Conditions: Recurrent Anaplastic Large Cell Lymphoma Recurrent Diffuse Large B-Cell Lymphoma Recurrent Mantle Cell Lymphoma Recurrent Transformed Non-Hodgkin Lymphoma Refractory Anaplastic Large Cell Lymphoma Refractory Diffuse Large B-Cell Lymphoma Refractory Mantle Cell Lymphoma Refractory Transformed Non-Hodgkin Lymphoma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 25
Healthy volunteers: no

Brief summary:
This phase II trial studies how well onalespib works in treating patients with anaplastic large cell lymphoma, mantle cell lymphoma, or diffuse large B-cell lymphoma that has not responded to previous treatment (refractory) or that has returned after a period of improvement (recurrent). Onalespib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVE:

I. Overall response rate (ORR) to single agent AT13387 (onalespib) as measured by the proportion of partial and complete responses (PR + CR) in patients with relapsed/refractory ALK positive (+) anaplastic large cell lymphoma (ALCL), mantle cell lymphoma (MCL), and BCL6+ diffuse large B cell lymphoma (DLBCL).

SECONDARY OBJECTIVES:

I. Progression free survival (PFS) and overall survival (OS), as well as duration of response (DOR) of single agent AT13387 (onalespib) in patients with ALK+ ALCL, MCL, and BCL6+ DLBCL.

II. Safety and tolerability of single agent AT13387 (onalespib) in patients with ALK+ ALCL, MCL, and BCL6+ DLBCL.

EXPLORATORY OBJECTIVES:

I. Measurement of on-target activity of AT13387 (onalespib) in ALK+ ALCL, MCL, and BCL6+ DLBCL through immunoblotting and immunohistochemistry of pre-treatment, on-treatment, and time of progression tumor biopsies for HSP90 clients.

II. Determination of genetic and transcriptional markers for response and resistance to AT13387 (onalespib) in patients with ALK+ ALCL, MCL, and BCL6+ DLBCL.

OUTLINE:

Patients receive onalespib intravenously (IV) over 1 hour on days 1, 2, 8, 9, 15, and 16. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 1 year.

Arms:
arm 1: Patients receive 160-mg/m2 onalespib by IV over 1 hour on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Patients will continue on treatment indefinitely as long as they are responding and tolerating treatment. arm 2: Patients receive 160-mg/m2 onalespib by IV over 1 hour on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Patients will continue on treatment indefinitely as long as they are responding and tolerating treatment. arm 3: Patients receive 160-mg/m2 onalespib by IV over 1 hour on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Patients will continue on treatment indefinitely as long as they are responding and tolerating treatment.

Interventions: intervention 1: Onalespib
Intervention descriptions: intervention 1: Given IV

Protocol document:
Prot_SAP_000.pdf: 
NCI Protocol #:9875 
Version Date: October 31, 2019 
 
 
i 
Protocol Type / Version # / Version Date: Version #17 / October 31, 
2019 
 
SUMMARY OF CHANGES – Protocol 
 
NCI Protocol #: 9875 
Local Protocol #: 16-712 
Protocol Version Date:  October 31, 2019 
 
Protocol Title:  
Phase 2 Study of AT13387 (onalespib) in ALK+ ALCL, MCL, and BCL-6+ DLBCL  
 
Protocol Version Date: October 31, 2019 
 
 
# 
Section 
Comments 
1. 
Contacts  
Updated study coordinator. 
2. 
4.3.1 Patient Registration 
Updated enrollment status to closed.  
3. 
5.1 Agent Administration 
Added end-date of study drug availability. 
4. 
5.3 Duration of Therapy 
Added end-date of study drug availability. 
5. 
9.1.1.3 Integral Laboratory or 
Imaging Studies 
 
Updated sample shipment information. 
6. 
9.2.1.3 Exploratory/Ancillary 
Correlative Studies: 
Immunoblotting for HSP90 clients 
 
 
Updated sample shipment information. 
7. 
9.2.1.3 Exploratory/Ancillary 
Correlative Studies: Whole exome 
sequencing and transcriptome 
analysis 
 
Updated sample shipment information. 
8. 
13.1 Study Design and Endpoints 
Updated enrollment status to closed. 
 
 


NCI Protocol #:9875 
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1 
 NCI Protocol #: 
9875 
 
Local Protocol #: 
16-712 
 
ClinicalTrials.gov Identifier:  NCT02572453 
 
TITLE:  Phase 2 Study of AT13387 (onalespib) in ALK+ ALCL, MCL, and BCL-6+ DLBCL 
 
Corresponding Organization: LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO  
 
Principal Investigator: 
Caron Jacobson, MD 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
Boston, MA 02215 
617-632-5847 (tele) 
617-582-7890 (fax) 
cajacobson@partners.org 
 
Co-Investigator(s): 
Geoffrey Shapiro, MD PhD 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
Boston, MA 02215 
617-632-4942 (tele) 
6170632-1977 (fax) 
Geoffrey_Shapiro@dfci.harvard.edu 
 
David Weinstock, MD 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
Boston, MA 02215 
617-632-4245 (tele) 
617-632-5167 (fax) 
DavidM_Weinstock@dfci.harvard.edu 
 
 
 
 
 
 
 
 
 
 
 
 


NCI Protocol #:9875  
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2 
 
Statistician: 
 
Study Coordinator:  
 
Robert Redd 
Jessica Lowney 
 
Department of Data Sciences 
Dana-Farber Cancer Institute 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
450 Brookline Avenue  
LG100 
CLS 11007 
Boston, MA 02115 
 
Boston, MA 02115 
617-632-5126 (tele) 
 
617-632-2455 (tele) 
617-632-6625 (fax)   
 
 
 
 
 
Robert_Redd@DFCI.HARVARD.EDU 
Erin_Jeter@dfci.harvard.edu 
 
Responsible Research Nurse: 
Responsible Data Manager: 
 
Jaynie Davis, RN 
Grace Fairchild 
 
Dana-Farber Cancer Institute 
Dana-Farber Cancer Institute 
 
450 Brookline Avenue 
450 Brookline Avenue 
 
Boston, MA 02215 
LG100 
 
617-632-3656 (tele) 
Boston, MA 02115 
 
617-582-7756 (fax) 
617-632-6840 (tele)   
 
Jaynie_Davis@DFCI.HARVARD.EDU 
Grace_Fairchild@dfci.harvard.edu 
 
 
 
 
 
 
PARTICIPATING ORGANIZATIONS  
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
EDDOP / Early Drug Development Opportunity Program 
 
 
NCI-Supplied Agent:  AT13387 (onalespib) (NSC 749712) 
IND Sponsor:  DCTD, NCI 
 
 


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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relapsed ALK+ ALCL, following 
Brentuximab and transplant ineligible 
(10 patients) 
 
Relapsed MCL, following Ibrutinib and 
transplant ineligible  
(20 patients) 
 
Relapsed BCL6+ DLBCL, transplant 
ineligible  
(20 patients) 
 
AT13387 
 
Primary endpoint: 
•
Overall response rate 
(PET/CT evaluation every 
2 cycles until 
progression) 
Secondary endpoints: 
•
Progression-free and 
overall survival 
•
Safety and tolerability 
Exploratory endpoints: 
•
On target activity via 
immunohistochemistry 
and immunoblotting for 
known HSP90 clients  
•
Genetic and 
transcriptional analysis 
for markers of response 
and resistance 
 
    


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TABLE OF CONTENTSPARTICIPATING ORGANIZATIONS...............................................2 
1. OBJECTIVES ..............................................................................................................................7 
1.1 
Primary Objectives...................................................................................................7 
1.2 
Secondary Objectives...............................................................................................7 
1.3 
Exploratory Objectives ............................................................................................7 
2. 
BACKGROUND .................................................................................................................7 
2.1 
ALK+ Anaplastic Large Cell Lymphoma (ALCL), Mantle Cell 
Lymphoma (MCL), and BCL6+ Diffuse Large B Cell Lymphoma 
(DLBCL) ..................................................................................................................7 
2.2 
AT13387 (onalespib) .............................................................................................10 
2.3 
Rationale for the use of AT13387 (onalespib) in ALK+ ALCL, MCL and 
BCL6+ DLBCL .....................................................................................................15 
2.4 
Correlative Studies Background ............................................................................17 
3. 
PATIENT SELECTION ....................................................................................................18 
3.1 
Eligibility Criteria ..................................................................................................18 
3.2 
Exclusion Criteria ..................................................................................................20 
3.3 
Inclusion of Women and Minorities ......................................................................21 
4. 
REGISTRATION PROCEDURES ...................................................................................22 
4.1 
Investigator and Research Associate Registration with CTEP ..............................22 
4.2 
Site Registration .....................................................................................................23 
4.3 
Patient Registration ................................................................................................25 
4.4 
General Guidelines.................................................................................................26 
5. 
TREATMENT PLAN ........................................................................................................26 
5.1 
Agent Administration.............................................................................................26 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................27 
5.3 
Duration of Therapy ...............................................................................................30 
5.4 
Duration of Follow Up ...........................................................................................30 
5.5 
Criteria for Removal from Study ...........................................................................30 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................31 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................32 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR).....................33 
7.2 
Adverse Event Characteristics ...............................................................................36 
7.3 
Expedited Adverse Event Reporting ......................................................................37 
7.4 
Routine Adverse Event Reporting .........................................................................39 
7.5 
Secondary Malignancy...........................................................................................39 
7.6 
Second Malignancy ................................................................................................40 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................40 
8.1  
Drug Information ...................................................................................................40 
8.2  
Useful Links and Contacts Related to Drug Information ......................................42 


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9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................43 
9.1 
Integral Laboratory or Imaging Studies .................................................................43 
9.2 
Exploratory/Ancillary Correlative Studies ............................................................46 
10. 
STUDY CALENDAR .......................................................................................................51 
11. 
MEASUREMENT OF EFFECT........................................................................................53 
11.1 
Antitumor Effect ....................................................................................................53 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .........................................................................................................................55 
12.1 
Study Oversight .....................................................................................................55 
12.2 
Data Reporting .......................................................................................................56 
12.3 
CTEP Multicenter Guidelines ................................................................................58 
12.4 
Collaborative Agreements Language .....................................................................58 
13. 
STATISTICAL CONSIDERATIONS...............................................................................59 
13.1 
Study Design/Endpoints.........................................................................................59 
13.2 
Sample Size/Accrual Rate ......................................................................................61 
13.3 
Stratification Factors ..............................................................................................62 
13.4 
Analysis of Secondary Endpoints ..........................................................................62 
13.5 
Reporting and Exclusions ......................................................................................63 
REFERENCES ..............................................................................................................................64 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................72 
APPENDIX B__PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 73 
APPENDIX C 
 ANTI-ALK IMMUNOHISTOCHEMISTRY STANDARD 
OPERATING PROCEDURE, BRIGHAM AND WOMEN’S HOSPITAL 
HEMATOPATHOLOGY, CLIA CERTIFIED CORE LABORATORY ..............................75 
APPENDIX D 
 ANTI-CYCLIN D1 IMMUNOHISTOCHEMISTRY STANDARD 
OPERATING PROCEDURE, BRIGHAM AND WOMEN’S HOSPITAL 
HEMATOPATHOLOGY, CLIA CERTIFIED CORE LABORATORY ..............................75 
APPENDIX E 
 ANTI-BCL6 IMMUNOHISTOCHEMISTRY STANDARD 
OPERATING PROCEDURE, BRIGHAM AND WOMEN’S HOSPITAL 
HEMATOPATHOLOGY, CLIA CERTIFIED CORE LABORATORY ..............................75 
APPENDIX F 
PROCEDURES FOR FORMALIN FIXATION ..................................76 
APPENDIX G 
PROCEDURES FOR SNAP FREEZING .............................................76 
APPENDIX H 
9875 SPECIMEN SUBMISSION FORM ..............................................76 
APPENDIX I 
EXAMPLE OPHTHALMOLOGIC EXAMINATION WORKSHEET


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78 


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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 Overall response rate (ORR) to single agent AT13387 (onalespib) as measured by the 
proportion of partial and complete responses (PR + CR) in patients with 
relapsed/refractory ALK+ anaplastic large cell lymphoma (ALCL), mantle cell 
lymphoma (MCL), and BCL6+ diffuse large B cell lymphoma (DLBCL). 
 
1.2 
Secondary Objectives 
 
1.2.1 Progression free survival (PFS) and overall survival (OS), as well as duration of 
response (DOR) of single agent AT13387 (onalespib) in patients with ALK+ ALCL, 
MCL, and BCL6+ DLBCL. 
1.2.2 Safety and tolerability of single agent AT13387 (onalespib) in patients with ALK+ 
ALCL, MCL, and BCL6+ DLBCL. 
 
1.3 
Exploratory Objectives 
 
1.3.1 Measurement of on-target activity of AT13387 (onalespib) in ALK+ ALCL, MCL, 
and BCL6+ DLBCL through immunoblotting and immunohistochemistry of pre-
treatment, on-treatment, and time of progression tumor biopsies for HSP90 clients. 
 
1.3.2 Determination of genetic and transcriptional markers for response and resistance to 
AT13387 (onalespib) in patients with ALK+ ALCL, MCL, and BCL6+ DLBCL. 
 
2. BACKGROUND 
 
2.1 
ALK+ Anaplastic Large Cell Lymphoma (ALCL), Mantle Cell Lymphoma (MCL), 
and BCL6+ Diffuse Large B Cell Lymphoma (DLBCL) 
 
2.1.1 ALK+ Anaplastic Large Cell Lymphoma (ALCL) 
 
ALK+ Anaplastic Large Cell Lymphoma (ALCL) is a peripheral T cell lymphoma (PTCL) 
generally associated with a favorable prognosis compared to other PTCL subtypes.  Its hallmark 
genetic lesion involves translocations or inversions involving the gene for ALK on chromosome 
2p23 and results in ALK expression and constitutive activation of this kinase.  The most 
common translocation involves the NPM gene on chromosome 5q23.1  Expression of the NPM-
ALK fusion gene in vitro and in mouse models results in B and T cell lymphoproliferative 
disorders.1  Worldwide, ALK+ ALCL accounts for approximately 7% of peripheral T cell 
lymphomas, although within the United States it represents 16% of cases.2  As a rare subset of a 
rare disease, this accounts for 0.25 cases per 100,000 people in the US, affecting men more 
commonly than women (2:1) and generally affecting younger individuals (median age at 
diagnosis 34 years).3  It generally presents with lymphadenopathy and systemic symptoms of 
fever, night sweats and/or weight loss, although extranodal presentations may occur.  The 
majority of patients will have advanced stage disease at diagnosis (65%).4  Prognosis is best 


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predicted by the International Prognostic Index, initially developed from a cohort of patients with 
diffuse large B cell lymphoma (DLBCL), which identifies older age, elevated LDH, advanced 
stage, poor performance status, and 2 or more extranodal sites of disease as poor prognostic 
features.5  Although patients with ALK+ ALCL generally do better than patients with ALK- 
ALCL, five year progression free survival  (PFS) is only 64% with CHOP chemotherapy and 
patients with intermediate high- and high-risk disease do especially poorly with a 5 year PFS of 
only 23-33%.4,6 
 
Initial treatment for ALK+ ALCL is generally with CHOP (cyclophosphamide, doxorubicin, 
vincristine, prednisone) or a CHOP-like regimen, specifically CHOEP (cyclophosphamide, 
doxorubicin, vincristine, etoposide, prednisone).  CHOEP has been associated with improvement 
in outcomes amongst younger patients with PTCLs, and specifically patients with ALK+ ALCL 
(3 year event free survival [EFS] 91% versus 57% for CHOEP compared to CHOP in ALK+ 
ALCL).6,7  Patients who fail to respond to, or relapse, after their upfront therapy are typically 
treated with a salvage chemotherapy regimen, often containing gemcitabine, and high dose 
chemotherapy with autologous stem cell transplant (HDC-ASCT).4,6  However, for patients who 
relapse after or are ineligible for autologous stem cell transplant, durable treatment options are 
limited.  The drug-antibody conjugate brentuximab (CD30 conjugated to MMAE) is associated 
with excellent response rates (86%, with a CR rate of 57%) but the duration of response is 12-14 
months.8  The ALK inhibitor crizotinib has been tested in a small cohort of 11 patients with 
relapsed/refractory disease with response rate of 100% but a 2 year progression free response of 
only 64%.9  Thus, a significant fraction of patients with ALK+ ALCL are not cured with current 
therapies. 
 
