Clinical trial NCT03914742
Conditions: IDH1 Mutation IDH2 Mutation Recurrent Glioblastoma Recurrent WHO Grade II Glioma Recurrent WHO Grade III Glioma
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Start date: 2020-02-16; Completion date: 2023-10-31
Enrollment: 67 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This phase I/II trial studies the side effects and how well BGB-290 and temozolomide work in treating patients with gliomas (brain tumors) with IDH1/2 mutations that have come back. BGB-290 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving BGB-290 and temozolomide may work better in treating patients with recurrent gliomas.

Detailed description:
PRIMARY OBJECTIVES:

(Phase I) I. Determine the safety and tolerability of the combination of PARP inhibitor BGB-290 (BGB-290) and temozolomide (TMZ) in patients with recurrent IDH1/2 mutant glioma, including the maximum tolerated dose (MTD) and characterization of dose-limiting toxicities (DLTs) in the Phase I portion.

(Phase II) II. Determine the overall response rate of BGB-290 with TMZ in patients with recurrent IDH1/2-mutant gliomas that have progressed on TMZ and another alkylator (Arm A) in the Phase II portion.

III. Determine the overall response rate of BGB-290 with TMZ in patients with recurrent IDH1/2-mutant glioma that have failed one alkylator with \>= 12 months since last treatment (Arm B) in the Phase II portion.

SECONDARY OBJECTIVES:

I. Determine the progression-free survival (PFS) and overall survival (OS) after treatment with BGB-290 and TMZ in recurrent IDH1/2-mutant gliomas in Arms A and B.

II. Determine the duration of response to therapy in recurrent IDH1/2-mutant glioma.

III. Confirm the safety and tolerability of BGB-290 in combination with TMZ.

EXPLORATORY OBJECTIVES:

I. Assess tumor response rates, PFS, and OS in patients with World Health Organization (WHO) grade IV glioblastoma (GBM) treated with BGB-290 and TMZ.

II. Assess the mutational landscape via whole-exome sequencing (WES). III. Assess gene expression patterns using ribonucleic acid (RNA) sequencing (RNAseq).

IV. Assess the methylation profiling with Infinium methylation assays. V. Quantify 2-hydroxyglutarate (2HG) in archival formalin-fixed paraffin-embedded (FFPE) specimens via liquid chromatography mass spectrometry (LC-MS) detection and correlate with treatment response.

VI. Correlate response with 2HG levels, somatic alterations, gene expression/methylation patterns in FFPE tumor tissue.

VII. Assess tumor tissue BGB-290 levels, 2HG, and PolyADP-ribosylation (PARylation) in a patient subset treated with drug prior to re-resection.

VIII. Evaluate changes in tumor growth rate in subjects with non-enhancing glioma based on fluid attenuated inverse recovery (FLAIR) tumor volume measurements of serial MRI exams.

IX. Assess if change in tumor growth rate (based on FLAIR tumor volume) in subjects with non-enhancing glioma before and after treatment is associated with progression by Response Assessment in Neuro-Oncology for Low Grade Gliomas (RANO LGG; phase II patients only) or survival.

OUTLINE: This is a phase I, dose de-escalation study of temozolomide followed by a phase II study.

PHASE I: Patients receive PARP inhibitor BGB-290 orally (PO) twice daily (BID) on days 1-28 and temozolomide PO once daily (QD) on days 1-28, 1-21, 1-14, or 1-7. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

SURGICAL PORTION: 10 patients eligible for re-resection at the time of recurrence receive PARP inhibitor BGB-290 PO BID on days 1-6 and QD on day 7 (the morning of surgery). Within 45 days after surgery, patients receive PARP inhibitor BGB-290 PO BID on days 1-28 and temozolomide on the schedule established in Phase I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients receive PARP inhibitor BGB-290 PO BID on days 1-28 and temozolomide PO QD on the schedule established in Phase I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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

Arms: arm 1: Recurrent IDH1/2-mutant grade II-III glioma: BGB290: Days 1-28, 60 mg PO BID TMZ: Days 1-28, 20 QD starting dose

TMZ de-escalated treatment schedule if necessary (days 1-21; days 1-14; days 1-7) BGG held constant at 60mg PO BID arm 2: Grade II-III: Recurrent IDH1/2-mutant glioma (WHO grades II/III) who have failed TMZ AND another alkylator

BGB290 + TMZ at dose combination established in Phase 1 arm 3: Grade II-III:Recurrent IDH1/2-mutant glioma (WHO grades II/III) Failed TMZ OR another alkylator;

\>/=12 months since last treatment

BGB290 + TMZ at dose combination established in Phase 1 arm 4: Exploratory grade IV patients only BGB290 at Ph II dose for 7 days pre-surgery Progressed following RT + Chemo arm 5: Recurrent IDH1/2-mutant glioma (WHO grade II-IV) eligible for re-resection BGB-290: 60mg PO BID for 6 days AND day once day of surgery (day 7)
Interventions: intervention 1: PARP Inhibitor BGB-290 intervention 2: Temozolomide intervention 3: Therapeutic Conventional Surgery
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: resection surgery

Protocol documents:
Prot_SAP_000.pdf: 
Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
Version Date – 07/07/2022 
Previous Version: 01/30/19, 7/26/19, 12/16/19, 4/9/20, 7/29/20 
Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent 
Gliomas with IDH1/2 Mutations 
A Protocol of the Adult Brain Tumor Consortium (ABTC) 
Coordinating Center: ABTC Central Operations Office, 
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 
Investigational Agents: Pamiparib (BGB-290) 
IND # 141204 NSC# 803412 
Commercial Agent: Temozolomide 
IND Sponsor: David Schiff, MD, ABTC Consortium 
Other Sponsors: BeiGene & CTEP/DCTD/NCI 
Study Chair 
Ranjit Bindra, MD, PhD 
Yale University 
 
Smilow Cancer Center 
35 Park Street 
New Haven, CT, 06511 
Phone: 203-200-2100 
Fax: 203-785-4622 
Email: ranjit.bindra@yale.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 
Study Co-Chair 
David Schiff, MD 
University of Virginia 
Neuro-Oncology Center 
Box 800432 
Charlottesville, VA 22908-0432 
Phone: 434-243-7034 
Mobile: 434-981-8529 
Fax: 434-982-4467 
Email:ds4jd@hscmail.mcc.virginia.edu 
Imaging Chair 
Benjamin M. Ellingson, Ph.D. 
University of California – Los Angeles 
UCLA Brain Tumor Imaging Laboratory 
924 Westwood Blvd., Suite 615 
Los Angeles, CA 90024 
Phone: 310-481-7572 
Fax: 310-794-2796 
Email: bellingson@mednet.ucla.edu 
NCT03914742


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
2 
 
 
Version 07/07/22 
 
 
 
PARTICIPATING INVESTIGATORS: Adult Brain Tumor Consortium participating members 
 
 
ABTC Manager 
Joy Fisher 
Johns Hopkins University 
Phone: 410-955-3657 
Email: jfisher@jhmi.edu 
ABTC Data Coordinator 
Serena Desideri 
Johns Hopkins University 
Phone: 410-614-4400 
Email: sdeside1@jhmi.edu 
 
Protocol Development Coordinator 
Eleni Kostalas-Lentis   
Johns Hopkins University 
Phone: 410-955-8837 
Email: ekostal1@jhmi.edu  
 
 
ABTC Database Coordinator 
Neeraja Danda 
Johns Hopkins University 
Phone: 410-502-5929 
Email: ndanda1@jhmi.edu 
 
ABTC Regulatory Specialist 
 Trisha Surakus 
Johns Hopkins University 
Phone: 410-955-8837 
Email: tsuraku1@jhmi.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nursing Contact  
Michaella Iacoboni, RN, MSN 
 
Johns Hopkins University 
Phone: 410-955-4009 
Fax: 410-614-9335 
 
 
 
Email:  msheeh13@jhmi.edu 
 
Pharmacy Contact 
Anne Delisa, PharmD, BCOP 
Sidney Kimmel Comprehensive Cancer 
Center at Johns Hopkins 
Phone: 410- 502-1036 
Email: adelisa@jhmi.edu 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
3 
 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................................ 3 
1.0 
  OBJECTIVES ................................................................................................................................................ 5 
1.1 
PRIMARY OBJECTIVES .................................................................................................................................... 5 
1.2 
 SECONDARY OBJECTIVES .............................................................................................................................. 5 
1.3 
EXPLORATORY OBJECTIVES ........................................................................................................................... 5 
2.0 
  BACKGROUND AND RATIONALE ......................................................................................................... 6 
2.1 
 STUDY DISEASE ............................................................................................................................................. 6 
2.2 
 RATIONALE FOR SELECTED APPROACH AND TRIAL DESIGN ............................................................................ 7 
2.3 
 CORRELATIVES STUDIES BACKGROUND ...................................................................................................... 20 
3.0 
 PATIENT SELECTION .............................................................................................................................. 22 
3.1 
 PATIENT POPULATION ................................................................................................................................. 22 
3.2 
 ELIGIBILITY CRITERIA ................................................................................................................................. 23 
3.3 
 INELIGIBILITY CRITERIA .............................................................................................................................. 26 
4.0 
 STUDY DESIGN AND TREATMENT PLAN .......................................................................................... 27 
4.1 
 PHASE I TREATMENT PLAN ......................................................................................................................... 28 
4.1.1 
Dose Finding ....................................................................................................................................... 30 
4.2 
PHASE II TREATMENT PLAN ......................................................................................................................... 31 
4.3 
 SURGICAL PORTION ..................................................................................................................................... 32 
4.4 
 TREATMENT REQUIREMENTS....................................................................................................................... 34 
4.5 
DRUG ADMINISTRATION .............................................................................................................................. 35 
4.5.1 
Pamiparib (BGB-290) Administration ................................................................................................. 35 
4.5.2   Temozolomide Administration .................................................................................................................. 36 
4.6 
 GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ............................................ 37 
4.6.1 
Prohibited/Restricted Concomitant Medications during Study ........................................................... 37 
4.6.2 
Anticonvulsants .................................................................................................................................... 39 
4.6.3 
Corticosteroids .................................................................................................................................... 39 
4.6.4 
Antiemetics ........................................................................................................................................... 39 
5.0 
 DOSE MODIFICATION FOR TOXICITY ............................................................................................... 39 
5.1 
 DOSE LIMITING TOXICITY (DLT) ................................................................................................................ 39 
5.2 
 DOSE DELAY AND DOSE REDUCTION .......................................................................................................... 41 
5.2.1 
Dose Modification for Temozolomide and Pamiparib (BGB-290) .................................................... 44 
5.3 
 MAJOR EVENTS ........................................................................................................................................... 45 
5.4 
 USE OF HEMATOLOGIC GROWTH FACTORS ................................................................................................. 45 
5.5 
 TOXICITY CRITERIA ..................................................................................................................................... 45 
6.0 
 PHARMACEUTICAL INFORMATION ................................................................................................... 45 
6.1 
 PAMIPARIB (BGB-290) (NSC# 803412) ...................................................................................................... 45 
6.1.1  
Agent Ordering .................................................................................................................................... 46 
6.1.2  
Agent Accountability ............................................................................................................................ 46 
6.2 
 TEMOZOLOMIDE .......................................................................................................................................... 47 
7.0 
 PROCEDURES FOR PATIENT ENTRY ON STUDY ............................................................................ 48 
7.1 
 CTEP REGISTRATION PROCEDURES ............................................................................................................ 48 
INVESTIGATOR AND RESEARCH ASSOCIATE REGISTRATION WITH CTEP ................................................................. 48 
7.2 
 SITE REGISTRATION REQUIREMENTS – INSTITUTIONAL REVIEW BOARD APPROVAL .................................. 49 
7.3 
 PATIENT REGISTRATION .............................................................................................................................. 51 
8.0 
 RESPONSE ASSESSMENT / SAFETY AND QUALITY ASSURANCE ............................................... 52 
8.1 
 CRITERIA FOR RESPONSE ASSESSMENT ....................................................................................................... 52 
8.1.1 
HGG RANO ......................................................................................................................................... 53 
8.1.2 
LGG RANO .......................................................................................................................................... 54 
8.2 
 ASSESSMENT OF RESPONSE ......................................................................................................................... 55 
8.3 
 SAFETY ASSESSMENTS ................................................................................................................................ 56 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
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8.4 
 QUALITY ASSURANCE ................................................................................................................................. 56 
9.0 
 MONITORING OF PATIENTS ................................................................................................................. 58 
9.1 
 TABLES OF REQUIRED OBSERVATIONS ........................................................................................................ 58 
9.1.1 
Phase I and Phase II (28-Day Cycles) ................................................................................................. 58 
9.1.2 
Surgical Portion (includes pre-surgical dosing).................................................................................. 59 
9.2 
 ADVERSE EVENTS ....................................................................................................................................... 61 
9.2.1 
Adverse Events and Potential Risks ..................................................................................................... 61 
9.2.2 
Adverse Event Characteristics ............................................................................................................. 62 
9.3 
 SERIOUS ADVERSE EVENTS AND EXPEDITED ADVERSE EVENT REPORTING ................................................ 63 
9.3.1 
Definition – Serious Adverse Event (SAE) ........................................................................................... 63 
9.3.2 
Expedited Adverse Event Reporting ..................................................................................................... 63 
9.3.3 
Other SAE Reporting ........................................................................................................................... 64 
9.4 
 ROUTINE ADVERSE EVENT REPORTING ....................................................................................................... 65 
9.5 
 CORRELATIVE STUDIES ............................................................................................................................... 66 
9.5.1 
Archival Tumor Tissue (all patients) ................................................................................................... 66 
9.5.2 
Brain Tissue Concentrations and Plasma Pharmacokinetics (Surgical Portion) ................................ 67 
10.0 
OFF-TREATMENT/OFF-STUDY CRITERIA .......................................................................................... 68 
10.1 
 OFF-TREATMENT CRITERIA ......................................................................................................................... 68 
10.2 
OFF-STUDY CRITERIA AND SURVIVAL FOLLOW-UP ..................................................................................... 69 
11.0 
STATISTICAL CONSIDERATIONS ......................................................................................................... 69 
12.0 
STUDY ADMINISTRATION ...................................................................................................................... 74 
12.1 
INVESTIGATOR’S STUDY FILE ...................................................................................................................... 74 
12.2 
SOURCE DATA/DOCUMENTS ........................................................................................................................ 74 
12.3 
DOCUMENT RETENTION AND ARCHIVING .................................................................................................... 74 
12.4  
DATA COLLECTION/REPORTING ................................................................................................................... 75 
12.5 
STUDY MONITORING .................................................................................................................................... 76 
12.6 
AUDITS AND INSPECTIONS ............................................................................................................................ 76 
13.0 
REFERENCES .............................................................................................................................................. 77 
14.0  ETHICAL AND LEGAL CONSIDERATIONS ......................................................................................... 79 
APPENDIX I – PATIENT MEDICATION DIARIES ........................................................................................... 80 
APPENDIX II – PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD .............................. 86 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
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1.0  
OBJECTIVES  
 
1.1 
Primary Objectives 
 
Phase I Portion: 
 
• Determine the safety and tolerability of the combination of pamiparib (BGB-290) and 
temozolomide (TMZ) in patients with recurrent IDH1/2 mutant glioma, including the 
maximum tolerated dose (MTD) and characterization of dose-limiting toxicities 
(DLTs) in the Phase I portion. 
 
Phase II Portion: 
 
• Determine the overall response rate of pamiparib (BGB-290) with TMZ in patients with 
recurrent IDH1/2-mutant gliomas that have progressed on TMZ and another alkylator 
(Arm A) in the Phase II portion. 
• Determine the overall response rate of pamiparib (BGB-290) with TMZ in patients with 
recurrent IDH1/2-mutant glioma that have failed one alkylator with ≥ 12 months since 
last treatment (Arm B) in the Phase II portion. 
1.2  
Secondary Objectives 
 
• Determine the progression-free survival (PFS) and overall survival (OS) after 
treatment with pamiparib (BGB-290) and TMZ in recurrent IDH1/2-mutant gliomas 
in Arms A and B. 
• Determine the duration of response to therapy in recurrent IDH1/2-mutant glioma. 
• Confirm the safety and tolerability of pamiparib (BGB-290) in combination with 
TMZ. 
 
1.3 
Exploratory Objectives 
 
1. Assess tumor response rates, PFS, and OS in patients with WHO grade IV 
glioblastoma (GBM) treated with pamiparib (BGB-290) and TMZ. 
2. Assess the mutational landscape via whole-exome sequencing (WES). 
3. Assess gene expression patterns using RNA sequencing (RNAseq). 
4. Assess the methylation profiling with Infinium Methylation Assays. 
5. Quantify 2-hydroxyglutarate (2HG) in archival FFPE specimens via LC-MS detection 
and correlate with treatment response. 
6. Correlate response with 2HG levels, somatic alterations, gene expression/methylation 
patterns in FFPE tumor tissue. 
7. Assess tumor tissue pamiparib (BGB-290) levels, 2HG, and PARylation in a patient 
subset treated with drug prior to re-resection. 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
6 
 
 
Version 07/07/22 
 
8. Evaluate changes in tumor growth rate in subjects with non-enhancing glioma based 
on fluid attenuated inverse recovery (FLAIR) tumor volume measurements of serial 
MRI exams. 
9. Assess if change in tumor growth rate (based on FLAIR tumor volume) in subjects 
with non-enhancing glioma before and after treatment is associated with progression 
by Response Assessment in Neuro-oncology for Low Grade Gliomas (RANO LGG; 
phase II patients only) or survival. 
 
 
2.0  
BACKGROUND AND RATIONALE 
 
2.1  
Study Disease 
 
The estimated incidence of primary neuroepithelial tumors in the United States is 6.62 
per 100,000 person-years, with 15% of those WHO grade II-III gliomas and 60% WHO 
grade IV glioblastoma (GBM)1. Though treatment and natural history vary widely 
depending on histology and molecular markers, most patients are recommended to 
undergo maximal safe resection and subsequent radiotherapy and/or chemotherapy. The 
presence or absence of IDH1/2 mutation is essential to the updated 2016 WHO 
classification of central nervous system tumors2, informing prognosis and optimal 
treatment selection. Among patients with WHO grade II and III glioma, the majority 
exhibit IDH1/2 mutation3. Patients with lower-grade glioma (LGG) and IDH1/2 mutation 
are most responsive to treatment and have the best prognosis, especially when combined 
with codeletion of 1p/19q. Patients with GB exhibit IDH1/2 mutation in about 10% of 
cases and also have a more favorable course than patients who are IDH1/2 wildtype. 
Regardless of molecular markers, most patients eventually succumb to their disease with 
local recurrence and progression once effective systemic therapy and radiation therapy 
options run out. The present trial will enroll patients diagnosed with recurrent glioma 
WHO grades II-III with IDH1/2 mutation. As an exploratory analysis, patients with GB 
will also be enrolled and analyzed separately. 
 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
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Version 07/07/22 
 
2.2  
Rationale for selected approach and trial design 
2-Hydroxyglutarate (2HG) exists as two enantiomers, 
(R)-2HG and (S)-2HG, and both are implicated in 
tumor progression via their inhibitory effects on α-
ketoglutarate (KG)-dependent dioxygenases. The 
former is an oncometabolite that is induced by the 
neomorphic activity conferred by isocitrate 
dehydrogenase-1 and -2 (IDH1/2) mutations, while the 
latter is produced under pathologic process such as 
hypoxia. A recent novel discovery was made that 
IDH1/2 mutations induce a homologous recombination 
(HR) defect that renders tumor cells exquisitely 
sensitive to Poly (ADP-Ribose) polymerase (PARP) 
inhibitors. Remarkably, this “BRCAness” phenotype 
can be completely reversed by treatment with small 
molecule inhibitors of mutant IDH1, and, conversely, it 
can be entirely recapitulated by treatment with exogenous 2HG addition. We localized 
the mechanism of action to two KG-dependent dioxygenase targeted by 2HG, KDM4A 
and KDM4B, which mediate HR suppression. IDH1-dependent PARP inhibitor 
sensitivity can be demonstrated in a range of clinically relevant models, including 
primary patient-derived glioma cells in culture and genetically-matched tumor xenografts 
in vivo. A proposed model is presented in Fig. 1. In parallel, two laboratories 
independently reported a similar synthetic lethal interaction between IDH1/2 mutations 
and PARP inhibitors, which further strengthens the validity of this interaction 4. 
Collectively, these findings directly challenge the current therapeutic strategy to block 
IDH-mutant function, and they instead provide a novel approach to treat these tumors 
with PARP inhibitors. Furthermore, these results uncover an unexpected link between 
oncometabolites, altered DNA repair, and genetic instability. 
 
In this concept proposal, these findings are directly translated into a biomarker-driven 
Phase I/II clinical trial. The efficacy of pamiparib (BGB-290), a potent PARP inhibitor 
known to have adequate central nervous system (CNS) penetration, will be tested in two 
separate arms (both with TMZ) in patients with recurrent IDH1/2-mutant glioma. While 
PARP inhibitors have been tested previously in clinical trials with newly diagnosed and 
recurrent glioblastoma (GB) patients, these trials did not adequately enrich for gliomas 
harboring IDH1/2-mutations. IDH1/2 mutations are less commonly seen in GB (only 5-
10%), and nearly all of these studies inadvertently excluded tumors most likely to harbor 
mutations in these genes (e.g., tumors that had transformed from a lower grade). The 
present study will be among the first of its kind specifically to target IDH1/2-mutant 
gliomas using a cytotoxic, rather than a cytostatic approach.  
 
The prevailing strategy to treat IDH1/2-mutant cancers has been to suppress 2HG 
production with small molecule inhibitors of the mutant proteins. The rationale for this 
approach is as follows: oncometabolites appear to drive tumorigenesis, and thus 
removing them will stop tumor growth. However, there is conflicting pre-clinical data 
supporting this approach in glioma, which is highlighted by two publications: (1) Rohle 
Fig. 1. Proposed mechanism of action 
of mutant IDH1/2-induced BRCAness 
and consequent PARP inhibitor 
synthetic lethality. 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
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Version 07/07/22 
 
et al. demonstrated modest mutant IDH1 inhibitor activity in a single patient-derived 
glioma in vivo, and similar results were observed using shRNAs which target both WT 
and mutant IDH1 proteins in cells 5; versus (2) Johannessen et al. suggested that while 
mutant IDH1/2-induced 2HG is critical for initial transformation in glioma, it is 
dispensable after tumor formation 6. Three other independent groups have also shown 
that mutant IDH1/2 inhibitors have modest or no growth inhibitory effects, using both 
patient-derived models and primary glioma cell lines 7-9.  
 
In clinical trials, these inhibitors do not appear to have activity in contrast-enhancing 
gliomas, and at best they maintain stable disease in non-enhancing gliomas, although the 
latter tumor type is known for indolent growth10. In cholangiocarcinoma, a recent phase I 
trial reported a 5% partial response (PR) rate; 56% patients had stable disease (SD), and 
the remaining progressed. The 12-month progression-free survival rate was 20.7%  11. 
For comparison, a review of 2nd line chemotherapy in cholangiocarcinoma reported 
median response rates (RRs) of ~8% 12. These findings suggest that inhibiting mutant 
IDH1/2 activity may not be effective in solid tumors. In contrast, these inhibitors appear 
to show activity in IDH1/2-mutant AML. For example, the mutant IDH2 inhibitor, 
enasidenib, is now FDA-approved for relapsed IDH2-mutant AML. The approval was 
based on a non-randomized phase I/II trial 13 which demonstrated an overall RR of 40%, 
with a median response duration of 5.8 months. Of note, the mutant IDH2 clone persisted 
in the bone marrow of all patients treated. Thus, while these inhibitors have shown 
promise in AML, they are unlikely to be curative for most cancers with IDH1/2 
mutations. 
 
