Birinapant and Intensity Modulated Re-Irradiation Therapy (IMRRT) for Locoregionally Recurrent Head and Neck Squamous Cell Carcinoma (HNSCC)
Phase: PHASE1
Conditions: Locally Recurrent Head and Neck Squamous Cell Carcinoma, Nasopharyngeal Squamous Cell Carcinoma, Sinonasal Squamous Cell Carcinoma
Sponsor: National Cancer Institute (NCI)

 
i 
Date: 
 
December 15, 2022 
From:           
Vassiliki Saloura, MD, TGMB, NCI 
To:              
CTEP, NCI  
Subject:        
Response to Amendment to CTEP for protocol 19C0041_10184 entitled, 
Birinapant and Intensity Modulated Re-Irradiation Therapy (IMRRT) for 
Locoregionally Recurrent Head and Neck Squamous Cell Carcinoma 
(HNSCC)
We respectfully submit an amendment to protocol #10184 (version date 12/15/2022) to CTEP 
for urgent review.  The main purpose of this amendment is to allow 3 participants at a time to be 
enrolled in each dose cohort.  The protocol currently allows just one participant to be enrolled at 
a time.  There are currently 2 eligible participants awaiting enrollment at 2 participating sites.  
This study has been very slow to accrue and this change will allow both participants to enroll 
soon for treatment and concurrently.  The risk profile of the study so far has been very safe, with 
no DLTs that mandated enrollment of 3 more participants in each of the first two dose cohorts. 
Furthermore, the safety of birinapant as monotherapy at much higher doses (47mg/m2) has 
already been established in other phase I studies (https://pubmed.ncbi.nlm.nih.gov/26333381).   
This amendment has been discussed with Dr. Steven Gore who agrees this may be submitted as 
an urgent amendment for expedited review.
Thank you for your consideration of this amendment.  The changes are detailed below.
SUMMARY OF CHANGES – Protocol  
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Section
Change 
1.
Header
The version date was updated in the header throughout. 
2.
Title Page
x
Carter VanWaes has been removed as a co-investigator.  
He has left the NIH.
x
Study coordinator and contact info has been updated. 
x
The protocol version number and date were updated. 
3.
Section 6.1.1, Dose 
Escalation Cohort
Language has been added in order to allow up to 3 patients 
to be enrolled in each remaining cohort for the remainder of 
the trial. The protocol currently allows just one participant 
to be enrolled at a time. There are currently 2 eligible 
participants awaiting enrollment at 2 participating sites.  
This study has been very slow to accrue and this change 
will allow both participants to enroll soon for treatment and 
concurrently. The risk profile of the study so far has been 

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Change 
very safe, with no DLTs that mandated enrollment of 3 
more patients in each of the first two dose cohorts. 
Furthermore, the safety of birinapant as monotherapy at 
much higher doses (47mg/m2) has already been established 
in other phase I studies 
(https://pubmed.ncbi.nlm.nih.gov/26333381) 

NCI Protocol # 10184 
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NCI Protocol #: 10184 
Local Protocol Number: 19-C-0041 
ClinicalTrials.gov Identifier: NCT03803774  
 
Title: Birinapant and Intensity Modulated Re-Irradiation Therapy (IMRRT) for 
Locoregionally Recurrent Head and Neck Squamous Cell Carcinoma (HNSCC) 
 
Corresponding Organization: National Cancer Institute LAO-NCI  
 
Principal Investigator: 
Vassiliki Saloura, MD   
Thoracic & GI Malignancies Branch 
CCR, NCI 
Building 10, Rm 4-5330 
Bethesda, MD 20892 
Phone: 240-760-6352 
 
 
 
 valia.saloura@nih.gov 
 
Participating Organizations:  
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
CATCHUP / Creating Access to Targeted Cancer Therapy for Underserved Populations 
 
Co-Investigators:                        Christina Annunziata, MD, PhD 
WMB, CCR, NCI 
Building 10, Rm 3B43C 
Bethesda, MD 20892 
Phone: 240-760-6125 
 
 
 
 ca180n@nih.gov  
 
Responsible Research Nurse/    Chris Feierabend, RN 
Study Coordinator:   
 
      Bldg. 10/Rm 8D44 
Bethesda, MD 20892 
Phone: 240-858-7397 

NCI Protocol # 10184 
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chris.feierabend@nih.gov 
  
Statistician:  
Seth M. Steinberg, PhD, OCD, CCR, NCI  
9609 Medical Center Dr., Room 2W334 
Phone: (240) 276-5563  
 
      steinbes@mail.nih.gov 
 
NCI-Supplied Agent:   
Drug Name: 
Birinapant (NSC 756502) 
IND #: 
 
Sponsor 
DCTD, NCI 
Manufacturer 
IGM Biosciences 
 
Protocol Type / Version # / Version Date:   Amendment / Version 20 / December 15, 2022 
 
 

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SCHEMA

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TABLE OF CONTENTS 
SCHEMA ........................................................................................................................................iii 
TABLE OF CONTENTS................................................................................................................iv 
1 
OBJECTIVES ....................................................................................................................vii 
1.1 
Primary Objectives.................................................................................................vii 
1.2 
Secondary Objectives.............................................................................................vii 
1.3 
Exploratory Objectives ..........................................................................................vii 
2 
BACKGROUND ...............................................................................................................vii 
2.1 
Head and Neck Squamous Cell Carcinoma ...........................................................vii 
2.2 
CTEP Agent ..........................................................................................................viii 
2.3 
Prior Phase I/II Studies ...........................................................................................xi 
2.4 
Rationale ................................................................................................................xii 
2.5 
Correlative Studies Background ...........................................................................xiv 
3 
PATIENT SELECTION ...................................................................................................xiv 
3.1 
Inclusion Criteria....................................................................................................xv 
3.2 
Exclusion Criteria .................................................................................................xvi 
3.3 
Inclusion of Women and Minorities ....................................................................xvii 
4 
REGISTRATION PROCEDURES .................................................................................xvii 
4.1 
Investigator and Research Associate Registration with CTEP ............................xvii 
4.2 
Site Registration ..................................................................................................xviii 
4.3 
Patient Registration ................................................................................................xx 
4.4 
General Guidelines...............................................................................................xxii 
5 
BIOMARKERS, CORRELATIVES AND SPECIAL STUDIES .....................................23 
5.1 
Summary Table for Specimen Collection ..............................................................23 
5.2 
Specimen Procurement Kits and Scheduling .........................................................24 
5.3 
Specimen Collection Procedures ...........................................................................25 
5.4 
Specimen Tracking System Instructions................................................................28 
5.5 
Shipping Specimens from Clinical Site to the EET Biobank ................................31 
5.6 
Shipping of Specimens to Other Laboratories .......................................................35 
5.7 
Biomarker Plan ......................................................................................................37 

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5.8 
Integral Laboratory Studies....................................................................................38 
6 
TREATMENT PLAN ........................................................................................................42 
6.1 
Agent Administration.............................................................................................43 
6.2 
Definition of Dose-Limiting Toxicity....................................................................46 
6.3 
Dose Expansion Cohort .........................................................................................48 
6.4 
General Concomitant Medication and Supportive Care Guidelines ......................48 
6.5 
Duration of Therapy...............................................................................................48 
6.6 
Duration of Follow Up ...........................................................................................49 
7 
DOSING DELAYS/DOSE MODIFICATIONS................................................................49 
7.1 
Birinapant...............................................................................................................49 
7.2 
Radiation treatment ................................................................................................55 
8 
PHARMACEUTICAL INFORMATION..........................................................................56 
8.1 
CTEP AGENT BIRINAPANT (NSC 756502)......................................................56 
9 
STATISTICAL CONSIDERATIONS...............................................................................59 
9.1 
Study Design/Endpoints.........................................................................................59 
9.2 
Sample size/ Accrual Rate .....................................................................................59 
9.3 
Stratification Factors ..............................................................................................61 
9.4 
Analysis of Secondary Endpoints ..........................................................................61 
9.5 
Analysis of exploratory objectives: .......................................................................62 
10 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .............................62 
10.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPR) for .............62 
10.2 
Adverse Event Characteristics ...............................................................................64 
10.3 
Expedited Adverse Event Reporting......................................................................65 
10.4 
Routine Adverse Event Reporting .........................................................................67 
10.5 
Pregnancy...............................................................................................................68 
10.6 
Secondary Malignancy...........................................................................................68 
10.7 
Second Malignancy................................................................................................68 
11 
STUDY CALENDAR .......................................................................................................69 
12 
MEASUREMENT OF EFFECT........................................................................................72 
12.1 
Antitumor Effect – Solid Tumors ..........................................................................72 

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13 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS.............................................................................................................77 
13.1 
Study Oversight......................................................................................................77 
13.2 
Data Reporting .......................................................................................................78 
13.3 
Collaborative Agreements Language.....................................................................80 
13.4 
Genomic Data Sharing Plan ...................................................................................81 
14 
REFERENCES ..................................................................................................................83 
15 
APPENDICES ...................................................................................................................86 
15.1 
Appendix A: Performance Status Criteria .............................................................86 
15.2 
Appendix B: Patient Drug Information Handout and Wallet Card........................87 
15.3 
Appendix C: Tissue Biopsy Verification.............................................................89 
 
 
 

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1 
OBJECTIVES 
1.1 
Primary Objectives 
x Determine the toxicities and maximum tolerated dose (MTD) of birinapant concurrent 
with intensity modulated re-irradiation therapy (IMRRT). 
1.2 
Secondary Objectives 
x Determine the objective response rate of patients with locoregionally recurrent head and 
neck squamous cell carcinoma (HNSCC) treated with re-irradiation and birinapant.  
x Determine the local-regional control, progression free survival (PFS), and overall 
survival. 
x Determine if FADD and/or BIRC2/3 copy gain in tumor tissue are associated with 
improved response, locoregional control (LCR), progression-free survival and overall 
survival. 
x Determine the feasibility of detecting effects of birinapant and re-irradiation on pilot 
pharmacodynamic biomarkers in tumor tissue, by using microwestern to assess decrease 
in drug targets IAP1/2 and increase in apoptosis/necroptosis markers Caspase 3 and 
MLKL. 
1.3 
Exploratory Objectives 
x Explore if mutational load detected with whole exome sequencing of tumor tissue 
influences objective response rate. 
x Explore if PD-L1, CD8 T-cell tumor infiltration, and other immune related biomarkers in 
tumor tissue are associated with objective response rate. 
x Explore the pharmacokinetics of birinapant in combination with radiotherapy in blood 
samples. 
x Explore whether specific germline single-nucleotide polymorphisms (SNPs) are 
associated with response to birinapant and reirradiation. 
2 
BACKGROUND 
2.1 
Head and Neck Squamous Cell Carcinoma 
Head and neck squamous cell carcinomas (HNSCC) affect ~52,000 new patients and cause 
~11,000 deaths in the U.S. annually(1). HNSCC include a subset linked to human papillomavirus 
(HPV+) with better prognosis, and an HPV- subtype linked to tobacco use and worse prognosis 
in patients receiving standard treatment. The Cancer Genome Atlas recently uncovered 
amplifications of chromosome 11q13/22 in ~30% of HNSCC associated with an HPV- subtype 
and worse 5-year survival of<50% (2). The 11q13/22 loci harbor genes Fas Associated Death 
Domain (FADD) and Baculovirus Inhibitor of apoptosis Repeat Containing (BIRC2/cIAP1). A 
mutually exclusive subset harboring mutations of caspase 8 (CASP8) affects an additional 10% 
of HPV- cases (2, 3). Further, deletions in Tumor Necrosis Factor Associated Factor 3 and 
overexpression of BIRC3 (cIAP2) are detected in ~20% of HPV+ HNSCC(2). Together, these 
genes encode proteins that form critical components of the Tumor Necrosis Factor 