2.1.2 Mantle cell lymphoma (MCL) 
 
Mantle cell lymphoma (MCL) is a mature B cell non-Hodgkin lymphoma (NHL) that is probably 
best characterized as intermediate between an indolent and an aggressive lymphoma.  It accounts 
for 7% of adult NHL, or 4-8 cases per million person years, in the US and Europe.10  Like the 
indolent lymphomas, it is incurable with conventional chemoimmunotherapy and can be 
retreated at the time of relapse, but its clinical behavior is more aggressive with a markedly 
shorter median OS.  More intensive chemotherapy strategies are associated with longer treatment 
responses and PFS but not cure.11-15  While there is a subset of MCL that behaves more 
indolently, best identified by either a low Ki67, or circulating disease and splenomegaly in the 
absence of lymphadenopathy, and can be initially observed, the majority of patients will present 
in advanced stage with symptomatic disease.16-19  Prognosis is best defined by the MCL 
International Prognostic Index (MIPI), which uses patient age, performance status, LDH, 
leukocyte count and Ki67 (the latter for the biologic MIPI only) to identify three risk groups.20 
Overexpression of cyclin D1, as a result of a translocation between the CCND1 gene on 
chromosome 11q13 and the immunoglobulin heavy chain gene (IGH@) locus on chromosome 
14q23, is present in the vast majority of cases, but not sufficient for the pathogenesis of this 
disease.21,22  Other molecular and/or genetic events resulting in either cell cycle progression 
(deletions in INK4a/ARF, expression of SOX11), impaired DNA damage response (TP53 or 
ATM mutations), and/or enhanced survival (BCL2 overexpression, tonic B cell receptor 
signaling and/or activation of the PI3K/AKT and NFκB pathways) are also needed.23-29 
 


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Initial therapy with R-CHOP chemotherapy alone results in poor outcomes with a median PFS of 
less than two years.14,30  Consolidation of R-CHOP with HDC-ASCT, or maintenance rituximab 
for patients who are older and/or ineligible for autologous stem cell transplant, improved 
outcomes and extended the median PFS to approximately 4 years.14,31  Regimens that incorporate 
cytarabine and consolidate with HDC-ASCT have perhaps resulted in the best outcomes, with 
median EFSs approaching 7 years.11,12  HyperCVAD (hyperfractionated cyclophosphamide, 
vincristine, doxorubicin, and dexamethasone alternating with high dose methotrexate and 
cytarabine) is associated with a median time to treatment failure (TTF) and PFS of 
approximately 4-5 years.13,14  More recently bendamustine, in combination with rituximab, has 
been identified as a highly effective treatment for MCL with an improvement in PFS compared 
to R-CHOP (35.4m v 22.1m).30  The use of bendamustine and rituximab (BR) in combination 
with cytarabine with or without consolidation HDC-ASCT is being explored.15 
 
When MCL patients relapse after initial therapy, additional chemotherapy may be tried but 
alternative treatment approaches are needed for chemorefractory disease.  Targeting Bruton’s 
tyrosine kinase (BTK), which links constitutive B cell receptor (BCR) signaling to PI3K/AKT 
and NFκB signaling, with ibrutinib has been highly successful in relapsed/refractory MCL, with 
a response rate of 68% and an 18 month median duration of response.32  Importantly, between 
10-25% have mutations that result in nonclassical NFκB signaling, and thus are refractory to 
ibrutinib29.  The use of the proteosome inhibitor, bortezomib, possibly through its activity against 
NFκB, results in single agent response rates of 30-50%, lasting 7-10 months in 
relapsed/refractory disease.33,34   These responses may be enhanced in combination with 
chemoimmunotherapy.  Lenalidomide has been investigated, benefiting about 30% of patients 
for up to 17 months.35  Finally, the use of the CDK4/6 inhibitor palbociclib, resulted in disease 
stabilization for over a year in 5 of 17 patients enrolled in a small proof of concept study.36  For 
younger patients with a more aggressive disease course who are able to achieve a minimal 
disease state with salvage therapies, allogeneic stem cell transplant offers a potentially curative 
option, with long term disease free survivals of 15-82% depending on the series.37-39  Most of the 
remaining patients, both those ineligible for allogeneic transplant and those who relapse after 
transplant will die from their disease. 
 
2.1.3 Diffuse Large B cell Lymphoma (DLBCL) 
 
Diffuse large B cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults, 
accounting for approximately 25,000-30,000 new cases each year in the United States.40  Patients 
with DLBCL can be stratified into prognostic groups using several factors including age, stage, 
performance status, lactate dehydrogenase (LDH), and number of extranodal sites by the 
international prognostic index (IPI).41  Distinct subtypes of DLBCL have been defined by gene 
expression profiling, termed germinal center B-cell (GCB) or activated B-cell (ABC) DLBCL.  
Approximately 60% of DLBCL will be GCB and these carry a more favorable prognosis.42  In 
addition, DLBCL with translocations involving both the MYC gene locus on chromosome 8 and 
another oncogenic translocation, most commonly involving the BCL2 gene on chromosome 18, 
the so-called “double hit” lymphomas, do especially poorly with long term disease free survival 
of only 20-30%.43  Patients with limited stage disease can be effectively treated with 
combination chemotherapy with or without radiotherapy, achieving very favorable outcomes44-46; 
however a majority of patients present with advanced disease and do not fare as well.41,47  


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Combination chemotherapy with R-CHOP is effective initial therapy, though nearly half of 
patients will ultimately relapse.47  Dose escalation, addition of newer agents, and HDC-ASCT 
have not been able to improve outcomes compared to CHOP.48-50  The addition of rituximab to 
CHOP has increased the cure rate in DLBCL by nearly 15%, though a significant number of 
patients will still relapse and ultimately die of their disease.51,52  Patients who are primary 
refractory to, or relapse after, R-CHOP are treated with additional salvage chemotherapy 
regimens such as dexamethasone, high dose cytarabine, and cisplatin (DHAP), rituximab, 
ifosfamide, carboplatin, and etoposide (RICE), or rituximab, gemcitabine, dexamethasone, and 
cisplatin (R-GDP).53-57 While definitive data do not yet exist, there are indications that since the 
routine inclusion of rituximab with initial combination chemotherapy, relapsing patients may be 
more difficult to salvage due to selection for more aggressive disease.58-60  Those able to obtain 
an objective response are then consolidated with HDC-ASCT resulting in both a progression free 
and overall survival advantage compared to salvage chemotherapy alone,53,54,56 though half of 
patients who undergo stem cell transplant still relapse, highlighting the need for novel 
therapies.53,54,56,61 Additionally, a significant number of patients are not eligible to undergo HDC-
ASCT due to chemotherapy insensitivity, advanced age, or comorbid disease. 
 
2.2 
AT13387 (onalespib) 
 
AT13387 (onalespib) ((2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-
1,3-dihydroisoindol-2-yl]-methanone, L-lactic acid salt) is a small molecule inhibitor of HSP90 
derived by high-performance liquid chromatography (HPLC) analysis and chosen based on good 
stability at elevated temperatures, non-hygroscopicity, absence of hydrate formation, and the 
required aqueous solubility.  HSP90 is a chaperone responsible for correctly folding its client 
proteins into their active confirmation, thereby preventing them from ubiquitination and 
proteasomal degradation.62  Inhibition of the ATP-dependent function of HSP90 with small 
molecule inhibitors results in the degradation of many oncogenes, including BCR-ABL, c-KIT, 
EGFR, HER2, AKT, BCL6, ALK and cyclin D1.63-65 Targeting HSP90, then, has the ability to 
inhibit multiple oncogenic pathways simultaneously.  In vitro and in vivo studies of AT13387 
(onalespib) have demonstrated its ability to bind to the ATP binding site at the N-terminal 
domain of HSP90, decrease the levels of multiple known HSP90 client proteins important in cell 
proliferation and survival, and inhibit cell proliferation across a wide panel of tumors at 
nanomolar concentrations.   
 
AT13387 (onalespib) and other HSP90 inhibitors potently inhibit the in vitro growth of mantle 
cell lymphoma, DLBCL and ALK+ ALCL cell lines and the in vivo growth of xenografts (as 
described in section 2.2.2).  Similar sensitivity was observed non-small cell lung cancer 
(NSCLC) lines, irrespective of sensitivity to the EGFR inhibitor erlotinib or the ALK inhibitor 
crizotinib, at IC50s of 14-69nM.  Exposure to AT13387 (onalespib) (0.03-10µM) resulted in the 
reduction in levels of wild-type and mutant EGFR, EML4-ALK, and AKT, with associated 
decreases in levels of phosho-ERK, phospho-AKT, and phospho-S6 when measured by 
immunoblotting at 24 hours.  In xenograft models of both erlotinib sensitive and erlotinib 
insensitive EGFR mutant NSCLC, AT13387 (onalespib) inhibited tumor growth at doses of both 
55mg/kg and 70mg/kg once weekly.  Combination of erlotinib and AT13387 (onalespib) in 
erlotinib sensitive EGFR mutant NSCLC xenografts results in additive efficacy over either agent 
alone, as did combinations of AT13387 (onalespib) with the antimicrotubule chemotherapeutic 


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agent paclitaxel.  Similar effects were seen in xenograft models of ALK rearranged NSCLC, 
with better efficacy when AT13387 (onalespib) was combined with crizotinib compared to either 
agent alone.  Furthermore, while there was tumor regrowth observed with single agent AT13387 
(onalespib) or single agent erlotinib or crizotinib, there was no tumor regrowth seen with the 
combinations, suggesting that the combination may delay the emergence of TKI resistance 
clones.  As with erlotinib-resistant EGFR mutant models, AT13387 (onalespib) maintained 
activity in ALK rearranged NSCLC models that were resistant to crizotinib. 
 
AT13387 (onalespib) was similarly effective against a panel of vemurafenib sensitive and 
insensitive melanoma cell lines with IC50s of 22-190nM, with depletion of BRAF and CRAF 
levels as well as AKT and associated decreases in levels of phospo-ERK and phospho-S6.  
Efficacy was maintained in cell lines that were resistant to both BRAF and MEK inhibitors, with 
inhibition of MAPK and AKT signaling observed.  Xenograft mouse models of both 
vemurafenib sensitive and insensitive melanoma were sensitive to AT13387 (onalespib).  
Although there did not appear to be additive efficacy of AT13387 (onalespib) in combination 
with vemurafenib in the vemurafenib sensitive model, the combination did result in the lack of 
eventual tumor regrowth seen in mice treated with vemurafenib alone, indicative that the 
combination may delay the emergence of a resistance clone as was likewise seen in the NSCLC 
models.  Resistant outgrowth tumors demonstrated upregulation of PDGFR and EGFR, both of 
which were subsequently downregulated following treatment with AT13387 (onalespib), in vitro.  
After a single dose of AT13387 (onalespib), BRAF, AKT, CRAF, and CDK4 were all 
downregulated in tumors from these melanoma xenograft models and ERK and AKT pathways 
were inhibited. 
 
Similar data exists for GIST and hormone-resistant, androgen-receptor positive prostate cancer.  
Together these data demonstrate the on-target and anti-tumor activity of AT13387 (onalespib) at 
nanomolar concentrations, and that combination strategies of AT13387 (onalespib) with kinase 
inhibitors may delay the development of resistance.  They also support the development of once 
or twice weekly dosing schedules, as this dosing was effective and best tolerated in xenograft 
models.   
 
A CNS safety pharmacology study, conducted in the rat with AT13387 (onalespib) administered 
by 1-hr IV infusion, demonstrated no adverse CNS effects at doses up to 200 mg/kg in males and 
125 mg/kg in females, compared with control vehicle-treated animals. A CV/R safety 
pharmacology study was conducted in Beagle dogs. Vehicle only or AT13387 (onalespib) 
(ascending doses of 1, 4 and 15 mg/kg) were administered via a 1-hr IV infusion. A dose-related 
increase in heart rate was observed at 4 mg/kg and above from 10 minutes after the start of 
infusion which peaked at the end of infusion and returned to control levels by approximately 5 
hours after the end of infusion. The increased heart rate observed at 15 mg/kg was associated 
with a concomitant decrease in blood pressure (systolic, diastolic and mean arterial).  AT13387 
(onalespib) did not have any significant effect on QT interval or QTc at any dose level tested. TK 
data showed good characterization of AT13387 (onalespib) concentration-time profiles achieved 
for 1-hr IV infusion, and plasma concentration-time profiles were consistent with the IV route of 
administration. Cmax was clearly defined by targeting a sample immediately prior to end of the 1-
hr infusion. AUC was well characterized as indicated by low % AUC extrapolated (<17%). 


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AT13387 (onalespib) was essentially completely cleared from plasma by 24 hours (23 hours 
post-infusion) in both species. 
 
Toxicology studies were done in both rat and dog species.  A clear dose-related toxicity was 
established in dogs, including identification of target organs of toxicity; the NOAEL was 1 
mg/kg/dose given 2QWx3 and the nominal HNSTD was 3 mg/kg/dose given 2QWx3. The dog 
was found to be more sensitive than the rat on a mg/kg and mg/m2 basis, as well as in exposure 
terms (Cmax and AUC). The human clinical start dose was calculated on a mg/m2 basis using 
accepted body surface area conversion factors (FDA, 2005). Given its high sensitivity to 
AT13387 (onalespib), the dog was deemed an appropriate species for this purpose; therefore, the 
start dose was estimated as one-sixth of the nominal dog HNSTD (HNSTD = 3 mg/kg = 60 
mg/m2), giving a human start dose of 10 mg/m2/dose given 2QWx3. The human start dose 
calculated from the dog HNSTD is 3-fold lower than would be derived from the rat NOAEL 
(start dose based on one tenth of the rat NOAEL on a body surface area basis = 30 mg/m2/dose). 
 
2.2.1 
Clinical experience 
 
There have been two completed clinical study of AT13387 (onalespib) as monotherapy in 
advanced solid tumors, and there are three ongoing studies (in combination) with a total of 171 
patients having received at least one dose of the drug.66,67 
 
2.2.1.1 
AT13387 (onalespib) Pharmacokinetics 
 
Sixty-two patients were treated in the first-in-human phase 1 study of AT13387 (onalespib) in 
advanced solid tumors, either once or twice weekly for 3 weeks every 28 days, at doses up to 
310mg/m2.66   Blood samples were collected predose and through 72 hours post-infusion on 
Days 1 and 18 for the twice-weekly regimen, or Days 1 and 15 for the once-weekly regimen. 
Urine samples were collected for time periods of 0-7 hours, 7-24 hours and 24-48 hours during 
and after infusion.  Concentrations of AT13387 (onalespib) in plasma clinical samples were 
determined using an analytical method for AT13387 (onalespib)-specific liquid chromatography 
with mass spectrometric detection (LC-MS/MS).  Quantitation of AT13387 (onalespib) was 
shown to be unaffected by the presence of putative metabolites which were capable of breaking 
down from parent compounds.  Within cohorts, the PK of AT13387 (onalespib) showed inter-
individual variability of 2-5 fold for AUC0-t and t1/2 but up to 9-fold for Cmax. The t1/2 was dose- 
independent with mean cohort values ranging from 6.6 to 11.5 hrs. Maximum t1/2 observed for 
any individual profile was 14 hrs. There was no notable accumulation or reduction in exposure 
between Day 1 and Day 18 of Cycle 1 for the twice-weekly dosing schedule or between Day 1 
and Day 15 of Cycle 1 for the once-weekly dosing schedule.  Plasma clearance of AT13387 
(onalespib) was independent of dose (range 0.96–1.45 L/hour/kg over all 10 cohorts). This high 
value for plasma clearance is consistent with that predicted from the PK of the drug in 
nonclinical studies. Measurement of the concentrations of AT13387 (onalespib) excreted in urine 
showed that renal elimination is of minor importance in the total clearance of the drug. Less than 
5% of the administered dose was recovered in the urine during 48 hours post-dose. The volume 
of distribution was high (9.8-22.9 L/kg). 
 


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Limited information on the metabolism, elimination, and safety of AT13387 (onalespib) is 
currently available.   AT13387 (onalespib) appears to be metabolized by the liver and both parent 
compound and metabolites eliminated by the kidneys.  Drug-drug interaction studies in humans 
have not been conducted with AT13387 (onalespib) administered as a monotherapy or in 
combination with other cancer therapies. 
 
Results from the first-in-human phase 1 study of AT13387 (onalespib) in advanced solid tumors 
identified a maximally tolerated dose of 120mg/m2 twice weekly for 3 weeks every 28 days, or 
260mg/m2 weekly for 3 weeks every 28 days.66  One dose-limiting toxicity (DLT) of visual 
disturbance occurred at the 120 mg/m2 twice-weekly schedule, and accordingly was declared the 
RP2D on the twice-weekly administration schedule. No formal DLTs occurred on the once-
weekly schedule, though multiple severe toxicities, including diarrhea, nausea, vomiting, fatigue, 
and systemic infusion reactions, led to selection of 260 mg/m2 as the RP2D on the once-weekly 
administration schedule. Sixty-two patients with a variety of solid tumors were treated, with one 
partial response in an imatinib-resistant gastrointestinal stromal tumor (GIST).  Stable disease 
was observed in 36% of patients, one-third of whom experienced disease stabilization for over 4 
months. 
 
It has been shown with other HSP90 inhibitors, like ganetespib, that although once weekly 
dosing results in a prolonged intertumor ½ life, the effect on downregulation of client proteins is 
short lived, with an initial protein depletion at 24 hours post-dosing followed by a steady 
increase to normal protein levels at 48-72 hours.68  Furthermore, once weekly dosing results in a 
tumor growth delay with a transient reduction in client protein levels, while consecutive daily 
dosing (5 days in this study) results in tumor regression with a persistent reduction in client 
protein levels out to 168 hours.  It has been difficult to do daily dosing of HSP90 inhibitors over 
5 consecutive days in humans due to toxicity, so dosing over 2 consecutive days has been 
adopted.  For AT13387, this dosing schedule was explored in a phase 1 study in solid tumors and 
the RP2D was 160mg/m2 on d1, 2, 8, 9, 15, an 16 of a 28 day cycles and this dosing schedule 
was safe and tolerated.67  Given the high proliferative index of the lymphomas included in this 
study, the variable sensitivity of their pathogenic HSP90 clients to HSP90 inhibition, and the 
target suppression advantage of consecutive day dosing, we chose to use this schedule in this 
lymphoma study. 
 
2.2.1.2 
Safety 
 
Overall, 97.7% of patients having received AT13387 (onalespib) reported any adverse event, and 
49.1% of patients report a CTCAE grade 3/4 adverse event.  The most common adverse events 
seen in clinical studies include diarrhea (78%), fatigue (60%), nausea (53%), decreased appetite 
(40%), vomiting (32%), dizziness (28%), dry mouth (23%), anemia (22%), constipation (21%), 
headache (21%), abdominal pain (20%), weight loss (19%), insomnia (19%), cough (16%), back 
pain (15%), muscle spasms (16%), peripheral edema (16%), hypokalemia (15%), visual 
impairment (15%), increases in aspartate aminotransferase (AST) (12%), chills (13%), 
dehydration (12%), dyspnea (13%), injection site reactions (12%), dysgeusia (12%), and infusion 
site pain (11%). The most common serious adverse events, regardless of relationship, were 
categorized under Gastrointestinal Disorders (18/104; 17%); Infections and Infestations (14/104; 
14%); and Respiratory, Thoracic, and Mediastinal Disorders (14/104; 14%). The only individual 


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event terms reported for >2 subjects were 5/104 (4.8%) for diarrhea (all resolved); 4/104 (3.8%) 
each for dehydration (3 resolved and 1 resolved with sequelae) and pneumonia (2 resolved and 2 
fatal); and 3/104 (2.9%) each for chest pain (2 resolved and 1 not resolved), muscular weakness 
(1 resolved and 2 not resolved), and dyspnea (3 resolved). There was one unexpected SAE, 
convulsions (grade 2) that was felt to possibly be related to the study drug, occurring two weeks 
after the last treatment; the patient had received 2 cycles of treatment in total and did not receive 
further treatment.  Four subjects died within 30 days of receiving treatment with AT13387 
(onalespib) from causes not attributed to progression of disease. The causes of all deaths were 
considered to be not treatment-related. 
 
