor acidity/hypoxia (imaging categorical variable) and tumor radiographic response.  
  
  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
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PI: R. Strowd  
  
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12.0   STUDY ADMINISTRATION  
   
    
  
   
   
  
The Investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified.  
  
 
12.1  Investigator’s Study File  
  
The Investigator’s Study File must contain all essential documents as required by ICH 
E6, including IRB and governmental approvals with correspondence, informed consent 
forms, patient enrollment and identification logs, drug accountability records, staff 
curriculum vitae, authorization forms and other appropriate documents/correspondence 
etc.  
  
 
12.2  Source Data/Documents  
  
Patient source documents used to record key efficacy/safety parameters, independent of 
the CRFs, may include for example, patient hospital/clinic records, original laboratory 
reports, ECG read-outs, MRI reports, pathology and special assessment reports, etc.  
  
Source documents are part of the study documents and must be maintained, and direct  
access to source documents made available upon request, for monitoring visits, IRB 
review, audits or inspections.  All source documents used to verify answers on CRFs will 
be uploaded to RAVE, including all documentation to prove eligibility criteria was meet.  
  
 
12.3  Document Retention and Archiving  
  
The Investigator must keep all study documents on file for at least 5 years after 
completion or discontinuation of the study. Subsequently, the Sponsor will inform the  
Investigator when the study documents can be destroyed, subject to local regulations.   
  
These files must be made available for inspection, upon reasonable request, to authorized 
representatives of Sponsor or regulatory authorities.   
  
Should the Investigator wish to assign the study records to another party, or move them to 
another location, the Sponsor must be notified in advance.  
  
If the Investigator cannot guarantee the archiving requirement at the investigational site 
for any or all of the documents, arrangements must be made between the Investigator and 
the Sponsor for appropriate storage.  
  
12.4  Data Collection/Reporting  
  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
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PI: R. Strowd  
  
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Data collection for this study will be done exclusively through CTEP’s Medidata 
Rave.    
  
Access to the trial in Rave is granted through the iMedidata application to all persons 
with the appropriate roles in the Regulatory Support System (RSS).  To access 
iMedidata/Rave the site user must have an active CTEP IAM account 
(https://eappsctep.nci.nih.gov/iam).  In addition, site users that are a member of the 
ABTC must have the Rave CRA role in RSS at the enrolling site.  
  
Upon initial site registration approval for the study in RSS, all persons with Rave roles 
assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata.   
Please note, site users will not be able to access the study in Rave until all required 
Medidata and study specific trainings are completed.  Trainings will be listed in the 
upper right pane of the iMedidata screen.    
  
Users that have not previously activated their iMedidata/Rave accounts will also receive an 
invitation from iMedidata to activate their account.  If you have any questions please contact 
the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.   
  
• 
All data are due within 14 days of evaluation time point.  Please see Section 9.1 
for evaluation time points. Note:  Source documentation to verify each CRF must 
be uploaded into Rave.  
• 
Serious Adverse Events, PHONE IMMEDIATELY, SEE SECTION 9.3  
  
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to  
CTEP on a quarterly basis by FTP burst of data.  Reports are due January 31, April 30, 
July 31, and October 31. The ABTC Central Office is responsible for compiling and 
submitting CDUS data to CTEP for all participants and for providing the data to the 
Principal Investigator for review.  
  
 
12.5  Study Monitoring   
  
The ABTC Study Monitor (Sponsor) will remotely monitor the Investigator and study 
team on a regular basis throughout the study to verify the adherence to Good Clinical 
Practice (GCP), the protocol and the completeness, consistency and accuracy of the data 
being entered into the CRFs. The Study Monitor will also ensure that the study drug is 
being stored, dispensed, and accounted for according to specifications.    
  
The Study Monitor will only conduct target on-site monitoring (See ABTC Monitoring 
plan for details).   If on sight monitoring is necessary, the Investigator shall ensure that 
the study monitor has direct access to all required study data (source documents) during 


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
ABTC # 1602  
NCI # ABTC-1602  
PI: R. Strowd  
  
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the visits. This includes all patient records needed to verify the entries in the CRFs, 
regulatory documents, pharmacy records or any other documents of concern.  
  