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Receptor/Death Domain Receptor signaling complex, which is deregulated and implicated in cell 
survival and therapeutic resistance in cancer (3, 4). Significantly, our pan-cancer comparison of 
TCGA data reveals that HNSCC are among the cancers with the highest frequency of genomic 
alterations in these cell death pathway genes, making them a potentially important target for 
therapy(5). Of clinical importance, since FADD/BIRC2 are associated with worse prognosis in 
patients with HPV- HNSCC receiving standard treatment(2), patients with recurrent HNSCC 
should be enriched for FADD/BIRC2 amplification or CASP8 mutations. 
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FADD through the activation of caspase-8 and induction of apoptosis, or alternatively, by 
activation of RIP kinase 1 (RIPK1), MLKL, and induction of necroptosis(6, 7); Figure 1. 
However, the cellular Inhibitor of Apoptosis proteins cIAP1 and 2 encoded by BIRC2/3, are key 
antagonists of cell death signaling by TNF/FADD/CASP8 and cytotoxic therapies. Of 
therapeutic significance, IAP degradation and cell death signaling may be enhanced by Second 
Mitochondrial Activator of Caspases (SMAC) released during cell death, or SMAC 
peptidomimetics(4, 8). 
 
Figure 1: The intrinsic cell death pathway, induced by mitochondria in response to cell injury, and the extrinsic 
pathway, triggered by ligands of the death receptor ligand family are two pathways that converge on caspase-3 to 
induce apoptosis. Death ligand binding via the extrinsic pathway results in cytoplasmic complex that includes 
RIPK1 and FADD. 
2.2 
CTEP Agent 
Birinapant is a novel bivalent small molecule peptidomimetic of SMAC, shown to preferentially 
target cIAP1, relative to cIAP2 and XIAP(9, 10). Birinapant demonstrated anti-tumor activity in 
preclinical models of hematological cancers and solid tumors including melanoma, colorectal, 
ovarian, and breast cancer (11, 12). In early phase clinical trials, birinapant has demonstrated 
tolerability and safety at effective doses, with a prolonged plasma half-life of 31 hours and tumor 

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half-life of 52 hours(12). In a 5-arm phase I/II dose escalation study of birinapant administered 
intravenously in combination with different chemotherapies (docetaxel, irinotecan, gemcitabine, 
carboplatin/paclitaxel, liposomal doxorubicin) in patients with solid tumors, safety and 
tolerability was confirmed and a phase II dose was established (13). Interestingly, birinapant 
demonstrated prolonged progression free survival in previously relapsed or refractory patients 
ZKHQFRPELQHGZLWKFKHPRWKHUDSLHVWKDWLQGXFH71)ĮVXFKDVLULQRWHFDQ(13). Importantly, 
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a major modality in treatment of patients with HNSCC(14, 15).  
In pre-clinical studies, we identified several HNSCC cell lines harboring FADD/BIRC2 
amplifications by exome sequencing (5) (Figure 2). Birinapant, a novel SMAC mimetic that 
promotes cIAP degradation, sensitized multiple HNSCC lines to cell death by agonists TNFĮ or 
TRAIL, including lines harboring FADD-/+BIRC2 amplification (Figure 2).  
 
 
Figure 2: A, UM-SCC cell lines with focal amplifications of Chromosome 11q13/22 harboring FADD and 
BIRC2/3. B, Birinapant (1mM) plus death ligands TNFa (20ng/ml) or TRAIL (100ng/ml) inhibit UM-SCC11B and 
46. Inhibition was reversed by inhibitors of pan-caspase (ZVAD), caspase 8 (ZIEDT) and/or necrosis (necrostatin). 
 
The HNSCC varied in mechanisms of cell death mediated by caspase-dependent apoptosis 
inhibited by ZVAD or ZIEDT and/or RIPK1/MLKL-mediated necroptosis inhibited by 
necrostatin, corresponding with genomic amplification and overexpression of FADD-/+ BIRC2 
(Figure 2). We confirmed that FADD or BIRC2 siRNA knockdown inhibited these HNSCC 
displaying gene amplification and increased expression, while transfection of a plasmid 
overexpressing FADD in the UM-SCC38 line lacking FADD amplification (Figure 2) sensitized 
it to the combination of birinapant and TNFĮ, supporting their functional importance(5) (data not 

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shown).  
Western blot confirmed that birinapant plus TNF-Į induces cIAP1 degradation and is 
accompanied by predominantly sustained caspase 8 and 3 cleavage in UM-SCC11B, and 
predominant induction of necroptosis marker MLKL in UM-SCC46 Figure 3. 
  
Figure 3. Birinapant (1mM) plus TNFa (20ng/ml) promotes degradation of cIAP1 and enhances caspase 8 and 3 
activation in UM-SCC11B, and caspase 3 and MLKL activation in UM-SCC46.  Fold change normalized to 
untreated control and beta-tubulin loading control is indicated  
 
In vivo, birinapant monotherapy (15 or 30 mg/kg) every 3 days for 21 days significantly 
inhibited tumor growth and prolonged host survival in xenograft models of the UM-SCC 46 and 
11B lines overexpressing FADD+/-BIRC2 (Figure 4). 

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Figure 4: Birinapant slows tumor growth and improves survival in two mouse models of HNSCC with FADD-
/+BIRC2 co-amplification. 5x106 UM-SCC-46 (FADD) or -11B (FADD+BIRC2) amplified cells were injected 
subcutaneously into the right hind flanks of SCID/NCr-Balb mice. Mice were randomized into treatment groups 
(UM-SCC-46 n=15 mice/group; UM-SCC-11B n=9 mice/group), and treatment was initiated 15 (UM-SCC-46) or 
35 (UM-SCC-11B) days after tumor inoculation, when tumors reached 200 mm3.  Mice received control vehicle, 15 
or 30 mg/kg birinapant i.p. every 3 days as indicated for a total of 10 doses.  A, B, In the UM-SCC46 model, 
birinapant-treated mice showed significant inhibition of tumor volume versus control vehicle (+, p<0.05; ++, 
p<0.01), and improved median survival of 58 days compared with 39 days for control (median survival advantage of 
19 days). C, D, In the UM-SCC-11B model, birinapant-treated mice showed significant inhibition of tumor volume 
versus control vehicle (+, p<0.05; ++, p<0.01), and increased survival was seen with medians of 82 days (control), 
186 days (15 mg/kg group), and 137 days (30 mg/kg group). For survival analysis, the Gehan-Breslow-Wilcoxon 
test was used and significance set to 0.05 using the Bonferroni method. 
2.3 
Prior Phase I/II Studies 
Up to October 2016, approximately 400 patients with solid tumors or hematological 
malignancies had been treated with birinapant at doses up to 63 mg/m2/dose, either as a single 
agent or in combination with chemotherapies.  
The MTD of birinapant administered IV weekly for 3 consecutive weeks followed by 1 week off 
has been determined to be 47 mg/m2 when administered as a single agent in subjects with solid 
tumors. Birinapant-related Grade 3 or 4 adverse events (AEs) have included nausea, vomiting, 
rash, hypophosphatemia, headache, fatigue, amylase increase, lipase increase, lymphopenia, and 
thrombocytopenia, and have been reversible without sequelae. Other subjects have experienced a 
constellation of AEs that appeared to be dose-related and included rash, fever, chills, 
hypotension, nausea, headache, and hypophosphatemia; however, other etiologies of these events 
may have been possible. These AEs occurred with first drug exposure and resolved without 
sequelae.  
Cranial nerve palsies (most commonly Bell’s palsy) have occurred in subjects who have received 
birinapant. The cranial nerve palsies are typically mild to moderate in severity and in those cases 

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treated with corticosteroids, symptoms have either resolved or were resolving at the last follow-
up visit. Some subjects who reported cranial nerve palsy elected to continue birinapant treatment, 
and of those that continued on treatment, none had a recurrent event. The onset of cranial nerve 
palsy may be preceded by a prodromal syndrome of headache, ear, facial pain and/or diplopia.  
Other safety considerations observed with birinapant treatment are events of Grade 3 or greater 
increases in serum amylase and serum lipase. Most of these events were reversible and all 
subjects remained asymptomatic. 
2.4 
Rationale  
Radiation therapy is a major modality in treatment of patients with HNSCC. Radiation therapy 
induces reactive oxygen species that mediate DNA damage, intrinsic death pathway activation, 
as well as TNFĮ that induces extrinsic death pathway activation (Figure 1). Remarkably, 
concurrent birinapant 15mg/kg every 3 days plus radiation 2 Gy/day M-F for 2 weeks followed 
by an additional 2 weeks of birinapant induced durable cures >100 days and potentiated 
expression of TNFĮ (Figure 5). 
 
Figure 5: Combination of birinapant plus radiation induces tumor regression and durable cure in the UM-SCC-46 
xenograft model. A, Effects of birinapant, radiation, and combination therapy on growth of UM-SCC-46 xenografts. 
2.5 × 106 UM-SCC-46 cells were implanted into the upper portion of the right leg in athymic nu/nu mice.  Mice 
were randomized into four treatment groups (vehicle control n=12, 15 mg/kg birinapant n=12, 10 × 2 Gy radiation 
n=12, or combination n=12) seven days after tumor inoculation (day 7) when average tumor volume reached ~200 
mm3.  Radiation treatment began on day 7: 2 Gy of radiation given M-F for two weeks—a total of 20 Gy (double 
headed arrows).  Birinapant treatment began on day 8:  15 mg/kg birinapant i.p. every three days for a total of ten 
doses (purple double headed arrow).  Treated mice in all groups showed significantly decreased tumor volume 
compared to the control.  Combination treated animals showed durable regression compared to all other groups. 
Statistical difference vs control by student t-test (+; p < 0.05). Error bars, SEM. B, treated mice showed significantly 
enhanced survival.  Survival analysis was performed using the Gehan-Breslow-Wilcoxon test to determine p-value.  
Median survival times were 27 days (control), 42 days (birinapant, p=0.003), 80 days (radiation, p=0.0002), and 
combination treatment group is currently without death, at 130 days.  C, Photos of tumors on right hind leg of 

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representative mice from each treatment group on day 21 (after five doses of birinapant and 20 Gy radiation). D, 
Relative TNFa gene expression in tumors from each treatment group on day 21. Endogenous mTNFa was compared 
by qRT-PCR as described in methods. Statistical difference by Student t-test (+; p < 0.05).  
 