The one dose-limiting toxicity (DLT) observed on the first-in-human, phase 1 single agent study 
of AT13387 (onalespib) in advanced solid tumors was visual impairment; one subject developed 
blurred vision, chloropsia and photopsia on C1D22-23 after receiving AT13387 (onalespib) at 
120mg/m2/dose twice weekly for three weeks.  An electroretinogram (ERG) on C1D24 showed 
significant cone suppression (grade 3), the study medication was discontinued permanently, and 
the visual changes and ERG changes resolved within 21 days of study drug cessation.   A range 
of visual disturbances (collectively grouped under Visual Impairment) have been reported in 
subjects receiving AT13387 (onalespib) in phase 1-2 trials. These include peripheral flashes 
(photopsia), blurred or double vision, floaters, color distortion and dimness, difficulties with 
light/dark accommodation, tunnel vision or other field defects, halos, apparent movement of 
stationary objects, and complex disturbances. The symptoms were generally Grade 1 in severity. 
Based on data from Studies AT13387-01 and -02, symptoms were intermittent, reversible and 
transient, lasting a few seconds to a few minutes and occurring on 1 to 3 days per cycle. The 
onset was generally in the first cycle, although in some subjects, the onset was in the first half of 
the second cycle. The symptoms were more frequent in the evening or at night and generally did 
not interfere with activities of daily living. Visual symptoms were dose-related. 
 
Additional safety analysis was done based on central ECG recording.  ECGs were analyzed in 60 
subjects who met ECG analysis population criteria (Clinical Cardiac Report, AT13387-01). ECG 
data revealed no change in heart rate, atrioventricular conduction as measured by the PR interval, 
or depolarization as measured by the QRS duration. There were no clear signals of any change in 
morphology or new rhythms. No effect of AT13387 (onalespib) was observed on cardiac 
repolarization, as measured by the QTcF duration, in the twice-weekly dosing schedule up to a 
dose of 120 mg/m2. The once-weekly dosing regimen of 220 to 310 mg/m2/dose shows a QTcF 
increase in the 10-15 ms range, with PK pharmacodynamic analysis showing a predicted change 
at Cmax of 7 ms (upper confidence interval, 11 ms). This result indicates that AT13387 
(onalespib) probably does not affect cardiac repolarization; however, the data do not exclude a 
small effect, <10 ms in magnitude. An effect of this magnitude is not likely to be clinically 
relevant. 
 
 
 
 
 


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2.3 
Rationale for the use of AT13387 (onalespib) in ALK+ ALCL, MCL and BCL6+ 
DLBCL 
 
2.3.1 AT13387 (onalespib) in ALK+ ALCL 
 
Oncogenic rearrangements involving ALK are involved in the pathogenesis and survival of more 
than half of ALCLs.  ALK+ ALCL is associated with a better prognosis than ALK- ALCL, but 
patients with high risk or relapsed/refractory disease do poorly.  In addition, among the two 
patients who had an early relapse after an initial response to crizotinib, deep sequencing of the 
NPM/ALK fusion gene revealed a mutation in the kinase domain of ALK that preserved ALK 
signaling.  Crizotinib has been similarly effective in EML4-ALK rearranged non-small cell lung 
cancer (NSCLC) but relapses are frequent and associated with acquired mutations in the ALK 
kinase domain of the rearranged gene.69,70   
 
ALK and its fusion proteins are known clients of HSP90.71-73  ALK+ ALCL is sensitive to 
treatment with an older generation HSP90 inhibitor geldanamycin with 50% inhibitory 
concentration (IC50) between 10-30µM, resulting in G2/M cell cycle arrest and caspase-3-
mediated apoptosis.74  Treatment resulted in a reduction in NPM-ALK protein levels and 
cleavage of PARP.  The HSP90 inhibitor AUY922, which is structurally related to AT13387 
(onalespib), results in potent growth inhibition and cell death of the ALK+ ALCL cell line 
SUDHL-1 with an IC50 of <10nM, and this is associated with a reduction in total ALK protein as 
well as phospho-ALK, AKT, STAT3, and phospho-STAT3.75  AUY922 was similarly effective 
in vivo in SUDHL-1 mouse xenografts with tumor growth inhibition, early FLT-PET signal 
reduction, and decreases in Ki67 with evidence of apoptosis determined by caspase-3 staining.75   
HSP90 inhibition with the newer generation HSP90 inhibitor ganetespib exhibited more potent 
cytotoxic affects against ALK-rearranged NSCLC than crizotinib (IC50 10-13nM v 200-300nM) 
and was able to suppress tumor growth in vivo in ALK-rearranged NSCLC xenograft models.  
Importantly, HSP90 inhibition was able to overcome acquired crizotinib resistance that resulted 
from a mutation in the ALK fusion, with evidence of continued destabilization of the mutant 
fusion gene product.76,77  Thus, HSP90 inhibition can target multiple tumorigenic pathways and 
overcome acquired resistance to ALK inhibitors, making it an attractive strategy for the 
treatment of ALK+ ALCL. 
 
2.3.2   AT13387 (onalespib) in MCL 
 
MCL is characterized by overexpression of cyclin D1, which drives G1/S cell cycle transition 
through cyclin-dependent kinase 4 (CDK4).  A recent study led by our colleague Geoff Shapiro 
demonstrated that the CDK4 inhibitor PD0332991 led to sustained clinical responses (mostly 
stable disease) in a subset of patients with MCL.36  MCL also appears to be reliant on B cell 
receptor (BCR) signaling, as a subset of MCL has a very restricted immunoglobulin gene 
repertoire consistent with antigen-driven selection and some of the most abundantly expressed 
peptides in MCL belong to proteins involved in BCR signaling.78,79  Inhibition of BTK with 
ibrutinib has been highly successful in relapsed MCL. However, up to 40% of patients do not 
respond and progression-free survival among responders averages only 18 months.32  Intrinsic 
resistance to ibrutinib has been associated with activation of the non-classical NFκB pathway.29  
Gain-of-function mutations in TRAF2 and TRAF3 that constitutively drive non-classical NFκB 


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signaling occur in MCL cell lines and primary patient samples.29  In addition, the BTK C481S 
mutation that confers resistance to ibrutinib can occur in patients with MCL.80   
 
Work in the Weinstock lab has shown that newer-generation heat shock protein 90 (HSP90) 
inhibitors potently induce apoptosis in primary MCL samples and MCL lines, including lines 
with constitutive activation of non-classical NFκB, in the 5-300nM range.  Specifically, 
AT13387 (onalespib) has an IC50 of 50-130nM in established MCL cell lines.  This is associated 
with degradation of factors essential for MCL survival, including cyclin D1, CDK4, AKT, BTK, 
and IKKα, with resulting loss of MAP kinase and NFκB signaling.  HSP90 inhibitors appear to 
downregulate both wild-type and BTK C481S in vitro.  In addition, the HSP90 inhibitor 
AUY922 was highly active in vivo in mice with MCL cell line xenografts and in a patient-
derived xenograft of disseminated, ibrutinib-resistant MCL.  These mice develop mantle cell 
lymphoma involving the bone marrow, spleen, lymph nodes, and GI tract that is evident on 18F-
FLT-PET scans.  HSP90 inhibition resulted in a significant reduction in 18F-FLT uptake in these 
sites of disease, as well as a reduction in cyclin D1, BTK, and CDK4 by immunoblotting, 
compared to vehicle treated mice.  Thus MCL is an attractive target for HSP90 inhibition, and 
can overcome both intrinsic and acquired resistance to ibrutinib. 
 
2.3.3 AT13387 (onalespib) in BCL6+ DLBCL 
 
BCL6 is an important oncogene in many DLBCLs.  It is normally expressed during the germinal 
center reaction, where it represses the expression of genes like TP53 to prevent apoptosis 
induced by the DNA strand breaks that initiate immuoglobulin class switching and somatic 
hypermutation.81  Overexpression of BCL6 can be identified by immunohistochemistry in 
approximately 60% of DLBCL, and often results from mutations or translocations involving the 
BCL6 locus.82  Overexpression of BCL6 has been associated with BCL6 dependency.83  HSP90 
complexes with BCL6, and inhibition of HSP90 with the newer generation HSP90 inhibitor PU-
H71 in BCL6-dependent DLBCL resulted in depletion of BCL6, the upregulation of genes that 
are downregulated by BCL6 like ATR and TP53, and cell death84. PU-H71 also resulted in a 
significant reduction in tumor burden and improvement in survival in xenografts derived from 
BCL-6-dependent DLBCL cell lines.  We treated BCL6 dependent DLBCL lines with AT13387 
(onalespib), the geldanamycin derivative 17AAG, or ibrutinib.  AT13387 (onalespib) was the 
most potent compound (IC50 10-100nM) and promoted the downregulation of BCL6.  Together, 
these data support the investigation of AT13387 (onalespib) in BCL6-overexpression DLBCLs. 
 
We chose AT13387 (onalespib) for this study as it belongs to a class of newer, more potent 
HSP90 inhibitors, which generate enhanced tumor cell killing across a variety of cancer types, 
including lymphoma.  The side effect and safety profile to date has shown this to be a well-
tolerated drug, with diarrhea, fatigue, nausea/vomiting, abdominal pain, and decreased appetite 
being among the most commonly reported toxicities.  Thus, we do not anticipate any specific 
safety concerns using AT13387 (onalespib) dosed at 160mg/m2/dose on days 1,2, days 8,9, and 
days 15,16 of a 4 week cycle, as the same dosing strategy was previously shown to be tolerated 
in a phase II trial.  We chose this dosing over the once weekly dosing as it has been shown with 
other HSP90 inhibitors, like ganetespib, that although once weekly dosing results in a prolonged 
intertumor ½ life, the effect on downregulation of client proteins is short lived, with an initial 
protein depletion at 24 hours post-dosing followed by a steady increase to normal protein levels 


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at 48-72 hours.68  Furthermore, once weekly dosing results in a tumor growth delay with a 
transient reduction in client protein levels, while consecutive daily dosing (5 days in this study) 
results in tumor regression with a persistent reduction in client protein levels out to 168 hours.  It 
has been difficult to do daily dosing of HSP90 inhibitors over 5 consecutive days in humans due 
to toxicity, so dosing over 2 consecutive days has been adopted.67  Given the high proliferative 
index of the lymphomas included in this study, the variable sensitivity of their pathogenic HSP90 
clients to HSP90 inhibition, and the target suppression advantage of consecutive day dosing, we 
chose to use this schedule in this lymphoma study. 
 
In summary, we anticipate that AT13387 (onalespib) will demonstrate single-agent activity in 
this treatment-refractory population and could then be tested in a randomized trial.  In addition, 
we anticipate that correlative studies from this trial will inform both patient selection and our 
understanding of the determinants of response and resistance to HSP90 inhibition in patients 
with these subtypes of lymphoma. 
 
2.4 
Correlative Studies Background 
 
2.4.1 Immunohistochemical and immunoblotting studies of on-target efficacy 
 
Blood, bone marrow or lymph node biopsy sampling for malignant cells will take place prior to 
treatment initiation, on cycle 1 day 17-22, and at the time of disease progression for several 
biomarker studies.  These will include immunohistochemical quantification of ALK in ALK+ 
ALCL, cyclin D1 in MCL, and BCL6 in DLBCL, as well as immunoblotting of tumor samples 
for known HSP90 clients important to the proliferation and survival of these lymphomas 
including CDK4, cyclin D1, AKT and pAKT, ERK and pERK, IKKα, BTK (in DLBCL and 
MCL), HSP70, ALK (in ALCL), BCL6 (in DLBCL), and p53.  We will compare protein levels 
prior to and on treatment and at the time of disease progression.  These studies will serve to 
evaluate if we are achieving on-target activity of the drug and will be correlated with response.   
 
2.4.2 Genetic and transcriptional analysis for markers of disease response and resistance 
 
Samples will also be submitted for whole exome sequencing (with paired germline samples) and 
RNAseq, and results will be compared between pre-treatment, on-treatment, and time of 
progression tumor samples for markers of disease response and resistance.  For exome 
sequencing, the ABSOLUTE algorithm will be applied to determine the cancer cell fraction.  
Variant allele fractions for mutations present in the progression sample can then be compared to 
those in the pre-treatment sample after adjustment for cancer cell fractions to determine whether 
AT13387 (onalespib) results in a shift in the clonal architecture of lymphomas.85  Although 
HSP90 classically acts at the post-translational level, some evidence indicates that it also can 
affect transcription.86   We previously demonstrated in human leukemia cells that transcriptional 
profiling can highlight downstream pathways that are suppressed or activated in response to the 
degradation of HSP90 clients.87 Transcriptional assessment will be performed on specimens 
obtained prior to beginning treatment, during treatment with AT13387 (onalespib) and then upon 
progression. In cases with bone marrow or peripheral blood involvement, lymphoma cells will be 
purified, for example by CD19 selection. Markers of response and progression will be 
determined by: 1) comparing gene expression patterns using GSEA88, 2) interrogation of the 


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Broad Institute Molecular Signatures Database88  (MSigDB; 
http://www.broadinstitute.org/gsea/msigdb/index.jsp) and 3) Ingenuity Pathway Analysis89,90, as 
we previously performed.91 In addition, we will interrogate the signature of progression during 
AT13387 (onalespib) treatment in the Connectivity Map, a database linking gene expression 
with drug sensitivity.92  Build 2.0 contains over 7,000 expression profiles representing the effects 
of 1,309 compounds. Compounds that correlate inversely with the signature, and therefore may 
abrogate it, are readily available therapeutics to block pathways that bypass HSP90 inhibition.  
The analysis of these exploratory biomarker studies will be retrospective, with assays performed 
after response evaluation for biomarker identification. 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have histologically confirmed, relapsed/refractory ALK+ ALCL (with ALK 
positivity defined by immunohistochemistry and/or FISH/cytogenetics from any prior 
biopsy), MCL, or BCL6+ DLBCL (with BCL6 positivity defined by 
immunohistochemistry from any prior biopsy) and meet the following criteria: 
 
3.1.2 Patients must have measurable disease that has not been previously irradiated, defined as 
at least one lesion that can be accurately measured in at least one dimension (longest 
diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm 
(≥2 cm) with conventional imaging or > 10mm with spiral CT scan.  If the patient has 
been previously irradiated, there must be evidence of progression since the radiation.  See 
Section 11 for the evaluation of measurable disease. 
Please note, this trial includes mandatory tumor biopsies pre-treatment, during cycle 
1 and at the time of disease progression of accessible tumor.  Having accessible 
tumor for biopsy is not required for eligibility.  We expect that at least 80% of 
patients will have accessible tumor for these biopsies, however. 
 
3.1.3 Prior therapy 
    Please note, the washout period for prior therapies cannot be shortened. 
    Please note, prior therapies can be from any time in the past. 
 
3.1.3.1 ALK+ ALCL 
Patients must have disease that has relapsed and or is refractory to prior therapy, 
which must have included a multiagent chemotherapy regimen including an 
anthracycline, if not contraindicated, and prior brentuximab.  Prior crizotinib or other 
ALK inhibitor therapy, while recommended, is not mandatory.  Patients must have 
relapsed following or be ineligible for, or refuse, autologous stem cell transplant. 
 
3.1.3.2 MCL 
Patients must have disease that has relapsed and or is refractory to prior therapy, 
which must have included a multiagent chemotherapy regimen and prior ibrutinib or 
other BTK inhibitor therapy.  Patients must have relapsed following or be ineligible 
for, or refuse, autologous stem cell transplant. 


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3.1.3.3 BCL6+ DLBCL 
Patients must have disease that has relapsed and or is refractory to prior therapy, 
which must have included an anthracycline, if not contraindicated.  Patients must 
have relapsed following or be ineligible for, or refuse, autologous stem cell 
transplant. 
 
3.1.4 Age ≥18 years.  Because no dosing or adverse event data are currently available on the 
use of AT13387 (onalespib) in patients <18 years of age, children are excluded from this 
study, but will be eligible for future pediatric trials. 
 
3.1.5 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
 
3.1.6 Life expectancy of greater than 3 months 
 
3.1.7 Patients must have normal organ and marrow function, and electrolyte balance (allowing 
for repletion) as defined below: 
 
− 
absolute neutrophil count 
≥1,000/mcL 
− 
platelets 
≥75,000/mcL, unless due to marrow involvement by 
lymphoma in which case a platelet count of > 
30,000/mcL will be used 
− 
total bilirubin 
< 1.5x ULN, unless due to Gilbert’s syndrome or  
 
 
hemolysis, in which case < 3.0x ULN is allowed. 
− 
AST(SGOT)/ALT(SGPT) 
≤3.0 × institutional upper limit of normal 
− 
creatinine 
< 1.5x ULN or a creatinine clearance ≥50 mL/min/1.73  
m2 for patients with creatinine levels above institutional 
normal. 
- 
Potassium  
above the institutional lower limit of normal 
(supplementation to meet this is allowed) 
- 
Magnesium 
above the institutional lower limit of normal 
(supplementation to meet this is allowed) 
 
3.1.8  HIV+ patients are eligible for the trial provided they meet the other study criteria in 
addition to the following: 
• CD4+ T-cells > 250/mm3 
• HIV sensitive to antiretroviral therapy 
• Zidovudine not allowed 
• Long term survival anticipated on the basis of HIV alone were it not for the 
lymphoma 
• No concurrent AIDS-defining illness other than the lymphoma 
 


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3.1.9 The effects of AT13387 (onalespib) on the developing human fetus are unknown.  For 
this reason, women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to study 
entry, for the duration of study participation, and for 4 months after the completion of 
AT13387 (onalespib) administration.  Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately.  Men treated or enrolled on this protocol must also agree 
to use adequate contraception prior to the study, for the duration of study participation, 
and 4 months after completion of AT13387 (onalespib) administration. 
 