Clinical data supporting the hypothesis that oncometabolite production should be 
exploited rather than suppressed, is therefore needed in an expedited fashion. The 
planned correlative studies will investigate appropriate pharmacokinetic and 
pharmacodynamic endpoints associated with this therapeutic approach. Should this 
hypothesis be correct, a new and effective standard of care could be identified for patients 
with recurrent glioma and IDH1/2 mutations, which would potentially impact both PFS 
and OS in a positive manner.  
 
IDH1/2-Mutant Tumors Harbor an HR Defect and are Sensitive to PARP inhibitors 
 
Overview of our recent discovery. IDH1/2 mutations induce an HR defect that renders 
tumor cells sensitive to PARP inhibition. The mechanism of action for this interaction is 
summarized in Fig 1 above. This novel and unexpected phenotype was validated across 
five unique and genetically diverse cell line pairs that were engineered to express either 
the wild-type (WT) or the mutant IDH1/2 proteins, and the observed DSB repair defect 
was confirmed using multiple orthogonal functional assays. This interaction has been 
demonstrated in a number of clinically relevant models, including IDH1/2-mutant 
primary patient-derived cell lines and genetically-matched tumor xenografts. This work 
was recently published in Science Translational Medicine 14. Representative data from 
this study are presented below to support the rationale for the proposed clinical study. In 
addition, new and unpublished preliminary data are presented here which support the 
rationale for testing PARP inhibitors in IDH1/2-mutant gliomas. 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
9 
 
 
Version 07/07/22 
 
 
IDH1/2-mutants harbor an intrinsic HR defect leading to exquisite PARP inhibitor 
sensitivity. 2HG induces BRCAness using a collection of engineered, isogenic IDH1/2-
WT and -mutant cell lines. These cell lines were created using three orthogonal 
approaches: (a) recombinant adeno-associated virus (rAAV) targeting, (b) CRISPR/Cas-
based gene targeting, and 
(c) stable transfection 
with doxycycline (dox)-
inducible IDH1/2-WT 
and -mutant open reading 
frames (ORFs). Mutant 
IDH1/2 protein 
expression and 2HG 
production in these 
systems was validated by 
LC-MS/MS, and then 
profiled them for DNA repair defects and DNA repair inhibitor sensitivity. Cells with 
DSB repair defects have elevated rates of baseline DSBs that engage DDR proteins, 
which can be detected using neutral comet assays and via DDR foci visualization 9,15-17. 
Marked elevations in unrepaired DSBs in all of the IDH1/2-mutant cells were detected 
tested using comet assays, which correlated with increased H2AX and 53BP1 foci at 
baseline. Of note, 53BP1 foci formation are indicative of true DNA DSBs 18. In parallel, 
exquisite PARP inhibitor sensitivity was identified in IDH1/2-mutant cells, which was 
observed with multiple unique drugs in this class (nearly 50-fold with olaparib). 
Representative data are shown for the HCT116 IDH1-WT and -mutant cell line pair in 
Fig. 2. Of note, HCT116 are and ideal system to assess metabolic changes associated 
with TCA disruption 19, and they were used previously in seminal work on mutant IDH1 
function 20,21.  
 
R- and S-2HG block directly block HR repair. The mutant IDH1/2 phenotype presented 
above is strikingly similar to that seen in BRCA-deficient cells, which prompted the 
interrogation of the integrity of HR. Using a plasmid HR reporter assay, the expression of 
mutant, but not WT, IDH1/2 
was found to have significantly 
suppressed HR. Based on these 
data, the effects of R-2HG 
directly on HR were tested using 
the chromosomally- integrated 
HR reporter assay, DR-GFP, in 
IDH1-WT U2OS cells. These 
cells were chosen because they 
are widely used as a tool to 
measure factors that impact HR 
22. R-2HG significantly 
suppressed HR in a dose-
dependent manner, and similar phenotypes were observed with the (S) enantiomer. HR 
Fig. 2. Representative data in HCT116 IDH1-WT/mutant cells demonstrating: 
(A) mutant protein expression, (B) upregulated R-2HG; which correlates with 
(C) increased baseline DDR foci, and (D) exquisite PARP inhibitor sensitivity. 
Fig. 3. 2HG suppresses HR. DR-GFP reporter assay schematic 
and representative flow cytometry data shown in (A). Dose-
dependency for both R- and S-2HG, but not KG, shown in (B). 


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suppression approached levels seen with siRNAs targeting two key HR genes, RAD51 
and BRCA2. In contrast, treatment with a cell permeable KG did not affect HR repair 
under these same conditions. Representative are shown in Fig. 3 from recently published 
work 18.  
 
2HG-mediated HR suppression is mediated via 
KDM4A/B inhibition. There are over 60 
dioxygenases which utilize -KG as a co-factor 23,24, 
which includes JmjC domain-containing KDMs and 
the TET family of 5-methylcytosine (5mC) 
hydroxylases 25-27. A focused siRNA screen of all 
genes in this family to identify mediators of the 
mutant IDH1/2-induced HR defect, using a 
miniaturized DSB repair profiling platform 
developed by the Bindra laboratory 28. This screen 
identified KDM4A and KDM4B, which was 
confirmed using multiple unique siRNAs targeting 
each gene. Representative data are shown in Fig. 5, 
using comet assays to monitor the mutant IDH1/2-
induced DNA repair defect. In these experiments, 
siRNAs targeting either KDM4A or KDM4B in IDH1-WT cells led to an increase in 
unrepaired DSBs, which was similar to that observed in IDH1-mutant cells (Fig. 4a). 
However, these siRNAs did not increase DSBs further in the IDH1-mutant cells, which 
suggests an epistatic interaction. Conversely, overexpression of KDM4A or KDM4B, but 
not other key dioxygenase proteins, specifically rescued the mutant IDH1-induced DNA 
repair defect (Fig. 4b).  
 
IDH1/2 mutants confer exquisite in vivo PARP inhibitor sensitivity. Using a flank 
xenograft model in mice, the activity of PARP inhibitors against IDH1-mutant tumors 
were tested in 
vivo. A mutant 
IDH1-dependent 
synthetic lethal 
interaction in 
isogenic 
HCT116 and 
HeLa cell line 
pairs with 
olaparib was 
confirmed, and 
olaparib activity 
in tumor xenografts derived from HT0180, a fibrosarcoma cell line which harbors an 
endogenous IDH1 R132C mutation, was demonstrated. Significant in vivo activity was 
demonstrated with another PARP inhibitor, BMN-673. Representative data are shown for 
the HCT116 cell line pair with olaparib in Fig. 5. 
 
Fig. 5. (A) PARP inhibitors selectively kill HCT116 IDH1-mutant tumor xenografts with (B) 
minimal effects on IDH1-WT cells; (C) BLI monitoring of treatment responses. 
IDH1 Mutants 
Fig. 4. The mutant IDH1/2-induced DNA 
repair defect is (A) phenocopied by siRNA 
knockdown of KDM4A/B, and (B) rescued by 
overexpression of the corresponding ORFs.   


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Demonstration of PARP inhibitor sensitivity in IDH1/2-mutant glioma models. Attempts 
were made to detect a mutant IDH1/2-induced PARP inhibitor sensitivity phenotype in 
model tumor cell lines which were more relevant to glioma. To this end, PARP inhibitor 
sensitivity in well-characterized, previously published immortalized astrocyte cell line 
containing a doxycycline (dox)-inducible R132H-mutant IDH1 ORF were tested 29. As 
shown in Fig. 6, both transient and long-term induction of mutant IDH1 protein 
expression conferred marked levels of BMN-673 sensitivity, as detected by clonogenic 
survival analysis. Next, similar dox inducible mutant IDH1 systems were created in two 
additional human glioma cell lines, KNS42 and LN299, and were treated with several 
unique PARP inhibitors. As shown in Fig. 7, mutant IDH1 expression in KNS42 induced 
robust sensitivity to both olaparib and BMN-673. Similar results were obtained in our 
engineered LN229 cell line (Fig. 8).   
 
In addition, multiple aspects of the IDH1/2-induced BRCAness phenotype were 
demonstrated in a range of clinically relevant, primary models in vitro, including patient-
derived glioma cell lines. For example, a collection of early-passage, patient-derived 
IDH1-WT and -mutant glioma cell lines available at our institution were tested (clinical 
characteristics are shown Fig. 9a, which includes tumors with oligodendroglioma 
features). IDH1 mutations were confirmed by sequencing previously 30, and 2HG 
production was confirmed in the corresponding samples (Fig. 9b). Baseline persistence of 
DSBs were demonstrated by comet assay in the IDH1-mutant cell lines (Fig. 9c), which 
is a classic approach to assess functional DSB repair activity. Although these are early-
passage, primary cells obtained directly from fresh glioma resection tissue, clonogenic 
survival assays in a subset were performed. We detected PARP inhibitor sensitivity in the 
IDH1-mutant primary glioma cultures #96 compared to two IDH1-WT cultures (#2 and 
#129) by clonogenic survival, and once again we found that 2HG exposure recapitulated 
PARP inhibitor sensitivity in WT cultures (Fig. 9d). These data confirm the ability to 
detect an IDH1-associated DSB repair defect in grades 2-4 glioma. 
Fig. 6. PARP inhibitor 
sensitivity in an 
immortalized astrocyte 
cell line with a stable, 
dox-inducible mutant 
Fig. 7. PARP inhibitor sensitivity a 
model glioma cell line, KNS42, with a 
dox-inducible mutant IDH1 ORF. 
Fig. 8. PARP inhibitor 
sensitivity a model 
glioma cell line, LN229, 
with a dox-inducible 
mutant IDH1 ORF. 


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Mutant IDH1/2 synthetic lethality correlates with PARP trapping activity of PARP 
inhibitors. Recent studies indicate that PARP inhibitors that specifically “trap” PARP 
protein at sites of DNA damage are most effective against 
IDH1/2-mutant cells. Examples of PARP-trapping PARP 
inhibitors include: BMN-673, niraparib, rucaparib pamiparib 
(BGB-290), and olaparib 31. In contrast, veliparib, while very 
effective as a catalytic inhibitor of PARP function, is an 
extremely poor PARP-trapper 31. These PARP inhibitors 
were profiled for 
synthetic lethality with 
IDH1-mutant vs. –WT 
cells, which 
confirmed activity 
with these PARP-
trapping PARP 
inhibitors, and also that veliparib was not effective 
under these conditions. Representative data for 
pamiparib (BGB-290) are presented below in Figs. 
10 and 11, and data for olaparib and BMN-673 were 
presented above.  
 
Fig. 9. Demonstration of the HR-defective and PARP inhibitor sensitivity phenotype in 
primary, patient-derived glioma cultures. 
Fig. 10. Confirmation of PARP-
trapping PARP inhibitor 
sensitivity with BGB-290 in IDH1-
mutant versus –WT cells.  
Fig. 11. Veliparib is not synthetic lethal 
with IDH1-mutant cells. 


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Enhanced synergistic interactions between PARP inhibitors and DNA damaging agents in 
IDH1/2-mutant cells. Synergistic interactions have been reported when PARP inhibitors 
are combined with DNA damaging agents in both HR-deficient and -proficient tumors 
32,33, which prompted testing for synergy here. Synergy interactions were assessed using 
the Combenefit program, an open-access software tool that enables the visualization, 
analysis and quantification of drug combination effects 34. IDH1-WT and -mutant cells 
were profiled in short-term growth inhibition assays with a collection of DNA damaging 
agents to assess baseline differential sensitivity. These studies revealed modest, but 
detectable sensitization with cisplatin, methyl methanesulfonate (MMS), and irinotecan 
as single agents (data not shown). However, substantial synergistic interaction was 
observed between cisplatin and BMN-673 in IDH1-mutant tumor cells (Fig. 12). 
Similarly, substantial synergy between TMZ and PARP inhibitors in IDH1-mutant cells 
was observed (representative data is shown in Fig. 13 for reference). 
 
 
IDH1/2 Mutations Persist in Recurrent Glioma  
 
Recent data from the Gunel laboratory at Yale indeed showed that IDH1 mutations in 
gliomas that are initially present at diagnosis appear to persist after recurrence 30, though 
there are rare exceptions35. Similarly, persistence of the IDH1 mutation has also been 
found in relapsed AMLs that harbored the mutation at initial diagnosis 36. Thus, it would 
be expected that there will be persistent 2HG production and HR deficiency in recurrent 
IDH1/2-mutant tumors, making this group a suitable population for the current study. 
 
Clinical Efficacy of Synthetic Lethal Targeting of HR Defects with PARP inhibitors 
 
Olaparib is an orally bioavailable PARP inhibitor that has been approved by the FDA as 
the first monotherapy to treat BRCA-mutant advanced ovarian cancer 37. PARP is 
involved in surveillance and maintenance of genome integrity and functions as a key 
molecule in the repair of DNA single-stranded breaks (SSBs) 38. PARP-inhibited cells 
accumulate unrepaired SSBs leading to double strand breaks when encountered by the 
replication machinery. Based on the principle of synthetic lethality, treatment with single-
agent PARP inhibitor has a dramatic therapeutic impact in a proportion of patients with 
germ-line or tumor-based (somatic) mutations in BRCA1 or BRCA2. Favorable response 
Fig. 12. PARP inhibitor synergism 
with cisplatin, which is most 
pronounced in IDH1-mutant cells 
(blue=synergistic interaction). 
Fig. 13. PARP inhibitor synergism with 
TMZ in IDH1-mutant cells 
(blue=synergistic interaction). 


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data have also been observed in a subset of patients without evidence of BRCA1/2 
mutations, and there is emerging consensus that other molecular alterations in DNA 
repair pathways, including HR deficiency, can increase the likelihood of response to 
PARP inhibitors 39,40. There are now three FDA-approved PARP inhibitors for the 
treatment of HR-deficient ovarian cancer, and it is likely that several more will be 
approved in the next 2-3 years. Robust response rates have been observed with these 
agents, often with PFS improvements in the range of 2-5 fold compared to control groups 
41. 
 
The use of PARP inhibitors in IDH1/2-mutant tumors is analogous to the rationale used 
for treating BRCA-deficient cells with a PARP inhibitor. As 2HG accumulates in IDH1-
mutant cells, HR is disrupted which causes cells to rely on alternative low fidelity DNA 
repair pathways, thus hastening genomic instability and cell death. This creates a 
“BRCAness” phenotype that renders them increasingly susceptible to agents that impair 
the DNA damage response and to those that cause additional DNA damage, including 
ionizing radiation and platinum-containing drugs.  
 
PARP Inhibitor Testing in Glioma Clinical Trials  
 
Several PARP inhibitors have been tested in glioma clinical trials thus far. Prior to the 
discovery that IDH1/2 mutations induce BRCAness and PARP inhibitor sensitivity, the 
rationale for these trials was in part based on findings that GBs are known to harbor a 
high prevalence of genetic alterations that affect DNA repair pathways. Alterations in 
PTEN are reported in 34% of GBs, leading to upregulation of epidermal growth factor 
(EGFR)/phosphatidylinositol-3-OH kinase (PI3K) signaling pathway resulting in defects 
in homologous recombination 42. In mouse embryonic PTEN -/- cells, defects in the 
regulation of RAD51 expression are notable 43. Synthetic lethality with PTEN loss and 
PARP inhibition with veliparib have shown preferential sensitivity in human GB cell 
lines compared to those cells with intact PTEN 44. For this reason, PARP inhibition has 
been hypothesized to offer a particularly strong benefit in GB patients and thus several 
clinical trials have enrolled these patients (NCT02152982 as above, NCT01390571, 
NCT00687765, and NCT02974621).  
 
In this context above, PARP inhibitors are typically combined with DNA damaging 
chemotherapies such as TMZ. TMZ induces methylation predominantly at the O-6 and 
N-7 positions of guanine which are repaired by different mechanisms. The generation of 
O-6-methylguanine is repaired in cells expressing the suicide enzyme, O-6-
methylguanine methyl transferase (MGMT). Silencing of the MGMT gene by promoter 
methylation occurs in slightly over one-half of all GB patients 45 conferring a significant 
prognostic benefit and increased sensitivity to TMZ. Low grade oligodendrogliomas, 
oligoastrocytomas, and astrocytomas frequently have high frequencies of MGMT 
promoter methylation and are sensitive to TMZ. Of note, it is now well accepted that 
IDH1/2-mutations correlate with MGMT promoter methylation, with the former likely 
driving the latter via the induction of a methylator phenotype 29. 
 


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With regard to the mechanism of action of TMZ sensitivity, O-6-methylguanine mispairs 
with thymine during replication. Mismatch repair machinery identifies this mispairing, 
attempts futile cycles of thymine reinsertion and excision, and ultimately results in 
replication fork collapse, double strand breaks, and cell death via apoptosis 46. With 
regard to the N-7-methylguanine base damage, this lesion is repaired by a combination of 
base excision repair (BER) and single strand break repair. PARP inhibitors interfere with 
the completion step of BER leading to increased DNA damage and apoptosis with TMZ 
47,48. Taken together, PARP inhibitors are thought to sensitize tumor cells to TMZ by 
inhibiting repair of the induced N-7-methylguanine base damage. This sensitization likely 
is magnified in the setting of MGMT promoter methylation, in which O-6-methylguanine 
base damage also accumulates. As noted above, TMZ has also been shown to synergize 
with PARP inhibitors in HR defective cells via a separate mechanism of action, which 
likely can be attributed to an increase in collapsed replication forks and consequent one-
ended DSBs that require HR for resolution. As such, it is believed that the combination of 
TMZ and PARP inhibitors, specifically in IDH1/2-mutant gliomas has great potential for 
marked synergistic interactions; by simultaneously exploiting the HR defect and the 
effect on alkylation damage repair. 
 
It is important to note that the current trial is the first study that will test the efficacy of 
PARP inhibition specifically in IDH1/2-mutant gliomas. It is now well established that 
while 70+% of lower grade gliomas harbor IDH1/2 mutations, these mutations are much 
less commonly observed in GBs 49. Specifically, over 90% of GBs arise de novo (termed 
“primary GB”), and IDH1 mutations are rarely found in these tumors. The remaining 
10% of GBs predominantly 
arise from lower grade 
gliomas (termed “secondary 
GB”), and thus these tumors, 
although a minority of all 
newly diagnosed GBs, 
frequently harbor IDH1/2 
mutations. These relative 
differences are critical, as 
they indicate that clinical 
trials that use a histologic 
diagnosis of GB as the sole 
eligibility criteria will not 
capture a significant 
proportion of IDH1/2-mutant 
tumors in their cohorts. The 
relative frequencies of 
IDH1/2 mutations in all grades and sub-types of gliomas are presented in Fig. 14, which 
is taken from a comprehensive review on this subject 49. Another factor is likely to have 
even further reduced the proportion of IDH1/2-mutant tumors that have been tested in 
clinical trials with PARP inhibitors: most studies specifically excluded secondary GB 
and/or tumors with features suggestive of components arising from lower grade gliomas. 
For example, a Phase II/III randomized Alliance trial (A071102; NCT02152982) is 
 Fig. 14. Overview and distribution of IDH1/2 mutations in glioma. 


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testing the efficacy of the PARP inhibitor, veliparib, in combination with adjuvant 
temozolomide in newly diagnosed GB, but it specifically excludes GBs with 
oligodendroglial features with a 1p19q co-deletion; these tumors commonly harbor IDH1 
mutations 50. As another example, the aforementioned Oparatic Trial in recurrent GB 
specifically excludes secondary GB 51. Collectively, these findings suggest that the target 
glioma population in whom PARP inhibitors have been tested thus far may not have been 
the optimal experimental cohort. Instead, an ideal group would be composed of patients 
with IDH1/2-mutant gliomas, and the proposed trial will test this specific group of 
patients. 
 
Since the initial concept for this trial was developed, additional information regarding the 
combination of pamiparib (BGB-290) and TMZ has become available. BGB-290-104, a 
phase I study for patients with first recurrence of glioblastoma, utilized our proposed dose 
level 1 of pamiparib (BGB-290) 60 mg twice daily and TMZ 40 mg Days 1-21 every 28 
days and found this combination exceeded MTD because of neutropenia and 
thrombocytopenia. Similarly, BGB-290-103, a solid tumor study using the same 
pamiparib (BGB-290) schedule with TMZ 40 mg daily, noted excessive hematologic 
toxicity. Both of these studies have de-escalated TMZ to 20 mg daily.  
 
Pre-clinical data supporting the activity of the PARP inhibitor Pamiparib (BGB-
290) 
 
As presented above, we have already confirmed that pamiparib (BGB-290) is active 
against IDH1/2-mutant versus WT cells. However, pamiparib (BGB-290) also has 
undergone extensive in vitro and in vivo testing to 
confirm its activity as (a) a PARP inhibitor that is 
synthetic lethal with BRCA-deficient tumor cells, 
(b) a TMZ sensitizer in MGMT WT (um-methylated 
promoter) tumor cells, and (c) a TMZ sensitizer in 
MGMT promoter-methylated glioma models. As 
will be discussed below, these data have formed the 
basis for pamiparib (BGB-290) testing in several 
clinical trials, including a trial in newly diagnosed 
and recurrent GB (not stratified by IDH1/2 mutation 
status; noting once again that these mutations are 
rare in GB). In this section, representative pre-
clinical data is presented that highlight the activity 
of pamiparib (BGB-290) both as a monotherapy 
synthetic lethal agent, and as a TMZ sensitizer. 
 
As shown in Fig. 15, monotherapy treatment with pamiparib (BGB-290) at a dose of 1.6 
mg/kg BID showed similar activity as olaparib dosed at 25 mg/kg BID with regard to 
tumor growth delay in a BRCA1-mutant mouse xenograft model (MDA-MB-436). This 
constituted a roughly 16-fold increase in potency for pamiparib (BGB-290) over olaparib. 
No body weight loss was observed for pamiparib (BGB-290) at all doses tested, and the 
MTD was 25 mg/kg BID. In a pharmacokinetic (PK)/pharmacodynamic (PD) study, oral 
Fig. 15 (AZD2281) in a BRCA1 
mutant xenograft mouse model. 


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administration of pamiparib (BGB-290) resulted in time- and dose-dependent inhibition 
of PARylation in the MDA-MB-436 xenografts in mice. Importantly, inhibition of 
PARylation in the tumor tissues correlated well with tumor drug concentrations of 
pamiparib (BGB-290). These data indicate that pamiparib (BGB-290) is equally 
efficacious to, but significantly more potent than olaparib, which is FDA-approved for 
the treatment of BRCA-mutant metastatic ovarian cancer. 
 
pamiparib (BGB-290) was also 
shown to synergize with TMZ in 
vivo in an H209 small cell lung 
cancer xenograft model (Fig. 16). 
In this model, pamiparib (BGB-
290) (2.73 mg/kg BID x 21 days) 
given as a single-agent treatment 
had no significant effect on tumor 
growth. TMZ (50 mg/kg QD, Days 
1-5 of each 28-day cycle) as 
single-agent treatment was quite 
effective in this model resulting in 
objective responses in all animals 
(1 PR and 7 CRs in 8 animals) 
after the first cycle of treatment. 
However, 6 of these 8 animals 
developed TMZ resistance after 
three cycles, and the mean tumor 
volume reached 505 mm3 on Day 
66. The addition of pamiparib 
(BGB-290) (0.68 mg/kg BID, Days 
1-5 of each 28-day cycle) resulted in objective responses in all animals (2 PRs and 6 CRs 
in 8 animals) after the first cycle of treatment. After completion of 3 cycles of treatment 
(on Day 66), most animals were still tumor-free (6/8), and the mean tumor volume was 
12 mm3. Thus, the combination of pamiparib 
(BGB-290) and TMZ significantly enhanced 
TMZ anti-tumor activity and delayed resistance. 
This is particularly important for the present 
study, since subsets of patients will have had 
prior exposure to alkylators such as TMZ. 
 