Birinapant and radiation treated mice trended toward lower weight but showed no evidence of 
worse acute radiation dermatitis or decrease in mobility or contracture involving the irradiated 
limb (Figure 5, right panel). Together, these findings unveil a novel therapeutic approach for 
HNSCC harboring FADD/BIRC2 genomic alterations associated with worse prognosis.  
Current standard treatment for advanced stage III/IV HNSCC typically includes surgery with 
post-operative radiotherapy, or definitive concurrent chemo-radiotherapy alone(16). About 50% 
recur within 5 years. The majority of these are patients with HPV- cancers. Survival analysis of 
243 TCGA patients with HPV- cancers harboring 11q13 amplification of FADD indicate they 
are enriched among those recurring in the first two years(2). Based on these observations, 
patients with local-regionally recurrent HNSCC who are otherwise unselected would thus be 
expected to be enriched for FADD-/+BIRC2 amplification. 
The treatment of such patients with recurrent HNSCC after prior surgery and irradiation or 
chemo-radiation presents a unique challenge, as many patients present with unresectable disease. 
Median survival with palliative chemotherapy is ~5-9 months, with 1-yr survival of ~20-30% 
(16, 17). Reirradiation remains the only potentially curative treatment option. Salvage 
reirradiation with concurrent radiosensitizing chemotherapy is the current standard of care (17). 
The data supporting this approach are mainly derived from Phase I/II trials, and investigation of 
a number of different radiation and chemotherapy regimens have been considered acceptable in 
this setting. With targeting of re-irradiation to recurrent tumor, dosing to 60Gy or higher is 
associated with greater local control, and is usually feasible, with sparing of the spinal cord and 
acceptable toxicities (18). In a phase I study of bortezomib and re-irradiation at NIH, 15/17 
patients completed re-RT to 60-70Gy(19). At Ohio State University, 60-70Gy re-RT is given as 
standard of care with acceptable toxicity. Local control rates for reirradiation with chemotherapy 
are nearly 50% at 1 year (18), and demonstrate improved overall survivals (OS) of 8-28 months, 
with 2-year OS rates of 15-38%(20, 21), but greater toxicity when combined with cisplatin(18), 
highlighting the potential benefit for more efficacious and tolerable regimens.  
Based on our pre-clinical studies, birinapant plus radiation demonstrates anti-tumor activity and 
improved survival, but the dose, schedule and tolerability in human studies needs to be 
determined. We propose a phase I trial for patients with local-regionally recurrent HNSCC who 
are candidates for irradiation, to determine the feasibility, toxicities and maximally tolerated dose 
(MTD) and schedule of concurrent therapy with birinapant. The dose steps proposed include 5.6, 
11, 17 and 24 mg/m2 IV, which in prior studies has been administered week 1 and 2 every three 
weeks, and tolerated in single agent and combination regimens with several cytotoxic 
chemotherapy agents (12, 13). The starting dose of 5.6 mg/M2 is the lowest dose along the 
previously used dose escalation schedule predicted to be potentially therapeutically active, and 
the first dose below 1/6 the MTD of 47mg/M2 for single agent birinapant, considered a margin 
of safety for starting combination with radiation, for which toxicities are unknown. Doses above 
24mg/M2 in chemotherapy combinations were associated with dose limiting toxicities (12, 13).  
Weekly dosing is consistent with the prolonged half-life demonstrated in tumors. Dose limiting 
toxicities have included facial nerve and other cranial neuropathies, reversible with cessation or 
delayed dosing of birinapant. Because of the potential for the combination to exacerbate cranial 

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neuropathy or mucosal toxicity, the schedule incorporating the 1 week break every 3 weeks and 
weekday visits to radiation oncology provides an added level of safety for observation and drug 
dose modification or cessation, if detected.  
2.5 
Correlative Studies Background 
Included as secondary objectives are several hypotheses generating candidate biomarkers, based 
on prior preclinical and clinical findings. We have demonstrated the feasibility of detecting 
FADD, BIRC2 and other genomic alterations in human HNSCC by exome sequencing(2) (5). At 
the conclusion of the study, whole exome sequencing and microwesterns will be performed on 
tumor biopsy specimens as an integrated biomarker for the proposed biomarkers to be 
investigated as secondary endpoints. More specifically, we will assess pretreatment specimens 
for copy number alteration compared to DNA from patient-matched blood, to explore if patients 
with recurrent HNSCC are enriched for FADD and BIRC2, and if these correlate with response. 
We further demonstrated the feasibility of detecting birinapant-mediated IAP1 degradation, and 
activation of caspase-dependent apoptosis or MLKL-dependent necroptosis by western blot in 
HNSCC lines and xenografts(5), and piloted capillary western assays for cIAP1 and caspase 3 in 
a recent Phase II study of birinapant in ovarian cancer (20). In preclinical studies, we observed 
inhibition of IAP1 expression and increased cell death markers in human HNSCC xenografts on 
day 4 at the end of a week of RT given daily M-F (days 0-4), and birinapant given on day 1 
(Tuesday). Thus, at the conclusion of the study, we will compare matched day 4 on-treatment 
and pretreatment biopsies for degradation of target cIAP1, cleaved caspase 3, and/or increased 
MLKL, as candidate pharmacodynamic markers. These genomic alterations and cell death 
proteins may help determine the feasibility of incorporating their study as biomarkers for 
selection and pharmacodynamic effects in future phase II studies and will not be used for patient 
selection in the present study.  
With regard to the exploratory objectives, recent trials for immune checkpoint expression and 
inhibitors in recurrent HNSCC have demonstrated increased expression of PDL1 and activity. As 
birinapant and radiation could enhance immunogenic cell death and PDL1 expression, pilot 
studies comparing pre- and on treatment effects of birinapant and radiation on the immune 
checkpoint molecule PD-L1, and CD8 effector T cells will be explored, provided sufficient 
tumor specimens remain. 
Pharmacokinetic assessment of birinapant will be pursued, because we want to know how 
radiotherapy may alter the pharmacokinetic properties of birinapant. 
Pharmacogenomic studies (SNP analysis) will also be conducted. OATP1B3 and P-glycoprotein 
are each expressed both the liver and in head and neck cancers. Since birinapant is a substrate of 
the OATP1B3 transporter and inhibits P-glycoprotein, variation in genes encoding these 
transporters may be associated with pharmacokinetic or pharmacodynamic variability, 
potentially affecting birinapant clinical outcome. 
3 
PATIENT SELECTION 
In order to determine eligibility, subjects will be screened per the STUDY CALENDAR once 
the subject has signed the appropriate consent.  In addition, the following minimal risk activities 
may be performed prior to obtaining subject consent:  

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a. Email, written, in person or telephone communications with prospective subjects  
b. Review of existing medical records to include H&P, laboratory studies, etc.   
c. Review of existing MRI, x-ray, or CT images 
d. Review of existing photographs or videos 
e. Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes  
 
3.1 
Inclusion Criteria 
3.1.1 
Patients must have histologically or cytologically confirmed locally 
recurrent HNSCC, including nasopharyngeal or sinonasal cancer for 
whom re-irradiation for local control is considered standard of care.    
3.1.2 
Patients with HPV-negative or HPV-positive head and neck cancer are 
eligible. 
3.1.3 
Patients who have had prior treatment with immune therapies are 
eligible. 
3.1.4 
Patients must have received curative-intent platinum- and/or 
cetuximab-based chemoradiotherapy or radiotherapy alone.  
3.1.5 
Patients must have completed their last treatment dose with 
chemotherapy or immunotherapy at least 4 weeks (6 weeks for 
nitrosoureas or mitomycin C) before enrolling on study. 
3.1.6 
Patients must have completed their last treatment dose with 
radiotherapy at least 6 months before enrolling on study. 
3.1.7 
Patients who have had major surgery must be fully recovered and 
require a recovery period of at least 4 weeks prior to enrolling on study.  
3.1.8 
$JH\HDUV  
3.1.9 
(&2*SHUIRUPDQFHVWDWXVVHH Appendix A). 
3.1.10 
Patients must have normal organ and marrow function as defined 
below: 
 
Hemoglobin 
9 g/dL (transfusion permitted) 
 
Absolute neutrophil count 
500/mcL 
 
Platelets 
100,000/mcL 
 
Total bilirubin 
within 1.5 x the upper limit of normal (ULN) 
institutional limits 
 
AST(SGOT)/ALT(SGPT) 
îLQVWLWXWLRQDOXSSHUOLPLWRIQRUPDO 
 
Serum creatinine  
 
[XSSHUOLPLWRIQRUPDO8/1OR: 
Creatinine clearance  
50 mL/min according to Cockcroft Gault formula or 
other institutional methods.  
 
Cardiac function  
 
Patients must have a QTcF  480 msec. 
 
INR 
 
 
 
 
 
INR  1.5 and no clinically significant bleeding event 

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within the past six months 
3.1.11 
Ability to understand and the willingness to sign a written informed 
consent document. 
3.1.12 
Patients must have measurable disease, per RECIST 1.1. See Section 12 
for the evaluation of measurable disease. 
3.1.13 
The effects of birinapant 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) beginning at study entry and for the duration of 
study participation. Male study participants should use an additional 
barrier method of contraception for 30 days following the last dose of 
birinapant. 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. 
3.2 
Exclusion Criteria 
3.2.1 
Eligibility for curative-intent surgery, unless the patient is considered a 
poor surgical candidate related to resectability, functional outcome, or 
prefers non-surgical therapy. 
3.2.2 
More than 2 lines of palliative systemic therapy (platinum-, taxane- or 
cetuximab-based chemotherapy or immunotherapy) 
3.2.3 
Patients who are receiving any other investigational agents. 
3.2.4 
Patients with known 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. 
3.2.5 
History of allergic reactions attributed to compounds of similar 
chemical or biologic composition to birinapant. 
3.2.6 
Uncontrolled intercurrent illness including, but not limited to, ongoing 
or active infection, symptomatic congestive heart failure, unstable 
angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements. 
3.2.7 
Pregnancy or lactation period. Pregnant women are excluded from this 
study because birinapant may have 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 birinapant, breastfeeding should be discontinued prior to 
enrollment.  A negative pregnancy test is required for women of 
childbearing potential. Women who are postmenopausal (age-related 
DPHQRUUKHDFRQVHFXWLYHPRQWKVRUZKR had undergone 
hysterectomy or bilateral oophorectomy are exempt from pregnancy 
testing. If necessary, to confirm postmenopausal status, a FSH level 
may be included at screening.   
3.2.8 
HIV positive patients on combination antiretroviral therapy are 

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ineligible because of the potential for pharmacokinetic interactions with 
birinapant. 
3.2.9 
Patients requiring the use of anti-tumor necrosis factor (anti TNF) 
therapies, such as infliximab, or patients who have received treatment 
with anti-TNF therapies within 5 half-lives of the drug (48 days for 
infliximab, 55 days for golimumab, 70 days for certolizumab and 
adalimumab, and16 days for etanercept). 
3.2.10 
Patients with previous exposure to birinapant. 
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 
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. 
4 
REGISTRATION PROCEDURES 
4.1 
Investigator and Research Associate Registration with CTEP 
Food and Drug Administration (FDA) regulations require IND sponsors to select qualified 
investigators. NCI policy requires all persons participating in any NCI-sponsored clinical trial to 
register and renew their registration annually. To register, all individuals must obtain a CTEP 
Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam). In addition, 
persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).  
RCR utilizes five person registration types. 
x IVR:  MD, DO, or international equivalent, 
x NPIVR:  advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD), 
x AP:  clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
such as the Roster Update Management System (RUMS), OPEN, Rave, acting as a 
primary site contact, or with consenting privileges, 
x Associate (A):  other clinical site staff involved in the conduct of NCI-sponsored trials, 
and 
x Associate Basic (AB):  individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
 
Documentation requirements per registration type are outlined in the table below. 