3.1.10 Although the PK data in humans is still unknown, the potential for drug-interaction 
cannot be ruled out.  Pre-clinical studies suggest that AT13387 (onalespib) is a substrate 
of P-gp, a moderate inhibitor of BCRP and P-gp, and a strong inhibitor of MATE ½-K.  
Patients must be willing to not take St. John wort or grapefruit juice while participating in 
this trial and should avoid drugs that are strong inducers of P-gp, and to switch to 
alternative drugs when available. 
 
3.1.11  Hepatitis B positive patients are eligible. Prophylactic HBV therapy is recommended but 
only if there is no circulating virus detectible. 
 
3.1.12  Transformed lymphoma patients are eligible. 
 
3.1.13  Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered 
from adverse events due to agents administered more than 4 weeks earlier.  Steroids for 
symptom palliation are allowed but must be either discontinued or on stable doses at the 
time of initiation of protocol therapy. 
 
3.2.2 Patients who are receiving any other investigational agents.  All investigational agents 
other than ibrutinib must have been discontinued at least 4 weeks prior to beginning 
treatment.  Prior ibrutinib therapy must have been discontinued at least 2 weeks prior to 
beginning therapy. 
 
3.2.3 Patients with known leptomeningeal or brain metastases should be excluded from this 
clinical trial because of their poor prognosis and because they often develop progressive 
neurologic dysfunction that would confound the evaluation of neurologic and other 
adverse events.  Imaging or spinal fluid analysis to exclude CNS involvement is not 
required, unless there is clinical suspicion by the treating investigator. 
 
3.2.4 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to AT13387 (onalespib). 
 


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3.2.5 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
There will be no exclusion of patients with known visual impairment or symptoms, 
including by not limited to peripheral flashes (photopsia), blurred or double 
vision, floaters, color distortion and dimness, difficulties with light/dark 
accommodation, tunnel vision or other field defects, halos, apparent movement of 
stationary objects, and complex disturbances.  Patients will have a baseline 
ophthalmologic exam to serve as a point of comparison and further exams as 
needed should visual symptoms develop. No pre-treatment eye exam findings or 
ocular symptoms have been associated with an increased risk of ocular toxicity 
seen with AT13387. 
 
3.2.6 Pregnant women are excluded from this study because AT13387 (onalespib) has the 
potential for teratogenic or abortifacient effects.  Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the mother 
with AT13387 (onalespib), breastfeeding should be discontinued if the mother is treated 
with AT13387 (onalespib). 
 
3.2.7 Patients, who have had a major surgery or significant traumatic injury within 4 weeks of 
start of study drug, patients who have not recovered from the side effects of any major 
surgery (defined as requiring general anesthesia) or patients that may require major 
surgery during the course of the study. 
 
3.2.8 Prior history of another malignancy (except for non-melanoma skin cancer or in situ 
cervical or breast cancer) unless disease free for at least three years. Patients with prostate 
cancer are allowed if PSA is less than 1. 
 
3.2.9 Patients should not receive immunization with attenuated live vaccine within one week of 
study entry or during study period. 
 
3.2.10 History of noncompliance to medical regimens. 
 
3.2.11 Consistent QTc > 450 msec for men and > 470 msec for women by Fridericia formula, on 
3 separate ECGs. 
 
3.2.12 Left ventricular ejection fraction (LVEF) < 50%, regardless of whether there are 
symptoms of heart failure. 
 
3.3 
Inclusion of Women and Minorities 
 
NIH policy requires that women and members of minority groups and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH-
defined clinical research unless a clear and compelling rationale and justification establishes to 
the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate 
with respect to the health of the subjects or the purpose of the research.  Exclusion under other 


NCI Protocol #:9875  
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22 
 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC 
Director based on a compelling rationale and justification.  Cost is not an acceptable reason for 
exclusion except when the study would duplicate data from other sources.  Women of 
childbearing potential should not be routinely excluded from participation in clinical research.  
Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
Both men and women of all races and ethnic groups are eligible for this trial. Accrual of women 
and minorities to clinical trials in the DF/HCC generally reflects the population of the state of 
Massachusetts and the New England catchment area. The 2010 census indicated that the 
population of the state of Massachusetts is 51.6% female and 48.4% male. Additionally, the 
population is 80.4% white, 6.6% African American, 5.3% Asian, 2.6% of more than one race, 
and 0.3% Native American. These data were used to generate the planned distribution of subjects 
table for this trial. The DF/HCC has established the Initiative to Eliminate Cancer Disparities 
(IECD) to address cancer disparities with regard to recruitment of minorities to clinical trials. We 
will continue to work closely with the IECD to ensure that we are participating in all of the 
mechanisms developed through the Initiative to support efforts to enhance diversity in accrual 
and to address cancer disparities. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
4.1.1 CTEP Registration Procedures 
 
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 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. 
 
Documentation Required 
IVR 
NPIV
R 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 


NCI Protocol #:9875  
Version Date: October 31, 2019 
 
23 
 
Documentation Required 
IVR 
NPIV
R 
AP 
A 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
• Added to a site roster 
• Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• Act as the site-protocol PI on the IRB approval 
• Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
Additional information can be found on the CTEP website at  
< https://ctep.cancer.gov/investigatorResources/default.htm >.  For questions, please contact the 
RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office 
before they can be approved to enroll patients.  Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a determination of whether 
a site has fulfilled all regulatory criteria including but not limited to the following:  
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the Lead Network or a participating organization 
• A valid IRB approval 
• 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 


NCI Protocol #:9875  
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24 
 
not required to submit IRB approval documentation to the CTSU Regulatory Office.  For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process.  Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally.  
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
 
All ETCTN sites are part of an LAO (Lead Academic Organization), which must use their own 
funding to participate in any ETCTN trial.  Other comprehensive cancer centers can participate 
in ETCTN trials via the EDDOP program and are awarded funding that can used be to facilitate 
their participation in NCI-CTEP trials. (https://ctep.cancer.gov/initiativesprograms/eddop.htm)   
 
4.2.1 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the 9875 protocol page located on the CTSU 
Web site.  Permission to view and download this protocol is restricted and is based on person and 
site roster data housed in the CTSU RSS.  To participate, Investigators and Associates must be 
associated with the Corresponding or Participating protocol organization in the RSS.  
 
• Go to https://www.ctsu.org and log in using your CTEP IAM username and password. 
• Click on the Protocols tab in the upper left of your screen.  
• Either enter the protocol # in the search field at the top of the protocol tree, or 
• Click on the “By Lead Organization” folder to expand, then select LAO-MA036, and 
protocol #9875. 
• Click on LPO Documents, select the Site Registration documents link, and download and 
complete the forms provided.  (Note: For sites under the CIRB initiative, IRB data will 
load to RSS as described above.) 
 
4.2.2 Requirements For 9875 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) 
 
4.2.3 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: https://www.ctsu.org (members’ area) → Regulatory Tab 


NCI Protocol #:9875  
Version Date: October 31, 2019 
 
25 
 
→Regulatory Submission  
 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction and 
support. 
 
4.2.4 Checking Site Registration Status 
 
You can verify your site registration status on the members’ section of the CTSU website.   
• Go to https://www.ctsu.org and log in using your CTEP IAM username and password. 
• Click on the Regulatory tab at the top of your screen. 
• Click on the Site Registration subtab. 
• Enter your 5-character CTEP Institution Code and click on Go. 
 Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does not 
reflect compliance with protocol requirements for individuals participating on the protocol or the 
enrolling investigator’s status with the NCI or their affiliated networks. 
 
4.3 
Patient Registration 
 
4.3.1 OPEN / IWRS 
 
Study-wide, new enrollment is permanently closed, as of October 2019. 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available to users on a 24/7 basis.  It 
is integrated with the CTSU Enterprise System for regulatory and roster data interchange 
and with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
4.3.2 OPEN/IWRS User Requirements 
 
OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 


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26 
 
• To enroll patients:  Be on an ETCTN Corresponding or Participating Organization 
roster with the role of Registrar. Registrars must hold a minimum of an AP 
registration type.  
• Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes.  If 
applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
 
4.3.3 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 7 days.  Issues that would 
cause treatment delays should be discussed with the Principal Investigator.  If a patient does not 
receive protocol therapy following registration, the patient’s registration on the study may be 
canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
Except in very unusual circumstances, each participating institution will order DCTD-supplied 
agents directly from CTEP.  Agents may be ordered by a participating site only after the initial 
IRB approval for the site has been forwarded by the Coordinating Center to the CTEP PIO 
(PIO@ctep.nci.nih.gov) except for Group studies. 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
Regimen Description 
Agent 
Premedications 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
AT13387 (onalespib) No 
premedications 
are required 
160mg/m2 
in 250 cc 
5% 
dextrose or 
0.9% NS 
IV over 1 hour  
Days 1, 2, 
8, 9, 15 and 
16 
28 days  
(4 weeks) 
 
 
 


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27 
 
 
Patients will be dosed at 160mg/m2/dose on days 1, 2, days 8, 9, and days 15, 16 of a 4 week 
cycle.  There will be a response assessment by PET/CT and CT scans every 2 cycles.  If the CT 
portion of the PET/CT is of diagnostic quality, then an additional CT scan is not necessary. 
However, if CT portion of the PET/CT is a low-resolution CT, then a separate CT scan is 
necessary.  
 
Treatment can be moved up or delayed to accommodate holidays, inclement weather, or other 
reasons for clinic closures. Patients can continue on treatment as long as they are responding and 
tolerating treatment. However, all patients will have to come off this study treatment by May 31, 
2020, as the study treatment will no longer be available. 
 
5.1.1 
AT13387 (onalespib) 
 
The study drug AT13387 (onalespib) will be administered by intravenous infusion via peripheral 
or central venous access at a dose of 160mg/m2 (using actual body weight from cycle 1 day 1 to 
calculate body surface area) over 1 hour.  The dosing frequency will be on days 1, 2, 8, 9, 15, 
and 16 of every 4 week cycle.  AT13387 (onalespib) will be provided by CTEP. 
 
On the first day of treatment each week (days 1, 8, and 15), patients must meet the following pre-
treatment criteria: ANC > 1000/mcL, platelet count > 75,000/mcL (or > 30,000/mcL if due to 
disease), potassium and magnesium above the institutional lower limit of normal (repletion is 
allowed). 
 
Astex has recommended that vital signs (temperature, heart rate, blood pressure, oxygen 
saturations) be performed pre-AT13387 (onalespib) infusion. Additional vital signs will be 
performed during the course of infusion as clinically indicated. No extended post-administration 
monitoring will be required, except as indicated in the protocol for research-related assays. 
   
5.1.2 Other Modalities or Procedures 
N/A 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
All patients receiving treatment with AT13387 (onalespib) may receive antiemetics and anti-
motility agents for symptomatic management while on treatment. Both antiemetics and anti-
motility agents may be given to alleviate expected drug-related toxicity on an as required basis 
and gastrointestinal toxicity should not be considered to be dose limiting in the absence of 
maximal supportive therapy. Patients receiving treatment with a bisphosphonate are not excluded 
from participating in the trial and bisphosphonate therapy may be initiated while on trial 
provided the patient does not have disease progression according to RECIST criteria. 
 
5.2.1 Growth factors 
The use of white blood cell growth factors (G-CSF) is acceptable for patients who 
experience grade 4 neutropenia or have a history of febrile neutropenia.  For these 
acceptable circumstances, growth factors can be administered both at the time of the 


NCI Protocol #:9875  
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28 
 
event and preventively in subsequent cycles.  Growth factors should not be administered 
to allow for patient eligibility at screening. Growth factors should not be administered on 
the same day as onalespib; wait 24 hours after an administering onalespib to administer 
growth factors. 
 
5.2.2 Transfusions 
Symptomatic anemia should be treated with red blood cell transfusion and is 
recommended if the hemoglobin falls below 8 g/dL. The initiation of erythropoietic 
therapy for the management of chemotherapy-induced anemia follows the American 
Society of Hematology/ASCO clinical practice guidelines (WWW.ASCO.ORG). 
 
Thrombocytopenia will be treated conservatively. In the absence of bleeding, or a 
necessary invasive procedure, platelet transfusions should be given for a platelet count ≤ 
10 x 109/L. If invasive procedure(s) is (are) planned, or the patient develops bleeding, 
platelet transfusions should be administered in accordance with the standard of practice, 
usually maintaining a platelet count above 50 x 109/L. 
 
5.2.3 Electrolyte repletion 
Oral and IV potassium and magnesium electrolyte repletion is allowed to meet both study 
eligibility and treatment criteria. 
 
5.2.4 Antiemetics 
Antiemetics will not be administered routinely prior to receiving AT13387 (onalespib). 
However, if a patient develops nausea/vomiting, anti-emetics such as but not limited to 
prochlorperazine, metochlopramide, or aprepitant may be given. 5-HT3 antagonists like 
ondansetron are not allowed given their prolonging effecting on the QTc interval.  In 
addition, if a patient develops nausea and/or vomiting at any dose level that is Grade 2 or 
greater, anti-emetics may be instituted prophylactically at the discretion of the 
investigator. Nausea and vomiting will be considered refractory if it does not resolve to ≤ 
Grade 1 with treatment with combination antiemetics within 48 hours. 
 
5.2.5 Anti-motility agents 
If diarrhea develops and does not have an identifiable cause other than AT13387 
(onalespib) administration, anti-motility agents will be administered. Diarrhea will be 
considered refractory if it does not resolve within 48 hours to ≤ Grade 1 with 
administration of anti-motility agent(s). If the patient develops blood or mucous in the 
stool, dehydration, or hemodynamic instability, or fever along with the diarrhea, anti-
motility agents may be discontinued at the discretion of the Principal Investigator and the 
patient will be treated with intravenous fluids and antibiotics as medically indicated. 
 
5.2.6 Antibiotics 
Prophylactic antibiotics are not required on this trial. 
 
5.2.7 Pre-medications 
No premedication with acetaminophen, corticosteroids, or antihistamines will be 
routinely administered.   


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29 
 
Local infusion-related irritation and systemic infusion reactions may occur during or shortly 
after the administration of AT13387 (onalespib).  The local infusion adverse events are 
formulation-related (pH of current formulation is 5.0). Systemic adverse events (e.g.; 
flushing, itching, rigors, chills, nausea, tachycardia/bradycardia, dizziness) are reversible.  If 
that occurs, slow the infusion rate and/or hydrate.  If participants experience an infusion 
reaction they may subsequently receive acetaminophen (650mg orally), diphenhydramine 
(25-50mg IV), hydrocortisone (25-100mg IV), +/- famotidien (20mg IV) or equivalent as 
pre-medications per institutional standard of practice. 
 
5.2.8 Hydration 
No pre-hydration or hydration is required with this regimen. 
 
5.2.9 Tumor lysis prevention and management 
Participants with bulky disease and/or circulating disease ≥ 15,000 circulating malignant 
cells/ mm3 may receive allopurinol 300mg orally daily for 7-10 days starting with the first 
dose of AT13387 (onalespib).  Patients deemed at risk for tumor lysis syndrome (TLS) 
should have their labs monitored per standard practice.  The management of established 
TLs should also follow standard practice. 
 
5.2.10 Hyperglycemia 
AT13387 (onalespib) is known to cause hyperglycemia in patients.  Patients with pre-
existing diabetes will be asked to keep a log of their fasting and post-prandial blood 
glucose measurements and adjustments to their diabetes medications will be adjusted 
accordingly.  Referral to an endocrinologist will be made in cases with blood glucose 
management is challenging. 
 
5.2.11 Potential drug-drug interactions 
 
The potential for AT13387 (onalespib) to inhibit cytochromes P450 (CYP) 1A2, 3A4, 
2D6, 2C9, and 2C19 was assessed, and results indicate a low potential for inhibition (IC50 
> 10 mM), suggesting a low potential for clinically significant drug-drug interactions 
mediated by these enzymes.  Because the lists of these agents are constantly changing, it 
is important to regularly consult a frequently-updated list such as 
http://medicine.iupui.edu/clinpharm/ddis/; medical reference texts such as the Physicians’ 
Desk Reference may also provide this information.  As part of the enrollment/informed 
consent procedures, the patient will be counseled on the risk of interactions with other 
agents, and what to do if new medications need to be prescribed or if the patient is 
considering a new over-the-counter medicine or herbal product.  Appendix B presents 
guidelines for identifying medications/substances that could potentially interact with the 
study agent(s), as well as a Patient Drug Handout Information and Wallet Card that will 
be provided to each patient. 
 
AT13387 (onalespib) is a substrate of UGT with a relatively low affinity to inhibit 
UGT1A1, -1A3 and -1A9.  Pre-clinical studies suggest that AT13387 (onalespib) is a 
substrate of P-gp; thus, avoid St. John’s wort, rifampin, etc. AT13387 (onalespib) is also a 


NCI Protocol #:9875  
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30 
 
moderate inhibitor of BCRP and P-gp and a strong inhibitor of MATE1/2-K; thus, use 
caution with concomitant drugs that are substrates of these enzymes. 
 
5.2.12 QTc prolonging drugs 
 
Every attempt will be made to avoid medications that have been associated with QT 
interval prolongation or Torsades de Pointes (see Appendix B). Antiemetics and 
diphenhydramine will be permitted on study with the exception of 5-HT3 antagonists like 
ondansetron. Patients who are stable on antidepressants known to prolong QTc will be 
permitted to continue on their medication at the discretion of the Principal Investigator, 
provided the QTc at enrollment meets eligibility criteria. 
 
5.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies or until May 31, 2020. All patients must be off this study treatment 
by May 31, 2020, as the study treatment will no longer be available. 
 
• 
Disease progression, 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), 
• 
Patient decides to withdraw from the study, or 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
5.4 
Duration of Follow Up 
 
Patients who discontinue treatment for reasons other than disease progression will be followed 
with CT scans at 6 and 12 months or until disease progression or next therapy for PFS and DOR 
endpoints.  Follow-up after treatment discontinuation for progression, or after documented 
progression following discontinuation of therapy for reasons other than progression initially, will 
be by phone every 6 months for up to 1 year after the discontinuation of treatment for OS 
endpoints.  Patients removed from study for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event. 
 