As shown in Table 1, pamiparib (BGB-290) was 
confirmed to have high levels of CNS 
penetration in mouse models relative to other PARP inhibitors. Though veliparib was 
found to have superior CNS penetration, its inferiority in terms of PARP trapping makes 
pamiparib (BGB-290) an appropriate candidate for this particular study. As such, it was 
also tested whether pamiparib (BGB-290) was active against H209 xenografts grown as 
Table 1. CNS penetration of selected 
PARP inhibitors. 
Fig. 16. Combination Activity of BGB-290+TMZ in a H209 
Small Cell Lung Cancer Xenograft Model. 
Diamonds=vehicle; squares=BGB-290 2.73 mg/kg BID on 
Days 1 to 21; circles=TMZ 50 mg/kg once per day on Days 
1 to 5, Days 29 to 33 and Days 57 to 61; triangles=TMZ 50 
mg/kg once per day and BGB-290 0.68 mg/kg twice per 
day on Days 1 to 5, Days 29 to 33 and Days 57 to 61. 


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intracranial xenografts. In this particular series of experiments, a TMZ-resistant clone of 
H209 was tested. This clone was generated by treating H209-xenografted tumors with 
multiple cycles of TMZ in vivo (essentially as presented in Fig. 16). In this model, 
pamiparib (BGB-290) (2.73 mg/kg BID) as single-agent treatment had no significant 
effect on tumor growth, with a median survival 
of 24 days compared to median survival of 22.5 
days in the vehicle-treated group (Fig. 17). 
H209-T intracranial xenografts showed 
resistance to the TMZ treatment alone (50 
mg/kg), with median survival of 26.5 days. 
However, the combination of pamiparib (BGB-
290) and TMZ significantly prolonged animal 
survival compared to TMZ (p<0.01), with 
median survival of 54 days. The result suggests 
pamiparib (BGB-290) in combination with 
TMZ can overcome TMZ resistance in this 
intracranial model. 
 
Next, the anti-proliferative effect of pamiparib 
(BGB-290) in combination with TMZ was 
evaluated in 8 human GBM cell lines resistant 
to single-agent TMZ (EC50 of 32 μM or 
greater). In 7 of 8 cell lines, pamiparib (BGB-
290) demonstrated synergism with TMZ with a shift in EC50 for TMZ of 5-fold or 
greater (Fig. 
18). This was 
further 
extended to an 
in vivo GBM 
PDX 
intracranial 
model, in 
which it was 
shown that the 
combination of 
pamiparib 
(BGB-290) and 
TMZ 
maximally 
extended 
overall survival 
(Fig. 19). Taken together, these data indicate that pamiparib (BGB-290) is a potent PARP 
inhibitor and robust TMZ sensitizer, with clear activity in CNS tumor models. 
 
 
 
Fig. 17. Combination Activity of BGB-290 
and TMZ in an H209-T Intracranial Model. 
Dashed black line = vehicle; solid black line 
= BGB-290 2.73 mg/kg twice daily; dashed 
gray line = TMZ 50 mg/kg once per day for 
five days; solid gray line = TMZ 50 mg/kg 
once per day and BGB-290 0.68 mg/kg 
twice per day on Days 1 to 5, Days 15 to 
19 and Days 29 to 33. 
Fig. 18. Assessment of synergistic interactions between pamiparib (BGB-290) and 
TMZ in GB cell lines. EOB=excess over bliss. 


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Experience with Pamiparib (BGB-290) in Clinical Trials 
 
PARP inhibition with pamiparib (BGB-290) is currently being studied in two Phase Ia 
studies (BGB-290-AU-002 in Australia and BGB-290-102 in China), as well as one 
Phase Ib study (BGB-A317/BGB-290_Study_001) in combination with an anti-PD-1 
antibody. The maximum tolerated dose (MTD) was found in the Australian study to be 
80 mg PO BID with 
persistent Grade 2 nausea 
despite optimal medical 
therapy being the dose 
limiting toxicity. 
Complete or partial 
responses were observed 
in subjects with ovarian 
and related cancers in 
this study group 
(representative data is 
shown in Fig. 20).  
 
A Beigene industry-
sponsored trial (IST) 
with pamiparib (BGB-
290) is currently 
enrolling for newly 
diagnosed and recurrent 
GBM. The primary goal 
of this study is to test 
whether pamiparib 
(BGB-290) is active as a 
radiosensitizer, with or 
without TMZ, against 
IDH1/2-WT, MGMT 
promoter un-methylated 
GBM. In addition, 
pamiparib (BGB-290) 
with TMZ in recurrent GBM is being tested in a separate cohort. As mentioned earlier, 
these cohorts will not have significant numbers (if any) of IDH1/2-mutant gliomas; and 
there is no pre-stratification for patients with these tumors. 
 
Background and Rational for low dose Temozolomide  
While temozolomide was initially developed as a sensitizer for chemotherapy 52, 
subsequent laboratory-based studies suggested that the synergistic interaction between 
PARP inhibitor and chemotherapy often occurred at much lower doses of the latter agent 
than used previously, most notably for TMZ53-56. This has led to a “paradigm shift”, 
which TMZ is used as a sensitizer for PARP inhibitors. As such, a number of trials have 
Fig. 20. Pamiparib (BGB-290) response data from the ovarian cancer 
Fig. 19. Activity of Pamiparib (BGB-290)/TMZ in an Intracranial GBM 
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emerged which are testing markedly lower TMZ doses in combination with PARP 
inhibitors, including pamiparib (BGB-290), dosed at or near their MTD (e.g., 
NCT03150862, NCT03672773, NCT02049593, and NCT02392793). Of note, Beigene 
recently presented there preliminary results testing 60 mg BID of pamiparib (BGB-290) 
with low doses of TMZ (e.g., 20 mg flat dosing) in extracranial metastatic solid tumors, 
with substantial numbers of responses independent of BRCA1/2-mutation status (ESMO 
2018, Poster# 421P). As such, we propose to combine a maximum dose of pamiparib 
(BGB-290) with low dose TMZ, based on these findings. 
 
Safety Profile of daily low dose Temozolomide  
There are extensive safety data on the safety profile of daily low dose temozolomide. 
Although temzolomide was initially studied using 150-200 mg/m2 on a 5/28 schedule, a 
published phase II study showed safety and efficacy of 75 mg/m2 on a daily basis during 
radiation therapy 57. This same daily schedule was proven to have efficacy and has 
become the standard of care 58. Protracted daily dosing of temozolomide at 50 mg/m2 has 
been utilized with excellent safety and tolerability in the RESCUE study59. In ABTC 
1801, the dose of temozolomide administered is < 25% that of the RESCUE study; thus, 
no new safety signals are anticipated. 
 
 
2.3  
Correlatives Studies Background 
 
Overview. A number of exploratory biomarker/correlative studies are proposed in this 
protocol, which are all essentially focused on identifying key molecular correlates of 
treatment response.  
 
• Mutational landscape studies.  We now understand that there are distinct molecular sub-
groups in glioma which are associated with distinct patterns of co-occurring mutations, 
mRNA expression, and DNA methylation 19. In addition to IDH1/2 mutations, a number 
of genes are found to be mutated in glioma, including ATRX, CIC, FUBP1 and CDK4. 
CIC is of particular relevance to this study, because mutations in this gene may correlate 
with the magnitude of 2HG production that is seen in IDH1/2-mutant tumor cells 20. 
Importantly, a recent study reveals that there are three distinct molecular sub-groups, even 
within IDH1/2-mutant gliomas, each with unique co-occurring gene mutations 21. These 
findings have been corroborated by other groups, with implications for treatment response 
and overall survival 22. We thus seek to assess the mutational landscape in tumor 
specimens from patients treated with pamiparib (BGB-290) and TMZ in this study, and to 
assess whether these mutations correlate with treatment response. We will utilize whole-
exome sequencing (WES) to achieve this goal. 
 
• Assessment of gene expression patterns and methylation profiles. As noted above, 
each of the three molecular sub-groups within IDH1/2-mutant gliomas have unique 
mutational spectra 18. Low and high glioma CpG Island Methylator Phenotype (G-CIMP) 
clusters are found within these sub-groups, which correlate with distinct gene expression 
changes, and which segregate independent of grade and histology 23. MGMT promoter 
methylation is found in the majority of IDH1/2-mutant gliomas, although clear 


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correlations with G-CIMP with regard to MGMT mRNA expression have yet to be 
defined clearly 24. MGMT status is important for both TMZ response 25 and also PARP 
inhibitor sensitization 26, and thus is likely to be an important factor to consider in the 
response to pamiparib (BGB-290) and TMZ in our study. Collectively, these data suggest 
that both methylation profiles and gene expression patterns may be important for 
understanding treatment response this study. As such, we will perform both methylation 
and gene expression profiling in for all patients using Infinium Methylation Assays and 
RNA sequencing (RNAseq), respectively.  
 
• Oncometabolite profiling via LC/MS-MS. 2HG levels can be significantly affected by 
(a) allelic and subcellular compartment differences based on specific IDH1/2 mutations 27 
and (b) by co-occurring mutations as noted above 28. As we found a dose-dependent 
relationship between 2HG and homologous recombination (HR) suppression, these two 
features many affect the response to pamiparib (BGB-290). The Li laboratory, working in 
collaboration with the Bindra laboratory, recently established at set of LC-MS/MS 
protocols to detect oncometabolites in both FFPE and frozen tissue. The Li laboratory has 
extensive expertise in the use of LC-MS/MS to measure small molecules in tissue for pre-
clinical studies and clinical trials 29-31. Here, we will correlate 2HG levels with pamiparib 
(BGB-290) and TMZ treatment response using these protocols. 
 
• Intratumoral drug level assessments via LC/MS-MS. It is now well-established that the 
blood-brain barrier (BBB) is a significant obstacle to treatment efficacy for many drugs 32. 
Pre-clinical studies indicate that pamiparib (BGB-290) is CNS penetrant, with a brain-to-
plasma ratio of ~18%, and intracranial xenograft studies have demonstrated activity of the 
drug against glioma tumors. However, the extent to which pamiparib (BGB-290) 
penetrates both enhancing and non-enhancing disease in glioma, in human subjects, is not 
yet known. As such, we will perform a phase 0 study within this trial, in which patients 
will be administered pamiparib (BGB-290) for 7 days prior to re-resection. Biopsies will 
be taken from both enhancing and non-enhancing areas of disease, which will be tested for 
the presence of pamiparib (BGB-290) by LC-MS/MS. A guide for acceptable approaches 
to identify and biopsy enhancing and non-enhancing is provided in the study lab manual. 
  
The molecular landscape of cancer is just beginning to be defined. However, there is 
inadequate knowledge about the genomic and molecular landscape of tumors from 
patients who enter early phase clinical trials. With this study, the goal is to learn more 
about specific molecular features of cancers from this patient subgroup. It is particularly 
important to learn, as early as possible, if there are molecular features within a particular 
malignant histology or across malignant histologies that can inform about potential 
response or resistance to treatments in early phase clinical trials. Such knowledge will be 
used to design more efficient later stage clinical trials for more efficient and more 
effective drug development. 
 
Measurements of Tumor Growth Rate on FLAIR: Radiographic response rate is not 
the sole imaging endpoint of interest. It is recognized that low-grade gliomas commonly 
shrink with cytotoxic chemotherapy, but this shrinkage is slow and usually does not meet 
the 50% threshold to qualify as a partial response by RANO criteria. Additionally, 


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response rates specifically for molecularly defined (IDHmt) lower-grade gliomas treated 
with chemotherapy are difficult to glean from the literature. For these reasons, several 
recent studies (e.g. AG120-881-C-001, AG120-C-002, DFCI/HCC 14-045) have utilized 
assessment of the rate of growth of FLAIR tumor volume on study treatment compared to 
the growth rate over the preceding six months to seek a biological signal of activity of the 
study treatment. Our hypothesis is that even if we do not see an adequate number of 
RANO-defined responses to meet our primary objective, we may see a marked decline in 
tumor growth rate in some subjects indicative of meaningful biological activity. The use 
of volumetric growth rate to determine whether an investigational therapy has an 
antitumor effect has precedent. For example, ivosidenib was reported to decrease the 
average tumor growth rate from 24% in the six months preceding treatment to 11% for the 
six months following treatment initiation in a cohort of 24 patients with progressing non-
enhancing IDHmt gliomas (https://doi.org/10.1093/neuonc/nox168.037). Defining a 
meaningful decrease in growth rate for an individual patient is admittedly somewhat 
arbitrary; a 100% decrease in growth rate would be an excessive threshold tantamount to 
completely stable disease. We are proposing a > 50% decrease as potentially biologically 
meaningful. 
 
3.0  PATIENT SELECTION 
 
3.1  
Patient Population 
Sample Size: 
Phase I, Dose Finding: 6-18 patients. 
Phase II: 39-78 
Surgical Portion: 10 patients 
Accrual Rate: 
2–3 patients per month.  
Gender: 
Male and female. 
Age: 
Patients must be at least 18 years of age.  
Race: 
Minorities will be actively recruited. No exclusion to this study will be based on race or 
ethnicity.  
 
 


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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 
4 
5 
1 
1 
11 
Native Hawaiian or Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
7 
10 
2 
4 
23 
White 
21 
31 
5 
7 
64 
More Than One Race 
2 
3 
1 
2 
8 
Total 
34 
49 
9 
14 
106 
 
3.2  
Eligibility Criteria 
 
1. Phase I patients must have one of the following:  (a) histologically confirmed WHO 
grade II-III glioma that is progressive or recurrent following at least one prior 
chemotherapy plus or minus radiation therapy regimen or (b) Grade IV disease in 
their recurrent resection or biopsy specimen or (c) Grade IV glioma at initial 
diagnosis, with recurrent disease. 
Phase I patients may have failed an unlimited number of prior systemic regimens. 
 
Phase II patients must have histologically confirmed WHO grade II-IV glioma that is 
progressive or recurrent following therapy: 
 
Phase 1, Phase II & Surgical Portion: Recurrence in non-enhancing tumors will be 
defined as 25% or more increase in bi-dimensional product of FLAIR signal 
abnormality (measurable disease) per the low-grade glioma (LGG) RANO criteria. 
Contrast-enhancing tumors with measurable enhancing targets will be defined as 
recurrent based on standard RANO criteria. Please refer to the Imaging Core Manual 
for further imaging requirements and submission information.  
 
Patients with recurrent glioma <12 weeks after completion of radiotherapy must have 
new enhancement outside of the RT field (beyond the high-dose region or 80% isodose 
line), or evidence of viable tumor on histopathologic sampling. 
 
• Arm A patients must have WHO grade II-III glioma and have failed TMZ and 
another alkylator (e.g., carmustine, lomustine, procarbazine). Patients in Arm A may 
have failed an unlimited number of prior systemic regimens. Prior radiotherapy (RT) 
is not required for eligibility.  
 
• Arm B patients must have WHO grade II-III glioma and have experienced tumor 
progression after TMZ or another alkylator (maximum one prior chemotherapy 
regimen), and have gone ≥ 12 months since last treatment (chemotherapy or RT). 
Prior RT is allowed but not mandated. 
 
 


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• GBM Arm patients must have WHO grade IV glioblastoma following radiotherapy 
(45-60 Gy in 1.8-2.0 Gy fractions) plus chemotherapy and may have failed an 
unlimited number of prior systemic regimens. 
 
2. Surgical Portion patients must have histologically confirmed WHO grade II-IV 
glioma that is progressive or recurrent following therapy and must be undergoing repeat 
surgery that is clinically indicated as determined by their care providers. Surgical 
Portion patients may have had an unlimited number of prior therapy regimens. 
 
3. Phase I and Phase II patients must have available at least 3 prior full sets of MRI scans 
(not including screening), each separated by at least 2 months. Sites must agree to 
provide MRI Imaging form within four weeks after treatment start. Please refer to the 
Imaging Core Manual for further imaging requirements and submission information. 
 
4. Patients must have IDH1/2-mutant glioma. IDH1/2-mutation status can be confirmed 
by immunohistochemistry (IHC) or direct DNA sequencing, provided that it is 
performed in a CLIA/CAP-certified laboratory. IDH1/2 mutations must be associated 
with neomorphic activity of the encoded proteins (i.e. IDH1 R132, IDH2 R172, IDH2 
R140, IDH1 R100, IDH1 G97, IDH1 Y13929). 
 
5. Patients must have archival FFPE specimens and mutations will be verified centrally, 
although this will not preclude patients with appropriate documentation of IDH1/2-
mutant status from trial enrollment. Patients must have a tumor tissue form indicating 
availability of archived tissue from a previous surgery, completed and signed by a 
pathologist; sites must agree to provide this form within 14 days after treatment start. 
See Section 9.5.1. 
 
6. Patients must have measurable (defined by at least 1 cm x 1 cm) contrast-enhancing 
disease or measurable abnormal T2/FLAIR hyperintensity indicative of tumor by MRI 
imaging within 21 days of starting treatment. Please refer to the Imaging Core Manual 
for further imaging requirements and submission information. 
 
7. Patients must have documented molecular 1p/19q and MGMT testing. If either of these 
studies has not been performed previously, they can be done prior to enrollment. 
 
8. 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. Please refer to the Imaging Core Manual for further 
imaging requirements and submission information. 
 
 


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9. Patients must have recovered (<CTCAE grade 2 or baseline) 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.) 
 
10. Patients must be 18 years of age or older.  
 
10. 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). 
 
11. Patients must have the following organ and marrow function: 
 
Absolute neutrophil count 
>1,500/ µL 
Platelets 
>100,000/ µL 
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 × institutional upper limit of normal 
 
12. Patients must be able to provide written informed consent. 
 
13. Women of childbearing potential must have a negative serum pregnancy test within 7 
days of first dose. Women of childbearing potential and men must agree to use highly 
effective contraception (refer to Appendix III for more details) prior to study entry, 
for the duration of study participation, and for at least 6 months after the last dose of 
study drug.  
 
Patients should consult their physician regarding what contraceptive method should 
be used. It should be noted, however, that barrier contraception (including male and 
female condoms with or without spermicide) is not considered a highly effective 
method of birth control or pregnancy prevention and if used must be combined with a 
highly effective contraceptive method. 
 
Women of childbearing potential (defined in Appendix III) must also agree to monthly 
pregnancy tests through 6 months after completion of pamiparib (BGB-290) or 
temozolomide administration. Should a woman become pregnant or suspect she is 


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pregnant while she or her partner is participating in this study or within 6 months after 
completing the study treatment, she should inform her treating physician immediately. 
The study doctor will monitor the pregnancy at least up to completion and at most up 
to 8 weeks following the delivery date (refer to Monitoring Pregnancy Section for 
more details). In addition, women who become pregnant while participating in the 
study must immediately stop taking study treatment. Men treated or enrolled on this 
protocol must also agree to use condoms in addition to 1 of the highly effective 
methods of contraception (listed in Appendix III) prior to the study, for the duration 
of study participation, and through 6 months after completion of pamiparib (BGB-
290) or temozolomide administration. If a female partner of a male patient is already 
pregnant, the male patient must use condoms during sexual intercourse for the 
duration of the study and for at least 6 months after the last dose of pamiparib (BGB-
290)  
 
Women and men should not donate and/or freeze egg/sperm while participating in the 
study and for at least 6 months after completing study treatment.  
 
                    If a woman or man is in an exclusive same-sex relationship and is not engaged in   
                    attempts to become pregnant or father a child, it is not necessary to use a highly 
                    effective contraceptive method. 
 
14. Patients must have no concurrent malignancy except curatively treated basal or 
squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or 
bladder. Patients with prior malignancies must be disease-free for  5 years. 
 
15. Patients must be able to swallow tablets and capsules. 
 
3.3  
Ineligibility Criteria 
 
1. 
Patients receiving any other investigational agents are ineligible. 
 
2. 
Patients previously treated with a small molecule inhibitor of mutant IDH1/2 proteins 
are ineligible. 
 
3. 
Patients with a history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to pamiparib (BGB-290) are ineligible. 
 
4. 
Patients who have received bevacizumab within the last 6 months are ineligible.  
 
5. 
Patients with a known hypersensitivity to TMZ are ineligible. 
 
6. 
Patients who have received a PARP inhibitor previously are excluded. 
 
7. 
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 


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EIAEDs may be enrolled if they have been off the EIAED for 10 days or more prior 
to the first dose of pamiparib (BGB-290). 
 
8. 
Patients who have not recovered to <CTCAE grade 2 toxicities apart from alopecia 
related to prior therapy are ineligible. 
 
9. 
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.  
 
10. Pregnant women are excluded from this study because the effects of pamiparib (BGB-
290) 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 pamiparib 
(BGB-290), breastfeeding should be discontinued if the mother is treated with 
pamiparib (BGB-290). 
 
11. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral 
therapy with undetectable viral load within 6 months are eligible for this trial  
 
 
4.0  
STUDY DESIGN AND TREATMENT PLAN 
 
This is a multicenter, open-label Phase I/II study of pamiparib (BGB-290) in combination 
with TMZ in patients with IDH1/2-mutant WHO grade II-IV recurrent glioma. Due to the 
potential for markedly divergent differences in prognosis between patients with WHO 
grade II-III versus WHO grade IV tumors, the subset of WHO grade IV tumor patients will 
be enrolled in a separate exploratory arm in the Phase II portion, utilizing only descriptive 
statistics to assess response to therapy.  
 
Grade II-III patients in the Phase II portion will be stratified into 2 arms based on the timing 
of prior alkylator chemotherapy exposure; a third arm will include the subset of 
glioblastoma (grade IV) patients.  
 
Arm A includes alkylator-refractory, poor risk patients. These patients have recurrent 
IDH1/2-mutant glioma (WHO grades II/III) who have failed TMZ and another 
alkylator. 
 
Arm B includes distant alkylator failure, favorable risk patients. These patients have 
recurrent IDH1/2 mutant glioma (WHO grades II/III) who have failed TMZ or another 
alkylator (at most one chemotherapy regimen) and have gone ≥ 12 months since last 
treatment (chemotherapy or RT). 
 
 


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Patients will receive pamiparib (BGB-290) at a dose of 60 mg PO BID on days 1 to 28 of 
28-day cycles plus TMZ at a dose to be established in the Phase I portion, until disease 
progression, unacceptable toxicity, withdrawal of consent, or death.  
 
A subset of patients planning to undergo a biopsy or re-resection will be eligible for a 
correlative sub-study, in which pamiparib (BGB-290) will be administered for 7 days prior 
to surgery.  
 
Correlative studies will include pamiparib (BGB-290) drug levels, 2HG production, and 
PARylation levels in tumor tissue specimens from enhancing and non-enhancing sites of 
disease in the sub-study.  
 
4.1  
Phase I Treatment Plan  
 
The Phase I portion will determine the MTD of the combination of pamiparib (BGB-290) 
and TMZ and will be open to patients with IDH1/2-mutant WHO grade II-IV recurrent 
glioma. 
 