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Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
D 
D 
 
 
Financial Disclosure Form 
D 
D 
D 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
D 
D 
D 
 
HSP/GCP training 
D 
D 
D 
 
Agent Shipment Form (if applicable) 
D 
 
 
 
CV (optional) 
D 
D 
D 
 
 
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: 
x Added to a site roster 
x Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
x Act as the site-protocol PI on the IRB approval 
x Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  
In addition, all investigators acting as the Site-Protocol PI (Investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the Clinical 
Investigator (CI) on the DTL must be rostered at the enrolling site with a participating 
organization.  
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: 
x An active Federal Wide Assurance (FWA) number 

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x An active roster affiliation with the Lead Network or a participating organization 
x A valid IRB approval 
x Compliance with all protocol specific requirements. 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
x Active registration status 
x The IRB number of the site IRB of record listed on their Form FDA 1572 
x An active status on a participating roster at the registering site. 
Sites participating on the NCI Central Institutional Review Board (CIRB) initiative that are 
approved by the CIRB for this study are not required to submit IRB approval documentation to 
the CTSU Regulatory Office. For sites using the CIRB, IRB approval information is received 
from the CIRB and applied to the RSS in an automated process. Signatory Institutions must 
submit a Study Specific Worksheet for Local Context (SSW) to the CIRB via IRB Manager to 
indicate their intent to open the study locally. The CIRB’s approval of the SSW is then 
communicated to the CTSU Regulatory Office. In order for the SSW approval to be processed, 
the Signatory Institution must inform the CTSU which CIRB-approved institutions aligned with 
the Signatory Institution are participating in the study. 
4.2.1 Downloading Regulatory Documents 
Site registration forms may be downloaded from the NCI protocol # 10184 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.  
x Go to https://www.ctsu.org and log in using your CTEP-IAM username and 
password. 
x Click on the Protocols tab in the upper left of your screen.  
x Either enter the protocol # 10184 in the search field at the top of the protocol tree, 
or 
x Click on the By Lead Organization folder to expand, then select LAO-NCI, and 
protocol #10184. 
x 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 NCI Protocol # 10184 Site Registration: 
x 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.) 
x For applicable ETCTN studies with a radiation and/or imaging (RTI) component, 

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the enrolling site must be aligned to a RTI provider. To manage provider 
associations access the Provider Association tab on the CTSU website at 
https://www.ctsu.org/RSS/RTFProviderAssociation, to add or remove associated 
providers. Sites must be linked to at least one IROC credentialed provider to 
participate on trials with an RT component. Enrolling sites are responsible for 
ensuring that the appropriate agreements are in place with their RTI provider, and 
that appropriate IRB approvals are in place) 
x Theradex-led ETCTN Specimen Tracking Training by one individual per 
participating site is required prior to site registration.  Certificates of completion 
will be submitted to the CTSU through the Regulatory Submission Portal. 
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: www.ctsu.org (members’ area) Æ Regulatory Tab 
ÆRegulatory 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.  
x Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
x Click on the Regulatory tab at the top of your screen 
x Click on the Site Registration tab 
x 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 
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 

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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. 
As this trial has a slot reservation requirement, OPEN will connect to IWRS at enrollment 
initiation to check slot availability. Registration staff should ensure that a slot is available and 
secured for the patient before completing an enrollment. Slots can be reserved for a maximum of 
14 calendar days.  
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: 
x Have a valid CTEP-IAM account (i.e., CTEP username and password). 
x To enroll patients or request slot reservations: Be on an ETCTN Corresponding or 
Participating Organization roster with the role of Registrar. Registrars must hold a 
minimum of an AP registration type. 
x To approve slot reservations or access cohort management: Be identified to 
Theradex as the “Client Admin” for the study.  
x Have regulatory approval for the conduct of the study at their site. 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
x All eligibility criteria have been met within the protocol stated timeframes.  
x If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
4.3.3 Special Instructions for Patient Enrollment 
The following information will be requested: 
x Protocol Number 
x Investigator Identification  
o Institution and affiliate name 
o Investigator’s name 
x Eligibility Verification:  Patients must meet all the eligibility 
requirements listed in Section 3.1. 
x Additional Requirements: 
o Patients must provide a signed and dated, written informed 
consent form. 
Upon enrolling a patient, IWRS will communicate with OPEN, assigning two 
separate and unique identification numbers to the patient, a Universal patient ID 
(UPID) and a Treatment patient ID.  The UPID is associated with the patient and 
used each and every time the patient engages with the ETCTN Biobanking and 
Molecular Characterization portion of this protocol.  The UPID contains no 

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 xxii 
 
information or link to the treatment protocol.  IWRS will maintain an association 
between the UPID for ETCTN biobanking and molecular characterization and any 
treatment protocols the patient participates in, thereby allowing analysis of the 
molecular characterization results with the clinical data.   
Immediately following enrollment, the institutional anatomical pathology report 
for the diagnosis under which the patient is being enrolled must be uploaded into 
Rave.  The report must include the surgical pathology ID (SPID) and the IWRS-
assigned UPID for this trial.  Important:  Remove any personally identifying 
information, including, but not limited to, the patient’s name, initials, and 
patient ID# for this treatment trial, from the institutional pathology report 
prior to submission. 
4.3.4 OPEN/IWRS Questions? 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU website at 
https://www.ctsu.org or at https://open.ctsu.org. For any additional questions contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
Theradex has developed a Slot Reservations and Cohort Management User Guide, which is 
available on the Theradex website:  http://www.theradex.com/clinicalTechnologies/?National-
Cancer-Institute-NCI-11. This link to the Theradex website is also on the CTSU website OPEN 
tab. For questions about the use of IWRS for slot reservations, contact the Theradex Helpdesk at 
609-619-7862 or Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
4.4 
General Guidelines 
Following registration, patients should begin protocol treatment within 30 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.

5 
BIOMARKERS, CORRELATIVES AND SPECIAL STUDIES 
5.1 
Summary Table for Specimen Collection 
Research specimens should be collected only after subject has signed consent and all eligibility 
criteria have been met. 
 
Of the requested samples in the table below, the following are mandatory (see Section 5.7): 
x Archival FFPE tumor block or a minimum of 20 unstained + 2 H&E slides at baseline, if 
fresh biopsies cannot be obtained 
x One 10ml blood sample in ETDA (for control DNA) at baseline 
x Blood samples for PK assessments (C1D2, C1D9, C2D2, C2D9) 
 
M=mandatory  O=optional 
Time Point 
Specimen and Quantity  
(see Section 5.3.1.1 for specimen allocation details) 
Send Specimens to: 
Baseline 
 
Tissue: 
1 archival FFPE tumor block or 22-32 slides5: 1 leading H&E 
3-5 micron stained slide, 20-30 unstained uncharged 10-
micron slides, 1 lagging H&E 3-5 micron stained slide. 
NOTE: slides must be serially sectioned and numbered 1 (See 
Section 5.3.2.2) [M]  OR 
x 
1-2 tissue cores in formalin1 [O] and 
x 
1-2 cores snap-frozen1,3 [O] 
 
EET Biobank3   
 
Blood: 
x 
10 mL blood in EDTA - PBMCs for control DNA [M] 
EET Biobank 
x 
10 mL blood in EDTA (for pharmacogenomic studies)6 
[O] 
NCI Blood Processing 
Core (BPC, Figg lab)  
Cycle 1 Day 2 (C1D2) 
 
x 
6 mL blood in EDTA4 for PK [M] 
o Pre-infusion (within 60 minutes prior to 
infusion) 
o Post-infusion (within 60 minutes post-infusion) 
NCI Blood Processing 
Core (BPC, Figg lab) 
Cycle 1 Day 4 (C1D4) 
 
x 
1-2 cores snap-frozen1,3 [O] 
x 
1-2 cores in formalin1 [O] 
EET Biobank3 (for 
cores)   
x 
6 mL blood in EDTA4 (+/- 4 hr from scheduled tumor 
biopsy, for PK) [O] 7 
NCI Blood Processing 
Core (for PK) 
Cycle 1 Day 9 (C1D9) 
 
x 
6 mL blood in EDTA4 for PK [M] 
o Pre-infusion (within 60 minutes prior to 
infusion) 
o Post-infusion (within 60 minutes post-infusion) 
NCI Blood Processing 
Core  

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Cycle 2 Day 2 (C2D2) 
 
x 
6 mL blood in EDTA4 for PK [M] 
o Pre-infusion (within 60 minutes prior to 
infusion) 
o Post-infusion (within 60 minutes post-infusion) 
NCI Blood Processing 
Core  
Cycle 2 Day 9 (C2D9) 
 
x 
6 mL blood in EDTA4 for PK [M] 
o Pre-infusion (within 60 minutes prior to 
infusion) 
o Post-infusion (within 60 minutes post-infusion) 
NCI Blood Processing 
Core  
1 A copy of the radiology and operative reports from the tissue removal procedure and the diagnostic anatomic 
pathology report must be sent with the tissue to the EET Biobank. When completed, upload the corresponding 
pathology reports to Rave and send a copy to the EET biobank. Formalin cores collected from all sites will be 
shipped to the EET Biobank. 
2 For archival tissue, a copy of the corresponding anatomic pathology report must be sent with the tissue and 
uploaded to Rave. Archival tissues will also be shipped to the EET Biobank. 
3 Snap frozen specimens will be shipped to the EET Biobank.  
4 Blood in EDTA for PK specimens will be processed and plasma will be aliquoted and stored frozen at sites for 
shipment to the NCI Blood Processing Core.   
5 20 unstained plus 2 H&E slides are required. 10 additional unstained slides, for a total of 30 unstained plus 2 
H&E would be preferred to pursue exploratory biomarkers. 
6 10ml blood in EDTA for pharmacogenomic studies may be collected at baseline, C1D1 or C1D2. 
7C1D4 6ml EDTA blood is required only if fresh biopsy is performed on C1D4.  It is not required if archival tissue is 
submitted. 
 