5.5 
Criteria for Removal from Study 
 
Patients will discontinue study treatment when any of the criteria listed in Section 5.3 applies.  
Patients will be removed from study after the follow-up period outlined in Section 5.4, or if they 
decide to withdraw from the study.  The reason for study removal and the date the patient was 
removed must be documented in the Case Report Form. 
 
In the event of unusual or life-threatening complications, participating investigators must 
immediately notify the Principal Investigator Dr. Caron Jacobson at 617-632-5847 or 617-632-
3352 (page through operator). 
 


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31 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
There will be up to two dose reductions allowed (120mg/m2 and 80mg/m2) for intolerable grade 
2 toxicity or the equivalent of dose limiting toxicities.  Dose delays up to 14 days will be allowed 
for any persistent grade 2 adverse events (AE) (with the exception of fatigue, weakness, skin 
toxicity, and/or laboratory abnormalities) with treatment resumption when the AE resolves to 
grade 1 or better; AST or ALT > 3x the upper limit of normal, with treatment resumption when 
the AE resolves to grade 1 or better; and any AE, laboratory abnormality or condition that, in the 
judgment of the investigator, warrants delaying the dose of study medication.   
 
The dose is determined by the patient’s weight on Cycle 1 Day 1, regardless of changes in body 
weight. The dose can be rounded base on the intuitional guidelines of the treating institution. 
 
 
Dose Level 
AT13387 (onalespib) Dose 
-2 
80 mg/m2/dose d1,2,8,9,15,16 
-1 
120 mg/m2/dose d1,2,8,9,15,16 
0 
160 mg/m2/dose d1,2,8,9,15,16 
 
Below are dose modification tables for the following adverse events:  nausea, vomiting, diarrhea, 
neutropenia, and thrombocytopenia.   
 
Nausea 
Management/Next Dose for 
AT13387 (onalespib) 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at 
same dose level. 
Grade 3 
Hold* until < Grade 1.  Resume at 
one dose level lower, if indicated.** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management:  antiemetics. 
 
Vomiting 
Management/Next Dose for 
AT13387 (onalespib) 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at 
same dose level. 
Grade 3 
Hold* until < Grade 1.  Resume at 
one dose level lower, if indicated.** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management:  antiemetics. 
 


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32 
 
Diarrhea 
Management/Next Dose for 
AT13387 (onalespib) 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at 
same dose level. 
Grade 3 
Hold* until < Grade 1.  Resume at 
one dose level lower, if indicated.** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management:  Loperamide antidiarrheal therapy 
Dosage schedule:  4 mg at first onset, followed by 2 mg with each loose motion until diarrhea-
free for 12 hours (maximum dosage:  16 mg/24 hours) 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
 
Neutropenia 
Management/Next Dose for 
AT13387 (onalespib) 
≤ Grade 2 
No change in dose 
Grade 3,4 
Hold* until < Grade 2.  Resume at 
one dose level lower, if indicated.** 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management:  G-CSF support. 
 
Thrombocytopenia 
Management/Next Dose for 
AT13387 (onalespib) 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at 
same dose level. 
Grade 3,4 
Hold* until < Grade 1.  Resume at 
one dose level lower, if indicated.** 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management:  platelet transfusion support per institutional guidelines. 
 
Visual impairment including peripheral flashes (photopsia), blurred or double vision, floaters, 
color distortion and dimness, difficulties with light/dark accommodation, tunnel vision or other 
field defects, halos, apparent movement of stationary objects, and complex disturbances. 
Symptoms are generally Grade 1, intermittent, reversible, and transient, lasting a few seconds to 
a few minutes and occurring on 1- 3 days/cycle.  Doses may need to be held in the setting of 
grade 1-2 toxicity, and treatment may need to be discontinued if toxicity is > grade 3. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 


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33 
 
determine whether the event requires expedited reporting via the CTEP Adverse Event Reporting 
System (CTEP-AERS) in addition to routine reporting.  Adverse events will be assessed at each 
visit by the clinical trial personnel. 
 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  In addition to the comprehensive list, a subset of AEs, 
the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column 
and is identified with bold and italicized text.  The SPEER is a list of events that are protocol-
specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 'CTEP, 
NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm for further clarification.  
 
The CAEPR may not provide frequency data; if not, refer to the Investigator’s Brochure for this 
information. 
 
NOTE:  The highest grade currently reported is noted in parentheses next to the AE in the 
SPEER.  Report ONLY AEs higher than this grade expeditiously.  If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is required. 
7.1.1 CAEPRs for CTEP IND Agent 
 
7.1.1.1 
CAEPR for AT13387 (onalespib) 
 
Below is the CAEPR for AT13387 (Onalespib). Frequency is provided based on 119 patients. 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
IMPORTANT: Below is the CAEPR list with the current version of CTCAE terms (version 
5.0).  
 
 
 
 
 
 
 
 


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34 
 
 
Version 2.1, December 28, 20181 
 
 Adverse Events with Possible  
 Relationship to AT13387 (Onalespib) 
 (CTCAE 5.0 Term) 
[n= 119] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 2) 
EYE DISORDERS 
  
 
Blurred vision 
 
  
 
Vision decreased 
 
 Vision decreased (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Flatulence 
 
 Flatulence (Gr 2) 
 
Gastrointestinal hemorrhage2 
 
  
 
Hemorrhoids 
 
 
 Hemorrhoids (Gr 2) 
Nausea 
 
 
 Nausea (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever3 
 
 Fever3 (Gr 2) 
Injection site reaction4 
 
 
 Injection site reaction4 (Gr 2) 
 
Malaise 
 
 Malaise (Gr 2) 
INFECTIONS AND INFESTATIONS 
  
 
Infection5 
 
 Infection5 (Gr 2) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction3 
 
 Infusion related reaction3 (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase increased  
 Alanine aminotransferase increased 
(Gr 2) 
 
Alkaline phosphatase increased 
 
 Alkaline phosphatase increased (Gr 2) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase increased 
(Gr 2) 
 
CPK increased 
 
 CPK increased (Gr 2) 
 
Electrocardiogram QT corrected 
interval prolonged 
 
  
 
Lymphocyte count decreased 
 
 Lymphocyte count decreased (Gr 2) 
 
Platelet count decreased 
 
 Platelet count decreased (Gr 2) 
 
Weight loss 
 
 Weight loss (Gr 2) 
 
White blood cell decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
 Dehydration (Gr 2) 
 
Hypocalcemia 
 
 Hypocalcemia (Gr 2) 
 
Hypokalemia 
 
  
 
Hypomagnesemia 
 
  


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35 
 
 
 Adverse Events with Possible  
 Relationship to AT13387 (Onalespib) 
 (CTCAE 5.0 Term) 
[n= 119] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Hyponatremia 
 
 Hyponatremia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Muscle cramp 
 
 Muscle cramp (Gr 2) 
 
Myalgia 
 
 Myalgia (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Dysgeusia 
 
  
 
Headache 
 
 Headache (Gr 2) 
PSYCHIATRIC DISORDERS 
  
 
Insomnia 
 
 Insomnia (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
Hiccups 
 
 Hiccups (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Dry skin 
 
 Dry skin (Gr 2) 
 
Hyperhidrosis3 
 
 Hyperhidrosis3 (Gr 2) 
 
Rash acneiform 
 
  
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
VASCULAR DISORDERS 
  
 
Flushing 
 
 Flushing (Gr 2) 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
2Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal 
hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal 
hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal 
hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper 
gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 
 
3Infusion-related reactions may include, tachycardia/bradycardia, hypotension/hypertension, flushing, chills, fever, 
hyperhidrosis, itching, rigors, and abdominal cramps. 
 
4Injection site reaction may include injection site irritation, injection site pain, injection site inflammation or redness, 
or erythema. 
 
5Infection may include all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
 
Adverse events reported on AT13387 (Onalespib) trials, but for which there is insufficient evidence to suggest 
that there was a reasonable possibility that AT13387 (Onalespib) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 
CARDIAC DISORDERS - Cardiac disorders - Other (atrioventricular block NOS); Left ventricular systolic 
dysfunction; Palpitations 


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EYE DISORDERS - Dry eye; Eye disorders - Other (color distortion); Eye disorders - Other (diplopia); Eye 
disorders - Other (halos); Eye disorders - Other (loss of visual acuity during changes in ambient light levels); Eye 
disorders - Other (tunnel vision); Eye disorders - Other (visual color darkening); Eye disorders - Other (visual 
disturbances); Eye pain; Flashing lights; Floaters; Keratitis; Night blindness; Papilledema; Photophobia; 
Retinopathy 
GASTROINTESTINAL DISORDERS - Colitis; Mucositis oral; Oral dysesthesia; Oral pain; Salivary duct 
inflammation 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills3; Flu like symptoms 
HEPATOBILIARY DISORDERS - Hepatic hemorrhage 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood bilirubin increased; Creatinine 
increased; Ejection fraction decreased; Neutrophil count decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hypoalbuminemia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Bone pain; Generalized 
muscle weakness 
NERVOUS SYSTEM DISORDERS - Seizure; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Anxiety 
RENAL AND URINARY DISORDERS - Acute kidney injury; Proteinuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Pneumonitis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Palmar-plantar erythrodysesthesia syndrome; Pruritus; 
Skin hyperpigmentation 
VASCULAR DISORDERS - Hypertension3 
 
Note: AT13387 (Onalespib) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 
7.2 
Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 should be utilized for AE reporting. All appropriate treatment areas should have 
access to a copy of the current CTCAE version.  A copy of the CTCAE versions can be 
downloaded from the CTEP web site: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
section 7.3.4. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
 


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7.3 
Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (https://eapps-
ctep.nci.nih.gov/ctepaers).  The reporting procedures to be followed are presented in the 
“NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD 
(CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP 
Web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm.  
These requirements are briefly outlined in the tables below (Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
7.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization or Lead Organization, the local treating 
physician, and the Reporter and Submitter.  CTEP-AERS provides a copy feature for 
other e-mail recipients.  
 
The Coordinating Center of the Corresponding Organization is responsible for submitting 
to the CTSU documentation of AEs that they deem reportable for posting on the CTSU 
protocol web page and inclusion on the CTSU bi-monthly broadcast. 
 
7.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality.  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.  
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 


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of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.3.4 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting via 
CTEP-AERS.  However, they still must be reported through the routine reporting 
mechanism (Section 7.4): 
 
 


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39 
 
CTCAE SOC 
Adverse Event 
Grade 
Hospitalization/ 
Prolongation of 
Hospitalization 
Attribution 
Comments 
Investigations 
Lymphocyte count 
decreased 
Any 
 
 
 
Investigations 
INR increased, 
aPTT prolonged 
2 
 
 
 
Skin and 
subcutaneous 
tissue disorders 
Alopecia 
Any 
 
 
 
Metabolism and 
nutrition 
disorders 
Hyponatremia, 
Hypophosphatemia
Hypokalemia, 
Hypomagnesemia, 
Hypoalbuminemia, 
Hyperglycemia, 
Hyperuricemia 
2 
 
 
 
Blood and 
lymphatic 
system 
disorders 
Anemia 
2 
 
 
 
 
7.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
7.5 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  


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40 
 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
7.6 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
8.1  
Drug Information  
 
8.1.1 AT13387 (onalespib) (NSC 749712) 
 
The NCI does not provide a pharmacy manual. All drug information and preparation guidelines 
are provided below. 
 
Chemical Name: 
(2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-
1,3- dihydro-isoindol-2-yl]-methanone, L-lactic acid salt 
Other Name: 
AT13387 (onalespib)AU, AT13387 (onalespib) 
Classification: 
Heat shock protein 90 (HSP90) inhibitor 
Molecular Formula: 
C24H31N3O3.C3H6O3          M.W.: 499.61 
Mode of Action: 
AT13387 (onalespib) is a small molecule inhibitor of HSP90, an 
enzyme believed to be responsible for supporting malignant 
transformation of normal cells to tumor cells. HSP90 acts as a 
“molecular chaperone,” stabilizing and preventing the breakdown of 
key cancer forming (oncogenic) proteins. 
How Supplied: 
AT13387 (onalespib) is supplied by Astex Pharmaceuticals Inc. and 
distributed by CTEP, NCI as a 265 mg free base equivalent (as the L-
lactic acid salt) vial.  The formulation is a sterile white to off-white 
lyophilized powder with pH 5.0 (red cap vial). 
Preparation: 
Reconstitute the 265-mg lyophilized powder with 10 mL of Sterile 
Water for Injection (SWFI) resulting in 25.7 mg/mL concentration 
(10.3 mL total volume).  A sticky mass will be formed. Vigorously 
shake the vial. Agitate until the contents are fully dissolved (about 5 
minutes).  Leave the diluted vial at ambient temperature for 15-30 
minutes to allow any foam to dissipate. If not used immediately, store 
the reconstituted vial(s) at 20 to 80 C to not exceed 8 hours. 
 
Withdraw the calculated dose of AT13387 and further dilute it in 250 
mL of D5W or 0.9% NS. The prepared IV solution is compatible in 
PVC or non-PVC infusion bags.   
 
Store the prepared IV solution at 20 to 80 C (up to 8 hours) if not used 
immediately.  When removed from the refrigerator, allows the prepared 
IV solution to sit at room temperature between 15 to 30 minutes before 


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administering to patients. The prepared IV solution must be used within 8 
hours -i.e., from the time the drug vial is diluted to the time the IV 
administration is complete. Protection from light during the infusion 
period is not required. 
Storage: 
Store the intact vials at 150 to 25ºC (59 to 77ºF).  Protect from light. 
 
If a storage temperature excursion is identified, promptly return 
AT13387 to 150 to 25ºC (59 to 77ºF) and quarantine the supplies.  
Provide a detailed report of the excursion (including documentation of 
temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability: 
Shelf life surveillance of the intact vials is ongoing.   
Route of administration: 
Intravenous 
Method of administration: 
Infuse over 1 hour through a central line or a well-defined peripheral vein.  
If using a peripheral line, be sure to aspirate venous blood prior to starting 
the infusion.  The IV infusion does not require a 0.2 micron in-line filter.  
Check the infusion site every 15 minutes and change the site of infusion 
should evidence of swelling or discoloration is observed.  
If patient experiences pain along the infusion site, slow the infusion rate 
(i.e. > 1 hour duration) and/or infuse D5W through a “Y” connector.  The 
additional volume of D5W dilutes AT13387 (onalespib) concentration at 
the local site of the infusion and alleviates the irritation. 
Potential Drug 
Interactions: 
AT13387 (onalespib) is a substrate of UGT with a relatively low affinity 
for UGT isoforms. In vitro data demonstrate that AT13387 (onalespib) is a 
weak inhibitor of UGT1A1, UGT1A3 and UGT1A9.   AT13387 
(onalespib) is also a weak inhibitor of CYP1A2, -3A4, -2D6, -2C9 and -
2C19.  AT13387 (onalespib) metabolizes primary via the glucuronidation, 
sulphation and N-oxidation.  
Pre-clinical studies suggest that AT13387 (onalespib) is a substrate of P-
gp, the efflux ratios was above 2 (ranging from 3.4 to 4.6); a moderate 
inhibitor of BCRP (35.9% +/- 2%, p=0.0001) and P-gp (31.3% +/- 1.2%, 
p= 0.0009), and a strong inhibitor of MATE1 (94.6% +/- 0.2%, p=0.0001) 
and MATE2-K (91.2% +/- 1.2%, p= 0.0002). 
Patient Care Implications: 
There are no genotoxicity, carcinogenicity, developmental and 
reproductive studies conducted with AT13387 (onalespib).  Women of 
childbearing potential should not become pregnant or breastfeed and men 
should not father a child during the study.  All subjects must use 
acceptable contraceptive measures during the treatment of AT13387 
(onalespib) and 3 months after the last dose of the investigational drug. 
 
Local infusion-related irritation and systemic infusion reactions may occur 
during or shortly after the administration of AT13387 (onalespib).  The 
local infusion adverse events are a formulation-related (pH of current 
formulation is 5.0).  Systemic adverse events (e.g.; flushing, itching, 
rigors, chills, nausea, tachycardia/bradycardia, dizziness) are reversible.  If 
that occurs, slow the infusion rate and/or hydrate with D5W.  
Premedication with dexamethasone, antihistamine and 5HT3 antagonists 
can also be given. 


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Avoid extravasation. For local irritation, apply cold compress or 
topical pain medication. 
 
A list of the adverse events and potential risks associated with AT13387 (onalespib) 
administered in this study can be found in Section 7.1. 
 
8.1.2 Availability  
 
AT13387 (onalespib) is an investigational agent supplied to investigators by the Division 
of Cancer Treatment and Diagnosis (DCTD), NCI. 
 