The Investigator agrees to cooperate with the Study Monitor and ABTC to ensure that any 
deviations or issues detected in the course of monitoring visits are resolved.  
  
 
12.6  Audits and Inspections  
  
The study may be audited at any time, with appropriate notification, by qualified 
personnel from the Sponsor or its designees, to assess compliance with the protocol, GCP 
and regulatory requirements. These audits may also be conducted for quality assurance to 
ensure that complete and accurate data are submitted and that adverse events, 
complications and/or adverse reactions are being identified and reported.  
  
The study may also be inspected by health authority inspectors, after appropriate 
notification. In the event of an audit or an inspection, the Investigator must ensure that 
direct access to all study documentation, including source documents, is granted to the 
auditors or inspectors.  
  
  
13.0  REFERENCES  
  
Bordji, K., Grandval, A., Cuhna-Alves, L., Lechapt-Zalcman, E., & Bernaudin, M. 
(2014). Hypoxia-inducible factor-2α (HIF-2α), but not HIF-1α, is essential for hypoxic 
induction of class III β-tubulin expression in human glioblastoma cells. FEBS Journal, 
281(23), 5220–5236.  
Capper D, Weissert S, Balss J, Habel A, Meyer J, Jäger D, Ackermann U, Tessmer C,  
Korshunov A, Zentgraf H, Hartmann C, von Deimling A. (2010). Characterization of  
R132H mutation-specific IDH1 antibody binding in brain tumors. Brain Pathology, 2010 
Jan;20(1):245-54. http://doi.org/ 10.1111/j.1750-3639.2009.00352.x. PMID: 19903171  
Chen, W., Hill, H., Christie, A., Kim, M. S., Holloman, E., Pavia-Jimenez, A., …  
Brugarolas, J. (2016). Targeting Renal Cell Carcinoma with a HIF-2 antagonist. Nature, 
539(7627), 112–117. http://doi.org/10.1038/nature19796  
Courtney, K., Infante, J., Lam, E., Figlin, R., Rini, B., Brugarolas, J., & et al. (2016). A 
phase I dose escalation trial of PT2385, a first-in-class oral HIF-2a inhibitor, in patients 
with advanced clear cell renal cell carcinoma. JCO, June 3-7.  
Ferrandina, G., Zannoni, G. F., Martinelli, E., Paglia, A., Gallotta, V., Mozzetti, S., … 
Ferlini, C. (2006). Class III beta-tubulin overexpression is a marker of poor clinical 
outcome in advanced ovarian cancer patients. Clinical Cancer Research, 12(9), 2774– 
2779.  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
 