A single dose level of pamiparib (BGB-290) (60 mg BID) will be tested in combination 
with flat-dosing of TMZ. TMZ starting dose has been chosen to match active studies by 
Beigene in newly diagnosed and recurrent GBM (NCT03150862) and solid tumors.  
 
Arm A: Alkylator-resistant 
recurrent grade II/III glioma 
patients 
Failed TMZ and another 
alkylator  
Arm B: Not Alkylator-
resistant recurrent grade 
II/III glioma patients 
Failed TMZ or another 
alkylator;  
>12 months since last 
treatment 
GBM Arm (exploratory): grade IV 
patients 
Progressed following RT + chemo 
Surgical Portion 
(recurrent IDH1/2-mutant 
grade II-IV glioma: 
surgically eligible patients) 
Pamiparib (BGB-290) at Ph 
II dose for 7 days pre-
surgery 
Phase II Portion 
(recurrent IDH1/2-mutant grade II-IV 
glioma) 
Pamiparib (BGB-290) + TMZ at the dose 
combination established in the Ph I 
portion 
Phase I Portion – Dose Finding: 
(recurrent IDH1/2-mutant grade II-IV 
glioma) 
Pamiparib (BGB-290): Days 1-28, 60 
mg PO BID  
TMZ: Days 1-28, 20 QD 


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Pamiparib (BGB-290) will be administered orally, in capsule formation, at 60 mg PO BID. 
Flat-dosing will be used for TMZ. The first dose level of 20 mg QD days 1-28 every 28 
days corresponds to 11.5 mg/m2 assuming an average body surface area of 1.73 m2. If 
needed dose levels (-1, -2 and -3) will utilize the same dose for days 1-21, days 1-14, and 
days 1-7 every 28 days, respectively.  
 
Pamiparib (BGB-290) will be given orally twice daily on Days 1 to 28 of 28-day cycles. 
TMZ will be given orally once daily on treatment days as defined per the dose level. The 
safety evaluation period is at the completion of the initial cycle of treatment. The standard 
3+3 design will be used for dose-finding. Dose escalation will be done in a stepwise fashion 
to have 6 patients treated at a putative MTD.  The target DLT rate is 33%. The MTD is 
defined as the dose of pamiparib (BGB-290) in combination with TMZ that yields a dose 
limiting toxicity rate of less than or equal to 33%.  
  
 
 
 
 
 
 
 
 
 
 
 
 
Patients will be followed by routine blood work, general and neurological examination, 
and MR imaging. Please refer to the Imaging Core Manual for further imaging 
requirements and submission information. See Section 9.1 for schedule. 
 
Patients may continue to receive cycles of pamiparib (BGB-290) until tumor progression 
via LGG RANO (van den Bent et al., Lancet Oncol 2011; 12:583-93) or standard RANO, 
depending on tumor grade at time of treatment, development of unacceptable toxicity, or 
meeting other criteria for going off treatment (Section 10.1). Patients will be followed for 
adverse events for at least 30 days after the last dose of pamiparib (BGB-290). All patients 
will be followed for survival. 
 
 
Phase I: All Cycles (28-day cycles) 
(recurrent IDH1/2-mutant grade II-IV glioma) 
 
Pamiparib (BGB-290): 60 mg PO BID, Days 1-
28 
TMZ: starting dose 20 mg PO per day, Days 1-28 
  
MRI performed every 8 
weeks until progression 


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4.1.1 Dose Finding 
 
Pamiparib (BGB-290) will be given at 60 mg BID at each dose/schedule; the dose of 
TMZ will be de-escalated/changing the treatment schedule, as shown in the table below if 
necessary: 
 
Phase I dose/schedule de-escalation 
  
 
 
 
 
 
 
  
*Pamiparib (BGB-290) will be dose reduced only after discussion with Study Chair 
 
The standard 3+3 design will be used for dose finding. Three patients will be enrolled per 
dose/schedule cohort. If no DLTs are observed in the first 3 patients at Dose Level 1, 3 
additional patients will be enrolled at Dose Level 1 before pursuing Phase II of the 
protocol. If 1/3 of the patients develops a DLT during the first 4 weeks of treatment 
beginning from the first dose of pamiparib (BGB-290), Dose/Schedule Level 1 (or any 
subsequent dose/schedule level) will be expanded by 3 additional patients at the same 
dose/schedule level. The 3 additional patients must be followed for at least 4 weeks and 
toxicity evaluated before continuing.  
 
Number of Patients with DLT at a 
Given Dose/Schedule 
Decision Rule 
0 out of 3 
Enter 3 more patients at the same dose/schedule 
1 out of 3 
Enter 3 more patients at the same dose/schedule 
2 out of 6 
This is the maximum tolerated dose/schedule 
2-3 out of 3, or ≥3 out of 6 
MTD exceeded, enter 3 patients at next lower dose/schedule 
 
Dose-limiting toxicity (DLT) is defined in Section 5.1. No intra-patient dose escalation is 
allowed. Patients will be evaluable for the cohort if they have completed at least 80% of 
their expected dose of pamiparib (BGB-290) for the first treatment cycle (28 days). Patients 
who experience a DLT will be evaluable for the cohort if they have received at least one 
dose of pamiparib (BGB-290). The toxicity evaluation period is the first 4 weeks of 
treatment.  
 
The target DLT rate is 33%. If the MTD is not reached among the pre-specified 
doses/schedules, the dose for the Phase II portion will be the highest dose/schedule studied 
for which the DLT rate is ≤ 33% in 6 evaluable patients. 
 
Dose Level 
Pamiparib 
(BGB-290) 
Temozolomide Dose/Schedule 
1 (starting dose) 60 mg BID 
20 mg QD Days 1-28 
-1 
60 mg BID 
20 mg QD Days 1-21 
-2 
60 mg BID 
20 mg QD Days 1-14 
-3 
60 mg BID 
20 mg QD Days 1-7 


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4.2 
Phase II Treatment Plan 
 
The Phase II portion will determine the overall response rate of treatment with pamiparib 
(BGB-290) combined with TMZ at the recommended Phase II dose in patients with 
recurrent IDH1/2-mutant gliomas. Patients will be stratified into the following arms: 
 
Arm A  
 
Patients who have experienced recent tumor progression despite prior treatment with 
TMZ and another alkylating chemotherapy (e.g., BCNU, CCNU or procarbazine) have 
extremely poor treatment response to subsequent chemotherapies52. The primary endpoint 
for the phase II portion will be response rate based on measurable disease. The study 
assumes the null hypothesis of response rate at 5% and will accept a 25% response rate as 
a meaningful treatment effect for pamiparib (BGB-290) with TMZ to treat 
recurrent/progressive IDH1/2-mutant glioma.  
 
Initially, 15 patients will be enrolled into Arm A. This arm of the trial will be stopped if 
no response is obtained among the first 15 patients (0/15).  Otherwise, the study will 
continue and 10 additional patients will be enrolled into Arm A. 
 
Arm B  
 
Patients who have experienced recent tumor progression after failure of TMZ or another 
alkylator and have gone ≥ 12 months since last treatment have a more favorable 
prognosis and show a range from 0-44% response rate when challenged with an 
alternative alkylating agent-based regimen 60, 61. The study assumes the null hypothesis of 
response rate at 30% for the combination regimen and will accept a 50% response rate as 
a meaningful treatment effect for pamiparib (BGB-290) with TMZ.  
 
Initially, 24 patients will be enrolled into Arm B. This arm of the trial will be stopped if 7 
or fewer responses are obtained among the first 24 patients (≤ 7/24).  Otherwise, the 
study will continue and 29 additional patients will be enrolled into Arm B. 
 
GBM Arm (exploratory) 
 
Patients with recurrent WHO grade IV GBM that harbor an IDH1/2 mutation will be 
enrolled into the exploratory arm and also treated with pamiparib (BGB-290) combined 
with TMZ. Due to the small fraction of patients with these tumors among all recurrent 
grade IV GBM (~5%), the study will enroll no more than 10 patients into this arm. This 
group will be analyzed separately from the primary cohorts and their response rates will 
be reported using descriptive statistics 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
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NCI # ABTC-1801 
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Pamiparib (BGB-290) will be given orally twice daily at 60 mg PO BID on Days 1 to 28 
of 28-day cycles. TMZ 20 mg will be given orally once daily on the schedule established 
in the Phase I portion (dose to be determined). 
 
Patients will be followed by routine blood work, general and neurological examination, 
and MR imaging. See Section 9.1 for schedule. 
 
Patients may continue to receive cycles of pamiparib (BGB-290) until tumor progression, 
development of unacceptable toxicity, or meeting other criteria for going off treatment 
(Section 10.1). Patients will be followed for adverse events for at least 30 days after the 
last dose of pamiparib (BGB-290). All patients will be followed for survival. 
 
4.3  
Surgical Portion 
 
Following completion of the Phase I portion, 10 patients with recurrent IDH1/2-mutant 
glioma (WHO grade II-IV) who are eligible for re-resection at the time of recurrence may 
be enrolled on a surgical portion of the study (pre-surgical cohort) and will receive 
pamiparib (BGB-290) 60 mg BID as a single agent for 7 days pre-surgery, including the 
day of surgery. At surgery fresh tumor tissue will be collected for correlative studies. 
Following recovery from surgery all patients will receive pamiparib (BGB-290) 
combined with TMZ post-operatively. 
 
 
All Cycles (28-day cycles) 
 
Pamiparib (BGB-290): 60 mg PO BID, Days 1-28 
 
TMZ: Once daily PO on the schedule established in 
Phase I portion (dose to be determined)  
Arm A:  
Recurrent IDH1/2-mutant 
grade II/III glioma, 
progressive after TMZ and 
another alkylator, ± RT  
MRI performed 
every 8 weeks 
until progression 
Arm B:  
Recurrent IDH1/2- mutant 
grade II/III glioma, 
progressive after TMZ or 
another alkylator, ± RT;  
≥ 12 months since last 
treatment  
GBM Arm (exploratory):  
Recurrent IDH1/2-mutant 
grade IV glioma, progressive 
following TMZ + RT 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
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Patients should begin presurgical treatment with pamiparib (BGB-290) starting 6 days 
(Day 1) prior to the day of scheduled tumor resection (Day 7). Two additional days of 
dosing are permitted if unexpected logistical problems delay the surgery. 
 
Doses of pamiparib (BGB-290) should be taken 12 hours apart ± 2 hours. On the day of 
surgery, the last pre-surgical dose must be taken 3-6 hours before surgery. The time that 
the dose is taken on the day of tumor resection must be recorded.  
 
Blood samples for determining the concentration of drug in plasma will be collected from 
patients at baseline (prior to the first pre-surgical dose), on the day of surgery, 
immediately before the resection and immediately following the resection; see Section 
9.5.2. 
 
The tumor will be resected using neuronavigation or intraoperative MRI, enabling 
resection of enhancing tumor and resection or biopsy of non-enhancing tumor.  Surgical 
resection of the non-enhancing lesions should be performed only in the non-eloquent 
areas that show FLAIR changes on MRI. Tissue may be collected from both the 
Pre-Surgery (Days 1 to 7) 
(Recurrent IDH1/2-mutant glioma: 10 surgically eligible 
patients) 
 
Pamiparib (BGB-290): 60 mg PO BID for 6 days (Days 1-6),  
 
 
   60 mg PO once on the morning of surgery (Day 7) 
Surgery (Day 7) 
 
Surgical resection 3-6 hours after 
last dose of Pamiparib (BGB-290) 
Post-Surgery 
Upon recovery (within 45 days) patients will receive in 28-day cycles: 
 
Pamiparib (BGB-290): 60 mg BID, Days 1-28 
TMZ: Once daily PO on the schedule established in Phase I portion 
(dose to be determined)  
 
(MRI performed within 21 days prior to re-starting BGB-290) 
MRI performed every 8 weeks 
until progression 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
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PI: R. Bindra 
 
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enhancing core and non-enhancing edge of individual tumors. As a reminder, please refer 
to the Imaging Core Manual for further imaging requirements and submission 
information. 
 
The concentration of pamiparib (BGB-290) will be determined in a 0.05-0.10 cm3 (50-
100 mg) section of tumor tissue obtained from a contrast enhancing and non-contrast 
enhancing region of the tumor.  See Section 9.5.2.  
 
Following surgery, all patients will continue with standard post-operative management. 
 
Following recovery from surgical resection*, all patients will receive pamiparib (BGB-
290) 60 mg BID in 28-day cycles combined with TMZ at the dose established in the 
Phase I portion (dose to be determined).  
 
*Adequate recovery from surgical resection includes, but is not limited to, the following:  
• No signs or symptoms of infections related to the surgical wound (i.e., 
increasing erythema or cellulitis of the surrounding area, large amount of 
drainage, fever)  
• Wound edges have healed 
  
Post-operatively, patients must begin treatment within 45 days of surgical resection, and 
preferably within 3 weeks of the post-operative MRI; if more than 3 weeks elapse after 
the post-operative MRI, the patient will need a new MRI (please refer to the Imaging 
Core Manual for more information). 
 
Patients will be followed by routine blood work, general and neurological examination, 
and MR imaging. See Section 9.1 for schedule. 
 
Patients may continue to receive cycles of pamiparib (BGB-290) until tumor progression, 
development of unacceptable toxicity, or meeting other criteria for going off treatment 
(Section 10.1). Patients will be followed for adverse events for at least 30 days after the 
last dose of pamiparib (BGB-290). All patients will be followed for survival. 
 
4.4  
Treatment Requirements  
 
All eligible patients who consent to this study must have a baseline (post-operative, if 
surgery is applicable) pre-treatment MRI (please refer to the Imaging Core Manual for 
more information). 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. 
 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
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PI: R. Bindra 
 
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4.5 
Drug Administration 
 
Phase I portion: To ensure accurate dose level and administration, all participating 
pharmacies must confirm dose levels with the ABTC Central Office.  Please call 410-
614-4400 to confirm the current dose level before preparing drug for administration. 
 
Treatment will be administered on an outpatient basis. No investigational or commercial 
agents or therapies other than those described below may be administered with the intent to 
treat the patient's malignancy.  
 
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. 
 
4.5.1 Pamiparib (BGB-290) Administration 
 
Pamiparib (BGB-290) capsules should be taken orally with 8 ounces of water. Patients 
are required to fast for at least one hour before and two hours after each dose of 
pamiparib (BGB-290). Capsules should be swallowed whole, not chewed or crushed. 
 
Missed doses may be made up if taken within 2 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 should record each dose of pamiparib (BGB-290) on the pamiparib (BGB-290) 
Patient Medication Diary in Appendix I. 
 
Because Pamiparib (BGB-290) is intended for self-administration, if coming to the clinic 
presents a safety risk, it is permitted to ship the study drug and the appropriate medication 
diaries to the patient’s residence before the scheduled cycle Day 1.  The study drug 
should be shipped by a secure delivery method with package tracking and a delivery 
confirmation. The regulatory requirements for maintaining investigational product remain 
and should be addressed and documented. 
 
Phase I:  
 
Pamiparib (BGB-290) Dose: 60 mg BID  
 
Pamiparib (BGB-290) will be administered twice daily continuously for each 28 day 
cycle. Each dose should be taken 12 hours apart (±2 hours), at approximately the same 
times each day. 
 
 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
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PI: R. Bindra 
 
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Phase II:  
 
Pamiparib (BGB-290) will be administered twice daily continuously for each 28 day 
cycle. Each dose should be taken 12 hours apart (±2 hours), at approximately the same 
times each day. 
 
Surgical Portion:  
 
Pre-surgery, pamiparib (BGB-290) will be administered twice daily for 6 days prior to 
scheduled surgery to remove tumor. Each dose should be taken 12 hours apart (±2 hours), 
at approximately the same times each day. A final presurgical dose should be taken the 
morning of surgery, 3-6 hours before the surgical procedure begins. 
 
Post-surgery (upon recovery, within 45 days), pamiparib (BGB-290) will be administered 
at the dose established in the Phase I portion (dose to be determined) twice daily 
continuously for each 28 day cycle. Each dose should be taken 12 hours apart (±2 hours), 
at approximately the same times each day. 
 
 
4.5.2   Temozolomide Administration 
 
Temozolomide will be administered orally on an outpatient basis once a day for the 
number of days indicated by the assigned dose level in 28-day cycles. On the days that 
pamiparib (BGB-290) is also taken, TMZ should be taken at the same time as the 
morning dose of pamiparib (BGB-290). 
 
Because Temozolomide is intended for self-administration, if coming to the clinic 
presents a safety risk, it is permitted to ship the study drug and the appropriate medication 
diaries to the patient’s residence before the scheduled cycle Day 1.  The study drug 
should be shipped by a secure delivery method with package tracking and a delivery 
confirmation. The regulatory requirements for maintaining investigational product remain 
and should be addressed and documented. 
 
Phase I Starting Dose: The starting dose of TMZ for the first cohort of patients in the 
Phase I portion will be a flat dose of 20 mg/day.  
 
Phase II and Surgical Arm (post-surgical treatment cycles): TMZ will be administered at 
the dose established in the Phase I portion (dose to be determined). 
 
Prior to each treatment cycle with temozolomide, a complete blood count (CBC) must be 
obtained (within -5 days prior to dosing). The start of all TMZ treatment cycles will be 
scheduled every 4 weeks (28 days, +3 days) after the first daily dose of temozolomide of 
the preceding treatment cycle. 
 
If liver function tests (alkaline phosphatase, total bilirubin, SGOT, SGPT) are abnormal, 
the decision to initiate temozolomide treatment should carefully consider the benefits and 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
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PI: R. Bindra 
 
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risks for the individual patient. For patients with significant liver function abnormalities, 
the benefits and risks of continuing treatment should be carefully considered. 
 
Blood counts will be evaluated weekly.  Within -5 days prior to first dose of each TMZ 
treatment cycle, the patient must have an ANC  1500/ul and platelet count  100,000/ul.  
On Day 1 of each cycle (within -5 days) all non-hematological toxicity grades 3 or 4 
(except for alopecia, nausea and vomiting), related at least possibly to TMZ must have 
resolved (NCI Common Terminology Criteria for Adverse Events (CTCAE) grade  1).  
If toxicity persists, treatment should be delayed by one week for up to 3 consecutive 
weeks. If after 3 weeks of delay all toxicity has still not resolved then any further 
treatment with temozolomide should be stopped. See Section 5.2.  
 
Capsules of temozolomide to be used in this study are available in 20 mg strengths. The 
dose administered should be recorded in the CRF.  
 
Patients will be instructed to fast during at least one hour before and one hour after 
administration of temozolomide. Water is allowed during the fast period. Patients should 
be told to swallow the whole capsules in rapid succession without chewing them. If 
vomiting occurs during the course of treatment, no re-dosing of the patient is allowed 
before the next scheduled dose. Missed doses should not be made up. A dose will be 
considered missed, and should not be made up, if more than 6 hours have passed from the 
time the dose is normally taken. 
 
Antiemetic prophylaxis with a 5-HT3-antagonist is strongly recommended. 
 
4.6  
General Concomitant Medication and Supportive Care Guidelines 
 
  
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. 
 
4.6.1 Prohibited/Restricted Concomitant Medications during Study 
 
   
There must be a period of at least 10 days from discontinuation of prohibited drugs and 
initiation of therapy unless otherwise specified in the protocol. Requests for specific 
exceptions to the required wait time can be submitted to the ABTC Central Office by 
providing a pharmacological rationale that the washout period for a particular drug 
should be less than 10 days (or as specified in the protocol); this must be approved by the 
ABTC Central Office. 
 
The primary metabolic pathway for pamiparib (BGB-290) involves the CYP3A isoform. 
The compounds/substances below are prohibited, as they are associated with possible 
interactions with pamiparib (BGB-290) through the CYP3A metabolic pathway, as well 
as other various metabolic interactions. Based on preliminary in vitro screening assays, 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
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pamiparib (BGB-290) is a moderate inhibitor of CYP2C9 (IC50 = 6.48 µM). Investigators 
need to be aware that pamiparib (BGB-290) has the potential to interfere with the 
appropriate metabolism of medications that rely on CYP2C9 and follow the prescribing 
information recommendations for use with CYP2C9 inhibitors. Examples of these 
medications are also listed below, and these should be used cautiously with drug 
concentration monitoring where appropriate. In addition to CYP3A, pamiparib (BGB-
290) can also be metabolized by CYP2C8 in human liver microsomes, but to a lesser 
extent. See below for medications that should be used with caution for the above reasons. 
 
A handout with information for patients, their caregivers and non-study healthcare 
providers on possible interactions with other drugs and herbal supplements can be found 
in Appendix II, Patient Drug Information Handout and Wallet Card.   
 
Prohibited Medications  
 
The following medications and/or therapies should not be administered within the 
timeframes specified prior to enrollment and during the study: 
 
Strong and moderate CYP3A inhibitors and Strong CYP3A inducers 
 
Strong CYP3A Inhibitors: 
Antibiotics: clarithromycin, telithromycin, troleandomycin 
Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole 
Antivirals: boceprevir, telaprevir 
Other: cobicistat, conivaptan, elvitegravir, mibefradil, nefazodone 
Protease Inhibitors: indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir 
 
Moderate CYP3A Inhibitors: 
Antibiotics: ciprofloxacin, erythromycin 
Antifungals: fluconazole 
Protease inhibitors: amprenavir, atazanavir, darunavir, fosamprenavir 
Calcium channel blockers: diltiazem, verapamil 
Tyrosine kinase inhibitors (anticancer): imatinib 
Food products: grapefruit juice (citrus 38aradise fruit juice) 
Herbal medications: Schisandra sphenanthera 
Others: aprepitant, casopitant, cimetidine, cyclosporine, dronedarone, tofisopam 
 
Strong CYP3A Inducers: 
Avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, firabutin, rifampin 
(rifampicin), St. John’s wort (hypericumperforatum) 
 
Medications to be used with caution 
Sensitive CYP2C9 Substrates or CYP2C9 Substrates with Narrow Therapeutic Index:  
Celecoxib 
Phenytoin 
Warfarin 


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Strong CYP2C8 Inhibitors:  
Gemfibrozil 
  
Herbal and Non-Traditional Medications 
  
 
 
 
 
No data exist regarding the interaction of pamiparib (BGB-290) with commonly used 
herbal or non-traditional medications. Patients should be instructed not to use such 
medications while receiving pamiparib (BGB-290) therapy. 
 
4.6.2 Anticonvulsants 
 
No data exist regarding the interaction of pamiparib (BGB-290) with enzyme-inducing 
anti-epileptic drugs (EIAEDs). For this study, patients may not be on EIAEDs; patients 
who require anti-epileptic drugs (AED) may be on non-enzyme inducing anti-epileptic 
drugs (NEIAED). If a patient on this study protocol needs to have an AED started or needs 
to have a second AED added then only NEIAED should be used.  There must be a ≥ 10 
day period from discontinuation of an EIAED and initiation of therapy.  In the event that 
an EIAED drug must be used for a patient on study the patient will be removed from the 
protocol. 
 
4.6.3 Corticosteroids 
 
Postoperatively, corticosteroids should be tapered to a stable dose as determined by the 
clinical status of the patient. The lowest required steroid dose should be maintained 
throughout the duration of the study in order to eliminate steroid effects as a confounding 
variable in the interpretation of serial brain imaging studies. Corticosteroid doses can be 
tapered as clinically indicated if the patient appears to be responding to therapy as judged 
by serial scans. Corticosteroid dose may, of course, be increased in the event of clinical 
deterioration or at the discretion of the attending physician. In the event of suspected 
clinical deterioration, repeat brain imaging is recommended. 
 