5.2 
Specimen Procurement Kits and Scheduling  
5.2.1 Specimen Shipping Kits   
Kits for the collection and shipment of specimens to the EET Biobank can be ordered online via 
the Kit Management system: https://kits.bpc-apps.nchri.org.  
Users at the clinical sites will need to set up an account in the Kit Management system and select 
a specific clinical trial protocol to request a kit. Please note that protocol may include more than 
one type of kit. Each user may order two kit types per kit type per day (daily max = 6 kits).  Kits 
are shipped ground, so please allow 5-7 days for receipt. A complete list of kit contents for each 
kit type is located on the Kit Management system website. 
5.2.2 Scheduling of Specimen Collections 
Tumor tissue specimens collected during biopsy procedures and fixed in formalin must be 
shipped on the same day of collection.  Formalin fixed tissue can be collected Monday through 
Thursday and shipped overnight for arrival on Tuesday through Friday at the EET Biobank at 
Nationwide Children’s Hospital.  The EET Biobank must be notified on Wednesday or Thursday 
by e-mail at BPCBank@nationwidechildrens.org prior to shipping formalin fixed tissue for 
receipt on Friday. For centers that can accommodate the transition from formalin to 100% 
ethanol, 24 hours after collection, the C1D4 biopsy can be scheduled on a Friday (if C1D1 falls 
on a Tuesday, or for other treatment delays), and tissue shipped the next business day. Frozen 
specimens, such as frozen tissue, may be collected, processed and shipped to the EET Biobank 
on Monday through Thursday, since the Biorepository does not need to perform additional 
processing.  In the event that frozen specimens cannot be shipped immediately, they must be 

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maintained at -80°C. 
Fresh blood specimens for DNA may be collected and shipped to EET Biobank Monday through 
Friday.  Saturday delivery is only available for shipments of fresh blood for this protocol. 
Fresh blood specimens for PK studies will be processed and plasma aliquoted and stored frozen 
at non-NCI sites for shipment to NCI Blood Processing Core. Those from NCI will be sent 
directly to the NCI Blood Processing Core for processing. 
5.3 
Specimen Collection Procedures 
5.3.1 Biopsy Collection Procedure 
Core biopsies will be obtained under local or general anesthesia (depending on the accessibility 
of the tumor). Ideally, 4 core biopsies should be obtained. The site of locoregional recurrence 
will be biopsied. US or CT-guidance may be used depending on the accessibility of the biopsy 
site (per head and neck surgeon’s assessment) 
For the collection of biopsy specimens, core needle biopsy is the preferred technique.  It is 
preferred that 4 core biopsies 16-18 gauge in diameter and at least 1 cm in length, are obtained at 
baseline and 4 core biopsies on C1D4.  Allocation of the core biopsies is dependent on the total 
number of cores procured and is detailed as follows: 
5.3.1.1  Allocation of Core Biopsies at Baseline  
Number of cores 
procured 
FFPE 
(to 
ETCTN/MoCha) 
Snap-frozen 
(to 
ETCTN/Annunziata 
lab) 
FFPE 
(to ETCTN/van Waes/ 
Saloura labs) 
1 
1 
0 
0 
2 
1 
1 
0 
3 
1 
1 
1 
4 
1 
2 
1 
5.3.1.2 Allocation of Core Biopsies on C1D4 
Number of cores 
procured 
Snap-frozen 
(to ETCTN/Annunziata lab) 
FFPE 
(to ETCTN/van Waes lab) 
1 
1 
0 
2 
2 
0 
3 
2 
1 
4 
2 
2 
Each specimen must be properly labeled. See Section 5.4.3 for label instructions. 
 
5.3.2 Biopsy Processing Procedures 
5.3.2.1 Formalin-Fixed Core Biopsy 
1. Label formalin-filled containers according to instructions in section 5.4.2.  
2.  Following the allocation charts in 5.3.1, place tissue in cassettes, using a separate 
cassette for each tissue biopsy.  

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3. Snap the cassette lids closed and place cassettes in the pre-labeled formalin-filled 
container as soon as possible after collection to prevent air-drying. Up to 2 cassettes 
can be placed in one formalin container.  
4. Record the time of fixation.  
5. Secure container lids and package containers into the shipping kit according to 
instruction in section 5.5. Keep tissue in formalin jars at room temperature  
(20-25°C) until shipment to the EET Biobank.  
6. Enter time of fixation into the Sample Tracking System (Rave) for all submitted 
specimens.  
5.3.2.2 Archival Formalin Fixed Paraffin-Embedded (FFPE) Tumor Specimen  
If previously collected FFPE tissue will be submitted due to inaccessible or insufficient formalin 
fixed core tissue, then the following criteria must be met: 
o Tissue from the most recent biopsy is preferred; however, older samples, including from the 
primary tumor are acceptable 
o FFPE tumor tissue block(s) must be submitted.  The optimal block is at least 70% tumor.  
Specimen size requirement is as follows: 
 Surface area:  25 mm2 is optimal.  Minimum is 5 mm2. 
 Volume:  1 mm3 optimal.  Minimum volume is 0.2 mm3, however the success of 
DNA extraction decreases at suboptimal tissue volume. 
If an existing block cannot be submitted, the following are requested, if available: 
Sequentially processed and numbered slides:  
o One (1) H&E slide (3-5 μm) (slide #1) 
o Twenty to thirty* (20-30) 10 μm unstained air-dried uncharged slides* (slides #2-21 
or 31) 
o One (1) H&E stained slide (3-5 μm) (slide #22 or #32 if 10 more slides can be 
provided as per the footnote below) 
 
*20 slides are mandatory and an additional 10 unstained slides are requested, if available, for 
exploratory biomarkers (slides #2-31). 
 
FFPE tissues must be shipped on the days of collection, on Monday and Thursday, for arrival to 
the EET Biobank no later than Friday.  The EET Biobank must be notified on Wednesday or 
Thursday at the following email address:  BPCBank@nationwidechildrens.org prior to shipping 
formalin fixed tissue, for receipt on Friday. 
For centers that can accommodate the transition of formalin to ethanol 24h after collection, the 
C1D4 biopsy can be scheduled on a Friday (if C1D1 falls on a Tuesday). Then the sample can be 
shipped to the EET Biobank the next business day.  
 
All remaining tissue from FFPE blocks should be returned from EET Biobank to the NCI for 
optional immune-related biomarker studies, once request to distribute samples for MoCha has 
been fulfilled.   Tissue should be shipped to: 
 
ATTN: Dr. Paul Clavijo 

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National Institutes of Health 
Building 10, 7th Floor, Room 7S244 
Bethesda, MD 20892 
 
5.3.2.3 Snap-Frozen Core Biopsy 
1. Tissue should be frozen as soon as possible.  Optimally, freeze within 30 minutes 
from resection. 
2. Label cryovial(s) according to instructions in section 5.4.3. 
3. Using clean forceps place the tissue in a pre-chilled cryovial and freeze the tube in 
either vapor phase liquid nitrogen, on dry ice or by immediate placement in a -70 to -
80°C freezer. Keep frozen until shipment to the EET Biobank. 
5.3.3 Blood Collection  
5.3.3.1 Collection of Blood in EDTA Tubes for DNA studies 
1. Collect 10 mL blood in a pre-labeled EDTA tube(s) and gently invert tube to mix. 
Refer to Section 5.4.2 for labeling instructions. 
2. Ship on day of collection (whenever possible) to EET Biobank according to 
instructions below. 
3. If blood cannot be shipped on the day of collection (e.g. a late scheduled collection), 
then refrigerate until shipment.  
 
5.3.3.2 Collection of Blood in EDTA Tubes for Pharmacokinetics (PK) 
1. Label EDTA tubes with the Rave generated specimen ID (which includes the protocol 
number and Universal Patient ID), a patient study ID, specimen type (blood), and 
collection date. 
2. At each PK time point, collect 6 mL blood from the arm opposite the site of infusion 
or distal to the site of infusion in pre-labeled EDTA tube(s) and gently invert tube to 
mix.  
3. Immediately place on wet ice and within 1 hour after collection, centrifuge blood at 
1,500 x g for 10 minutes at 4°C. Aliquot plasma into 1.8 – 2 mL cryovials and store 
in a -70 to -80°C freezer until shipment. Ship to NCI Blood Processing Core (BPC) 
according to instructions below (see Section 5.6.1). Note: NCI site will send to the 
NCI Blood Processing Core (BPC) on wet ice for processing – see Section 5.6.1. 
 
5.3.3.3 Collection of Blood in EDTA Tubes for Pharmacogenomic studies 
1. Collect 10 mL blood in a pre-labeled EDTA tube and gently invert tube to mix. Refer 
to Section 5.4.2 for labeling instructions. 
2. Ship on day of collection (whenever possible) to NCI Blood Processing Core (BPC) 
according to instructions below (see Section 5.6.1). 
3. If blood cannot be shipped on the day of collection (e.g. a late scheduled collection), 
then refrigerate at 4ºC until time of shipment. Samples will be accepted no later than 
noon on Friday. 

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5.4 
Specimen Tracking System Instructions 
5.4.1 Specimen Tracking System Overview and Enrollment Instructions 
For the ETCTN STS, the following information will be requested: 
x Protocol Number 
x Investigator Identification  
o Institution and affiliate name 
o Investigator’s name 
x Eligibility Verification:  Patients must meet all the eligibility requirements listed in 
Section 3. 
x Additional Requirements: 
o Patients must provide a signed and dated, written informed consent form. 
Upon enrolling a patient, IWRS will communicate with OPEN, assigning two separate and 
unique identification numbers to the patient, a Universal patient ID (UPID) and a Treatment 
patient ID.  The UPID is associated with the patient and used each and every time the patient 
engages with the portion of this or any other protocol that uses the ETCTN Specimen Tracking 
System.  The UPID contains no information or link to the treatment protocol.  IWRS will 
maintain an association between the UPID for ETCTN biobanking and molecular 
characterization and any treatment protocols the patient participates in, thereby allowing analysis 
of the molecular characterization results with the clinical data.   
Immediately following enrollment, the institutional anatomical pathology report for the diagnosis 
under which the patient is being enrolled must be uploaded into Rave.  The report must include 
the surgical pathology ID (SPID), collection date, block number, and the IWRS-assigned UPID 
and patient study ID for this trial.  For newly acquired biopsies, the radiology and operative 
report(s) must also be uploaded into Rave.  Important:  Remove any personally identifying 
information, including, but not limited to, the patient’s name, date of birth, initials, medical 
record number, and patient contact information from the institutional pathology report 
prior to submission. 
Additionally, please note that the STS software creates pop-up windows when reports are 
generated, so you will need to enable pop-ups within your web browser while using the software.   
For questions regarding the Specimen Tracking System, please contact STS Support at 
STS.Support@theradex.com. 
A Shipping List report must be included with all sample submissions. 
5.4.2 Blood Specimen Labels 
Include the following on blood specimens (including whole blood and frozen, processed blood 
products – like serum and plasma): 
 
x Patient Study ID 
x Universal Patient ID (UPID) 
x Specimen ID (automatically generated by Rave) 
x Time point 
x Specimen type (e.g. blood, serum) 

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x Collection date (to be added by hand) 
x Note: PK labels must also include exact time of collection 
 
5.4.3 Tissue Specimen Labels 
Include the following on all tissue specimens or containers (e.g., formalin jar): 
 
x Patient Study ID 
x Universal Patient ID (UPID) 
x Specimen ID (automatically generated by Rave) 
x Time point 
x Specimen type (e.g., FFPE Block, Formalin Fixed Tissue, Fresh Tissue in Media, 
etc.) 
x Tissue type (P for primary, M for metastatic or N for normal) 
x Surgical pathology ID (SPID) number   
x Block number from the corresponding pathology report (archival only) 
x Collection date (to be added by hand) 
 
5.4.4 Example of Specimen Label Generated by STS 
STS includes a label printing facility, accessed via the Print Label CRF in the All Specimens 
folder. A generated PDF is emailed to the user as a result of saving that form.  
The following image is an example of a tissue specimen label printed on a label that is 0.5” high 
and 1.28” wide. 
 