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Harris, R.J., Cloughesy, T.F., Liau, L.M., et al. (2015). pH-weighted molecular imaging 
of gliomas using amine chemical exchange saturation transfer MRI. Neuro-Oncology, 
2015;17:1514-24.  
Harris, R.J., Cloughesy, T.F., Liau, L.M., et al. (2016). Simulation, phantom validation, 
and clinical evaluation of fast pH-weighted molecular imaging using amine chemical 
exchange saturation transfer echo planar imaging (CEST-EPI) in glioma at 3 T. NMR in 
Bomedicine, 2016.  
He, X., Yablonskiy, D.A. (2007). Quantitative BOLD: mapping of human cerebral 
deoxygenated blood volume and oxygen extraction fraction: default state. Magnetic 
Resonance in Medicine, 2007;57:115-26.  
Heddleston, J. M., Li, Z., Hjelmeland, A. B., & Rich, J. N. (2009). The Hypoxic 
Microenvironment Maintains Glioblastoma Stem Cells and Promotes Reprogramming 
towards a Cancer Stem Cell Phenotype. Cell Cycle, 8(20), 3274–84.  
Hirsch, N.M., Toth, V., Forschler, A., Kooijman, H., Zimmer, C., Preibisch C. (2016). 
Technical considerations on the validity of blood oxygenation level-dependent-based MR 
assessment of vascular deoxygenation. NMR in Bomedicine, 2014;27:853-62.  
Katsetos, C. D., Dráberová, E., Legido, A., Dumontet, C., & Dráber, P. (2009). Tubulin 
targets in the pathobiology and therapy of glioblastoma multiforme. I. Class III β-tubulin.  
Journal of Cellular Physiology, 221(3), 505–513.  
Li, Z., Bao, S., Wu, Q., Wang, H., Eyler, C., Shi, Q., … Rich, J. N. (2009). 
HypoxiaInducible Factors Regulate Tumorigenic Capacity of Glioma Stem Cells. Cancer 
Cell, 15(6), 501–513.  
Mao, X., Xue, X., Wang, L., Zhang, X., & Yan, M. (2013). CDH5 is specifically 
activated in glioblastoma stemlike cells and contributes to vasculogenic mimicry induced 
by hypoxia. Neuro-Oncology, 15(7), 865–79. http://doi.org/10.1093/neuonc/not029  
Reardon, D. A., Herndon, J. E., Peters, K. B, et al. (2012). Bevacizumab continuation 
beyond initial bevacizumab progression among recurrent glioblastoma patients. British 
Journal of Cancer, 2012 Oct 23;107(9):1481-7. http://doi.org/10.1038/bjc.2012.415   
Rong, Y., Durden, D. L., Van Meir, E. G., & Brat, D. J. (2006). “Pseudopalisading” 
necrosis in glioblastoma: a familiar morphologic feature that links vascular pathology, 
hypoxia, and angiogenesis. Journal of Neuropathology and Experimental Neurology, 
65(6), 529–539.  
Seidel, S., Garvalov, B. K., Wirta, V., Von Stechow, L., Schänzer, A., Meletis, K., … 
Acker, T. (2010). A hypoxic niche regulates glioblastoma stem cells through hypoxia 
inducible factor 2α. Brain, 133(4), 983–995.  
Stupp, R., Mason, W. P., van den Bent MJ, et al. (2005). Radiotherapy plus concomitant 
and adjuvant temozolomide for glioblastoma. New England Journal of Medicine, 2005 
Mar 10;352(10):987-96. http://doi.org/10.1056/NEJMoa043330  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
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Stupp, R., Hegi, M.E., Mason, W.P., et al. (2009). Effects of radiotherapy with 
concomitant and adjuvant temozolomide versus radiotherapy alone on survival in 
glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. 
Lancet Oncology, 2009 May;10(5):459-66. http://doi.org/10.1016/S1470-
2045(09)700257  
Taal, W., Oosterkamp, H. M., Walenkamp, A. M. E., Dubbink, H. J., Beerepoot, L. V., 
Hanse, M. C. J., … Van Den Bent, M. J. (2014). Single-agent bevacizumab or lomustine 
versus a combination of bevacizumab plus lomustine in patients with recurrent 
glioblastoma (BELOB trial): A randomised controlled phase 2 trial. The Lancet 
Oncology, 15, 943–953. http://doi.org/10.1016/S1470-2045(14)70314-6  
Toth, V., Forschler, A., Hirsch, N. M., et al. (2013). MR-based hypoxia measures in 
human glioma. Journal of Neurooncology, 2013;115:197-207.  
Wallace, E. M., Rizzi, J. P., Han, G., Wehn, P. M., Cao, Z., Du, X., … Josey, J. A. 
(2016). A Small-Molecule Antagonist of HIF2 a Is Efficacious in Preclinical Models of 
Renal Cell Carcinoma. Cancer Research, 76(18), 5491–5500. 
http://doi.org/10.1158/0008-5472.CAN-16-0473  
Wen, P. Y., Macdonald, D R., Reardon, D. A., et al. (2010). Updated response 
assessment criteria for high-grade gliomas: response assessment in neuro-oncology 
working group. Journal of Clinical Oncology, 2010;28:1963-72.  
Zhang, H.-L., Ruan, L., Zheng, L.-M., Whyte, D., Tzeng, C.-M., & Zhou, X.-W. (2012).  
Association 
between 
class 
III 
β-tubulin 
expression 
and 
response 
to 
paclitaxel/vinorebinebased chemotherapy for non-small cell lung cancer: A meta-analysis. 
Lung Cancer, 77(1), 9–15.  
  
  
14.0  ETHICAL AND LEGAL CONSIDERATIONS  
    
This study will be conducted in accordance with the Declaration of Helsinki and in 
compliance with all applicable laws and regulations of the locale where the study is 
conducted.  
  