4.6.4 Antiemetics  
 
 
The use of any antiemetic deemed necessary for the care of the patient is allowed.  The 
prophylactic use of a 5-HT3-antagonist or metoclopramide is strongly recommended 
before temozolomide administration. 
  
 
 
5.0  DOSE MODIFICATION FOR TOXICITY 
 
5.1  
Dose Limiting Toxicity (DLT) 
 
A DLT is defined as a clinically significant adverse event or abnormal laboratory value 
assessed as unrelated to disease progression, intercurrent illness, or concomitant 
medications and meets any of the criteria below. Any DLT must be a toxicity considered at 
least possibly related to pamiparib (BGB-290) or TMZ. 
 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
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Dose limiting toxicities (treatment related) are defined below. Dose limiting toxicities must 
have an attribution of possible, probable, or definite to pamiparib (BGB-290) or TMZ. For 
patients experiencing a DLT, pamiparib (BGB-290) and TMZ will be stopped.  If the patient 
recovers (≤ grade 1 [or tolerable grade 2 for non-hematologic toxicity] or ≤ baseline), refer 
to the Toxicity Management Table below for instruction on whether a dose reduction of 
TMZ or pamiparib (BGB-290) is required for subsequent doses, or whether pamiparib 
(BGB-290) and TMZ must be permanently discontinued. Skipped doses will not be made 
up. If there is any question or confusion concerning a DLT, the treating site should contact 
the ABTC Central Office to determine patient’s DLT status.  The ABTC Central Office, 
with the Study Chair, will make the final decision. 
 
➢ Hematological toxicities will be considered dose limiting if any of the following 
occur and complete blood counts and differentials were obtained according to the 
mandated schedule (CBC, differential, and platelets drawn twice a week until the 
ANC  1500/µL and platelets 100,000/µL): grade 3 or 4 lymphopenia will not be 
considered a DLT. 
   
• Grade 4 Neutrophil count decreased (ANC of < 500/µL) 
• Grade 4 Platelet count decreased (Platelets < 25,000/µL) 
• Grade 3 or 4 Febrile neutropenia 
• Any hematological toxicity that prevents administration of > 80% of the 
planned TMZ doses for the first cycle  
 
➢ Non-hematological toxicities will be considered dose limiting if any of the following 
occur: 
 
• Grades 3-4 seizure or intracranial hemorrhage 
o All 
other 
grade 
3 
neurologic 
toxicity 
(other 
than 
seizure/intracranial hemorrhage) responding within 3 days to 
steroids, anticonvulsants, or electrolyte correction will not be 
considered dose limiting. 
• Grades 3-4 severity with the following exceptions: 
o except nausea, vomiting, and diarrhea without sufficient 
prophylaxis lasting ≤3 days;  
o except alopecia;  
o except grade 3 hyperglycemia;  
o except grade 3 electrolyte disturbances that are asymptomatic 
and that respond to replacement therapy within 3 days;  
o A subject’s first episode of deep venous thrombosis (DVT) or 
pulmonary embolism (PE) will not require dose modification 
(not a DLT). 
  
ANY DLT (AS DEFINED ABOVE) CAUSING DELAY IN TREATMENT OF OVER 21 
DAYS (OR OVER 14 DAYS FOR GRADE 3 HEPATIC TOXICITY) WITHOUT 
RECOVERY TO A ≤ GRADE 1 OR BASELINE STATUS WOULD RESULT IN TAKING 
THE PATIENT OFF TREATMENT. 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
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5.2  
Dose Delay and Dose Reduction 
 
The dose levels and the approach to 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 documented on the case report form. 
 
Given the favorable safety profile of pamiparib (BGB-290), it is reasonable to assume that 
a Grade 3 or 4 toxicity is more likely to be due to the addition of TMZ to pamiparib (BGB-
290) rather than pamiparib (BGB-290) on its own. Therefore, the decision of a dose 
reduction will affect TMZ first. Should TMZ dose reduction be insufficient to ensure 
tolerability of the combination regimen, dose reduction of pamiparib (BGB-290) from 60 
mg to 40 mg or pamiparib (BGB-290)administered as a monotherapy may be discussed 
with the ABTC Central Office and the Study Chair. 
 
If pamiparib (BGB-290) is permanently discontinued, the patient will be off treatment. If TMZ 
is permanently discontinued, the patient may continue pamiparib (BGB-290) if discussed with 
and approval is received from the study co-chairs. 
 
Toxicity Management Table 
Toxicity 
Actions 
Non-hematological toxicity 
 
Grade 3 Any other 
 
Hold pamiparib (BGB-290) and TMZ until 
resolved to grade 1 or baseline and decrease 
TMZ by 1 dose level 
No dose reduction required for asymptomatic 
laboratory abnormalities 
Grade 4 Any other, with exception of fever 
Permanently discontinue pamiparib (BGB-
290) and TMZ. 
Grade 3 Cardiac 
Hold pamiparib (BGB-290) and TMZ until 
resolved to grade 1 or baseline and decrease 
TMZ by 1 dose level 
Grade 4 Cardiac 
Permanently discontinue pamiparib (BGB-
290) and TMZ. 
Prolonged QTc interval  
QTcF > 500 msec 
Obtain triplicate ECGs (5 minutes apart) ~1 
hour after initial ECG 
-If mean QTcF >500 ms, hold pamiparib 
(BGB-290) and TMZ until evaluation of 
ECGs by cardiologist 
-Cardiology evaluation as soon as practical 
but within 7 days of initial abnormal ECG 
-If mean QTcF >500 ms confirmed by 
cardiologist, permanently discontinue 
pamiparib (BGB-290) and TMZ 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
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Toxicity 
Actions 
Grade 3 or 4 Pancreatitis 
Permanently discontinue pamiparib (BGB-
290) and TMZ 
Grade 2 Hepatic (> 1.5-3 x ULN bilirubin) 
and 
Grade 3 Hepatic (> 3-10 x ULN bilirubin) 
Hold pamiparib (BGB-290) and TMZ until 
recovery to grade 1 or baseline. 
-if resolved ≤ 7 days, then maintain dose 
levels 
-if resolved > 7 days, then decrease TMZ by 
1 dose level 
Grade 4 Hepatic (> 10 x ULN bilirubin) 
Permanently discontinue pamiparib (BGB-
290) and TMZ. 
Note: if grade 3 or 4 hyperbilirubinemia is 
due to indirect (unconjugated) component 
only, and hemolysis as the etiology has been 
ruled out per institutional guidelines, then 
decrease TMZ by 1 dose level and continue 
treatment at the discretion of the investigator  
Grade 3 Hepatic (> 5 and  20 x ULN AST and/or 
ALT) 
Hold pamiparib (BGB-290) and TMZ until 
AST and/or ALT resolved to  5 x ULN or 
baseline. 
-if  5 x ULN within 14 days, then decrease 
pamiparib (BGB-290) and TMZ by 1 dose 
level 
-if second episode, permanently discontinue 
pamiparib (BGB-290) and TMZ 
-If persistent for > 14 days, permanently 
discontinue pamiparib (BGB-290) and TMZ 
Grade 4 Hepatic (> 20 x ULN AST and/or ALT) 
Permanently discontinue pamiparib (BGB-
290) and TMZ. 
Grade 3 Renal (> 3-6 x ULN serum creatinine) 
and 
Grade 4 Renal (> 6 x ULN serum creatinine) 
Permanently discontinue pamiparib (BGB-
290) and TMZ. 
Serum creatinine 2-3 x ULN 
Hold pamiparib (BGB-290) and TMZ until 
recovery to grade 1 or baseline. 
-if resolved ≤ 7 days, then maintain dose 
levels 
-if resolved > 7 days, then decrease TMZ by 
1 dose level 
 
 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
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Toxicity 
Actions 
Hematological toxicity 
 
Grade 3 Thrombocytopenia (platelets < 50,000 ≥ 
25,000/µL)  
Hold pamiparib (BGB-290) and TMZ until 
recovery to platelets   100000 µl or 
baseline. 
-if resolved ≤ 7 days, then maintain dose 
levels 
-if resolved > 7 days, then decrease TMZ by 
1 dose level 
Grade 4 Thrombocytopenia (platelets < 25,000/µL) Hold pamiparib (BGB-290) and TMZ until 
resolved to platelets   100000 µl or 
baseline and decrease TMZ by 1 dose level 
Grade 3 Neutropenia (neutrophils < 1,000 ≥ 500/µL) 
Hold pamiparib (BGB-290) and TMZ until 
resolved to ≥ 1500/µl  or baseline 
-if resolved ≤ 7 days, then maintain dose 
levels 
-if resolved > 7 days, then decrease TMZ by 
1 dose level 
Grade 4 Neutropenia (neutrophils < 500/µL) 
Hold pamiparib (BGB-290) and TMZ until 
resolved to Grade  1 or baseline and 
decrease TMZ by 1 dose level 
Febrile neutropenia (ANC < 1,000 with single 
temperature of > 38.3°C or sustained temperature of ≥ 
38°C for > 1 hour) 
Hold pamiparib (BGB-290) and TMZ until 
resolved and decrease TMZ by 1 dose level 
Grade 2 Anemia (Hb < 10 - 8 g/dL) 
First occurrence: continue dosing at current 
dose level. 
Second and subsequent occurrences: hold 
pamiparib (BGB-290) and TMZ until 
resolved to ≤ Grade 1 or baseline: 
-if resolved ≤ 14 days, then maintain dose 
levels 
-if resolved > 14 days, then ↓ TMZ by 1 dose 
level and continue pamiparib (BGB-290) at 
same dose 
Grade 3 Anemia (Hb < 8 g/dL) 
Hold pamiparib (BGB-290) and TMZ until 
resolved to Grade  1 or baseline 
-if resolved ≤ 7 days, then maintain dose 
levels 
-if resolved > 7 days, then decrease TMZ by 
1 dose level 
 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
44 
 
 
Version 07/07/22 
 
Toxicity 
Actions 
Grade 4 Anemia (life threatening consequences; 
urgent intervention indicated) 
Hold pamiparib (BGB-290) and TMZ until 
resolved to Grade  1 or baseline and 
decrease TMZ by 1 dose level 
 
 
5.2.1 Dose Modification for Temozolomide and Pamiparib (BGB-290) 
 
Dose reductions are required as indicated in the toxicity table above for any dose limiting 
toxicity (as defined in Section 5.1). Dosing will stop until the DLT has resolved to ≤ grade 
1 [or tolerable grade 2 for non-hematologic toxicity] or ≤ baseline. The maximum length 
of time that pamiparib (BGB-290) and TMZ can be held is 21 days, or as stipulated in the 
table. After resolution, the dose of TMZ will be modified as stipulated below, with a 
maximum of 2 dose reductions. If treatment-related toxicity is not resolved in  21 days 
(or as stipulated), the patient will be considered for monotherapy with pamiparib (BGB-
290). If there is any question, the ABTC Central Office and the study chair should be 
contacted. 
 
 
 
TMZ Dose Reduction Schedule 
Dose level 
Temozolomide dose 
Dose reduction 1 
Dose reduction 2 
1 (starting 
dose) 
20 mg QD Days 1-28 
20 mg QD Days 1-21 
20 mg QD Days 1-
14 
-1  
20 mg QD Days 1-21 
20 mg QD Days 1-14 
20 mg QD Days 1-7 
-2 
20 mg QD Days 1-14 
20 mg QD Days 1-7 
Either off study or 
pamiparib (BGB-
290) alone 
-3 
20 mg QD Days 1-7 
Either off study or 
pamiparib (BGB-290) 
alone 
N/A 
 
Blood counts will be evaluated weekly.  Within -5 days prior to first dose of each cycle 
the patient must have an ANC  1500/ul and platelet count  100,000/ul.  On Day 1 of 
each cycle (within -5 days) all non-hematological toxicity grade 3 or 4 (except for 
alopecia, nausea and vomiting) must have resolved (CTCAE grade  1).  If toxicity 
persists, treatment should be delayed by one week for up to 3 consecutive weeks. If after 
3 weeks of delay all toxicity has still not resolved then any further treatment with 
temozolomide should be stopped (patient is off treatment). 
 
If pamiparib (BGB-290) must be modified as stipulated in the Toxicity Management 
Table, the dose of pamiparib (BGB-290) will be modified as shown below, with a 
maximum of 2 dose reductions. 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
45 
 
 
Version 07/07/22 
 
 
Pamiparib (BGB-290) Dose Reduction Schedule 
Dose Level 
Pamiparib (BGB-290) 
Starting dose 
60 mg b.i.d. 
First dose reduction 
40 mg b.i.d. 
Second dose reduction 
20 mg b.i.d. 
5.3  
Major Events 
Major events are non-treatment-related grade 3 or 4 hematologic and non-hematologic 
adverse events. Treatment should be delayed for major events if pamiparib (BGB-290) may 
further complicate the non-treatment-related event.  If a major event requires a delay of 
treatment, treatment must be delayed until the event is resolved (≤ grade 1 or ≤ baseline). If 
the event 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. 
5.4  
Use of Hematologic Growth Factors 
No growth factors (G-CSF or GM-CSF) are to be used prophylactically in this protocol.  
Clinicians caring for patients on this protocol are permitted to use these growth factors to 
provide optimal care for patients with severe neutropenia in accordance with the ASCO 
guidelines, (JCO, 12, 1994: pp2471-2508).  If these growth factors are used in the acute 
setting of neutropenia and infection (documented or suspected), they will not be utilized 
prophylactically in subsequent cycles and they will not subsequently be used in lieu of dose 
reduction of pamiparib (BGB-290) or TMZ. 
5.5  
Toxicity Criteria 
All toxicities will be described and graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0.  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 9.2.1, Recording of Adverse Events. 
 
6.0  PHARMACEUTICAL INFORMATION 
 
6.1  
Pamiparib (BGB-290) (NSC# 803412) 
 
Chemical Name: (R)-2-fluoro-10a-methyl-5,8,9,10,10a,11-hexahydro-5,6,7a,11-
tetraazyacyclohepta[def]cyclopenta[a]fluoren-4(7H)-one 
Molecular Formula: C16H15FN4O 
Molecular Mass: 298 
 
Mode of Action: highly potent and selective PARP inhibitor, binds to PARP enzyme and 
prevents PARP-mediated repair of single-stranded DNA breaks via base-excision repair, 
thus enhancing the accumulation of DNA double strand breaks. 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
46 
 
 
Version 07/07/22 
 
 
How Supplied: supplied by BeiGene Ltd. pamiparib (BGB-290) pellet-in-capsules are 
provided in a container with a child-resistant closure. Each container is labeled with space 
to enter the subject’s ID, treatment and period number. The label is pre-printed and includes 
content and quantity of pamiparib (BGB-290), protocol number, batch number, 
administration instructions, storage instructions and expiry date. Subjects will receive 
pamiparib (BGB-290) as 10 mg, 20 mg or 40 mg capsules, depending on dose level and 
availability. 
 
Storage: Pamiparib (BGB-290) must be kept at 15°C to 30°C. An accurate study drug 
accountability log must be maintained and kept up to date at all times. 
 
Stability: Pamiparib (BGB-290) is an oral formulation. The drug should be stable at 
minimum until the expiration date on the bottle. 
 
Route of Administration: Pamiparib (BGB-290) is taken by mouth with 8 ounces of water 
while fasting. 
 
Known Potential Drug Interactions: Strong and moderate CYP3A inhibitors and strong 
CYP3A inducers are prohibited due to potential for drug interactions. Strong CYP2C8 
inhibitors and sensitive CYP2C9 substrates or CYP2C9 substrates with narrow 
therapeutic index should be used with caution. 
 
Contraindications: Pamiparib (BGB-290) should not be used in patients who are pregnant. 
 
6.1.1  Agent Ordering 
 
Pamiparib (BGB-290) may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution.  The eligible participating 
investigators at each participating institution must be registered with CTEP, DCTD through 
an annual submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent 
Shipment Form, and Financial Disclosure Form (FDF).   
 
Once a site has submitted all required regulatory documents to ABTC and BeiGene (Form 
1572, curriculum vitae, licenses, IRB approval of protocol and consent), 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 of 
the drug. The ABTC Central Office will forward the drug order form to BeiGene. Please 
allow 7 days from the receipt of the drug order form at BeiGene for drug shipment. 
 
6.1.2  Agent Accountability 
 
Each institutional Investigator, or a responsible party designated by the Investigator, agrees 
to supply drugs only to those subjects enrolled in the study and must maintain a careful 
record of the inventory and disposition of all drugs received from BeiGene, using the NCI 
Investigational Drug Accountability Record Form. Upon termination of the study, the 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
47 
 
 
Version 07/07/22 
 
Investigator or designee must complete a final inventory of supplies. 
 
6.2  
Temozolomide 
 
Generic name:  
Temozolomide 
 
Commercial name:  
Temodar® 
 
Chemical name:  
3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-as-
tetrazine-8 carboxamide 
 
Classification 
Antineoplastic agent, alkylating 
 
Molecular Formula:  
C6H6N6O2 
 
Molecular Weight:  
194.15 
 
Mechanism of Action: 
Temozolomide is not directly active but undergoes 
rapid nonenzymatic conversion at physiologic pH to 
the reactive compound 5-(3-methyltriazen-1-yl)-
imidazole-4-carboxamide (MTIC). The cytotoxicity 
of MTIC is thought to be primarily due to alkylation 
of DNA. Alkylation (methylation) occurs mainly at 
the O6 and N7 positions of guanine. 
 
Appearance:  
White to light tan/light pink powder 
 
Melting point:  
Decomposes at 206ºC 
 
How Supplied: 
Commercially available 
 
Stability:  
The molecule is stable at acidic pH (<5), and labile 
at pH >7, hence TEMODAR can be administered 
orally. The prodrug, temozolomide, is rapidly 
hydrolyzed to the active 5-(3-methyltriazen-1-
yl)imidazole-4-carboxamide (MTIC) at neutral and 
alkaline pH values, with hydrolysis taking place 
even faster at alkaline pH. The product label 
recommends Storage at 25°C (77°F); excursions 
permitted to 15°-30°C (59°-86°F).  
 
Half life:  
Temozolomide is rapidly eliminated with a mean 
elimination half-life of 1.8 hours 
 
 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
48 
 
 
Version 07/07/22 
 
 
Packaging, Dispensing and Storage 
 
Temozolomide capsules are available in 5-mg, 20-mg, and 100-mg, strengths. The 
capsules contain a white capsule body with a color cap and the colors vary based on the 
dosage strength. The 5-mg, 20-mg, 100-mg capsule strengths are available in 5-count and 
14-count packages. The product label recommends Storage at 25°C (77°F); excursions 
permitted to 15°-30°C (59°-86°F).  Labeling of the packages containing the capsules will 
be done in accordance with the local procedures (as required by law).  According to the 
dosing the hospital pharmacist delivers the temozolomide dosage for a complete cycle to 
the subject.  
 
 
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). 
 
7.1  
CTEP Registration Procedures 
 
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations require IND sponsors to select 
qualified investigators.  NCI policy requires all persons participating in any NCI-
sponsored clinical trial to register and renew their registration annually.  To register, all 
individuals must obtain a CTEP Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to Oncology Patient Enrollment Network (OPEN) 
or Rave or acting as a primary site contact) must complete their annual registration using 
CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration type are 
outlined in the table below. 
 
 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
49 
 
 
Version 07/07/22 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
NCI Biosketch (education, 
training, employment, 
license, and certification) 
 
 
 
 
HSP/GCP training 
 
 
 
 
Agent Shipment Form (if 
applicable) 
 
 
 
 
CV (optional) 
 
 
 
 
 
Additional information can be found on the CTEP website at < 
https://ctep.cancer.gov/investigatorResources/default.htm >.  For questions, please contact 
the RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
An active CTEP-IAM user account and appropriate RCR registration is required to access 
all CTEP and Cancer Trials Support Unit (CTSU) websites and applications.  In addition, 
IVRs and NPIVRs must list all clinical practice sites and IRBs covering their practice 
sites on the FDA Form 1572 in RCR to allow the following: 
• Added to a site roster 
• Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in 
OPEN 
• Act as the site-protocol PI on the IRB approval 
• Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 
 
7.2  
Site Registration Requirements – Institutional Review Board 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 be approved to enroll patients.  Assignment of site 
registration status in the CTSU Regulatory Support System (RSS) uses extensive data to 
make a determination of whether a site has fulfilled all regulatory criteria including but 
not limited to the following: 
 
 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
50 
 
 
Version 07/07/22 
 
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the Lead Network or a participating organization 
• A valid IRB approval 
• Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• Active registration status 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site. 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this 
study are not required to submit IRB approval documentation to the CTSU Regulatory 
Office. For sites using the CIRB, IRB approval information is received from the CIRB 
and applied to the RSS in an automated process. Signatory Institutions must submit a 
Study Specific Worksheet for Local Context (SSW) to the CIRB via IRB Manager to 
indicate their intent to open the study locally.  The CIRB’s approval of the SSW is then 
communicated to the CTSU Regulatory Office.  In order for the SSW approval to be 
processed, the Signatory Institution must inform the CTSU which CIRB-approved 
institutions aligned with the Signatory Institution are participating in the study. 
 
Requirements For ABTC-1801 Site Registration: 
 
• IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form, or combination is accepted ) 
 
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS.  
 
 
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab 
→Regulatory Submission  
 
 
When applicable, original documents should be mailed to: 
 
 
CTSU Regulatory Office 
 
1818 Market Street, Suite 3000 
 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
51 
 
 
Version 07/07/22 
 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the CTSU 
website.   
▪ Go to https://www.ctsu.org and log in to the members’ area using your CTEP-
IAM username and password 
▪ Click on the Regulatory tab  
▪ Click on the Site Registration tab 
▪ Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does 
not reflect compliance with protocol requirements for individuals participating on the 
protocol or the enrolling investigator’s status with the NCI or their affiliated networks. 
 
7.3  
Patient Registration 
 
Patient enrollment will be facilitated using OPEN. All site staff will use OPEN. OPEN is a 
web-based registration system available for ABTC studies from 9 a.m. to 4:30 p.m. Eastern 
Time.  To access OPEN, the site user must have an active CTEP-IAM account (check at < 
https://ctepcore.nci.nih.gov/iam >) and a 'Registrar' role on either the LPO or participating 
organization roster.  Registrars must hold a minimum of an AP registration type. 
 
All site staff will use OPEN to enroll patients to this study.  It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient 
in the Rave database. OPEN can be accessed at https://open.ctsu.org or from the OPEN tab 
on the CTSU members’ side of the website at https://www.ctsu.org. To assign an IVR or 
NPIVR as the treating, crediting, consenting, drug shipment (IVR only), or investigator 
receiving a transfer in OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR 
the IRB number used on the site’s IRB approval. 
 
Since this study includes a Phase I component, patient enrollment for this study will be 
facilitated using the Slot-Reservation System in conjunction with the registration system on 
OPEN. Prior to discussing protocol entry with the patient, all site staff must use the CTSU 
OPEN Slot Reservation System to ensure that a slot on the protocol is available to the 
patient. Once a slot- reservation confirmation is obtained, site staff may then proceed to 
enroll patients to this study.  
 
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).  
  
 
 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
52 
 
 
Version 07/07/22 
 
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.  
 
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 must 
contact the ABTC Central Office to obtain confirmation of the patient’s registration and 
dose assignment. The local investigational pharmacy should call the ABTC Central Office 
to confirm the actual dose prior to dispensing the first dose of the first cycle. No patient 
may begin treatment until registration AND dose have been confirmed by the ABTC 
Central Office. 
 