The QR code in the above example is for the Specimen ID shown on the second line.  
 
Labels may be printed on a special purpose label printer, one label at a time, or on a standard 
laser printer, multiple labels per page. Theradex recommends the use of these low temperature 
waterproof labels for standard laser printers: https://www.labtag.com/shop/product/cryo-laser-
labels-1-28-x-0-5-cl-23-colors-available/  
 
The last line item on the label includes the following data points joined together:  
1. Tissue only: Primary (P), Metastatic (M), Normal (N) tissue indicated at the 
beginning of the specimen ID; this field is blank if not relevant (e.g., for blood)  
2. Block ID or blank if not relevant  

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3. SPID (Surgical Pathology ID) or blank if none  
4. An optional alpha-numeric code that is protocol specific and is only included if the 
protocol requires an additional special code classification  
Space is provided at the bottom of the label for the handwritten date and optional time. The 
last line on the example label is for the handwritten date and optional time.  
5.4.5 Overview of Process at Treating Site 
5.4.5.1 OPEN Registration 
All registrations will be performed using the Oncology Patient Enrollment Network (OPEN) 
system. OPEN communicates automatically with the Interactive Web Response System (IWRS) 
which handles identifier assignments, any study randomization and any prescribed slot 
assignments. If specimen analysis is required to determine eligibility, the protocol will be setup 
with multi-step registration. 
Registration with eligibility specimen analysis:  
1. Site enters first step data into OPEN. 
2. IWRS receives data from OPEN, generates the Patient Study ID and the Universal 
Patient ID, both of which are sent back to OPEN. 
3. IWRS sends first step registration data, including the IDs and a TAC of “NOT 
REG” directly to Rave. 
4. The specimen tracking system in Rave is utilized for the specimen that contributes 
to eligibility determination. 
5. Site enters second and any subsequent step data into OPEN including results of 
specimen analysis. 
6. IWRS receives all data from OPEN, then sends it onto Rave with either the 
treatment TAC or a TAC of “SCRN FAIL”. 
7. In addition to the specimen tracking forms completed to determine eligibility, data 
entry for screen failure patients should include Histology and Disease, all forms in 
the Baseline folder, any lab forms connected to eligibility determination, and Off 
Treatment/Off Study. 
Any data entry errors made during enrollment should be corrected in Rave. 
5.4.5.2 Rave Specimen Tracking Process Steps 
Step 0: Log into Rave via your CTEP-IAM account, then navigate to the appropriate 
participant. 
Step 1:  Complete the Histology and Disease form (but do not upload reports until a 
specimen label can be applied to them) and the Baseline forms regarding Prior 
Therapies. Enter the initial clinical specimen data:  
x Specimen Tracking Enrollment CRF:  Enter Time Point, Specimen Category, 
Specimen Type, Block number, Tissue type, Surgical Path ID, number of labels 
needed (include extra labels to apply to reports to be uploaded). CRF generates 
unique Specimen ID.  
Step 2:  Print labels using the Print Labels CRF located in the All Specimens folder, 
then collect specimen. 

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x Label specimen containers and write collection date on each label. 
x After collection, store labeled specimens as described in Section 5.3. 
x Apply an extra specimen label to each report before scanning. Return to the 
Histology and Disease form to upload any initial Pathology, Radiology, 
Molecular Reports (up to 4), Surgical (or Operative) reports. Return to Specimen 
Tracking Enrollment CRF to upload any molecular report (one per specimen) 
and/or the Tissue Biopsy Verification form, when applicable (see Appendix C).  
Uploaded reports should have protected health information (PHI) data like name, 
date of birth, mailing address, medical record number or social security number 
(SSN), redacted. Do not redact SPID, block number, diagnosis or relevant dates 
(such as collection date) and include the UPID and patient study ID on each 
document (either by adding a label or hand writing).  
Step 3:  Complete specimen data entry. 
x Specimen Transmittal Form: Enter Collection date and time and other required 
specimen details. 
Step 4:  When ready to ship, enter shipment information. 
x Shipping Status CRF:  Enter tracking number, your contact information, 
recipient, number of sample containers and ship date once for the 1st specimen in 
a shipment. 
x Copy Shipping CRF:  In the specimens folders for additional specimens (if any) 
that will be shipped with the initial specimen, please use the Copy Shipping form 
to derive common data into additional Shipping Status forms.  A few unique 
fields will still need to be entered in Shipping Status. 
Step 5:  Print shipping list report and prepare to ship.  
x Shipping List report is available at the site level. 
x Print two copies of the shipping list, one to provide in the box, the other for your 
own records. 
x Print pathology or other required reports to include in the box. Be sure the printed 
copy includes the specimen label 
Step 6:  Send email notification.  
x For only one of the specimens in the shipment, click “Send Email Alert” 
checkbox on the Shipping Status CRF to email recipient. 
Step 7:  Ship the specimen(s).  
Step 8:  Monitor the Receiving Status form located in each specimen folder for 
acknowledgment of receipt and adequacy. 
5.5 
Shipping Specimens from Clinical Site to the EET Biobank  
5.5.1 General Shipping Information 
When kits are provided, the shipping container sent with kit contents should be used to ship 
specimens to the EET Biobank.  In winter months, please include extra insulation, such as bubble 
wrap, inside the shipping container. 

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Core biopsies that are fixed in formalin and whole blood in EDTA should be shipped as one 
shipment at ambient temperature, whenever possible. 
 
5.5.2 Required Forms for Tissue Submissions: 
Each document submitted with the specimen must be labeled with a label printed from the 
STS, or the Universal ID and Patient Study ID.  
Tissue  
Required Forms 
Archival 
1. Shipping List 
2. Corresponding Pathology Report 
3. The pathology report must also be uploaded 
in the ETCTN specimen tracking system*.  
 
New Biopsy 
 
1. Shipping List 
2. Corresponding Pathology Report* OR all 
three of the following:  
x Surgical and/or Radiology Report 
x Tissue Biopsy Verification Form (see 
Appendix C) 
x Diagnostic Pathology Report 
Research Blood  
1. Shipping List 
 
* If the pathology report is not available at the time of shipment, then it must be uploaded to the 
ETCTN specimen tracking system as soon as it’s available, or the specimen will not be 
processed. The pathology report must state the disease diagnosis made by the reviewing 
pathologist.  
 
5.5.3 Specimen Shipping Instructions 
Archival (FFPE) tissue may be shipped on Monday through Thursday.  
 
Frozen specimens may be shipped on Monday through Thursday. Ensure that sufficient dry ice 
is included to completely encase the specimens to maintain specimen integrity during shipment.   
 
Formalin-fixed tissue must be shipped on the day of collection, on Monday through Friday. 
 
Fresh blood may be shipped on Monday through Friday.  Please select “Saturday Delivery” 
when shipping fresh blood on a Friday.  
 
5.5.3.1 Shipping of FFPE Blocks and Glass Slides 
1. 
Before packaging blocks or slides, verify that each specimen is labeled according to 

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Section 5.4.3. 
2. 
Blocks should be placed in a hard-sided container, preferably a special block holder, to 
protect the specimen.  Glass slides are to be placed in plastic slide holders.  Place tissue 
paper on top of the separated slides prior to closing the slide holder to reduce slide 
movement during shipment. 
3. 
Place the blocks or slides in a reinforced cardboard shipping box with appropriate 
packaging filler to minimize movement of specimens within the shipping box. 
4. 
Include a copy of the forms listed above and a shipping manifest from the Specimen 
Tracking System with each shipment.  
5. 
Please include a cold pack when shipping on hot days and extra insulation on cold days. 
6. 
Ship specimens to the address listed below.  FedEx Priority Overnight is strongly 
recommended to prevent delays in package receipt.  
 
5.5.3.2 Shipping Ambient Blood Using Supplies Provided by the Institution 
1. 
Before packaging specimens, verify that the collection tube is labeled according to 
instructions in section 5.4.2. 
2. 
Place the blood collection tube into a zip-lock bag.   
3. 
Place zip-lock bag into a biohazard envelope with absorbent material.  Expel as much 
air as possible and seal the envelope securely.  
4. 
Place the biohazard envelope into a Tyvek envelope.  Expel as much air as possible and 
seal securely. 
5. 
Place the specimen(s) and a copy of the shipping manifest into a sturdy shipping 
container. In winter months please use an insulated container and include extra 
insulation, such as bubble wrap, inside the shipping container to prevent specimens 
from freezing.  
6. 
Close the container and tape shut. 
7. 
Attach a shipping label to the top of the shipping container.  
8. 
Attach an Exempt Human Specimen sticker to the side of the container. 
9. 
Ship specimens via overnight courier to the address below.  FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt.  
Archival tissue and research blood for EET Biobank may be shipped together.  
If new biopsies are performed, please follow instructions in the following section,  
5.5.3.3 Shipping Ambient and Frozen Specimens in a Dual-Chamber Kit 
The Dual Chambered Specimen Procurement Kit is constructed to allow the shipment of frozen 
(on dry ice) and ambient (room temperature) specimens in the same container. Dry ice may be 
placed in either compartment of the kit but should not be put in both.  The dual chambered kit 
is only used for shipments that contain both frozen and ambient specimens. If formalin-fixed or 
archival tissue is shipped separately (not in the same shipment as frozen specimens), then it must 
be shipped using institutional shipping supplies.    
 
1.   Before packaging specimens, verify that each specimen is labeled according to the 
instructions in 5.4.3 and that lids of all primary receptacles containing liquid are tightly 
sealed.  