8.1.3 Agent Ordering and Agent Accountability 
 
NCI-supplied agents may be requested by the responsible investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) 
policy requires that agent be shipped directly to the institution where the patient is to be 
treated.  PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained).  The CTEP-assigned protocol number must be used for 
ordering all CTEP-supplied investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), Biosketch, Agent Shipment 
Form, and Financial Disclosure Form (FDF).  If there are several participating 
investigators at one institution, CTEP-supplied investigational agents for the study should 
be ordered under the name of one lead investigator at that institution. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application. Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account and the maintenance of an “active” account status, a 
“current” password, and active person registration status. For questions about drug 
orders, transfers, returns, or accountability, call or email PMB any time. Refer to the 
PMB’s website for specific policies and guidelines related to agent management. 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, dispensing and final disposition of all agents received from 
the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record 
(DARF) available on the CTEP forms page. Store and maintain separate NCI 
Investigational Agent Accountability Records for each agent, strength, formulation and 
ordering investigator on this protocol 
 
8.2  
Useful Links and Contacts Related to Drug Information 
• CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ 
• NCI CTEP Registration: RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm 


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• PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/ 
• CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov 
•  IB Coordinator: IBCoordinator@mail.nih.gov 
• PMB email: PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 
am and 4:30 pm (ET) 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
Blood, bone marrow or lymph node biopsy sampling for malignant cells will take place prior to 
treatment initiation, on cycle 1 day 17-22, and at the time of disease progression for several 
biomarker studies.  These will include immunohistochemical quantification of ALK in ALK+ 
ALCL, cyclin D1 in MCL, and BCL6 in DLBCL using established dilutions of CLIA-approved 
immunostains that have been calibrated to detect changes in protein levels, as well as 
immunoblotting of tumor samples for known HSP90 clients including CDK4, cyclin D1, AKT 
and pAKT, ERK and pERK, IKKα, BTK (in DLBCL and MCL), HSP70, ALK (in ALCL), and 
BCL6 (in DLBCL).   Each of these proteins, with the exception of HSP70, are HSP90 clients and 
thus expected to decrease following treatment with the HSP90 inhibitor AT13387 (onalespib).   
HSP70 is known to increase in a compensatory fashion upon HSP90 inhibition.  Thus, changes 
in these proteins detected by immunohistochemistry or immunoblotting would be proof of 
principle that we are indeed depleting expected targets.  In addition we will perform whole 
exome sequencing (on pre-treatment and disease progression samples) and RNASeq (on 
pretreatment, day 17-22 and disease progression samples) to identify genetic and transcriptional 
markers of disease response and resistance. 
 
9.1 
Integral Laboratory or Imaging Studies 
 
9.1.1 Immunohistochemistry for ALK (ALCL), cyclin D1 (MCL) and BCL6 (DLBCL) 
 
Immunostains on pre-treatment samples are integral assays as they determine patient eligibility 
for this study (ALK for ALCL, cyclin D1 for MCL, and BCL6 for DLBCL).  See Appendix C-E 
for standard operating procedures (SOPs) for ALK, cyclin D1 and BCL6 respectively.  Because 
this immunostain is diagnostic in this lymphoma, it should by definition be positive in 100% of 
pre-treatment samples.  Because the standard concentration of the stains used for ALK, cyclin 
D1 and BCL6 is very sensitive for these proteins (i.e., saturating) and therefore not very specific 
regarding their quantification, we performed several titrations of these immunostains on known 
ALK+ ALCL, MCL, and BCL6+ DLBCL to determine the lowest concentrations that maintain 
strong baseline staining but allow for detection of differences in protein levels following 
treatment with AT13387 (onalespib) and at the time of progression.  For ALK, a dilution of 


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44 
 
1:24,000 appears to be optimal, while for BCL6 and cyclin D1 optimal staining dilutions would 
be 1:2000 and 1:160, respectively.  We will start with dilutions of 1:24,000 for ALK, 1:2000 for 
BCL6, and 1:160 for cyclin D1.  However, if using those dilutions we are unable to adequately 
detect antigen in the pre-treatment tumor sample, we will use serial lower dilutions for 
optimization of that individual tumor specimen, using that same dilution for the subsequent on-
treatment and time of progression tumor samples. 
 
The pre-treatment biopsy and the time of progression biopsy are intended to establish a baseline 
level of staining for comparison and to assess whether these protein levels are again upregulated 
at the time of treatment progression, and therefore a measure of treatment resistance.  We intend 
to evaluate these immunostains as an early marker of disease response and proof of concept that 
we are indeed achieving HSP90 inhibition and depleting the expected targets.  Given that we see 
changes in the protein levels of HSP90 clients within 12 hours of exposure to HSP90 inhibitors 
in vitro and after 5 days of treatment with an HSP90 inhibitor in vivo, we expect to see 
differences in HSP90 protein levels early in treatment.  The half life of AT13387 (onalespib) is 
between 6 and 12 hours and the dosing schedule to be used on this study is the twice weekly 
dosing for 3 weeks with one week off, or dosing on days 1 and 2, 8 and 9, and 15 and 16.  We 
therefore plan to get a biopsy on day 17, within 24 hours of the 6th dose of the drug, but will 
allow for a biopsy up to day 22 to accommodate scheduling, weekends, and holidays.  This 
biopsy schedule was based on the timing of biopsies done for pharmacodynamic evaluation of 
AT13387 (onalespib) on the first-in-human phase I study that was recently reported.66  
 
We will use an automated Aperio measurement to determine an automated H-score, which 
previously has been found to be highly concordant with manual H-score determination (R2= 
0.8795 for immunostains for MSI2 in AML for example).103  Specifically, the assessment of the 
percentage of tumor cells that is positive for the immunohistochemical stain will be 
quantitative/continuously distributed from 0 to 100%, whereas the intensity of staining in a given 
sample will be graded from 0-3+ (0=no staining, 1=weak staining, 2=moderate staining, and 
3+=strong staining).  An H-score, the product of the percentage of positive tumor cells and the 
grade of staining intensity, will be calculated (range 0-300).103  A reduction in the H-score of 
>50% will be considered meaningful.  While the biomarker is integral at diagnosis and study 
entry, the comparison of quantitative changes in these biomarkers and response is exploratory 
and our statistical analysis will be descriptive.  If there is a correlation between the comparative 
H-scores and treatment response, this provides a readily available standardized and technically 
feasible way to predict response to treatment early in a patient’s treatment course.  
 
9.1.1.1 
Collection of Specimens 
 
Tumor biopsy samples will be obtained by core needle biopsy.  A minimum of four, but ideally 
six, core needle biopsies will be requested: at least 3 for snap freezing for whole exome 
sequencing, RNA-seq, and immunoblotting, and one for formalin-fixation for 
immunohistochemistry (see section 9.2). It is recommended that tumor biopsies be collected 
using an 18 gauge needle, however this us up to the discretion of the Interventional Radiology 
Team of the treating institution. Standard approaches for formalin-fixation and frozen section 
will be used (See Appendix F and G).  Specimens will be obtained pre-treatment, on-treatment 
(cycle 1, day 17-22 of a 28 day cycle), and at the time of disease progression. 


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45 
 
 
It is not recommended to use the bone marrow biopsy instead of the tumor biopsy, however it is 
an option. If a bone marrow biopsy is used, please collect the following samples: 
 
• The 10mL green top (BD Vacutainer Sodium Heparin Tube), which should be 
ficolled and frozen viably  
• The non-heparin syringe that is transferred to a 15mL conical tube (centrifuge 
tube) should be snap frozen 
 
It is not recommended to collect blood as the source of the tumor biopsy, however it is an option. 
A bone marrow biopsy or core biopsy are much preferred. Sites should discuss this with Dr. 
Jacobson prior to proceeding with this option. Please email the DFCI CRC or contact Dr. 
Jacobson directly if this possibility arises. If blood is used, please collect the following sample: 
 
• whole blood in a Streck cell-free DNA tube, 4-6 mL of plasma obtained and 
frozen, then sent to CCPM on dry ice 
9.1.1.2 
Handling of Specimens 
 
Please see the SOPs and IHC templates provided in Appendices D-G.  
 
For formalin-fixed samples, each container should be labeled with: 
a. Protocol number (9875) 
b. Subject Study Number 
c. Pre/on/post treatment 
d. Date of collection 
 
For fresh frozen tissue samples, biopsies should be frozen on site within 5-10 minutes of 
devascularization and one cryomold per specimen should be used and submitted.  Each cryomold 
should we labeled on the bottom with the following: 
a. Protocol Number (9875) 
b. Subject Study Number 
c. Pre/on/post treatment 
d. Date of collection 
 
The lip of each cryomold should be labeled with the core #.   
 
9.1.1.3 
Shipping of Specimens 
 
Formalin-Fixed Samples should be sent in a securely closed container (one with a screw top/cap), 
this container should be placed in a secondary container (plastic zip loc bags work well) put a piece 
of absorbent material in the secondary container with the sample in case of leakage. This entire 
package along with a Specimen Submission Form (Appendix H) can then be shipped via FedEx (in 
their appropriate packaging), under current shipping requirements for non-infectious/hazardous 
human samples. Please keep SSF outside of the secondary container so it does not become wet 
should the primary container leak. A Specimen Submission Form should be included for each 


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46 
 
sample submitted (see Appendix H). An FFPE block of the samples is preferable, however the 
tissue can be sent in just formalin if needed. Kits for shipment will not be provided. 
 
Frozen tissue should be shipped on dry ice in a separate box from Formalin-Fixed tissue.  A 
Specimen Submission Form should be included for each sample submitted. 
Shipping container for Frozen Tissue should include: 
• Priority Overnight Frozen Material labeling 
• Dry Ice UN number 
• Class 9 label 
 
Please ship specimens via FedEx Overnight Priority to: 
Judy Chen 
Dana-Farber Cancer Institute 
Dana 950 
450 Brookline Avenue 
Boston, MA 02215 
Re: Protocol 16-712  
 
Please note: packages must be sent for Tuesday through Friday delivery only.  Do not ship 
on Friday or over the weekend/holidays. 
 
For each package, complete and send DFCI Shipping Manifest(s) (Appendix H) as detailed 
below: 
1. Complete one manifest for FFPE samples and a separate manifest for frozen 
tissue even if shipping on the same day. 
2. Email the DFCI Shipping Manifest(s) to 
CCPM_ResearchOps@dfci.harvard.edu at the time of shipment. This office 
can also be reached by phone at 617-582-9353. 
3. Include a printed copy of the DFCI Shipping Manifest(s) with the package. 
 
9.1.1.4 
Site(s) Performing Correlative Study 
All immunostains will be performed at the Dana-Farber Cancer Institute/Brigham and Women’s 
Hospital Hematopathology Core Laboratory (a CLIA approved laboratory) under the direction of 
Dr. Scott Rodig and Dr. Elizabeth Morgan.  This lab has extensive experience with these 
immunostains as they are standardly done on all ALCL, MCL, and DLBCL cases reviewed, 
respectively.     
 
9.2 
Exploratory/Ancillary Correlative Studies 
 
9.2.1 Immunoblotting for HSP90 clients 
 
We have extensive experience in the Weinstock lab with immunoblotting for several HSP90 
clients in MCL and DLBCL cell lines before and following exposure to HSP90 inhibitors, and in 
tissue from MCL cell line and patient derived xenografts treated with either vehicle or drug (see 
section 2.3.2).  These include BTK and pBTK, cyclin D1, CDK4, AKT and pAKT, ERK and 
pERK, IKKα, p100, p52, and BCL6.  Our lab will immunoblot for these HSP90 clients and 


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47 
 
others, and compare protein levels semi-quantitatively between pre- and on-treatment lymphoma 
cells, and at the time of disease progression.  We expect to see downregulation of these proteins 
on treatment, and possibly upregulation of some or all of these proteins at the time of progression 
on drug.  
 
9.2.1.1 
Collection of Specimens 
 
Tumor biopsy samples will be obtained by core needle biopsy.  A minimum of four, but ideally 
six, core needle biopsies will be requested: at least 3 for snap freezing for whole exome 
sequencing, RNA-seq, and immunoblotting, and one for formalin-fixation for 
immunohistochemistry (see section 9.1).  It is recommended that tumor biopsies be collected 
using an 18 gauge needle, however this us up to the discretion of the Interventional Radiology 
Team of the treating institution. Standard approaches for formalin-fixation and frozen section 
will be used (See Appendix F and G).  Specimens will be obtained pre-treatment, on-treatment 
(cycle 1, day 17-22 of a 28 day cycle), and at the time of disease progression. 
 
It is not recommended to use the bone marrow biopsy instead of the tumor biopsy, however it is 
an option. If a bone marrow biopsy is used, please collect the following samples: 
 
• The 10mL green top (BD Vacutainer Sodium Heparin Tube), which should be 
ficolled and frozen viably  
• The non-heparin syringe that is transferred to a 15mL conical tube (centrifuge 
tube) should be snap frozen 
 
It is not recommended to collect blood as the source of the tumor biopsy, however it is an option. 
A bone marrow biopsy or core biopsy are much preferred. Sites should discuss this with Dr. 
Jacobson prior to proceeding with this option. Please email the DFCI CRC or contact Dr. 
Jacobson directly if this possibility arises. If blood is used, please collect the following sample: 
 
• whole blood in a Streck cell-free DNA tube, 4-6 mL of plasma obtained and 
frozen, then sent to CCPM on dry ice 
 
9.2.1.2 
Handling of Specimens 
 
Please see the SOPs and IHC templates provided in Appendices D-G. 
 
For formalin-fixed samples, each container should be labeled with: 
a. Protocol number (9875) 
b. Subject Study Number 
c. Pre/on/post treatment 
d. Date of collection 
 
For fresh frozen tissue samples, biopsies should be frozen on site within 5-10 minutes of 
devascularization and one cryomold per specimen should be used and submitted.  Each cryomold 
should we labeled on the bottom with the following: 


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48 
 
a. Protocol Number (9875) 
b. Subject Study Number 
c. Pre/on/post treatment 
d. Date of collection 
 
The lip of each cryomold should be labeled with the core #.   
 
9.2.1.3 
Shipping of Specimen(s) 
 
Formalin-Fixed Samples should be sent in a securely closed container (one with a screw top/cap), 
this container should be placed in a secondary container (plastic zip loc bags work well) put a piece 
of absorbent material in the secondary container with the sample in case of leakage. This entire 
package along with a Specimen Submission Form (Appendix H) can then be shipped via FedEx (in 
their appropriate packaging), under current shipping requirements for non infectious/hazardous 
human samples. Please keep SSF outside of the secondary container so it does not become wet 
should the primary container leak.  A Specimen Submission Form should be included for each 
sample submitted (see Appendix H).  An FFPE block of the samples is preferable, however the 
tissue can be sent in just formalin if needed.  Kits for shipment will not be provided. 
 
Frozen tissue should be shipped on dry ice in a separate box from Formalin-Fixed tissue.  A 
Specimen Submission Form (Appendix H) should be included for each sample submitted. 
Shipping container for Frozen Tissue should include: 
• Priority Overnight Frozen Material labeling 
• Dry Ice UN number 
• Class 9 label 
 
Please ship specimens via FedEx Overnight Priority to: 
Judy Chen 
Dana-Farber Cancer Institute 
Dana 950 
450 Brookline Avenue 
Boston, MA 02215 
Re: Protocol 16-712  
 
Please note: packages must be sent for Tuesday through Friday delivery only.  Do not ship 
on Friday or over the weekend/holidays. 
 
For each package, complete and send DFCI Shipping Manifest(s) (Appendix H) as detailed 
below: 
1. Complete one manifest for FFPE samples and a separate manifest for frozen 
tissue even if shipping on the same day. 
2. Email the DFCI Shipping Manifest(s) to CCPM_ResearchOps@dfci.harvard.edu 
at the time of shipment. This office can also be reached by phone at 617-582-
9353. 
3. Include a printed copy of the DFCI Shipping Manifest(s) with the package. 
 


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49 
 
9.2.1.4 
Site(s) Performing Correlative Study 
 
All immunoblotting will be performed in the laboratory of Dr. David Weinstock at the Dana-
Farber Cancer Institute.   
 
9.2.2 Whole exome sequencing and transcriptome analysis 
 
Samples will also be submitted for whole exome sequencing (with paired germline samples) and 
RNAseq, and results will be compared between pre- and on-, and time or progression tumor 
samples for markers of disease response and resistance.  For exome sequencing, the ABSOLUTE 
algorithm will be applied to determine the cancer cell fraction.  Variant allele fractions for 
mutations present in the progression sample can then be compared to those in the pre-treatment 
sample after adjustment for cancer cell fractions to determine whether AT13387 (onalespib) 
results in a shift in the clonal architecture of lymphomas.85  Although HSP90 classically acts at 
the post-translational level, some evidence indicates that it also can affect transcription.86   We 
previously demonstrated in human leukemia cells that transcriptional profiling can highlight 
downstream pathways that are suppressed or activated in response to the degradation of HSP90 
clients.87 Transcriptional analysis by RNAseq will be performed on specimens obtained prior to 
beginning treatment, during treatment with AT13387 (onalespib) and then upon progression. In 
cases with bone marrow or peripheral blood involvement, lymphoma cells will be purified, for 
example by CD19 selection. Markers of response and progression will be determined by: 1) 
comparing gene expression patterns using GSEA88, 2) interrogation of the Broad Institute 
Molecular Signatures Database88  (MSigDB; 
http://www.broadinstitute.org/gsea/msigdb/index.jsp) and 3) Ingenuity Pathway Analysis89,90, as 
we previously performed.91 In addition, we will interrogate the signature of progression during 
AT13387 (onalespib) treatment in the Connectivity Map, a database linking gene expression 
with drug sensitivity.92  Build 2.0 contains over 7,000 expression profiles representing the effects 
of 1,309 compounds. Compounds that correlate inversely with the signature, and therefore may 
abrogate it, are readily available therapeutics to block pathways that bypass HSP90 inhibition.  
The analysis of these exploratory biomarker studies will be retrospective, with assays performed 
after response evaluation for biomarker identification. 
 
If new health information about inherited traits is found on research testing, the study doctor will 
let the participant know about this and the participant will then be able to choose whether or not 
to receive this information. 
 
9.2.2.1 
Collection of Specimens 
 
Tumor biopsy samples will be obtained by core needle biopsy.  A minimum of four, but ideally 
six, core needle biopsies will be requested: at least 3 for snap freezing for whole exome 
sequencing, RNA-seq, and immunoblotting, and one for formalin-fixation for 
immunohistochemistry (see section 9.1).  It is recommended that tumor biopsies be collected 
using an 18 gauge needle, however this us up to the discretion of the Interventional Radiology 
Team of the treating institution.  Standard approaches for formalin-fixation and frozen section 
will be used (See Appendix F and G).  Specimens will be obtained pre-treatment, on-treatment 
(cycle 1, day 17-22 of a 28 day cycle), and at the time of disease progression. 