It is the responsibility of the investigator that the patient is made aware and consent is given 
that personal information may be scrutinized during audits by competent authorities and 
properly authorized persons, but that personal information will be treated as strictly 
confidential and not be publicly available.  The investigator is responsible for the retention 
of the patient log and patient records.  
  
  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
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APPENDIX I – PATIENT MEDICATION DIARY  
  
PT2385 DIARY (PT2385 twice every day in 28-day cycles)  
  
Patient Name____________________________ (initials acceptable)   Patient Study ID ___________________    
  
Cycle # ____________  
  
INSTRUCTIONS TO THE PATIENT:  
1. You will take PT2385 ______ mg (___ tablets) twice per day on Days 1- 28 of every 28-day cycle. Take 
doses about 12 hours apart at approximately the same times each day.  
Take PT2385 with 8 ounces of water. PT2385 may be taken with or without food. Tablets should be 
swallowed whole, do not chew or crush.  
2. Record the date and the time you took each PT2385 dose.    
Record missed or skipped dose(s). If you miss a dose you may make up that dose if you take it within 4 hours 
of the time you normally take it. There must be at least 8 hours before the next dose.  
 If you vomit a dose, do not re-take the study drug. Take the next dose at the time that you normally take the 
next scheduled dose.   
3. Bring this form and any remaining PT2385 tablets when you return for each appointment.  
  
  
Week 
  
Day
  
 
Date  
 
Time of 
dose  
morning 
dose  
# of  
200 mg 
tablets 
 
Time of  
 
dose  
evening 
dose  
# of  
200 mg 
tablets 
Comments  
1  
1    
  
  
  
  
  
  
2  
  
  
  
  
  
  
  
3    
  
  
  
  
  
  
4  
  
  
  
  
  
  
  
5  
  
  
  
  
  
  
  
6  
  
  
  
  
  
  
  
7  
  
  
  
  
  
  
2  
8  
  
  
  
  
  
  
  
9  
  
  
  
  
  
  
  
10  
  
  
  
  
  
  
  
11  
  
  
  
  
  
  
  
12  
  
  
  
  
  
  
  
13  
  
  
  
  
  
  
  
14  
  
  
  
  
  
  
3  
15  
  
  
  
  
  
  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
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16  
  
  
  
  
  
  
  
17  
  
  
  
  
  
  
  
18  
  
  
  
  
  
  
  
19  
  
  
  
  
  
  
  
20  
  
  
  
  
  
  
  
21  
  
  
  
  
  
  
4  
22  
  
  
  
  
  
  
  
23  
  
  
  
  
  
  
  
24  
  
  
  
  
  
  
  
25  
  
  
  
  
  
  
  
26  
  
  
  
  
  
  
  
27  
  
  
  
  
  
  
  
28  
  
  
  
  
  
  
  
  
Patient’s Signature _________________________________________________________________________  
  
Date ________________________________  
  
Nurse’s Signature ________________________________________________________________________  
  
Date ________________________________   
  
  
  
  
  
  
  
  
 


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
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APPENDIX II – PARTIAL LIST OF STRONG CYP2C19 AND CYP3A4 INHIBITORS  
  
CYP2C19 Inhibitors  
CYP3A4 Inhibitors  
esomeprazole  
indinavir  
lansoprazole  
nelfinavir  
omeprazole  
ritonavir  
pantoprazole  
clarithromycin  
cimetidine  
itraconazole  
fluoxetine  
  
    
ketoconazole 
nefazodone 
saquinavir suboxone 
telithromycin  
 Consult a frequently updated medical reference for possible changes.  
  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
ABTC # 1602  
NCI # ABTC-1602  
PI: R. Strowd  
  
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APPENDIX III – PARTIAL LIST OF SUBSTRATES OF CYP3A4, CYP2B6, CYP2C9, 
AND CYP2C19  
  