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2. 
Pre-fill one of the kit chambers about 1/3 with dry ice. 
3. 
Prepare the frozen specimens for shipment: 
a. 
Place the specimens into zip-lock bags.  
b. 
Place the zip-lock bags into a biohazard envelope containing absorbent material.  
Expel as much air as possible before sealing the biohazard envelope. 
c. 
Put each biohazard envelope into a Tyvek envelope.  Expel as much air as possible 
and then seal the Tyvek envelope. 
4. 
Quickly place the Tyvek envelope containing frozen specimens in the kit compartment 
that is pre-filled with dry ice.  Place the Tyvek envelope on top of the dry ice.  Cover the 
specimens with additional dry ice until the compartment is almost completely full.   
5. 
Place the Styrofoam lid on top to secure specimens during shipment.  Do not tape the 
inner chamber shut. 
6. 
Prepare the ambient specimens for shipment: 
a. 
Seal the lids of the formalin jars with parafilm.  Place absorbent material around the 
primary container of each liquid specimen.  Place the specimens into zip-lock bags. 
b. 
Place specimens inside the secondary pressure vessel with bubble wrap.  
c. 
Secure the lid on the secondary pressure vessel and set it inside the kit chamber. 
7. 
Insert a copy of the required forms in the kit chamber with the ambient specimens. 
8. 
Place the Styrofoam lid on top of the kit compartment to secure specimens during 
shipment.  Do not tape the inner chamber shut. 
9. 
Close the outer lid of the Specimen Procurement Kit and tape it shut with durable 
sealing tape.  Do not completely seal the container. 
10. Complete a FedEx air bill and attach to top of shipping container. 
11. Complete a dry ice label. 
12. Attach the dry ice label and an Exempt Human Specimen sticker to the side of the 
shipping container. 
13. Ship specimens via overnight courier to the address below.  FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt.  
 
5.5.4 Shipping Address 
 
Ship to the address below. Ship formalin-fixed and fresh blood specimens the same day of 
specimen collection. Do not ship specimens the day before a holiday. 
 
EET Biobank 
The Research Institute at Nationwide Children's Hospital 
700 Children's Drive, WA1340 
Columbus, Ohio 43205 
Phone: (614) 722-2865 
Fax: (614) 722-2897 
Email: BPCBank@nationwidechildrens.org 
 
FedEx Priority Overnight service is very strongly preferred.   
 
Note:  The EET Biobank FedEx Account will not be provided to submitting institutions. There is 
no central Courier account for this study.  Sites are responsible for all costs for overnight 

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shipment per specimen shipment to the EET Biobank. 
 
5.5.5 Contact Information for Assistance 
 
For all queries, please use the contact information below: 
 
EET Biobank  
Toll-free Phone: (800) 347-2486 
E-mail:  BPCBank@nationwidechildrens.org 
 
5.6 
Shipping of Specimens to Other Laboratories  
5.6.1 Blood in EDTA for Birinapant Pharmacokinetics and Pharmacogenomic Studies – 
NCI Blood Processing Core (BPC/Figg Lab) 
Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting or shipping 
samples (the Friday before is preferred). 
For NCI sample pickup, page 102-11964. 
For immediate help, call 240-760-6180 (main BPC number) or, if no answer, 240-760-6190 
(main clinical pharmacology lab number). 
For questions regarding sample processing or shipment, contact NCIBloodcore@mail.nih.gov. 
For non-NCI sites, please ship PK samples to the NCI Blood Processing Core at the following 
address: 
National Cancer Institute 
NCI Blood Processing Core/Figg Lab 
10 Center Drive, Room 5A08 
Bethesda, MD 20892 
Ph: 240-760-6180 
 
5.6.2 Snap-frozen tissue for Microwestern for IAP1/2, CASP3 and MLKL in tumor 
tissue – Dr. Annunziata Laboratory 
Snap-frozen cores collected at baseline and C1D4 will be placed in dry ice and sent to the EET 
Biobank. In the event that frozen samples cannot be shipped immediately, maintain frozen 
specimens in a -80°C freezer. Once accrual is completed and all samples are collected, they will 
then be sent from the EET Biobank to Dr. Annunziata’s lab. 
The EET Biobank will contact Dr. Annunziata prior to shipping of specimens: 
Bldg 10 Room 3B43C 
10 Center Dr. 
Bethesda, MD 20814 
E-mail: ca180n@nih.gov 
Phone: 240-760-6125 
 

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5.6.3 FFPE for Immunohistochemistry for PD-L1 and CD8 T-cell infiltration, and other 
immune-related biomarkers in tumor tissue – Dr. Van Waes Laboratory 
FFPE specimens or slides will be collected by each site and sent to the EET Biobank. Once 
accrual is completed and all samples are collected, they will then be sent from the EET Biobank 
to Dr. Van Waes’ lab. 
Please page/contact Dr. Paul Clavijo in advance of shipping FFPE specimens or slides: 
 
Dr. Paul Clavijo 
Building 10 Room 7S250 
10 Center Dr 
Bethesda, MD 20814 
E-mail: paul.clavijo@nih.gov 
Phone: 301-594-6091 or alternate 240-449-6727  
 
The FFPE specimens or slides will be used commonly by Drs. Van Waes and Saloura’s labs for 
optional immune-related biomarker studies.  
 
 
 
 

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5.7 
Biomarker Plan 
List of Biomarker Assays in Order of Priority 
 
NOTE: For baseline and C1D4 biopsies, all remaining tissue from FFPE blocks should be 
returned to the NCI for optional immune-related biomarker studies, once request to distribute 
samples for MoCha has been fulfilled. 
NOTE FOR PARTICIPATING SITES: Please see Section 5.1 for details on specimens to 
collect.  The specimens tested are not always the same specimens that are submitted by the site, 
as processing of blood and tissue will occur at the Biobank prior to testing. 
 
Priority Biomarker Name 
Biomarker Assay 
Biomarker Type 
and Purpose 
M/O1 Specimen and 
Timepoint(s) 
 
Laboratory 
1 
FADD / BIRC2 
copy number gain 
 
Whole exome 
sequencing (normal 
DNA will be used 
as control for the 
FADD/BIRC2 
copy number gain 
assay) 
 
 
 
Integrated 
To determine if 
FADD/BIRC2 copy 
number gain is 
associated with 
response rate, LCR 
rate, OS and PFS 
M 
Baseline:  
1 archival 
FFPE block or 
20 unstained 
archival slides 
from the most 
recent biopsy 
available OR 
1-2 formalin-
fixed fresh 
tumor biopsies  
 
Mickey 
Williams /  
Molecular 
Characterization 
laboratory 
(MoCha) at NCI 
Frederick 
2 
 
 
 
 
FADD / BIRC2 
copy number gain 
Whole exome 
sequencing 
(germline) DNA 
will be used as 
control for the 
FADD/BIRC2 
copy number gain 
assay) 
 
 
Integrated 
To determine if 
FADD/BIRC2 copy 
number gain is 
associated with 
response rate, LCR 
rate, OS and PFS 
M 
Baseline: 
DNA from 
blood in 
EDTA   
Mickey 
Williams /  
Molecular 
Characterization 
laboratory 
(MoCha) at NCI 
Frederick 
Whole exome copy 
number and 
mutations  
Whole exome 
sequencing  
 
Exploratory 
To determine if 
other copy 
alterations or 
mutations detected 
with whole exome 
sequencing 
influences objective 
response rate 
3 
IAP1/2, CASP3, 
MLKL 
 
Microwestern for 
IAP1/2, CASP3 
and MLKL 
Performed with 
Simple Western™ 
system/capillary 
Integrated 
To determine the 
effect of birinapant 
and re-irradiation 
on the candidate 
pharmacodynamic 
O 
Baseline and 
C1D4: 1- 2 
cores snap-
frozen tumor 
biopsies  
Annunziata, 
NCI 

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1 Mandatory or optional 
2 C1D4 6ml blood in EDTA is required only if a fresh biopsy is performed on C1D4.   
 
5.8 
Integral Laboratory Studies 
5.8.1 FADD / BIRC2 copy number gain in tumor tissue  
5.8.1.1 Specimens and Processing  
x Tissue  
Formalin-fixed tissue at baseline (or archival FFPE if baseline biopsy tissue not 
available) will be used for this assay. Tissue in formalin will be processed and 
embedded upon receipt at the EET Biobank, and slides will be cut from the biopsies. 
For all tumor specimens, the first section will be stained with H&E for pathology 
quality control review to assess tumor content; unstained slides will be 
macrodissected, if needed, and scraped for DNA extraction. DNA will be banked in a 
stock vial; all nucleic acids will be stored in a -80°C freezer until distribution for 
testing. 
x Blood 
DNA will be extracted from blood collected in EDTA tubes at the baseline time point 
and will be stored in a -80°C freezer until distribution for testing.  For DNA 
sequencing, 250 ng of genomic DNA from tumor and blood is required. 
5.8.1.2 Site Performing Correlative Study 
Molecular Characterization laboratory (MoCha) at NCI Frederick directed by Dr. 
Mickey Williams. 
Priority Biomarker Name 
Biomarker Assay 
Biomarker Type 
and Purpose 
M/O1 Specimen and 
Timepoint(s) 
 
Laboratory 
Western 
biomarkers IAP1/2, 
CASP3 and MLKL  
4 
PD-L1, CD8 T-cell 
infiltration and 
other immune- 
related biomarkers 
Immunohistochemi
stry for PD-L1 and 
CD8 T-cell 
infiltration, and 
other immune-
related biomarkers  
 
Exploratory 
Pilot immune 
markers to explore 
correlation with 
objective response 
rate 
O 
Baseline: 1 
FFPE core or 
10 unstained 
archival FFPE 
slides  
CID4: 1 FFPE 
core 
Van Waes, 
Allen, NIDCD, 
Saloura, NCI 
5 
Birinapant 
Pharmacokinetics 
Birinapant 
Pharmacokinetics 
Exploratory 
 
M2 
6 mL whole 
blood in 
EDTA (see 
section 5.1 for 
timepoints) 
NCI Blood 
Processing Core 
6 
Birinapant 
Pharmacogenomics 
(single-nucleotide 
polymorphisms-
SNPs) 
Birinapant 
Pharmacogenomics 
Exploratory 
 
O 
Baseline: 10 
mL whole 
blood in 
EDTA 
NCI Blood 
Processing Core 

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5.8.1.3 Shipment of Specimens from the EET Biobank to Site Performing Correlative Study  
Specimens will be shipped from the EET Biobank to: 
 
MoCha, Frederick National Laboratory for Cancer Research (FNLCR) 
Attn: Alyssa Chapman or Ashley Hayes 
1050 Boyles St 
Bldg. 459, Rm. 125 
Frederick, MD 21702 
5.8.1.4 Contact Information for Notification of Specimen Shipment 
Thomas Forbes (mochasamplereceiving@nih.gov) 
5.8.2 Microwestern for IAP1/2, CASP3 and MLKL in tumor tissue 
5.8.2.1 Specimens and Processing  
Snap-frozen tumor at baseline and C1D4 time points will be used for this assay. Upon 
receipt at the EET Biobank, the snap-frozen tissue will be accessioned, barcoded, 
weighed, and banked in a liquid nitrogen vapor phase freezer until distribution for 
testing.  
If specimens collected on C1D4 (Thursdays) cannot be shipped to ETCTN the same day 
or on next day (Friday), they should be stored at -80ºC and sent to ETCTN on the 
upcoming Monday or Tuesday. 
Once all specimens are collected, they will be sent to Dr. Christina Annunziata’s 
Laboratory. 
Core tumor samples will be lysed in T-per buffer (Thermo Scientific) for protein 
quantification by an automated capillary electrophoresis immunoassay system (Simple 
Western™). 
5.8.2.2 Site Performing Correlative Study 
Dr. Christina Annunziata’s laboratory 
5.8.2.3 Shipment of Specimens from the EET Biobank to Site Performing Correlative Study  
Specimens will be shipped from the EET Biobank to: 
Refer to Section 5.6.2. 
5.8.2.4 Contact Information for Notification of Specimen Shipment 
Refer to Section 5.6.2. 
5.8.3 Whole exome copy number, mutations and expression 
The specimens used for the FADD/BIRC2 will be used for this assay; refer to Section 
5.8.1.1 for specimen handling and processing.   