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 
Patients with measurable enhancing disease will be assessed by the high grade glioma 
(HGG) RANO (radiographic assessment in neuro-oncology) criteria64, while patients with 
only T2/FLAIR abnormalities will be assessed by the low grade glioma (LGG) RANO 
criteria63.  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. As a reminder, all 
assessments should be in compliance with the Imaging Core Manual.   
 
Measurable disease. Bi-dimensionally, 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 
non-measureable for the purpose of objective response determination. Unless progression 
is observed, objective response can only be determined when all measurable and non-
measurable lesions are assessed.  
 
 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
53 
 
 
Version 07/07/22 
 
8.1.1 HGG RANO 
 
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. 
 
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 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
54 
 
 
Version 07/07/22 
 
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, 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. 
 
8.1.2 LGG RANO 
 
Complete Response – CR (requires all of the following): 
 
a) Complete disappearance of the lesion on T2 or FLAIR imaging (if enhancement 
had been present, it must have resolved completely);  
b) no new lesions, no new T2 or FLAIR abnormalities apart from those consistent 
with radiation effects, and no new or increased enhancement;  
c) patients must be off corticosteroids or only on physiological replacement doses;  
d) patients should be stable or improved clinically 
 
Partial Response – PR (requires all of the following compared with the baseline scan): 
 
a) greater than or equal to 50% decrease in the product of perpendicular diameters of 
the lesion on T2 or FLAIR imaging sustained for at least 4 weeks compared with 
baseline;  
b) no new lesions, no new T2 or FLAIR abnormalities apart from those consistent 
with radiation effects, and no new or increased enhancement;  
c) patients should be on a corticosteroid dose that should not be greater than the dose 
at time of baseline scan, and should be stable or improved clinically 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
55 
 
 
Version 07/07/22 
 
 
Minor Response – MR (requires all of the following): 
 
a) a decrease of the area of non-enhancing lesion on T2 or FLAIR MR imaging 
between 25% and 50% compared with baseline;  
b) no new lesions, no new T2 or FLAIR abnormalities apart from those consistent 
with radiation effect, and no new or increased enhancement;  
c) patients should be on a corticosteroid dose that should not be greater than the dose 
at time of baseline scan, and should be stable or improved clinically 
 
Stable Disease – SD (requires all of the following): 
 
a) does not qualify for complete, partial, or minor response, or progression 
b) stable area of non-enhancing abnormalities on T2 or FLAIR imaging;  
c) no new lesions, no new T2 or FLAIR abnormalities apart from those consistent 
with radiation effect, and no new or increased enhancement; and  
d) patients should be on a corticosteroid dose that should not be greater than the dose 
at time of baseline scan, and should be stable or improved clinically 
 
Progressive Disease – PD (defined by any of the following): 
 
a) development of new lesions or increase of enhancement (radiological evidence of 
malignant transformation);  
b) a 25% increase of the T2 or FLAIR non-enhancing lesion on stable or increasing 
doses of corticosteroids compared with baseline scan or best response after initiation 
of therapy, not attributable to radiation effect or to comorbid events;  
c) definite clinical deterioration not attributable to other causes apart from the tumor, 
or decrease in corticosteroid dose;  
d) failure to return for evaluation because of death or deteriorating condition, unless  
caused by documented non-related disorder 
 
8.2  
Assessment of Response 
 
Assessment of response will begin with the MRI performed just prior to every odd-
numbered treatment cycle. If during any scheduled MRI, the subject has a Complete 
Response or Partial Response, the MRI should be repeated prior to the next cycle.  All 
scans are to be compared to the smallest measurement scan to date.  The subject will then 
return to the every odd-numbered cycle schedule. This is required to confirm the duration 
of response.  Subjects will be classified as responders if they have a minimum duration of 
response for 4 weeks at any time after the first cycle of pamiparib (BGB-290). 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. As a reminder, 
all assessments should be in compliance with the Imaging Core Manual. 
 
 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
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NCI # ABTC-1801 
PI: R. Bindra 
 
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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.   
 
 
Monitoring Pregnancy  
 
Pregnancy in itself is not regarded as an AE or SAE, however all reports of congenital 
abnormalities/birth defects, elective terminations for medical reasons and any serious 
complications of pregnancy (including spontaneous miscarriage, still birth and blighted 
ovum) should be reported as SAEs.   
 
In the event of any occurrence of pregnancy in a patient or the female partner of a male 
patient, the site will complete and submit (via email of fax) the Pregnancy Notification 
Report (Appendix 5) within 24 hours of awareness. All pregnancy follow-up information 
should be sent to COV PV using the Pregnancy Follow-up Report (Appendix 6). 
Pregnancy Appendix 5 and 6 can be found at the ABTC Consortium Website 
www.abtconsortium.org 
 
Monitoring of the patient should continue until conclusion of the pregnancy. The 
outcome of all pregnancies (live birth, spontaneous miscarriage, elective termination, or 
congenital abnormality/birth defects) must be followed up and documented, including 
patients who have discontinued the study, provided that the patient/partner provides 
consent. In addition, information about the pregnancy, the birth of the baby, and the 
health of the baby for up to 8 weeks after birth, even after study treatment has stopped, 
should be collected.  
 
A female study participant who becomes pregnant must be withdrawn from the study; 
however, male study participants whose partner becomes pregnant can remain in the 
study.  
 
Pregnancy cases will be followed-up every 3 months until final pregnancy outcome has 
been provided and a request for the outcome will also be issued within two weeks of the 
anticipated delivery date. Pregnancy reports will be tracked on a separate tab of the SAE 
tracker. 
 
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 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
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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. Volumetric growth rates will be assessed by first 
performing volumetric (3D) contouring of the T2/FLAIR hyperintense lesion on historic 
(pre-treatment) and on-study scans by an imaging technologist. These segmentations will 
then be signed off by board-certified neuroradiologists prior to calculation of growth rates. 
Please refer to the Imaging Core Manual for further imaging requirements and submission 
information. 
 
 
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. 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
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9.0  
MONITORING OF PATIENTS 
 
9.1  
Tables of Required Observations   
 
9.1.1 Phase I and Phase II (28-Day Cycles) 
 
Baseline 
 
Days 1-28 
of every 
cycle 
Weekly 
During 
All 
Cycles 
Pre-Odd 
Cycles 
(cycles 3+) 
Pre-Even 
Cycles 
Off  
Treatment 
30 Days 
post-last 
dose  
Pamiparib (BGB-290) 
 
6 
 
 
 
 
 
Temozolomide 
 
7 
 
 
 
 
 
AE Evaluation 
1 
 
 
5 
5 
8,10 
11 
Glucocorticoids Dose 
Evaluation 
1 
 
 
5 
 
8 
 
MRI 
1 
 
 
5 
 
8 
 
H&P/Neuro Exam 
1 
 
 
5 
5 
8 
 
KPS 
1 
 
 
5 
5 
8 
 
Vital Signs  
1,2 
 
 
2,5 
2,5 
2,8 
 
CBC, Diff, Platelets 
1 
 
9,13,15 
5,9 
5,9 
8 
 
Serum Chemistry 
1,3 
 
 
3,5 
3,5 
3,8 
 
APTT or PTT 
1 
 
 
 
 
 
 
Serum Pregnancy Test 
14,4 
 
 
 
 
 
 
Urine Pregnancy Test 
 
 
 
4,5 
4,5 
4 
 
Archived Tumor Tissue 
12 
 
 
 
 
 
 
  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: monthly pregnancy tests through 6 months after completion of pamiparib 
(BGB-290) or temozolomide administration. 
  
  5– Within minus 5 calendar days of cycle start. 
  6– Pamiparib (BGB-290) is administered orally twice daily on Days 1-28 of each 28-day cycle (see Section 4.5.1). 
Patients are required to keep a medication diary. 
7– TMZ is administered orally once daily according to the specified dose level of each 28-day cycle (see Section 
4.5.2). Patients are required to keep a medication diary. 
  8– Evaluations done within +7 days of off treatment date unless indicated: do not repeat: if MRI within minus 14 
days of off-treatment date (please refer to the Imaging Core Manual for further imaging requirements and 
submission information) ; 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 pamiparib (BGB-290). 
11– Perform within +14 days of the 30-day post-last dose date. 
12– Archived tumor tissue from a prior resection for glioma, preferably from the initial diagnosis, will be collected 
from all patients. See Section 9.5.1.  
13– ± 1 day 
14-Perform within minus 7 days of first dose 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
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NCI # ABTC-1801 
PI: R. Bindra 
 
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15- In subjects whose CBC, Diff, Platelets have been stable through the first 6 cycles, the frequency of hematologic 
testing can be reduced to a q2 weeks schedule (Day 15 of every cycle and Pre-cycle evaluation) starting in Cycle 
7. CBC, Diff, Platelets will be considered “stable” if the following criteria are met: 1) No reports of ANC<1500/µl 
in ANY of the Cycles 1-6 weekly Labs and 2) No reports of Platelets<100,000/µl in ANY of the Cycles 1-6 
weekly Labs. If at any point during treatment on the revised q2 weeks schedule the above mentioned ANC and 
Platelets criteria are not met, CBC, Diff, Platelets should be repeated twice a week until counts are recovered 
(ANC ≥1500 or Platelets ≥100,000). Once counts are recovered, the schedule of CBC, Diff, Platelets should go 
back to, and stay at, weekly monitoring (NOT q2 weeks). 
 
IMPORTANT: The guidance below is subject to applicable local Institutional Policy on telemedicine. In the event 
that local Institutional Policy regarding telemedicine differs from this guidance, then please follow local 
Institutional Policy. 
 
Telemedicine visits may be substituted for in person clinical trial visits or portions of clinical trial visits where 
determined to be appropriate and where determined by the investigator not to increase the participants risks. Prior to 
initiating telemedicine for study visits the study team will explain to the participant, what a telemedicine visit entails 
and confirm that the study participant is in agreement and able to proceed with this method. Telemedicine 
acknowledgement will be obtained in accordance with the Guidance for Use of Telemedicine in Research. In the 
event telemedicine is not deemed feasible, the study visit will proceed as an in-person visit. Telemedicine visits will 
be conducted using HIPAA compliant method approved by the Health System and within licensing restrictions. 
 
Additionally, informed consent should be obtained in person, but if deemed necessary, via telemedicine. 
 
 
9.1.2 Surgical Portion (includes pre-surgical dosing) 
 
Baseline 
 
Pre- 
Surgery 
 
Day of 
Surgery 
Post-
Surgery 
 
Post-
Surgery 
Cycles 
Weekly 
During 
All 
Cycles 
Pre-
Odd 
Cycles  
Pre-
Even 
Cycles 
Off  
Treat-
ment 
30 Days 
post-last 
dose  
Pamiparib (BGB-290) 
 
6 
6 
 
6 
 
 
 
 
 
Temozolomide 
 
 
 
 
7 
 
 
 
 
 
AE Evaluation 
1 
 
15 
16 
 
 
5 
5 
8,10 
11 
Glucocorticoids Dose 
Evaluation 
1 
 
 
16 
 
 
5 
 
8 
 
MRI 
1 
 
 
16 
 
 
5 
 
8 
 
H&P/Neuro Exam 
1 
 
 
 
 
 
5 
5 
8 
 
KPS 
1 
 
 
 
 
 
5 
5 
8 
 
Vital Signs  
1,2 
 
 
 
 
 
2,5 
2,5 
2,8 
 
CBC, Diff, Platelets 
1 
 
 
 
 
9,18,19 
5,9 
5,9 
8 
 
Serum Chemistry 
1,3 
 
 
 
 
 
3,5 
3,5 
3,8 
 
APTT or PTT 
1 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test 
4,17 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test  
 
 
 
 
 
 
4,5 
4,5 
4 
 
Archived Tumor 
Tissue  
12 
 
 
 
 
 
 
 
 
 
Blood Samples for 
Pharmacokinetics 
13 
 
13 
 
 
 
 
 
 
 
Fresh Tumor Tissue  
 
 
14 
 
 
 
 
 
 
 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
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  1– All baseline measurements must be done within minus 21 calendar days of  treatment administration unless 
otherwise specified. 
  2– Including blood pressure, respiratory rate, heart rate, temperature, weight, height: height is required at baseline only; 
weight is required at pre-odd cycle evaluations only. 
  3– Including albumin, alkaline phosphatase, total bilirubin, calcium, creatinine, magnesium, phosphorus, potassium, 
SGOT, SGPT, sodium. 
  4– For women of child-bearing potential: monthly pregnancy tests through 6 months after completion of pamiparib 
(BGB-290) or temozolomide administration.   
  5– Within minus 5 calendar days of cycle start including Pre-Cycle 1.  MRI does not need to be repeated if post-
surgical MRI is within 21 days of Cycle 1 start. Please refer to the Imaging Core Manual for further imaging 
requirements and submission information. 
  6– Pre-surgery pamiparib (BGB-290) is administered twice daily for 7-9 days prior to scheduled surgery, including the 
day of surgery;  
Post-surgery pamiparib (BGB-290) is administered orally twice daily on Days 1-28 of each 28-day cycle. See 
Section 4.5.1. Patients are required to keep a medication diary. Patients are required to keep a medication diary. 
  7– Post-surgery, temozolomide is administered once daily on according to the specified dose level of each 28-day 
cycle. See Section 4.5.2.  
  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 (please refer to the Imaging Core Manual for further imaging requirements and submission 
information).; 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 pamiparib (BGB-290). 
11– Perform within +14 days of the 30-day post-last dose date. 
12– Archived tumor tissue from a prior resection for glioma, preferably from the initial diagnosis, will be collected from 
patients. See Section 9.5.1. 
13– Blood samples will be obtained for pharmacokinetics at baseline (prior to first pre-surgical dose), and shortly before 
and after surgical resection. Section 9.5.2. 
14–Fresh tumor tissue for drug concentration will be collected day of surgery. See Sections 9.5.2. 
15– Patient should be seen on the day of surgery (prior to surgery) to evaluate for AEs. 
16– Within 3 days post-surgery. 
17- Perform within minus 7 days of first dose. 
18-± 1 day 
19- In subjects whose CBC, Diff, Platelets have been stable through the first 6 cycles, the frequency of hematologic 
testing can be reduced to a q2 weeks schedule (Day 15 of every cycle and Pre-cycle evaluation) starting in Cycle 7. 
CBC, Diff, Platelets will be considered “stable” if the following criteria are met: 1) No reports of ANC<1500/µl in 
ANY of the Cycles 1-6 weekly Labs and 2) No reports of Platelets<100,000/µl in ANY of the Cycles 1-6 weekly 
Labs. If at any point during treatment on the revised q2 weeks schedule the above mentioned ANC and Platelets 
criteria are not met, CBC, Diff, Platelets should be repeated twice a week until counts are recovered (ANC ≥1500 or 
Platelets ≥100,000). Once counts are recovered, the schedule of CBC, Diff, Platelets should go back to, and stay at, 
weekly monitoring (NOT q2 weeks). 
 
 
 
  IMPORTANT: The guidance below is subject to applicable local Institutional Policy on telemedicine. In the event 
that local Institutional Policy regarding telemedicine differs from this guidance, then please follow local 
Institutional Policy. 
 
Telemedicine visits may be substituted for in person clinical trial visits or portions of clinical trial visits where 
determined to be appropriate and where determined by the investigator not to increase the participants risks. Prior to 
initiating telemedicine for study visits the study team will explain to the participant, what a telemedicine visit entails 
and confirm that the study participant is in agreement and able to proceed with this method. Telemedicine 
acknowledgement will be obtained in accordance with the Guidance for Use of Telemedicine in Research. In the 
event telemedicine is not deemed feasible, the study visit will proceed as an in-person visit. Telemedicine visits will 
be conducted using HIPAA compliant method approved by the Health System and within licensing restrictions. 
 
Additionally, informed consent should be obtained in person, but if deemed necessary, via telemedicine. 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
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 9.2 
Adverse Events 
 
Patients will be evaluated for safety if they have received at least one dose of pamiparib 
(BGB-290). 
 
The timely reporting of AEs (including deaths) is required by the U.S. Food and Drug 
Administration. The reporting of toxicities is part of the data reporting for this study. 
Adverse events will be collected for at least 30 days following the last dose of study drug. 
Beyond this time point only newly occurring adverse events that are serious and drug-
related will be recorded. 
 
Adverse events must be reported to the ABTC Central Office and the NCI by the 
investigative site in the manner described and per the requirements of the clinical site’s IRB. 
 
Adverse events will be entered into CTEP’s iMedidata Rave database by the investigative 
site in a timely manner. See Section  – Data Collection/Reporting. 
 
9.2.1 Adverse Events and Potential Risks 
 
9.2.1.1 Adverse Events and Potential Risks with Pamiparib (BGB-290) in 
combination with Temozolomide 
 
As of 18 June 2021, a total of 208 patients have received pamiparib with 
temozolomide. The most common pamiparib and/or temozolomide side effects reported 
by these patients are listed below. In most patients, the side effects were mild and 
responded to treatment. In some patients, the side effects were long-lasting, serious, or 
required urgent treatment. Some side effects may be life-threatening or fatal. 
 
The side effects are adapted from Section 5.2.5.2 (Treatment-Emergent Adverse Events 
Assessed as Related to Study Treatment) for the pamiparib plus TMZ combination pool 
in the Pamiparib Investigator’s Brochure (IB) Edition 7. The term “side effect” implies 
causality. 
 
Adverse Drug Reactions 
 
See the Informed Consent and Investigator Brochure for the risk tables.  
 
 
9.2.1.2 Known Potential Toxicities of Temozolomide  
 
Known potential toxicities of temozolomide are hematological toxicities (leucopenia, 
lymphopenia, thrombocytopenia, and anemia), renal insufficiency, nausea and vomiting, 
liver enzyme abnormalities, lethargy, rash, headache, alopecia, constipation, 
fatigue/malaise, anorexia, hyperglycemia and diarrhea are known toxicities. Recently, 
cases of hepatic injury, including fatal hepatic failure, have been observed in patients 
enrolled in clinical studies utilizing the agent temozolomide. In addition, it was noted that 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
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liver toxicity may occur several weeks or more after initiation of treatment or after 
temozolomide discontinuation. Refer to the package insert for additional information on 
adverse events observed to date.  
Rats given temozolomide in recent multidose toxicity studies have developed 
adenocarcinoma of the breast, fibrosarcomas, malignant Schwannomas (a variant of 
fibrosarcoma), keratoacanthomas and basal cell adenomas. Similar studies conducted in 
dogs did not reveal any similar findings. The significance of this finding for humans is 
not known presently. 
Temozolomide is potentially mutagenic and should be handled with appropriate 
precautions by both staff and subjects. Subjects with known or suspected hypersensitivity 
to temozolomide should not be treated with temozolomide. There are no data available on 
the effect or management of temozolomide overdose. 
Additional information is available in the temozolomide package insert 
(www.temodar.com) 
 
9.2.2 Adverse Event Characteristics 
 
Definition - Adverse Event (AE) 
 
Adverse event is defined as any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of a medical 
treatment or procedure regardless of whether it is considered related to the medical 
treatment or procedure (attribution of unrelated, unlikely, possible, probable, or definite). 
 
Recording of Adverse Events - ABTC AE Form  
 
• 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 5.0 will be utilized for AE reporting.  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. 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
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• Attribution of the AE: The investigator will be asked to document his/her opinion of 
the relationship of the event to study medication as follows: 
 
 
- Unrelated – The AE is clearly not related to the investigational agent(s). 
- Unlikely – The AE is doubtfully related to the investigational agent(s). 
- Possible – The AE may be related to the investigational agent(s). 
- Probable – The AE is most likely related to the investigational agent(s). 
- Definite – The AE is clearly related to the investigational agent(s). 
 
• All adverse events should be followed up in accordance with good medical practice.  
Abnormalities of laboratory events which, in the opinion of the investigator, 
constitute adverse events (even if not serious) should be followed. 
 
9.3  
Serious Adverse Events and Expedited Adverse Event Reporting 
 
9.3.1 Definition – Serious Adverse Event (SAE) 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
5) A congenital anomaly/birth defect 
6) Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
 
9.3.2 Expedited Adverse Event Reporting 
 
➢ 
Use CTEP-AERS Web Application and Document on ABTC AE Form  
 
• All SAEs must be documented on both the ABTC AE form and using the CTEP-
AERS Web Application within 24 hours of learning of the event. 
 
• Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse 
Event Reporting System), accessed via the CTEP web site (https://eapps-
ctep.nci.nih.gov/ctepaers). 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. 
 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
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• ABTC will be notified automatically when an SAE is reported through CTEP-
AERS (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. BeiGene is 
responsible for reporting all applicable SAEs to the FDA.  
 
• 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: 410-367-3208 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
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OR JOY FISHER, ABTC MANAGER: 410-955-3657 / 410-599-4610 
 
  
 
These events also must be reported by the investigator to the appropriate Institutional 
Review Board (IRB). 
 
Patients who are removed from study due to adverse events should be followed until the 
adverse event has resolved or stabilized.  Copies of relevant documentation, such as 
laboratory reports, should be kept with the patient's study records. 
 
Secondary Malignancy  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm.  
Any secondary malignancies that occur following treatment with pamiparib (BGB-290) 
should 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. 


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9.5  
Correlative Studies 
 
Exploratory biomarker and correlative studies are focused on identifying key molecular 
correlates of treatment response. A subset of patients will be accrued to a surgical 
component of the study in which pamiparib (BGB-290) is administered prior to re-
resection to assess intra-tumoral drug levels. 
 
30 unstained FFPE slides are required for all patients enrolled on this study, typically 
from the initial diagnosis specimen. Exceptions will be made in cases where there is 
limited tissue, upon approval by the study Chairs. All samples, including blood and 
tissue, will be sent to the Bindra laboratory for distribution to the study collaborators.  
 
9.5.1 Archival Tumor Tissue (all patients) 
 
2HG Quantification 
Quantification of 2HG in archival FFPE specimens via LC-MS detection and correlation 
with treatment response will be performed in collaboration with Jing Li, PhD 
(Pharmacology Core, Karmanos Cancer Institute [KCI], Wayne State University School 
of Medicine), using optimized protocols developed by Li and Bindra. 
Response Correlation with 2HG, Somatic Alterations, Gene Expression/Methylation 
Patterns 
Response correlation with 2HG, somatic alterations, and gene expression/methylation 
patterns in FFPE tumor tissue will be performed in collaboration with the Translational 
Genomics Research Institute (TGen). TGen investigators have participated in the initial 
TCGA efforts to sequence glioblastoma 33. Subsequently, prospective precision medicine 
trials in recurrent adult GBM (NCT02060890) and pediatric DIPG (NCT02274987) 
demonstrate core competencies to support correlative trials. Sequencing pipelines 
developed at TGen have also been utilized for identification of genomic signatures of 
vulnerability in adult GBM patients via a retrospective analysis 34.   
Archival FFPE Slide Preparation and Shipping Requirements: 
Each submitting institution should submit 30 unstained sections from a previous surgery 
for glioma, preferably the initial diagnosis specimen, 5 microns thick, mounted on 
standard glass microscope slides. 
Tissue Specimens should be mailed according to these instructions: 
1. 
Label the samples with the following information: 
 
ABTC Protocol Number (ABTC 1801) 
Description (FFPE slides) 
Patient Study ID Number 
Date of Collection  
Time of Collection 
  


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2. 
Complete the “shipping manifest for research specimen collection and shipping” (see 
SOP/Lab Manual) 
3. 
Place the FFPE slides in a plastic zip lock bag and wrap in bubble wrap or another 
type of padded material prior to shipping.  The zip lock bag can be placed into a 
FedEx envelope or small shipping box. 
4. 
Verify that the FedEx air bill is marked Standard Overnight Shipping. 
5. 
Call Courier Service to pick up specimens. 
6. 
Ship overnight (Mon-Thur). No shipments will occur over weekends or holidays.  
Prior to any shipment, please notify Dr. Ranjit Bindra via email and/or telephone. 
The samples will be shipped to the following address: 
 
Laboratory of Dr. Ranjit Bindra 
c/o Ranjini Sundaram 
Yale University School of Medicine 
15 York, HRT205 
New Haven, CT 06520 
Email:  ranjit.bindra@yale.edu 
 
9.5.2 Brain Tissue Concentrations and Plasma Pharmacokinetics (Surgical Portion) 
 
Tumor tissue pamiparib (BGB-290) levels, 2HG, and PARylation will be assessed in a 
patient subset treated with drug prior to re-resection (Surgical Portion), using optimized 
protocols in the Li group as noted in Section 9.5.1, and also based on methodology 
developed and validated in the Bindra laboratory.  
 