CYP3A4 Substrates  
CYP2B6 Substrates  
CYP2C9 Substrates  
CYP2C19 Substrates  
clarithromycin  
artemisinin  
ibuprofen  
esomeprazole  
erythromycin  
bupropion  
naproxen  
lansoprazole  
quinidine  
efavirenz  
tolbutamide  
omeprazole  
alprazolam  
ketamine  
glipizide  
pantoprazole  
diazepam  
meperidine  
losartan  
phenytoin  
midazolam  
methadone  
irbesartan  
amitriptyline  
cyclosporine  
nevirapine  
glyburide  
carisoprodol  
indinavir  
propofol  
glipizide  
citalopram  
nelfinavir   
selegiline  
celecoxib  
clopidogrel  
ritonavir  
sorafenib  
fluoxetine  
cyclophosphamide  
cisapride  
  
rosiglitazone  
imipramine  
chlorpheniramine  
  
tamoxifen  
labetalol  
terfenadine  
  
valproic acid  
nilutamide  
amlodipine  
  
zafirlukast  
progesterone  
diltiazem  
  
  
propranolol  
nifedipine  
  
  
teniposide  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
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atorvastatin 
lovastatin 
simvastatin 
estradiol 
testosterone 
carbamazepine 
codeine 
fentanyl 
haloperidol 
ondansetron  
   
   
  
  
  
  
  
  
   
   
  
  
  
  
  
  
voriconazole  
  
   
  
  
  
  
  
  
Consult a frequently updated medical reference for possible changes. 
APPENDIX IV – PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD  
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
   
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, PT2385.  This clinical trial is sponsored by the National Cancer 
Institute.  This form is addressed to the patient, but includes important information for others 
who care for this patient.   
  
These are the things that you as a healthcare provider need to know:  
   
PT2385 interacts with certain specific enzymes in the liver.   
  
 The enzymes in question are CYP2C19 and CYP3A4, and PT2385 is broken down by 
these enzymes and may be affected by other drugs that inhibit or induce these enzymes.     
  
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.    
  
PT2385 may interact with other drugs which can cause side effects. For this reason, it is very 
important to tell your study doctors of any medicines you are taking before you enroll onto this 
clinical trial.  It is also very important to tell your doctors if you stop taking any regular 
medicines, or if you start taking a new medicine while you take part in this study.  When you 
talk about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or any herbal supplements such as St. John’s Wort.  It is 
helpful to bring your medication bottles or an updated medication list with you.  
  


Single-arm, Open-label Phase II Efficacy Study of First-in-class HIF2-Alpha Inhibitor, PT2385, for Patients with  
Recurrent Glioblastoma  
  
ABTC # 1602  
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PI: R. Strowd  
  
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Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a 
clinical trial.   
  
These are the things that you and they need to know:   
  
PT2385 must be used very carefully with other medicines that use certain liver enzymes to be 
effective or to be cleared from your system.  Before you enroll onto the clinical trial, your study 
doctor will work with your regular health care providers  to review any medicines and herbal 
supplements  that are considered strong inducers/inhibitors or substrates of CYP2C19 and 
CYP3A4.  
  
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects  
  
• Your regular health care provider should check a frequently updated medical reference or  
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.  Your study doctor’s name is   
_____________________________________ and he or she can be contacted at   
  
_____________________________________.  
  
  
  
  
  
STUDY DRUG INFORMATION WALLET CARD    
You are enrolled on a clinical trial using the experimental study  drug 
PT2385.  This clinical trial is sponsored by the NCI.  PT2385 may 
interact with drugs that are processed by your liver.  Because of this, 
it is very important to:  
➢ 
Tell your doctors if you stop taking any medicines or if you 
start taking any new medicines.  
➢ 
Tell all of your health care providers (doctors, physician 
assistants, nurse practitioners, or pharmacists) that you are taking 
part in a clinical trial.  
➢ 
Check with your doctor or pharmacist whenever you need 
to use an over-the-counter medicine or herbal supplement.  
  
  
  
  
PT2385 interacts with specific liver enzymes called CYP2C19 and 
CYP3A4 and must be used very carefully with other medicines that 
interact with these enzymes.   
➢ Before you enroll onto the clinical trial, your study doctor will work 
with your regular health care providers to review any medicines  
and herbal supplements that are considered strong 
inducers/inhibitors or substrates of CYP2C19 and CYP3A4.   
➢ Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for 
a list of drugs to avoid, or contact your study doctor.    
➢ Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.