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50 
 
 
It is not recommended to use the bone marrow biopsy instead of the tumor biopsy, however it is 
an option. If a bone marrow biopsy is used, please collect the following samples: 
 
• The 10mL green top (BD Vacutainer Sodium Heparin Tube), which should be 
ficolled and frozen viably  
• The non-heparin syringe that is transferred to a 15mL conical tube (centrifuge 
tube) should be snap frozen 
 
It is not recommended to collect blood as the source of the tumor biopsy, however it is an option. 
A bone marrow biopsy or core biopsy are much preferred. Sites should discuss this with Dr. 
Jacobson prior to proceeding with this option. Please email the DFCI CRC or contact Dr. 
Jacobson directly if this possibility arises. If blood is used, please collect the following sample: 
 
• whole blood in a Streck cell-free DNA tube, 4-6 mL of plasma obtained and 
frozen, then sent to CCPM on dry ice 
 
9.2.2.2 
Handling of Specimens 
 
Please see the SOPs provided in Appendices F and G 
 
For formalin-fixed samples, each container should be labeled with: 
a. Protocol number (9875) 
b. Subject Study Number 
c. Pre/on/post treatment 
d. Date of collection 
 
For fresh frozen tissue samples, biopsies should be frozen on site within 5-10 minutes of 
devascularization and one cryomold per specimen should be used and submitted.  Each cryomold 
should we labeled on the bottom with the following: 
a. Protocol Number (9875) 
b. Subject Study Number 
c. Pre/on/post treatment 
d. Date of collection 
 
The lip of each cryomold should be labeled with the core #.   
 
9.2.2.3 
Shipping of Specimens 
 
Formalin-Fixed Samples should be sent in a securely closed container (one with a screw top/cap), 
this container should be placed in a secondary container (plastic zip loc bags work well) put a piece 
of absorbent material in the secondary container with the sample in case of leakage. This entire 
package along with a Specimen Submission Form (Appendix H) can then be shipped via FedEx (in 
their appropriate packaging), under current shipping requirements for non-infectious/hazardous 
human samples. Please keep SSF outside of the secondary container so it does not become wet 


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51 
 
should the primary container leak.  A Specimen Submission Form should be included for each 
sample submitted (see Appendix H).  An FFPE block of the samples is preferable, however the 
tissue can be sent in just formalin if needed.  Kits for shipment will not be provided. 
 
Frozen tissue should be shipped on dry ice in a separate box from Formalin-Fixed tissue.  A 
Specimen Submission Form (Appendix H) should be included for each sample submitted. 
Shipping container for Frozen Tissue should include: 
• Priority Overnight Frozen Material labeling 
• Dry Ice UN number 
• Class 9 label 
 
Please ship specimens via FedEx Overnight Priority to: 
Judy Chen 
Dana-Farber Cancer Institute 
Dana 950 
450 Brookline Avenue 
Boston, MA 02215 
Re: Protocol 16-712  
 
Please note: packages must be sent for Tuesday through Friday delivery only.  Do not ship 
on Friday or over the weekend/holidays. 
 
For each package, complete and send DFCI Shipping Manifest(s) (Appendix H) as detailed 
below: 
1. Complete one manifest for FFPE samples and a separate manifest for frozen 
tissue even if shipping on the same day. 
2. Email the DFCI Shipping Manifest(s) to 
CCPM_ResearchOps@dfci.harvard.edu at the time of shipment. This office 
can also be reached by phone at 617-582-9353. 
3. Include a printed copy of the DFCI Shipping Manifest(s) with the package. 
 
9.2.2.4 
Sites Performing Correlative Study   
 
Whole exome sequencing and RNASeq will be done at the Broad Institute. 
 
10. STUDY CALENDAR 
Baseline evaluations are to be conducted within 2 weeks prior to start of protocol therapy.  Scans 
and x-rays, including LVEF evaluation, must be done <6 weeks prior to the start of therapy and 
bone marrow biopsy must be done < 6 weeks prior to the start of therapy.  In the event that the 
patient’s condition is deteriorating, laboratory evaluations should be repeated within 48 hours 
prior to initiation of the next cycle of therapy. 
 
 
 
 


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52 
 
 
 
Cycle 1 
Cycle 2+ 
 
 
Pre- 
Studya 
D 
1 
D 
2 
D 
   8 
    D 
9 
D 
15 
D 
16 
D 
17 
D 
18 
D 
1,8,15 
D 
2,9,16 
Off 
Treatmenti 
AT13387 (onalespib) 
 
A 
A 
A 
A 
A 
A 
 
 
A 
A 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Detailed eye examb 
X 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X---------------------------------------------------------------------------------------------X 
 
Physical exam 
X 
X 
 
X 
 
X 
 
 
 
X 
 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Performance status 
X 
X 
 
X 
 
X 
 
 
 
X 
 
X 
CBC w/diff, plts 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Serum chemistryc 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
EKGd 
X 
X 
 
X 
 
X 
 
 
 
Xd 
 
X 
LVEF evaluation (TTE or 
MUGA) 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluatione 
 
X---------------------------------------------------------------------------------------------X 
X 
Bone marrow biopsy 
X 
. 
Xf 
Blood sample for germline 
sequencingg 
X 
 
 
Radiologic evaluation 
 
 
 
     FDG-PET/CT scans 
X 
 
 
FDG-PET/CT should be performed 
every 8 weeks +/- 3 days 
X 
CT chest/abdomen/pelvis 
X 
 
 
CT scans should be performed every 
8 weeks +/- 3 days 
Xj 
B-HCGh 
X 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsyk 
X 
 
 
 
 
 
 
X 
 
 
 
X 
A: 
AT13387 (onalespib):  160mg/m2/dose as assigned 
a:      All screening must take place within 2 weeks of the start of therapy, except for scans, which must occur within 6 weeks, and the 
screening bone marrow biopsy, which must occur within 6 weeks, prior to the start of therapy. 
b:      All patients will have a detailed eye exam by an ophthalmologist during screening to be used as a baseline eye exam for comparison, 
should ocular toxicity later develop.  There are no protocol-specific tests required for this eye exam. If patients develop eye symptoms 
during treatment, an additional eye examination may be conducted at the investigator’s discretion. See appendix I for an example of an 
eye exam work-up. Using this eye exam form is not required. 
c: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, 
magnesium, total protein, SGOT [AST], SGPT [ALT], sodium, uric acid. 
d:      Cycle 2 and on, electrocardiograms (EKGs) will be done on day 1 of each cycle. EKGs should be done per standard of care at the treating 
institution. EKGs are not required to be in triplicate, but if there is an issue with a QTc value on the single EKG, an average CTc is 
acceptable on three triplicate EKGs if it makes a patient eligible for treatment.  
e:       Adverse event and concomitant medication evaluation will be assessed at each visit by the clinical trial personnel. 
f:       If bone marrow biopsy is negative at screening, it does not need to be repeated.  If the bone marrow biopsy is involved at baseline, it 
must be repeated in order to confirm a complete response (CR). 
g:      To be collected in 1 x 4 mL purple top EDTA tube. However, a minimum of 1 mL of blood is needed so any tube size that meets this 1 
mL minimum is acceptable. This can be shipped along with the frozen tissue. 
h: 
Serum pregnancy test (women of childbearing potential). 
i: 
Off-treatment evaluation. Patients who come off treatment for progression will have telephone follow-up every 6 months for up to 1 year 


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53 
 
for OS endpoints.  Patients who come off treatment for reasons other than progression will have CT scans (see below) at 6 and 12 
months, or until the time of progression or next therapy, for PFS and DOR endpoints. 
j:      CT scans will be repeated at 6 and 12 months, or until the time of progression, for patients who come off study for reasons other than 
disease progression. 
k:      Biopsy or sample of most accessible tissue, which may be bone marrow, body fluid, lymph node, or other tumor site.  The sample should 
be from the same tumor source (ie body fluid, bone marrow, lymph node, or other tumor site) at each timepoint.  This is distinct from the 
bone marrow biopsy required at screening for lymphoma staging.  However, if the bone marrow is involved at screening, this can be used 
as the site of tumor biopsy for patients during pre-treatment, cycle 1 and at the time of progression.  Biopsies during cycle 1 should 
optimally be done on day 17, but can be done between days 17-22.  
 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect  
 
All patients will have a baseline PET/CT scan within 6 weeks prior to the start of therapy.  For 
the purposes of this study, patients should be re-evaluated for response by PET/CT scans every 8 
weeks.  In addition, a bone marrow aspirate and biopsy are required within 6 weeks before the 1st 
treatment for all patients.  If the initial marrow shows involvement, repeat marrow is required to 
confirm a CR.  If the initial marrow is negative, further bone marrow biopsy is not required.  The 
marrow should be sent for aspirate, core pathology, flow cytometry, and cytogenetics.  
 
Response and progression will be evaluated in this study using the International Harmonization 
Project for lymphoma criteria.104   
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with AT13387 (onalespib). 
 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  
 
11.1.2 Response Criteria 
 
11.1.2.1 
Evaluation of Disease 
 
Complete Response (CR):  Disappearance of all evidence of disease.  For FDG-avid 
or PET positive sites of disease prior to therapy, a mass of any size is permitted if 
PET negative; for variably FDG avid or PET negative lesions, regression to normal 
size on CT is necessary.  The spleen or liver must also be nonpalpable with 
disappearance of any nodules, and the bone marrow, if initially involved, must be 
cleared on repeat biopsy. 
 
Partial Response (PR):  Regression of measurable disease and no new sites of disease.  
This is defined as a > 50% decrease in the sum of the diameters of the up to 6 largest 
dominant masses with no increase in size of other masses.  If the sites of disease were 


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PET positive at baseline, there must be at least one previously involved site that 
remains PET positive.  For disease involving the spleen or liver, there must be a > 
50% decrease in the sum of the diameters of nodules (of if a single nodule, > 50% 
reduction in its greatest transverse diameter) and/or no increase in size of the liver or 
spleen. 
 
Progressive Disease (PD):  Any new lesion or an increase by > 50% of previously 
involved sites from nadir.  This includes the appearance of any new lesion(s) > 1.5cm 
in any axis, a > 50% increase in the sum of diameters of > 1 site of disease or > 50% 
increase in the longest diameter of a previously identified node >1cm in short axis.  If 
the sites of disease were PET positive at baseline, they must remain PET positive. 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD.  If sites of disease were FDG avid or PET positive prior to 
therapy, they remain PET positive with no new sites of disease.  If sites of disease 
were variably FDG avid or PET negative, there has been no change in the size of 
previous lesions.   
 
11.1.2.2 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
11.1.3 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
11.1.4 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
 


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11.1.5 Response Review 
 
For determination of response rate and response duration, central review of the PET/CT 
scans obtained at baseline, after every 2 cycles of therapy, and at final response 
evaluation is required.  
 
These scans should be burned onto CD and sent via FedEx to the head study coordinator 
(refer to study contact list at the beginning of the protocol) at DFCI.  
 
The CDs should be labeled with the following information:  
1. Patient initials 
2. Study number 
3. Patient date of birth 
4. Type of scan – please make sure you specify this 
5. Date of scan 
6. Timepoint (baseline, post cycle 2 etc.) 
 
The CDs should be sent to the following address: 
[Insert DFCI Study Coordinator’s name] #16-712 
Dana-Farber Cancer Institute 
450 Brookline Avenue, LG100 
Boston, MA 02215 
 
The scan will then be reviewed at the Tumor Imaging Metrics Core at DFCI. We will 
accept the decision of the treating investigator and local radiology review of scans, 
however, to determine if a patient remains on study in real time at the time of response 
assessment.  
 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug.  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
For this Phase 2 portion of the study, the Protocol Principal Investigator will have, at a 
minimum, quarterly conference calls with the Study Investigators and the CTEP Medical 
Officers to review accrual, progress, and pharmacovigilance.  Decisions to proceed to the second 


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stage of a Phase 2 trial will require sign-off by the Protocol Principal Investigator and the 
Protocol Statistician through IWRS and Medidata Rave. 
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
12.2 
Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the site 
user must have an active CTEP IAM account (check at < https://ctepcore.nci.nih.gov/iam  >) and 
the appropriate Rave role (Rave CRA, Read-Only, RAVE CRA, SLA or Site Investigator) on 
either the LPO or participating organization roster at the enrolling site. To hold the Rave CRA 
role or RAVE 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.   
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed.  Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen.   
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
 
12.2.1 Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP).  Information on CTMS reporting is available at:  
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-site 


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audits will be conducted on an 18-36 month basis as part of routine cancer center site visits. 
More frequent audits may be conducted if warranted by accrual or due to concerns regarding 
data quality or timely submission.  For CTMS monitored studies, after users have activated their 
accounts, please contact the Theradex Help Desk at (609) 799-7580 or by email at 
CTMSSupport@theradex.com for additional support with Rave and completion of CRFs. 
 
12.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all investigators at 
the ETCTN Sites understand the procedures for data submission for each ETCTN protocol and 
that protocol specified data are submitted accurately and in a timely manner to the CTMS via the 
electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once 
every 2 weeks.  The timeliness of data submissions and timeliness in resolving data queries will 
be tracked by CTMS.  Metrics for timeliness will be followed and assessed on a quarterly basis.  
For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it 
is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as 
data is received.  Queries will be issued by CTMS directly within Rave.  The queries will appear 
on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve.  Monthly web-
based reports are posted for review by the Drug Monitors in the IDB, CTEP.  Onsite audits will 
be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI 
policies and procedures with the overarching goal of ensuring the integrity of data generated 
from NCI-sponsored clinical trials, as described in the ETCTN Program Guidelines, which may 
be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm)  and 
CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the recommended 
phase 2 dose (RP2D), and a description of any dose-limiting toxicities (DLTs).  CTMS will 
utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository (caDSR) 
compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-resources/interoperability-and-
semantics/metadata-and-models).  Customized eCRFs will be included when appropriate to meet 
unique study requirements.  The PI is encouraged to review the eCRFs, working closely with 
CTMS to ensure prospectively that all required items are appropriately captured in the eCRFs 
prior to study activation.  CTMS will prepare the eCRFs with built-in edit checks to the extent 
possible to promote data integrity. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). 
 


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58 
 
12.3 
CTEP Multicenter Guidelines 
N/A 
 
12.4 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 


NCI Protocol #:9875  
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59 
 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
This is a phase II, multi-center study of an Hsp90 inhibitor in non-Hodgkin lymphomas. Study-
wide, new enrollment is permanently closed, as of October 2019. The study is comprised of three 
patient populations (cohorts) with the following designs: 
 
ALK+ ALCL: The primary objective of this cohort is objective response rate in relapsed ALK+ 
ALCL patients. Given the rarity of refractory disease in this patient population, we will aim for a 
sample size of ten patients and deem the treatment worthy of further consideration if at least 
three patients respond while on study. The 90% exact binomial confidence limits for three 
responses in ten patients is 9-61%. We will consider a response rate of 5% unworthy of further 
study for this patient population, and note the 3 responses in 10 patients is the smallest number of 


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responses that excludes a 5% response rate based on 90% exact binomial confidence. This cohort 
is now closed to new enrollment, as of February 2019. 
 
MCL: The primary objective of this arm is objective response rate in MCL patients who have 
failed multiple lines of therapy. This arm will follow a Simon two-stage design to allow for early 
termination due to a lack of efficacy. We will consider a response rate of 25% worthy of further 
study and a response rate of 5% as unworthy of further study. The first stage will enroll ten 
patients and assess response rate, and if zero responses are seen in the first ten patients, the study 
will stop early for lack of efficacy. However, if one or more responses are seen, we will enroll an 
additional ten patients for a total of 20. If three or more out of the 20 respond, we will consider 
this regimen worthy of further study. The study will be stopped early with a probability of 60% if 
the true response rate is 5% or with a probability of 5.6% if the true response rate is 25%. The 
regimen will be considered worthy of further study with a probability of 6.9% if the true 
response rate is 5% or with a probability of 88% if the true response rate is 25%. Therefore, this 
study has an overall type-I error rate of 6.9% and an overall power of 88%. This cohort is now 
closed to new enrollment, as of February 2019. 
  
BCL6+ DLBCL: The primary objective of this arm is objective response in relapsed BCL6+ 
DLBCL. We will consider a response rate of 25% worthy of further study in this patient 
population while a 5% response rate is unworthy. We will employ a Simon two-stage plan 
designed to allow for early study termination if the regimen lacks efficacy. We will distinguish 
between a response rate of 5% which will be considered unworthy of further study and a 
response rate of 25% which will be considered worthy of further study. According to this design, 
if none of the first ten patients respond, we will stop early for lack of efficacy. If one or more 
patients respond, we will accrue ten additional patients for a total of 20. If three or more of the 
20 respond, we will consider this regimen worthy of further study.  The study will stop early 
with a probability of 60% if the true response rate is 5% or with a probability of 5.6% if the true 
response rate is 25%. The regimen will be considered worthy of further study with a probability 
of 6.9% if the true response rate is 5% or with a probability of 88% if the true response rate is 
25%. Therefore, this study has an overall type-I error rate of 6.9% and an overall power of 88%. 
 
Our primary investigation of exploratory/correlative laboratory assays in this study involve 
comparisons between baseline, on treatment, or time of progression protein levels of ALK in 
ALK+ ALCL; cyclin D1 in MCL; and BCL6 in DLBCL.  These are primary endpoints of the 
laboratory component because they are biomarkers which are anticipated to be positive at study 
entry based on eligibility criteria, and our goal is to identify changes with the administration of 
AT13387 (onalespib), and, further, to examine the association between the magnitude of change 
and response to therapy.  We will use an H-score for each of these assays (IHC intensity grade 
[0-3+] multiplied by the proportion of IHC positive tumor cells [0-100%]).  Because of the 
limited sample size in ALK+ ALCL, these results (at each time point and as changes as a 
proportion of baseline levels) will be reported descriptively.  For changes in cyclin D1 levels in 
MCL, as well as for changes in BCL6 in DLBCL, we will investigate these markers in two ways.  
First, we will characterize the changes between baseline, on study, and at the time of progression 
and present them descriptively both as differences and as differences at the referenced time point 
as a proportion of the baseline levels.  We will present both mean and standard deviation, and 
median and IQR/range.  We will use the Wilcoxon rank sum test to compare these changes 


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61 
 
between responders to non-responders.  If there are 3 responders, we will have 84% power to 
detect a 1.5 standard deviation difference in the changes, testing at the 0.10 one-sided 
significance level.  If there are 6 clinical responses, we will have 75% power to detect a one 
standard deviation difference.   We use a one-sided significance level because we hypothesize 
that activity of AT13387 (onalespib) leading to response will reduce the protein levels of these 
markers.  Other biomarkers (immunoblotting, whole exome sequencing, RNASeq) are 
exploratory, and we can only investigate changes in those cases in which the marker is 
positive/measurable at study entry.  Statistics for these endpoints will be descriptive. This cohort 
is now closed to new enrollment, as of October 2019. 
 