Blood samples for pharmacokinetics will be drawn at baseline (prior to first pre-surgical 
dose) and immediately before and after surgery. The PK sample drawn immediately 
before surgery must be taken following the Day 7 dose (which is taken 3-6 hours prior to 
surgery). 
 
The concentration of pamiparib (BGB-290) will be determined in a 0.05-0.10 cm3 (50-
100 mg) section of tumor tissue obtained from a contrast enhancing and non-contrast 
enhancing region of the tumor. Doses of pamiparib (BGB-290) should be taken at 
approximately the same time, in the morning, for 7 days (up to 9 days if surgery is 
delayed) with the last preoperative dose taken 3 to 6 hours prior to surgery.  
 
Accurately record the time that the dose is taken prior to the tumor resection. The 
surgical procedure must be performed at least 3 hours but not longer than 8 hours after 
dosing.  The biopsy specimens submitted for drug concentration determinations should be 
resected as close to 3-6 hours after dosing as possible, but not more than 8 hours after 
dosing.  
 
Collection, preparation and shipping instructions for the frozen tissue specimens and the 
corresponding blood samples are provided in the study lab manual. 
 
 


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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 AEs 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(s) 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 AEs for at least 30 days from the last 
dose of pamiparib (BGB-290). 
 
 
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. Please refer 
to the Imaging Core Manual for further imaging requirements and submission 
information. 
 
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. 
 
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 the constraints of this 
protocol are detrimental to the patient’s health remove the patient from protocol 
therapy. 
 
 


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6. Protocol Defined Delay:  
• Patients will be off treatment who experience a treatment-related toxicity causing a 
delay in treatment >21 days.  Note: Patients who experience grade 3 hepatic toxicity 
will be off treatment if treatment-is delayed >14 days. 
• Delay in protocol >28 days for major events or other non-treatment related delays 
• Patients who require >2 dose reductions 
 
7. Death 
 
10.2 
Off-Study Criteria and Survival Follow-Up 
 
Patients will only be off study at the time of death. Patients will be followed every two 
months for progression, for up to one year from the off-treatment date. All patients will be 
followed for survival every 2 months for the first 2 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). 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
Phase I /Dose Finding  
 
The primary objective of the phase I study is to determine the safety combination 
treatment of pamiparib (BGB-290) given at a fixed dose level of 60 mg BID with TMZ 
20 mg starting at the dose level/schedule 1 (Days 1-28), then subsequently dose level -1 
(Days 1-21), dose level -2 (Days 1-14), and dose level -3 (Days 1-7) in patients with 
recurrent gliomas and IDH1/2 mutations. The standard 3+3 design will be used for dose 
finding. Three patients will be treated in a dose/schedule cohort and dose de-
escalation/changing treatment schedule, if required will take a stepwise fashion with 
expansion to a total of 6 patients at a putative MTD/ or highest safe dose/schedule. The 
target DLT rate is 33%.  
 
The MTD is defined as the combination regimen that yields a DLT rate less than, or 
equal to 33%.  
 
The safety evaluation period is 28 days (the first cycle of treatment) for dose escalation 
decisions. All safety and toxicity will be followed and data will be collected till 90 days 
after discontinuation of the treatment.       
 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be 
used for scoring toxicity and adverse events. The severity and frequency of toxicity will 
be tabulated by the tested doses 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. 
 


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The Phase II efficacy study will be warranted after a safe combination regimen is 
deemed.  
 
Phase II/ Safety and Efficacy  
 
The primary objective of the phase II portion of the study is to estimate treatment effect 
in terms of tumor radiographic response in two different patient populations 
independently. One is a poor risk patient population, alkylator resistant/alkylator-
refractory: Arm A. The other is favorable risk patients who had one distant alkylator 
failure: Arm B. 
 
Primary Endpoint:  
The primary endpoint for both Arm A and B is tumor radiographic response (CR+PR) 
using Response Assessment in Neuro-Oncology (RANO) criteria by measurable disease. 
 
Study Design /Sample Size: 
 
Arm A: It is a single arm design to test a hypothesis of clinical benefit of 25% 
radiographic response rate (PR+CR) for patients who failed multiple prior alkylator 
therapies and are treated with BCB290+TMZ to compare a null of 5%.  The sample size 
estimation is based on a 2-stage design (MiniMax). A total sample size of 25 patients 
yields 90% statistical power to detect 20% improvement from a null of 5% with a false 
positive rate at 5%. At the first stage, 15 patients will be enrolled onto the study. The trial 
will be stopped and the null hypothesis accepted if no response was obtained among the 
first 15 patients (0/15).  Otherwise, the study will continue to stage 2. The probability of 
early stopping for futility is 0.46 when the null is true and 0.01 when a true response is 
25%. Ten additional patients will be enrolled on the second stage of the trial. If 4 or more 
patients out of the 25 have objective response, the study will reject the null hypothesis to 
conclude that pamiparib (BGB-290) in combination with TMZ is effective to treat 
patients with recurrent, alkylator-refractory, and IDH1/2-mutant glioma.    
 
Arm B: It is a single arm study to test a hypothesis of clinical benefit of 50% 
radiographic response rate (PR+CR) for patients who failed one prior alkylator therapy 
and are treated with BCB290+TMZ to compare a null of 30%.  The sample size 
estimation is based on a 2-stage design (MiniMax). A total sample size of 53 patients 
yields 90% statistical power to detect a 20% improvement from a null of 30% with 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 7 or fewer responses were obtained 
among the first 24 patients (≤ 7/24). Otherwise, the study will continue to stage 2. The 
probability of early stopping for futility is 0.57 when the null is true and 0.03 when a true 
response is 50%. Twenty-nine additional patients will be enrolled in the second stage of 
the trial. If 22 or more patients out of the 53 have objective responses, the study will 
reject the null hypothesis to conclude that pamiparib (BGB-290) in combination with 
TMZ is effective to treat patients with recurrent, IDH1/2-mutant glioma who failed initial 
alkylator therapy.    
 


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Additional considerations on first stage/interim analysis:  
Pamiparib (BGB-290) is a potent and selective inhibitor of PARP1 and PARP2 showing 
potent DNA-trapping and anti-proliferative activity that may also interfere with DNA 
repair, delaying resistance of TMZ activity (IB). The possible mechanistic function of 
pamiparib (BGB-290) (a PARP inhibitor), might not result in tumor shrinkage directly 
but delay tumor growth when given in combination with TMZ. If the required number of 
tumor responses was not achieved at the first stage, at the same time if the tumor growth 
rate on FLAIR during 6 months of treatment is statistically significantly reduced 
compared to the growth rate 6 months prior to the treatment pre design below, *the 
findings will be presented and reviewed with CTEP to determine whether to proceed to 
the second stage of the trial.   
 
This additional interim analysis of tumor growth rate on FLAIR will be exercised, if and 
only if the expected tumor response per standard RANO criteria was not observed after 6 
months from the treatment.     
 
The estimate of tumor growth rate on FLAIR is specifically used for slow growing tumor, 
especially for low-grade gliomas to seek a biological signal of activity of a study 
treatment (e.g. AG120-881-C-001, AG120-C-002, DFCI/HCC 14-045). The tumor 
growth rate on FLAIR of 6 months is defined as a percentage change in T2 hyperintense 
volume with a minimum of 3 scans at 2 months apart during a 6-month period. 
 
Per patient, It will be considered a clinical meaningful treatment effect if there was a 
greater than or equal to a 50% reduction in the tumor growth rate on FLAIR of 6 months 
after treatment started compared to the growth rate of 6 months prior to the treatment.   
  
Arm A (High risk patients): the study will consider that a 50% of patients with the tumor 
growth rate reduction >= 50% is clinical meaningful to compare with a null of 20%. A 
total of 15 patients in the interim analysis per primary design will have a statistical power 
of857% to detect 30% difference at a target significance level of 0.06 (1-sided). It 
requires 6 or more patients out of the 15 to achieve tumor growth rate reduction on 
FLAIR of 6-month >= 50%.  
 
Arm B (Low risk patients): the study will consider that a 60% of patients with the tumor 
growth rate reduction >= 50% is clinical meaningful to compare with a null of 30%. A 
total of 24 patients in the interim analysis per primary design will have a statistical power 
of 89% to detect 30% difference at a target significance level of 0.05 (1-sided). It requires 
12 or more patients out of the 24 to achieve tumor growth rate reduction on FLAIR of 6-
month>= 50%. 
 
The definition of response for the primary endpoint will follow the response criteria 
(section 8.0) with a confirmatory MRI scan at least 4 weeks apart from the initial scan of 
response. Probability of responses will be estimated using binomial distribution along 
with 95% confidence interval. Arm A and B will be evaluated independently.    
 
 


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Secondary Endpoints:  
• Progression-free survival: the progression-free survival time is defined as the time 
from a date of treatment start to a date of the initial scan deemed tumor 
progression while patient is alive. The data will be censored if progressive disease 
was not observed at the time of data cut-off for analysis. Progression-free survival 
(PFS) and median PFS will be estimated using Kaplan-Meier method along with 
95% confidence interval.  
  
• Overall survival: survival time is defined as the time from a date of treatment 
started to a date of death. The data will be censored if patient was alive at the time 
of data cut-off for analysis. Overall survival (OS) and median OS will be 
estimated using Kaplan-Meier method along with 95% confidence interval.   
 
• Duration of the response (CR or PR): the duration of response is defined as the 
time from a date of initial scan of a response to a date of the initial scan deemed 
tumor progression. Results of the duration will be summarized using descriptive 
statistics.   
 
• Safety/toxicity: adverse events per CTCAE (version 5.0). The proportion of 
patients with serious or life threatening toxicities will be estimated along with 
95% confidence intervals.  
 
Exploratory Objectives: 
 
1. To assess tumor response rates, PFS, and OS in patients with WHO grade IV 
glioblastoma (GBM) treated with pamiparib (BGB-290) and TMZ. Ten grade IV 
recurrent IDH1/2 mutant GBM patients will be enrolled on to the GBM Arm to be 
treated with pamiparib (BGB-290)+TMZ using the combination doses defined in 
the phase I portion. The sample size is not based on a statistical considerations but 
clinical feasibility. The same tumor response criteria, definitions of OS and PFS 
for Arm A and B also apply in this GBM Arm. A tumor response rate will be 
estimated using binomial distribution (exact method) along with 95% confidence 
interval. Duration of tumor response, PFS and OS will be summarized and 
presented using standard methods.        
 
2. To assess the mutational landscape via whole-exome sequencing (WES) using the 
tumor tissue obtained from previous surgical resection or biopsy. Particular 
interests of mutated gene including ATRX, CIC, FUBP1 and CDK4. Overall 
description of possible mutations will be summarized descriptively using 
descriptive statistics. Possible association between mutations and treatment effect 
will be explored using statistical molding approach based on type of treatment 
outcomes. False discovery rate will be provided for any discovery results.              
  
3. To assess gene expression patterns using RNA sequencing (RNAseq). Overall 
description of possible gene expression patterns using RNA sequencing will be 
summarized descriptively using descriptive statistics. Possible association 


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between change in gene expression level and treatment effect will be explored 
using a statistical modeling approach based on type of treatment outcomes and 
patterns of change in gene expression. False discovery rate will be provided for 
any discovery outcomes.   
            
4. To assess the methylation profiling with Infinium Methylation Assays, 
methylation status will be quantified as either methylated or unmethylated. 
Methylation status will summarized using descriptive statistics. Possible 
association with treatment outcomes can be assessed using regression modeling. 
      
5. To quantify 2-hydroxyglutarate (2HG) in archival FFPE specimens via LC-MS 
detection and correlate with treatment response. The tumor tissues also will be 
used to quantify cellular metabolism marker (2HG) through Liquid 
Chromatography-mass Spectrometry. 2HG concentration will be measured as 
pmol/mg tissue. Output data will be normalized prior to analysis and data will be 
summarized using descriptive statistics such as mean, standard deviation, and 
quantiles etc. Regression model could be used to explore possible association with 
treatment outcomes such as stable disease versus progressive disease (primary 
clinical outcome per RANO) at a specific landmark time, or treatment responders 
(tumor response per RANO) versus non-responders, or progression-free survival 
and survival time etc. False discovery rate will be provided for any discovery 
results.                 
 
6. To explore possible association of 2HG levels, somatic alterations, gene 
expression / methylation patterns in FFPE tumor tissue, person correlation 
coefficient or spearman correlation coefficient could be used according to 
characteristics of the data. 
 
7. PK: to assess tumor tissue pamiparib (BGB-290) levels, 2HG, and PARylation in 
a patient subset treated with drug prior to re-resection. Ten clinically indicated 
surgical candidates will be enrolled onto the surgical arm for drug concentration 
and tissue biomarkers study.  The concentration of pamiparib (BGB-290) will be 
determined in a 0.05-0.10 cm3 (50-100 mg) section of tumor tissue obtained from 
a contrast enhancing and non-contrast enhancing region of the tumor. Data will be 
normalized (e.g. taking logarithms) prior to analysis. Concentration levels of 
pamiparib (BGB-290), 2HG, and PARylation will be summarized using 
descriptive statistics independently.  To characterize the steady state 
pharmacokinetics at a given dose and sampling time. Individual subject plasma 
concentration-time curves will be analyzed by non-compartmental methods using 
routines supplied in the WinNonlin Professional Version 5.0 software package 
(Pharsight Corp., Cary, NC).  The geometric mean ± standard deviation of the 
estimated values of the pharmacokinetic parameter for groups of subjects 
evaluated at the given dose level will be calculated. Pharmacokinetic parameters, 
such as Cmax, Cmin, and AUC etc will be summarized descriptively.    
 


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8. To evaluate changes in tumor growth rate of 6 months in subjects with non-
enhancing glioma based on fluid attenuated inverse recovery (FLAIR) tumor 
volume measurements of serial MRI exams. The tumor growth rate of 6 months is 
defined as a percent change of FLAIR tumor volume with non-enhancing glioma 
during a 6-month period. The difference of tumor growth rate of 6 months prior to 
treatment and during/ after treatment will be analyzed using paired t-test.    
 
9. To assess whether change in tumor growth rate (based on FLAIR tumor volume) 
in subjects with non-enhancing glioma before and after treatment is associated 
with progression by Response Assessment in Neuro-oncology for Low Grade 
Gliomas (RANO LGG; phase II patients only) or survival. Cox regression model 
will be used to assess such possible association adjusting for well-known clinical 
prognostic factors.   
 
 
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.  


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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 
 
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 Rave via 
iMedidata, the site user must have an active CTEP-IAM account (check at 
<https://ctepcore.nci.nih.gov/iam >) and the appropriate Rave role (Rave CRA, Read-
Only, CRA, Lab Admin, SLA, or Site Investigator) on either the LPO or participating 
organization roster at the enrolling site. To the hold Rave CRA role or CRA Lab Admin 
role, the user must hold a minimum of an AP registration type.  To hold the Rave Site 
Investigator role, the individual must be registered as an NPIVR or IVR.  Associates can 
hold read-only roles in Rave. 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) Abbreviated 
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. 
 


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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 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. 
 


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13.0 
REFERENCES 
 
1. Ostrom QT, Gittleman H, Fulop J, et al. CBTRUS Statistical Report: Primary Brain and Central Nervous 
System Tumors Diagnosed in the United States in 2008-2012. Neuro Oncol 2015;17 Suppl 4:iv1-iv62. 
2. Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the 
Central Nervous System: a summary. Acta Neuropathol 2016;131:803-20. 
3. Hartmann C, Meyer J, Balss J, et al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic 
and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol 2009;118:469-74. 
4. Lu Y, Kwintkiewicz J, Liu Y, et al. Chemosensitivity of IDH1-Mutated Gliomas Due to an Impairment in 
PARP1-Mediated DNA Repair. Cancer Res 2017;77:1709-18. 
5. Rohle D, Popovici-Muller J, Palaskas N, et al. An inhibitor of mutant IDH1 delays growth and promotes 
differentiation of glioma cells. Science 2013;340:626-30. 
6. Johannessen TA, Mukherjee J, Viswanath P, et al. Rapid Conversion of Mutant IDH1 from Driver to Passenger 
in a Model of Human Gliomagenesis. Mol Cancer Res 2016;14:976-83. 
7. Tateishi K, Wakimoto H, Iafrate AJ, et al. Extreme Vulnerability of IDH1 Mutant Cancers to NAD+ Depletion. 
Cancer cell 2015;28:773-84. 
8. Suijker J, Oosting J, Koornneef A, et al. Inhibition of mutant IDH1 decreases D-2-HG levels without affecting 
tumorigenic properties of chondrosarcoma cell lines. Oncotarget 2015;6:12505-19. 
9. Albarakati N, Abdel-Fatah TM, Doherty R, et al. Targeting BRCA1-BER deficient breast cancer by ATM or 
DNA-PKcs blockade either alone or in combination with cisplatin for personalized therapy. Mol Oncol 2015;9:204-
17. 
10. Mellinghoff IK. ACTR-46. AG-120, A FIRST-IN-class MUTANT IDH1 INHIBITOR IN PATIENTS WITH 
RECURRENT OR PROGRESSIVE IDH1 MUTANT GLIOMA: UPDATED RESULTS FROM THE PHASE 1 
NON-ENHANCING GLIOMA POPULATION Neuro-Oncology 2017;Volume 19:vi10–vi1. 
11. Lowery MA, Abou-Alfa GK, Burris HA, et al. Phase I study of AG-120, an IDH1 mutant enzyme inhibitor: 
Results from the cholangiocarcinoma dose escalation and expansion cohorts. Journal of Clinical Oncology 
2017;35:4015-. 
12. Lamarca A, Hubner RA, David Ryder W, Valle JW. Second-line chemotherapy in advanced biliary cancer: a 
systematic review. Ann Oncol 2014;25:2328-38. 
13. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid 
leukemia. Blood 2017;130:722-31. 
14. Sulkowski PL, Corso CD, Robinson ND, et al. 2-Hydroxyglutarate produced by neomorphic IDH mutations 
suppresses homologous recombination and induces PARP inhibitor sensitivity. Science translational medicine 
2017;9:eaal2463. 
15. Murfuni I, Basile G, Subramanyam S, et al. Survival of the replication checkpoint deficient cells requires 
MUS81-RAD52 function. PLoS genetics 2013;9:e1003910. 
16. Redon CE, Nakamura AJ, Zhang YW, et al. Histone gammaH2AX and poly(ADP-ribose) as clinical 
pharmacodynamic biomarkers. Clin Cancer Res 2010;16:4532-42. 
17. Stover EH, Konstantinopoulos PA, Matulonis UA, Swisher EM. Biomarkers of Response and Resistance to 
DNA Repair Targeted Therapies. Clin Cancer Res 2016;22:5651-60. 
18. Sulkowski PL, Corso CD, Robinson ND, et al. 2-Hydroxyglutarate produced by neomorphic IDH mutations 
suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci Transl Med 2017;9. 
19. Frezza C, Zheng L, Tennant DA, et al. Metabolic profiling of hypoxic cells revealed a catabolic signature 
required for cell survival. PLoS One 2011;6:e24411. 
20. Duncan CG, Barwick BG, Jin G, et al. A heterozygous IDH1R132H/WT mutation induces genome-wide 
alterations in DNA methylation. Genome Res 2012;22:2339-55. 
21. Reitman ZJ, Duncan CG, Poteet E, et al. Cancer-associated isocitrate dehydrogenase 1 (IDH1) R132H mutation 
and d-2-hydroxyglutarate stimulate glutamine metabolism under hypoxia. J Biol Chem 2014;289:23318-28. 
22. Pierce AJ, Johnson RD, Thompson LH, Jasin M. XRCC3 promotes homology-directed repair of DNA damage 
in mammalian cells. Genes Dev 1999;13:2633-8. 
23. Iyer LM, Tahiliani M, Rao A, Aravind L. Prediction of novel families of enzymes involved in oxidative and 
other complex modifications of bases in nucleic acids. Cell cycle 2009;8:1698-710. 
24. Loenarz C, Schofield CJ. Expanding chemical biology of 2-oxoglutarate oxygenases. Nature chemical biology 
2008;4:152-6. 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
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25. Lan F, Bayliss PE, Rinn JL, et al. A histone H3 lysine 27 demethylase regulates animal posterior development. 
Nature 2007;449:689-94. 
26. Tahiliani M, Koh KP, Shen Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in 
mammalian DNA by MLL partner TET1. Science 2009;324:930-5. 
27. Tsukada Y, Fang J, Erdjument-Bromage H, et al. Histone demethylation by a family of JmjC domain-
containing proteins. Nature 2006;439:811-6. 
28. Goglia AG, Delsite R, Luz AN, et al. Identification of novel radiosensitizers in a high-throughput, cell-based 
screen for DSB repair inhibitors. Molecular cancer therapeutics 2015;14:326-42. 
29. Turcan S, Rohle D, Goenka A, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator 
phenotype. Nature 2012;483:479-83. 
30. Bai H, Harmanci AS, Erson-Omay EZ, et al. Integrated genomic characterization of IDH1-mutant glioma 
malignant progression. Nat Genet 2016;48:59-66. 
31. Murai J, Huang SY, Das BB, et al. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Res 
2012;72:5588-99. 
32. Loser DA, Shibata A, Shibata AK, Woodbine LJ, Jeggo PA, Chalmers AJ. Sensitization to radiation and 
alkylating agents by inhibitors of poly(ADP-ribose) polymerase is enhanced in cells deficient in DNA double-strand 
break repair. Molecular cancer therapeutics 2010;9:1775-87. 
33. Michels J, Vitale I, Saparbaev M, Castedo M, Kroemer G. Predictive biomarkers for cancer therapy with PARP 
inhibitors. Oncogene 2014;33:3894-907. 
34. Di Veroli GY, Fornari C, Wang D, et al. Combenefit: an interactive platform for the analysis and visualization 
of drug combinations. Bioinformatics 2016. 
35. Mazor T, Chesnelong C, Pankov A, et al. Clonal expansion and epigenetic reprogramming following deletion or 
amplification of mutant IDH1. Proc Natl Acad Sci U S A 2017;114:10743-8. 
36. Schnittger S, Haferlach C, Ulke M, Alpermann T, Kern W, Haferlach T. IDH1 mutations are detected in 6.6% 
of 1414 AML patients and are associated with intermediate risk karyotype and unfavorable prognosis in adults 
younger than 60 years and unmutated NPM1 status. Blood 2010;116:5486-96. 
37. Kim G, Ison G, McKee AE, et al. FDA Approval Summary: Olaparib Monotherapy in Patients with Deleterious 
Germline BRCA-Mutated Advanced Ovarian Cancer Treated with Three or More Lines of Chemotherapy. Clin 
Cancer Res 2015;21:4257-61. 
38. Hu Y, Petit SA, Ficarro SB, et al. PARP1-driven poly-ADP-ribosylation regulates BRCA1 function in 
homologous recombination-mediated DNA repair. Cancer Discov 2014;4:1430-47. 
39. Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of 
poly(ADP-ribose) polymerase. Nature 2005;434:913-7. 
40. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic 
strategy. Nature 2005;434:917-21. 
41. Curtin NJ, Szabo C. Therapeutic applications of PARP inhibitors: anticancer therapy and beyond. Mol Aspects 
Med 2013;34:1217-56. 
42. Smith JS, Tachibana I, Passe SM, et al. PTEN mutation, EGFR amplification, and outcome in patients with 
anaplastic astrocytoma and glioblastoma multiforme. J Natl Cancer Inst 2001;93:1246-56. 
43. Shen WH, Balajee AS, Wang J, et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. 
Cell 2007;128:157-70. 
44. McEllin B, Camacho CV, Mukherjee B, et al. PTEN loss compromises homologous recombination repair in 
astrocytes: implications for glioblastoma therapy with temozolomide or poly(ADP-ribose) polymerase inhibitors. 
Cancer Res 2010;70:5457-64. 
45. Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide 
versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the 
EORTC-NCIC trial. Lancet Oncol 2009;10:459-66. 
46. Zhang J, Stevens MF, Bradshaw TD. Temozolomide: mechanisms of action, repair and resistance. Curr Mol 
Pharmacol 2012;5:102-14. 
47. Tentori L, Portarena I, Vernole P, et al. Effects of single or split exposure of leukemic cells to temozolomide, 
combined with poly(ADP-ribose) polymerase inhibitors on cell growth, chromosomal aberrations and base excision 
repair components. Cancer Chemother Pharmacol 2001;47:361-9. 
48. Tentori L, Turriziani M, Franco D, et al. Treatment with temozolomide and poly(ADP-ribose) polymerase 
inhibitors induces early apoptosis and increases base excision repair gene transcripts in leukemic cells resistant to 
triazene compounds. Leukemia 1999;13:901-9. 
 
 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
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49. Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009;360:765-73. 
50. Myung JK, Cho HJ, Kim H, et al. Prognosis of Glioblastoma With Oligodendroglioma Component is 
Associated With the IDH1 Mutation and MGMT Methylation Status. Transl Oncol 2014;7:712-9. 
51. Chalmers AJ, Jackson A, Swaisland H, et al. Results of stage 1 of the oparatic trial: A phase I study of olaparib 
in combination with temozolomide in patients with relapsed glioblastoma. JCO, 2014 ASCO Annual Meeting 
Abstracts 2014;32. 
52. Plummer R, Jones C, Middleton M, et al. Phase I study of the poly(ADP-ribose) polymerase inhibitor, 
AG014699, in combination with temozolomide in patients with advanced solid tumors. Clin Cancer Res 
2008;14:7917-23. 
53. Murai J, Zhang Y, Morris J, et al. Rationale for poly(ADP-ribose) polymerase (PARP) inhibitors in 
combination therapy with camptothecins or temozolomide based on PARP trapping versus catalytic inhibition. J 
Pharmacol Exp Ther 2014;349:408-16. 
54. Lok BH, Gardner EE, Schneeberger VE, et al. PARP Inhibitor Activity Correlates with SLFN11 Expression and 
Demonstrates Synergy with Temozolomide in Small Cell Lung Cancer. Clin Cancer Res 2017;23:523-35. 
55. Engert F, Schneider C, Weibeta LM, Probst M, Fulda S. PARP Inhibitors Sensitize Ewing Sarcoma Cells to 
Temozolomide-Induced Apoptosis via the Mitochondrial Pathway. Molecular cancer therapeutics 2015;14:2818-30. 
56. Smith MA, Reynolds CP, Kang MH, et al. Synergistic activity of PARP inhibition by talazoparib (BMN 673) 
with temozolomide in pediatric cancer models in the pediatric preclinical testing program. Clin Cancer Res 
2015;21:819-32. 
57. Stupp R, Dietrich PY, Ostermann Kraljevic S, et al. Promising survival for patients with newly diagnosed 
glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. 
J Clin Oncol 2002;20:1375-82. 
58. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for 
glioblastoma. N Engl J Med 2005;352:987-96. 
59. Perry JR, Belanger K, Mason WP, et al. Phase II trial of continuous dose-intense temozolomide in recurrent 
malignant glioma: RESCUE study. J Clin Oncol 2010;28:2051-7.60. 
van den Bent MJ, Chinot O, Boogerd W, et 
al. Second-line chemotherapy with temozolomide in recurrent oligodendroglioma after PCV (procarbazine, 
lomustine and vincristine) chemotherapy: EORTC Brain Tumor Group phase II study 26972. Ann Oncol 
2003;14:599-602. 
61. van den Bent MJ, Keime-Guibert F, Brandes AA, et al. Temozolomide chemotherapy in recurrent 
oligodendroglioma. Neurology 2001;57:340-2. 
62. Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high-grade gliomas: 
response assessment in neuro-oncology working group. J Clin Oncol 2010;28:1963-72. 
63. van den Bent MJ, Wefel JS, Schiff D, et al. Response assessment in neuro-oncology (a report of the RANO 
group): assessment of outcome in trials of diffuse low-grade gliomas. Lancet Oncol 2011;12:583-93. 
 
 
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. 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
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NCI # ABTC-1801 
PI: R. Bindra 
 
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APPENDIX I – PATIENT MEDICATION DIARIES 
Pamiparib (BGB-290) DIARY (Pamiparib (BGB-290) twice every day in 28-day cycles): Phase I patients; Phase 
II patients; Surgical Portion patients in post-surgical cycles 
 
Patient Name____________________________ (initials acceptable)   Patient Study ID ___________________   
 
Cycle # ____________ 
 
INSTRUCTIONS TO THE PATIENT: 
1. You will take pamiparib (BGB-290) ______ mg (___ capsules) twice per day. Take doses about 12 hours 
apart at approximately the same times each day. 
2. You must fast for at least 1 hour before and 2 hours after taking the study drug. Water is allowed during 
the fasting period.  
3. Take pamiparib (BGB-290) with 8 ounces of water. Capsules should be swallowed whole, do not chew or 
crush. 
4. Record the date and the time you took each pamiparib (BGB-290) dose.   
5. Record missed or skipped dose(s). If you miss a dose you may make up that dose if you take it within 2 
hours of the time you normally take it. There must be at least 8 hours before the next dose. 
6. 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.  
7. Bring this form and any remaining pamiparib (BGB-290) capsules when you come in for you clinic visits. 
Week Day 
Date 
Time of dose 
morning dose 
# of   
capsules 
Time of dose 
evening dose 
# of  
capsules 
Comments 
1 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
2 
8 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
3 
15 
 
 
 
 
 
 
 
16 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
4 
22 
 
 
 
 
 
 
 
23 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
Patient’s Signature __________________________________________________   Date__________________ 
 
Nurse’s Signature ___________________________________________________   Date _________________  


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
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Pamiparib (BGB-290) DIARY (Pamiparib (BGB-290) daily for 7-9 days before surgery): Surgical Portion 
patients–Pre-Surgical Treatment 
 
Patient Name____________________________ (initials acceptable)   Patient Study ID ___________________   
 
 
INSTRUCTIONS TO THE PATIENT: 
1. You will take pamiparib (BGB-290) ______ mg (___ capsules) twice per day staring 6 days prior to your 
scheduled surgery. Take doses about 12 hours apart at approximately the same times each day. 
2. You must fast for at least 1 hour before and 2 hours after taking the study drug. Water is allowed during the 
fasting period.  
3. Take pamiparib (BGB-290) with 8 ounces of water. Capsules should be swallowed whole, do not chew or 
crush. 
4. Record the date and the time you took each pamiparib (BGB-290) dose.   
5. Record missed or skipped dose(s). If you miss a dose you may make up that dose if you take it within 2 hours 
of the time you normally take it. There must be at least 8 hours before the next dose. 
6.  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.  
7. Bring this form and any remaining pamiparib (BGB-290) capsules when you come in for your surgery 
 
Day 
 
Dose of 
Pamiparib 
(BGB-290) 
 
Date 
 
Time of 
morning 
dose 
# of 
capsules 
 
Time of 
evening 
dose 
# of 
capsules 
Comments 
Day 1: 6 days prior to 
surgery  
 
 
 
 
 
 
 
Day 2: 5 days prior to 
surgery 
 
 
 
 
 
 
 
Day 3: 4 days prior to 
surgery 
 
 
 
 
 
 
 
Day 4: 3 days prior to 
surgery 
 
 
 
 
 
 
 
Day 5: 2 days prior to 
surgery 
 
 
 
 
 
 
 
Day 6: 1 day prior to 
surgery 
 
 
 
 
 
 
 
(additional day if surgery 
is delayed) 
 
 
 
 
 
 
 
(additional day if surgery 
is delayed) 
 
 
 
 
 
 
 
Day of surgical resection, 
3-6 hrs. before surgery  
 
 
 
 
 
 
 
 
 
Patient’s Signature __________________________________________________   Date__________________ 
 
Nurse’s Signature ___________________________________________________   Date _________________  
 
 
 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
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TEMOZOLOMIDE DIARY Temozolomide daily on Days 1-28 of every 28-day cycle) 
 
Patient Name____________________________ (initials acceptable)   Patient Study ID ___________________   
 
Cycle # _______ 
INSTRUCTIONS TO THE PATIENT: 
1. You will take 20 mg of Temozolomide (TMZ) on Days 1-28 of every 28-day cycle.  
Take the capsule on an empty stomach, 1 hour before a meal or 1 hour after, with water approximately the 
same times each day. 
2. On the days that the two drugs are given together, TMZ should be taken at the same time as the morning dose 
of pamiparib (BGB-290). 
3. If you miss a dose, you can take it within 6 hours after you normally take it. 
4. 
If you vomit after taking your TMZ, you should not retake that dose, resume taking your TMZ at the next 
scheduled dose. 
Dose: one 20 mg capsule. Record the date, the time you took the 20 mg capsule.  
Record missed or skipped dose(s). 
5. Bring this form and your bottles of TMZ capsules when you return for each appointment. 
 
Week Day 
 
Date 
 
Time of dose  
Comments 
1 
1 
 
 
 
2 
 
 
 
 
3 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
2 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
3 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
4 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
Patient’s Signature __________________________________________________   Date__________________ 
Nurse’s Signature ___________________________________________________   Date _________________  


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
83 
 
 
Version 07/07/22 
 
TEMOZOLOMIDE DIARY Temozolomide daily on Days 1-21 of every 28-day cycle) 
 
Patient Name____________________________ (initials acceptable)   Patient Study ID ___________________   
Cycle # _______ 
INSTRUCTIONS TO THE PATIENT: 
1. You will take 20 mg of Temozolomide (TMZ) on Days 1-21 of every 28-day cycle.  
Take the capsule on an empty stomach, 1 hour before a meal or 1 hour after with water approximately the 
same times each day. 
2. Except for on the days that the two drugs are given together, TMZ should be taken at the same time as the 
morning dose of pamiparib (BGB-290). 
3. If you miss a dose, you can take it within 6 hours after you normally take it. 
4. If you vomit after taking your TMZ, you should not retake that dose, resume taking your TMZ at the next 
scheduled dose. 
 Dose: one 20 mg capsule. Record the date, the time you took the 20 mg capsule.  
Record missed or skipped dose(s). 
1. Bring this form and your bottles of TMZ capsules when you return for each appointment. 
 
Week Day 
 
Date 
 
Time of dose  
Comments 
1 
1 
 
 
 
2 
 
 
 
 
3 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
2 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
3 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
4 
22 
(no dose) 
– 
 
 
23 
(no dose) 
– 
 
 
24 
(no dose) 
– 
 
 
25 
(no dose) 
– 
 
 
26 
(no dose) 
– 
 
 
27 
(no dose) 
– 
 
 
28 
(no dose) 
– 
 
 
Patient’s Signature __________________________________________________   Date__________________ 
Nurse’s Signature ___________________________________________________   Date _________________  
 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
84 
 
 
Version 07/07/22 
 
TEMOZOLOMIDE DIARY Temozolomide daily on Days 1-14 of every 28-day cycle) 
 
Patient Name____________________________ (initials acceptable)   Patient Study ID ___________________   
Cycle # _______ 
INSTRUCTIONS TO THE PATIENT: 
1. You will take 20 mg of Temozolomide (TMZ) on Days 1-14 of every 28-day cycle.  
Take the capsule on an empty stomach, 1 hour before a meal or 1 hour after with water approximately the 
same times each day 
2. Except for on the days that the two drugs are given together, TMZ should be taken at the same time as the 
morning dose of pamiparib (BGB-290) 
3. If you miss a dose, you can take it within 6 hours after you normally take it. 
4. If you vomit after taking your TMZ, you should not retake that dose, resume taking your TMZ at the next 
scheduled dose 
Dose: one 20 mg capsule. Record the date, the time you took the 20 mg capsule.  
Record missed or skipped dose(s). 
5. 
Bring this form and your bottles of TMZ capsules when you return for each appointment. 
 
Week Day 
 
Date 
 
Time of dose  
Comments 
1 
1 
 
 
 
2 
 
 
 
 
3 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
2 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
3 
15 
(no dose) 
– 
 
 
16 
(no dose) 
– 
 
 
17 
(no dose) 
– 
 
 
18 
(no dose) 
– 
 
 
19 
(no dose) 
– 
 
 
20 
(no dose) 
– 
 
 
21 
(no dose) 
– 
 
4 
22 
(no dose) 
– 
 
 
23 
(no dose) 
– 
 
 
24 
(no dose) 
– 
 
 
25 
(no dose) 
– 
 
 
26 
(no dose) 
– 
 
 
27 
(no dose) 
– 
 
 
28 
(no dose) 
– 
 
 
Patient’s Signature __________________________________________________   Date__________________ 
Nurse’s Signature ___________________________________________________   Date _________________  
 


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
85 
 
 
Version 07/07/22 
 
TEMOZOLOMIDE DIARY Temozolomide daily on Days 1-7 of every 28-day cycle) 
 
Patient Name____________________________ (initials acceptable)   Patient Study ID ___________________   
 
Cycle # _______ 
INSTRUCTIONS TO THE PATIENT: 
1. You will take 20 mg of Temozolomide (TMZ) on Days 1-7 of every 28-day cycle.  
Take the capsule on an empty stomach, 1 hour before a meal or 1 hour after, with water approximately the 
same times each day. 
2. Except for on the days that the two drugs are given together, TMZ should be taken at the same time 
as the morning dose of pamiparib (BGB-290). 
3. If you miss a dose, you can take it within 6 hours after you normally take it. 
4. If you vomit after taking your TMZ, you should not retake that dose, resume taking your TMZ at the next 
scheduled dose. 
Dose: one 20 mg capsule. Record the date, the time you took the 20 mg capsule.  
Record missed or skipped dose(s). 
5. Bring this form and your bottles of TMZ capsules when you return for each appointment. 
 
Week Day 
 
Date 
 
Time of dose  
Comments 
1 
1 
 
 
 
2 
 
 
 
 
3 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
2 
8 
(no dose) 
– 
 
 
9 
(no dose) 
– 
 
 
10 
(no dose) 
– 
 
 
11 
(no dose) 
– 
 
 
12 
(no dose) 
– 
 
 
13 
(no dose) 
– 
 
 
14 
(no dose) 
– 
 
3 
15 
(no dose) 
– 
 
 
16 
(no dose) 
– 
 
 
17 
(no dose) 
– 
 
 
18 
(no dose) 
– 
 
 
19 
(no dose) 
– 
 
 
20 
(no dose) 
– 
 
 
21 
(no dose) 
– 
 
4 
22 
(no dose) 
– 
 
 
23 
(no dose) 
– 
 
 
24 
(no dose) 
– 
 
 
25 
(no dose) 
– 
 
 
26 
(no dose) 
– 
 
 
27 
(no dose) 
– 
 
 
28 
(no dose) 
– 
 
 
Patient’s Signature __________________________________________________   Date__________________ 
Nurse’s Signature ___________________________________________________   Date _________________  


Phase I/II Study of Pamiparib (BGB-290) with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations 
 
ABTC # 1801 
NCI # ABTC-1801 
PI: R. Bindra 
 
86 
 
 
Version 07/07/22 
 
APPENDIX II – 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, pamiparib (BGB-290). 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: 
  
 Pamiparib (BGB-290) interacts with certain specific enzymes in your liver*.  
 
*The enzymes in question are CYP3A, CYP2C9, and CYP2C8, and pamiparib (BGB-
290) is broken down by these enzymes and may be affected by other drugs that inhibit or 
induce this enzyme.  
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
 
Pamiparib (BGB-290) 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. 
 
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:  
 
Pamiparib (BGB-290) 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/strong and moderate 
inhibitors or substrates of CYP3A: these medicines or supplements are prohibited while taking 
pamiparib (BGB-290). Medicines and herbal supplements that are considered CYP2C9 
substrates or strong CYP2C8 inhibitors should be used with caution. 
 
• 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 


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pharmacist to determine if there could be any side effects.  
• See the list below of medicines that are either prohibited on this trial or should only be used 
with caution 
• 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  
 
_____________________________________. 
 
Prohibited Medications 
 
Strong CYP3A Inducers: 
Avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, firabutin, rifampin 
(rifampicin), St. John’s wort (hypericumperforatum) 
 
Strong CYP3A Inhibitors: 
Antibiotics: clarithromycin, telithromycin, troleandomycin 
Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole 
Antivirals: boceprevir, telaprevir 
Other: cobicistat, conivaptan, elvitegravir, mibefradil, nefazodone 
Protease Inhibitors: indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir 
 
Moderate CYP3A Inhibitors: 
Antibiotics: ciprofloxacin, erythromycin 
Antifungals: fluconazole 
Protease inhibitors: amprenavir, atazanavir, darunavir, fosamprenavir 
Calcium channel blockers: diltiazem, verapamil 
Tyrosine kinase inhibitors (anticancer): imatinib 
Food products: grapefruit juice (citrus paradisi fruit juice) 
Herbal medications: Schisandra sphenanthera 
Others: aprepitant, casopitant, cimetidine, cyclosporine, dronedarone, tofisopam 
 
Medications to be used with caution: 
 
Sensitive CYP2C9 Substrates or CYP2C9 Substrates with Narrow Therapeutic Index:  
Celecoxib 
Phenytoin 
Warfarin 
 
Strong CYP2C8 Inhibitors  
Gemfibrozil 
 
 


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STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the experimental study  
drug Pamiparib (BGB-290).  This clinical trial is sponsored by the NCI.  
__________________ 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. 
 
 
 
Pamiparib (BGB-290) interacts with specific liver enzymes called 
CYP3A, CYP2C9, and CYP2C8, 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 CYP3A, CYP2C9, and CYP2C8.  
➢ 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 _________________________________.  


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APPENDIX III – CONTRACEPTION & PREGNANCY 
Women of childbearing potential must have a negative serum pregnancy test within 7 days of 
randomization. Women of childbearing potential and men must agree to use highly effective 
contraception (preferably those with low user dependency) prior to study entry, for the duration 
of study participation, and for at least 6 months after the last dose of study drug. 
The Clinical Trials Facilitation Group’s recommendations related to contraception and pregnancy 
testing in clinical trials include the use of highly effective forms of birth control.  
 
 
Highly effective contraception includes: 
• Combined (estrogen- and progestogen-containing) hormonal contraception (oral 
[also called “birth control pills”], intravaginal, or transdermal) 
• Progestogen-only hormonal contraception associated with the inhibition of 
ovulation (oral, injectable, or implantable*) 
• Intrauterine device (also called IUD)* 
• Intrauterine hormone-releasing system (also called IUS)* 
• Bilateral tubal occlusion (tying the tubes)* 
• Vasectomized male partner*, provided that the vasectomized partner is the only 
sexual partner of the woman of childbearing potential. Vasectomy is a surgical 
procedure to cut and seal the tube used to transport semen from the testicles to the 
penis. 
• Sexual abstinence (defined as refraining from having sex with a person from the 
opposite sex) during the entire period of exposure associated with the study treatment. 
 
NOTE: Total sexual abstinence should be used as a contraceptive method only if it is 
in line with the participant’s usual and preferred lifestyle. Periodic abstinence (for 
example, calendar, ovulation, natural family planning methods), declaration of 
abstinence for the duration of exposure to study treatment, and withdrawal 
(ejaculation outside of the sexual partner’s body) are not acceptable methods of 
contraception. 
*Contraception methods that in the context of this protocol are considered to 
have low user dependency. 
 
Patients should consult their physician regarding what contraceptive method should be used. It 
should be noted, however, that barrier contraception (including male and female condoms with or 
without spermicide) is not considered a highly effective method of birth control or pregnancy 
prevention and if used must be combined with a highly effective contraceptive method. 
 
Women of childbearing potential must also agree to monthly pregnancy tests through 6 months 
after completion of pamiparib (BGB-290) or temozolomide administration. Should a woman 
become pregnant or suspect she is pregnant while she or her partner is participating in this study 
or within 6 months after completing the study treatment, she should inform her treating physician 
immediately. The study doctor will monitor the pregnancy at least up to completion and at most 
up to 8 weeks following the delivery date (refer to Monitoring Pregnancy Section for more details). 
In addition, women who become pregnant while participating in the study must immediately stop 


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taking study treatment. Men treated or enrolled on this protocol must also agree to use condoms in 
addition to 1 of the highly effective methods of contraception (listed above) prior to the study, for 
the duration of study participation, and through 6 months after completion of pamiparib (BGB-
290) or temozolomide administration.  If a female partner of a male patient is already pregnant, 
the male patient must use condoms during sexual intercourse for the duration of the study and for 
at least 6 months after the last dose of pamiparib (BGB-290). 
Women and men should not donate and/or freeze egg/sperm while participating in the study and 
for at least 6 months after completing study treatment.  
 
If a woman or man is in an exclusive same-sex relationship and is not engaged in attempts to 
become pregnant or father a child, it is not necessary to use a highly effective contraceptive 
method. 
 
Definitions of “Women of Childbearing Potential”, “Women of No Childbearing Potential” 
As defined in this protocol, “women of childbearing potential” are females who are 
physiologically capable of becoming pregnant. 
Conversely, “women of no childbearing potential” are defined as females meeting any of the 
following criteria: 
• Surgically sterile (ie, through bilateral salpingectomy, bilateral oophorectomy, or 
hysterectomy) 
• Postmenopausal, defined as: 
o ≥ 55 years of age with no spontaneous menses for ≥ 12 months OR 
o < 55 years of age with no spontaneous menses for ≥ 12 months AND with a 
postmenopausal follicle-stimulating hormone concentration > 30 IU/mL and all 
alternative medical causes for the lack of spontaneous menses for ≥ 12 months 
have been ruled out, such as polycystic ovarian syndrome, hyperprolactinemia, etc. 
If an FSH measurement is required to confirm postmenopausal state, concomitant use 
of hormonal contraception or hormonal replacement therapy should be excluded. 
 
Adapted from Clinical Trials Facilitation Group (CTFG). Recommendations related to contraception and 
pregnancy testing in clinical trials. September 15,2014 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-CTFG/2014_09_HMA_CTFG_Contraception.pdf