13.2 
Sample Size/Accrual Rate 
 
For ALK+ ALCL, we expect accrual of 0-1 patients/month, with an estimated time to accrual of 
all ten patients of 18 months.  For DLBCL and MCL, we expect accrual of 1-2 patients/month, 
with an estimated time to accrual of all 20 patients of 12-18 months.  
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Racial Categories 
Ethnic Categories 
Total 
 
Not Hispanic or Latino 
Hispanic or Latino 
 
 
Female 
Male 
Female 
Male 
 
American Indian/  
Alaska Native 
0 
0 
0 
0 
0 
Asian 
1 
2 
0 
0 
3 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
3 
2 
0 
0 
5 
White 
18 
17 
1 
1 
37 
More than one Race 
2 
1 
1 
1 
5 
Total 
24 
22 
2 
2 
50 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015)  
OMB No. 0925-0001/0002 


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Accrual of women and minorities to clinical trials in the DF/HCC generally reflects the population of the 
state of Massachusetts and the New England catchment area. The 2010 census indicated that the 
population of the state of Massachusetts is 51.6% female and 48.4% male. Additionally, the population is 
80.4% white, 6.6% African American, 5.3% Asian, 2.6% of more than one race, and 0.3% Native 
American. These data were used to generate the planned distribution of subjects table for the AT13387 
(onalespib) trial. The DF/HCC has established the Initiative to Eliminate Cancer Disparities (IECD) to 
address cancer disparities with regard to recruitment of minorities to clinical trials. We will continue to 
work closely with the IECD to ensure that we are participating in all of the mechanisms developed 
through the Initiative to support efforts to enhance diversity in accrual and to address cancer disparities. 
 
13.3 
Stratification Factors 
 
All three cohorts will enroll simultaneously and independently.  There will be no stratification. 
 
13.4 
Analysis of Secondary Endpoints 
 
Secondary endpoints will be analyzed at the same time as the primary endpoint and assessed for 
each cohort separately and overall. Due to the small sample size in each cohort and all patients 
combined, secondary endpoints will be descriptive unless otherwise noted. All eligible patients 
who receive at least one dose of treatment will be included in efficacy endpoints, and all patients 
regardless of eligibility who receive at least one dose of treatment will be included in toxicity 
assessments. 
 
Patients receiving any treatment regardless of eligibility or study completion will be assessed for 
toxicity from the time of their first treatment. At each toxicity evaluation, patients with 
unacceptable toxicities will be removed from study but remain in safety evaluations. Toxicities 
will be summarized with counts and proportions within each cohort and overall. 
 
Time-to-event endpoints of progression-free and overall survival (PFS and OS, resp.) will be 
characterized using the Kaplan-Meier method. OS is defined from the date of study entry until 
the date of death by any cause. PFS will be measured from the date of study entry until 
documentation of first progression or death from any cause. Median follow-up time will be 
assessed using the reverse Kaplan-Meier method. 
 
Duration of response (DOR) is defined as the time from first objective response (PR or CR) until 
the first date of documented progression using [the response criteria] or death due to any cause. 
For patient who remain alive without progression, the DOR will be censored on the date of their 
last response assessment. Patients who begin a subsequent therapy without prior documented 
progression will be censored at the last response assessment prior to initiation of non-protocol 
therapy. DOR will be evaluated only in patients who respond with either a PR or CR while on 
study. 
 
 
 
 


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13.5 
Reporting and Exclusions 
 
13.5.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with 
AT13387 (onalespib) 
 
13.5.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories:  1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note:  By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those 
who received no study medication) should be included in the main analysis of the 
response rate.  Patients in response categories 4-9 should be considered to have a 
treatment failure (disease progression).  Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate.  Precise 
definitions for categories 4-9 will be protocol specific.  
 
All conclusions should be based on all eligible patients.  Sub-analyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.).  However, these 
subanalyses may not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis should be clearly 
reported.  The 95% confidence intervals should also be provided.  
  
 
 


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


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APPENDIX B__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, AT13387 (onalespib).  This clinical trial is sponsored by the National 
Cancer Institute (NCI).  This form is addressed to the patient, but includes important information 
for others who care for this patient.  
 
These are the things that your prescriber needs to know: 
  
Pre-clinical data show that AT13387 (onalespib) interacts with certain specific enzymes in the 
liver and certain transport proteins that help move drugs in and out of cells.  
 
The enzymes in question are UGT1A1, UGT1A3, UGT1A9 and CYP 1A2, 3A4, 2D6, 2C9, and 
2C19.   
 
• AT13387 (onalespib) is metabolized by UGT1A1 and UGT1A3 and may be affected by 
other drugs that inhibit or induce these enzymes.   
• AT13387 (onalespib) is a “weak” inhibitor of UGT1A1, UGT1A3, UGT1A9 and CYP 
1A2, 3A4, 2D6, 2C9, and 2C19 and may affect the metabolism of other drugs. 
• The proteins in questions are P-gp, BCRP, MATE-1, and MATE2-K.  AT13387 (AT13387 
(onalespib) is a P-gp substrate and may be affected by other drugs that inhibit/induce      
P-gp.  AT13387 is a “moderate inhibitor” of BCRP and P-gp, and a “strong inhibitor” of 
MATE1 and MATE2-K and may affect transport of other drugs in and out of cells.  
 
 
 
 
 
 
 
 
  
 
 
 
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
 
AT13387 (onalespib) 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 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, or pharmacists) you are taking part 
in a clinical trial.  
 
These are the things that you and they need to know:  
AT13387 (onalespib) must be used very carefully with other medicines that need certain liver 
enzymes or transport proteins to be effective or to be cleared from your body. Before you enroll 
onto the clinical trial, your study doctor will work with your regular health care providers to 


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review any medicines and herbal supplements that are considered “strong/moderate 
inhibitor/inducer or substrate of UGT1A1, UGT1A3, BCRP, P-gp, MATE1 and MATE2-K, 
CYP1A2, -3A4, -2D6, -2C9, and -2C19.”  
•  Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects.  
•  Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.   
Your study doctor’s name is: _____________________________________ and he or she can be 
contacted at _____________________________________.        
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                             
 
STUDY DRUG INFORMATION WALLET CARD 
You are enrolled on a clinical trial using the experimental drug AT13387 
(onalespib).  This clinical trial is sponsored by the NCI.  AT13387 
(onalespib)) interacts with drugs that are processed by your liver, or use 
certain transport proteins in your body.  Because of this, it is very important 
to: 
➢ Tell your doctors if you stop taking regular medicines or if you start 
taking any new medicines. 
➢ Tell all of your health care providers (doctors, physician assistant, nurse 
practitioners, 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. 
➢ AT13387 (onalespib) interacts with drugs that are processed via 
UGT1A1, UGT1A3.  It may also interact with transport proteins (P-gp, BCRP,  
 
MATE1, and MATE2K) and liver enzymes (CYP 1A2, -3A4, -2D6,  
-2C9, and -2C19); thus, it must be used very carefully with other 
medicines that interact with these enzymes and proteins.  
➢ Before you enroll onto the clinical trial, your study doctor will work 
with your regular health care providers to review any medicines that 
are considered ““strong or moderate inducers/inhibitors” of these 
enzymes and protein transporters.  
➢ 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 C 
 ANTI-ALK IMMUNOHISTOCHEMISTRY STANDARD 
OPERATING PROCEDURE, BRIGHAM AND WOMEN’S 
HOSPITAL HEMATOPATHOLOGY, CLIA CERTIFIED CORE 
LABORATORY 
 
Immunohistochemical staining of ALK (D5F3, Cell Signaling Technologies) was performed 
manually following the manufacturer’s protocols. 4um thick paraffin-embedded sections were 
pre-baked in 60 °C oven for one hour. ALK (D5F3) immunostaining was performed with 1:100 
dilution using Dako Antibody diluent with Background reducing reagents. Slides were first 
dewaxed and rehydrated. Heat induced antigen retrieval was performed in Decloaking Chamber 
(Biocare Medical). Slides were incubated in Peroxidase Block (Dako) for 5 minutes, followed by 
Protein Block (Dako) for 5 minutes. Primary antibody was incubated overnight at 4°C. Slides 
were then incubated with Envision+ Rabbit Polymer-HRP (Dako) for 30 minutes at ambient 
temperature. Slides were developed with Diaminobenzene (Dako) for 5 minutes then 
counterstained with hematoxylin, dehydrated and coverslipped.  
 
APPENDIX D 
 ANTI-CYCLIN D1 IMMUNOHISTOCHEMISTRY STANDARD 
OPERATING PROCEDURE, BRIGHAM AND WOMEN’S 
HOSPITAL HEMATOPATHOLOGY, CLIA CERTIFIED CORE 
LABORATORY 
 
Immunohistochemical staining of Cyclin D1 (SP4, Neomarkers) was performed using an 
automated staining system (Bond III, Leica Biosystems, Buffalo Grove, IL) following the 
manufacturer’s protocols. 4um thick paraffin-embedded sections were pre-baked in 60 °C oven 
for one hour. Adhesive labels for each protocol were printed and applied to slides. Slides were 
then loaded onto Bond III with “Bond Universal Covertiles” (Leica Biosystems). Cyclin D1 
(SP4) immunostaining was performed with 1:40 dilution using Bond Primary Antibody Diluent 
(Leica). The following steps were performed online. Slides were first dewaxed and rehydrated. 
Heat induced antigen retrieval was performed using ER2 solution (pH8) (Leica Biosystems) for 
20 minutes. Primary antibody was incubated for total of 30 minutes, followed by 10 minutes of 
horseradish peroxidase-labeled polymer, 5 minutes of peroxidase block, and 10 minutes of DAB 
developing. Slides were counterstained by hematoxylin for 10 minutes. All reagents were 
components of the Bond Polymer Refine detection system (Leica Biosystems). Slides were then 
taken off the autostainer, dehydrated and coverslipped.  
 
APPENDIX E 
 ANTI-BCL6 IMMUNOHISTOCHEMISTRY STANDARD 
OPERATING PROCEDURE, BRIGHAM AND WOMEN’S 
HOSPITAL HEMATOPATHOLOGY, CLIA CERTIFIED CORE 
LABORATORY 
 
Immunohistochemical staining of BCL6 (GI191E/A8, Cell Marque) was performed using an 
automated staining system (Bond III, Leica Biosystems, Buffalo Grove, IL) following the 
manufacturer’s protocols. 4um thick paraffin-embedded sections were pre-baked in 60 °C oven 
for one hour. Adhesive labels for each protocol were printed and applied to slides. Slides were 
then loaded onto Bond III with “Bond Universal Covertiles” (Leica Biosystems). BCL6 
(GI191E/A8) immunostaining was performed with 1:500 dilution using Bond Primary Antibody 


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Diluent (Leica). The following steps were performed online. Slides were first dewaxed and 
rehydrated. Heat induced antigen retrieval was performed using ER2 solution (pH8) (Leica 
Biosystems) for 20 minutes. Primary antibody was incubated for total of 30 minutes, followed by 
10 minutes of postprimary reagent, followed by 10 minutes of horseradish peroxidase-labeled 
polymer, 5 minutes of peroxidase block, and 10 minutes of DAB developing. Slides were 
counterstained by hematoxylin for 10 minutes. All reagents were components of the Bond 
Polymer Refine detection system (Leica Biosystems). Slides were then taken off the autostainer, 
dehydrated and coverslipped.  
 
APPENDIX F 
PROCEDURES FOR FORMALIN FIXATION 
 
Cores biopsies (skin or tumor) should be fixed in formalin.  The minimum fixation time in 
formalin is 4 hours prior to processing in pathology. The maximum fixation time in formalin is 
36 hours, so that phospho-epitopes are not compromised.  (Therefore, sites should not plan on 
procuring samples on Fridays.  It is also best not to ship on Fridays as well). 
  
Ideally, after 24 hours, the core should be transferred to 70-80% ethanol for longer term storage 
and transport. 
 
Samples should be sent in 70 to 80 percent ethanol in a securely closed container (one with a 
screw top/cap), this container should be placed in a secondary container (plastic zip loc bags 
work well) put a piece of absorbent material in the secondary container with the sample in case 
of leakage. This entire package along with any requisition/ paperwork can then be shipped via 
FedEx (in their appropriate packaging), under current shipping requirements for non-
infectious/hazardous human samples.  Please keep the requisition outside of the secondary 
container so it does not become wet should the primary container leak. 
 
APPENDIX G 
PROCEDURES FOR SNAP FREEZING 
 
1.  Each cryomold is labeled with the unique patient identifier and date of procedure. 
a. Please note: intermediate size (15 x 15 x 5 mm) cryomold is preferred. 
2. 
The labeled cryomold is filled half way with OCT medium and placed on dry ice for 10 
minutes.  
3. 
The tissue is placed directly on the frozen OCT cryomold. 
4. 
The tissue is fully covered with additional OCT compound and place on dry ice for an 
additional 10 minutes.  
5. 
Once the blocks are fully frozen, the frozen tissue can be stored in a -80 degree Celsius 
freezer until shipment. (A -70 degree Celsius freezer is also acceptable). 
 
APPENDIX H 
9875 Specimen Submission Form 
 
(on next page)


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Please provide a copy of the completed form with your specimen shipment to Dana-Farber Center for Cancer Precision Medicine 
 
 
SITE INFORMATION 
 
Contact person:___________________________________     Phone number: __________________________________ 
Site Location: _____________________________________   Date and time of procedure: ________________________ 
PATIENT INFORMATION 
 
Patient identifier (Subject Study #):  _________________________            Birth Year:  __ __ __ __  
 
Study Timepoint:  Pre-treatment   On-treatment   Post-progresssion  
 
 
SAMPLE INFORMATION 
 
Site of Tumor Tissue Biopsy/Resection (Check One):      Primary     Metastatic  
 
Tissue Collection:   Surgical Resection   Excisional Biopsy   Core Biopsy (_____gauge)   Fine Needle Aspirate   
 
For FORMALIN-FIXED TISSUE, please fill out following section: 
SPECIMEN SITE                               
1. ________________________      block number: ________________    number of slides: __________ 
2. ________________________      block number: ________________    number of slides: __________ 
3. ________________________      block number: ________________    number of slides: __________ 
 
For FROZEN TISSUE, please fill out following section: 
SPECIMEN SITE                                      TISSUE SIZE                                               SAMPLE MEDIA 
  
1. ________________________           ___ x __ _x ___ cm                   OCT     Other ____________ 
 
2. ________________________           ___ x ___ x ___ cm                   OCT    Other ____________ 
 
3. ________________________           ___ x ___ x ___ cm                   OCT     Other ____________ 
 
4. ________________________           ___ x ___ x ___ cm                   OCT     Other ____________ 
 
 


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APPENDIX I 
Example Ophthalmologic Examination Worksheet 
 
 
Date of Examination: ___________________ 
 
 
Right Eye  
Left Eye  
 
Refraction  
 
 
 
 
 
Visual Acuity  
 
 
_ _ /  _ _ _ 
 
Abnormal / Normal: _______  
 
 
_ _ / _ _ _ 
 
Abnormal/ Normal: ______ 
 
Slit Lamp Examination  
 
Conjunctiva 
Cornea 
Anterior Chamber  
Iris  
Lens  
Other (specify) 
 
 
 
 
Not Done/ Abnormal / Normal: _______  
Not Done/ Abnormal / Normal: _______  
Not Done/ Abnormal / Normal: _______  
Not Done/ Abnormal / Normal: _______  
Not Done/ Abnormal / Normal: _______  
Not Done/ Abnormal / Normal: _______  
 
 
 
 
Not Done/ Abnormal / Normal: _______  
Not Done/ Abnormal / Normal: _______  
Not Done/ Abnormal / Normal: _______  
Not Done/ Abnormal / Normal: _______  
Not Done/ Abnormal / Normal: _______  
Not Done/ Abnormal / Normal: _______  
 
 
 
 
Intraocular Pressure  
 
Fundoscopy  
Vitreous  
Optic disc  
Macula  
Peripheral retina  
Blood vessels  
Other (specify) 
 
 
Clinical relevant abnormalities only  
 
 
______mmHg 
 
 
Not Done/ Abnormal / Normal: _______  
Not Done/ Abnormal / Normal: _______  
Not Done/ Abnormal / Normal: _______  
Not Done/ Abnormal / Normal: _______  
Not Done/ Abnormal / Normal: _______  
Not Done/ Abnormal / Normal: _______  
 
Clinical relevant abnormalities only 
 
 
______mmHg 
 
 
Not Done/ Abnormal / Normal: _______  
Not Done/ Abnormal / Normal: _______  
Not Done/ Abnormal / Normal: _______  
Not Done/ Abnormal / Normal: _______  
Not Done/ Abnormal / Normal: _______  
Not Done/ Abnormal / Normal: _______  
 
 
Additional Ophthalmologic 
Examinations:  
 
___________________________ 
 
___________________________ 
 
___________________________ 
 
___________________________ 
 
Clinical relevant abnormalities only  
 
 
 
Not Done/ Abnormal / Normal: _______  
 
Not Done/ Abnormal / Normal: _______  
 
Not Done/ Abnormal / Normal: _______  
 
Not Done/ Abnormal / Normal: _______  
 
Clinical relevant abnormalities only  
 
 
 
 
Not Done/ Abnormal / Normal: _______  
 
Not Done/ Abnormal / Normal: _______  
 
Not Done/ Abnormal / Normal: _______  
 
Not Done/ Abnormal / Normal: _______  
 
 
 
 
Examination performed by: _________________________________ 
Signature of person performing examination: __________________ 
Date: __________________ 
 
 
(Form Version 1.0 dated 6 September 2016)