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5.8.4 Immunohistochemistry for PD-L1 and CD8 T-cell infiltration, and other immune-
related biomarkers in tumor tissue 
5.8.4.1 Specimens and Processing  
Formalin-fixed tissue at baseline will be used for this assay. Tissue cores in formalin 
will be processed and embedded or archival specimens or slides will be provided to the 
EET Biobank, where 10 5PM slides will be cut from the biopsies. For all tumor 
specimens, the first section will be stained with H&E for pathology quality control 
review to assess tumor content. The tissue cores will then be barcoded and banked at the 
ETCTN.  
Core biopsies collected on C1D4 will be placed in formalin and sent to ETCTN for 
delivery on Friday. If the sample is shipped on Friday for delivery on Saturday at 
ETCTN, the cores will then be placed in PBS or ethanol (to prevent overfixation) and 
stored until Monday, when they will be paraffin embedded. 
Once all cores are collected, they will be distributed to Dr. Van Waes’ Laboratory. If a 
biopsy cannot be obtained, 10 unstained slides will be instead distributed to Dr. Van 
Waes’ laboratory for use by Dr. Van Waes and Saloura’s labs. 
5.8.4.2 Handling of Specimens 
Tissues used for immunofluorescence analysis of PD-L1 expression and CD8 tumor 
infiltrating lymphocyte (TIL) will be fixed in 4% formalin for 24 hours, then transferred 
to 70% ethanol and stored at room temperature. Fixed tissue will be paraffin embedded 
and sectioned. CD8 TIL infiltration and PD-L1 expression will be assessed in 
appropriate sections by multiplex immunofluorescence (IF), performed by NIDCD 
Laboratory personnel in collaboration with LTIB Tissue Core personnel using standard 
IF staining techniques using Perkin-Elmer Opal staining kits, a Perkin-Elmer Vectra 
Polaris Image Analysis Platform and Perkin-Elmer inForm software. This platform has 
been validated for use in fixed human tissue analysis of CD8+ cell tissue infiltration and 
PD-L1 expression. (21, 22) 
5.8.4.3 Site Performing Correlative Study 
Dr. Van Waes laboratory 
5.8.4.4 Shipment of Specimens from the EET Biobank to Site Performing Correlative Study  
Specimens will be shipped from the EET Biobank to: 
Refer to Section 5.6.3. 
5.8.4.5   Contact Information for Notification of Specimen Shipment 
  Refer to Section 5.6.3. 
5.8.5 Birinapant Pharmacokinetics 
5.8.5.1 Specimens and Processing  
Upon receipt, frozen, processed plasma aliquots will be barcoded and banked in -80°C 
freezers until distribution for testing to the NCI Center for Cancer Research Clinical 
Pharmacology Program (see Section 5.6.1).  

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5.8.5.2 Handling of Specimens 
Upon arrival in the NCI Blood Processing Core (BPC), samples will be kept on wet ice 
until centrifugation at 1500 g for approximately 10 min at 4°C.  Samples will be 
processed within one hour of sample collection. Plasma will be transferred into 1.8 mL 
Nunc cryovials and stored at -70°C until the time of analysis. If sufficient plasma 
volume, each sample will be split into equal volume aliquots.  
All samples sent to the NCI Blood Processing Core (Figg Lab) will be barcoded, with 
data entered and stored in the Labmatrix utilized by the BPC. This is a secure program, 
with access to Labmatrix limited to defined BPC personnel, who are issued individual 
user accounts. Installation of Labmatrix is limited to computers specified by Dr. Figg. 
These computers all have a password restricted login screen. All Figg lab personnel 
with access to patient information are required to complete the Human Subjects 
Research course.  
Labmatrix creates a unique barcode ID for every sample and sample box, which cannot 
be traced back to patients without Labmatrix access. The data recorded for each sample 
includes the patient ID, name, trial name/protocol number, time drawn, cycle time 
point, dose, material type, as well as box and freezer location. Patient demographics 
associated with the clinical center patient number are provided in the system. For each 
sample, there are notes associated with the processing method (delay in sample 
processing, storage conditions on the ward, etc.).  
Sample bar-codes are linked to patient demographics and limited clinical information. 
This information will only be provided to investigators listed on this protocol, via 
registered use of the Labmatrix. It is critical that the sample remains linked to patient 
information such as race, age, dates of diagnosis and death, and histological information 
about the tumor, in order to correlate genotype with these variables. 
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -
80qC according to stability requirements. These freezers are located onsite in the BPC 
and offsite at NCI Frederick Central Repository Services in Frederick, MD. Visitors to 
the laboratory are required to be accompanied by laboratory staff at all times.  
Access to stored clinical samples is restricted. Samples will be stored until requested by 
a researcher named on the protocol. All requests are monitored and tracked in 
Labmatrix. All researchers are required to sign a form stating that the samples are only 
to be used for research purposes associated with this trial (as per the IRB approved 
protocol) and that any unused samples must be returned to the BPC. It is the 
responsibility of the NCI Principal Investigator to ensure that the samples requested are 
being used in a manner consistent with IRB approval.  
Following completion of this study, samples will remain in storage as detailed above. 
Access to these samples will only be granted following IRB approval of an additional 
protocol, granting the rights to use the material. 
If, at any time, a patient withdraws from the study and does not wish for their existing 
samples to be utilized, the individual must provide a written request. Following receipt 
of this request, the samples will be destroyed (or returned to the patient, if so requested), 
and reported as such to the IRB. Any samples lost (in transit or by a researcher) or 

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destroyed due to unknown sample integrity (i.e. broken freezer allows for extensive 
sample thawing, etc.) will be reported as such to the CTEP. 
5.8.5.3 Site Performing Correlative Study 
NCI Center for Cancer Research Clinical Pharmacology Program (CPP) 
5.8.5.4 Contact information for notification of specimen shipment  
               Refer to Section 5.6.1. 
5.8.6 Birinapant Pharmacogenomics (Single-nucleotide polymorphisms – SNPs) 
5.8.6.1 Specimens and Processing  
Upon receipt, EDTA blood samples will be barcoded and the buffy coat will be 
extracted. PBMCs of the buffy coat will be placed in media containing 10% DMSO and 
90% FBS and then frozen in a -80degree freezer using a Mr. Frosty isopropanol 
container. 
PBMCs will be processed using a QiaAmp DNA blood kit.  DNA will be extracted and 
SNP analysis will be run using the Pharmacoscan assay kit: 
(https://www.thermofisher.com/order/catalog/product/903010TS#/903010TS).  
Approximately 4500 SNPs in absorption, distribution, metabolism and excretion 
(ADME) genes will be evaluated. 
5.8.6.2 Handling of Specimens 
Upon arrival in the NCI Blood Processing Core, samples will be kept on wet ice until 
centrifugation at 1500g for approximately 10 minutes at 4°C.  Samples will be 
processed within one hour of sample collection as described above.  
All samples sent to the NCI Blood Processing Core will be barcoded, with data entered 
and stored in the Labmatrix utilized by the BPC.  The handling procedure will be the 
same as described in Section 5.8.5.2. 
5.8.6.3 Site Performing Correlative Study 
NCI Center for Cancer Research Clinical Pharmacology Program (CPP) 
5.8.6.4 Contact information for notification of specimen shipment  
Refer to Section 5.6.1. 
6 
TREATMENT PLAN 
This is an open-label Phase I study enrolling patients in 2 cohorts: dose escalation cohort and 
expansion cohort. 
Treatment will be delivered in 2 cycles, lasting 3 weeks each. 
Birinapant will be administered IV on Days 2 and 9 of each cycle in combination with IMRRT 
starting on Day 1 of cycle 1 and continuing for 5 days a week (Monday-Friday) for 6 weeks.  
If a dose of birinapant is missed due to a scheduled holiday, inclement weather, personal 
emergency, or other reasons, then it should be given the following day. 

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If daily radiation treatment is missed due to a scheduled holiday, inclement weather, personal 
emergency, or other reasons, then the day(s) and fraction(s) missed should be added at the end of 
the course to complete the total planned treatment dose (e.g. 60Gy).  
Patients in the dose escalation cohort will be treated with escalating doses of birinapant with 
IMRRT until MTD of birinapant in combination with IMRRT is established.  
Patients in expansion cohort will be treated with the estimated MTD of birinapant in combination 
with IMRRT. 
6.1 
Agent Administration 
Treatment will be administered primarily on an outpatient basis unless inpatient admission is 
indicated. Reported adverse events and potential risks are described in Section 10. Appropriate 
dose modifications are described in Section 7. No investigational or commercial agents or 
therapies other than those described below may be administered with the intent to treat the 
patient's malignancy. 
6.1.1 Dose Escalation Cohort  
Birinapant will be administered IV over 30 minutes on Days 2 and 9 of each 3-week cycle with 
starting dose 5.6 mg/m2 per dose in combination with IMRRT starting on Day 1 of cycle 1 at 
2Gy/day x 5 days/week/M-F for two cycles (6 weeks) to a total of 60-66Gy.  
IMRRT will start within 1-4 hours after the infusion of birinapant. 
Vital signs will be collected prior to and after every birinapant infusion. 
An ECG will be performed within 2 hours prior to the start of infusion and 2 hours after infusion 
completion to evaluate for pre- and post-treatment abnormalities, including QT/QTc 
prolongation.  Further continuous monitoring will be performed for ECG abnormalities 
following infusion until resolved. 
After the first and second infusion of birinapant, patients will be observed for 30-60 minutes for 
adverse events. 
Dose escalation (Table 1) will proceed in dose levels of 3–6 patients. The MTD is the dose level 
at which no more than 1 of up to 6 patients experience DLT during 42 days after the start of 
therapyDQGWKHGRVHEHORZWKDWDWZKLFKDWOHDVWRISDWLHQWVKDYH'/7DVDUHVXOWRIWKH
drug.  
Patients who have not received at least 80% of the total planned dose of birinapant and radiation 
therapy within the planned 42 days of treatment will not be evaluable for DLT assessment, even 
if they have not experienced any DLTs while receiving the treatment. 
The first subject in each dose level group will be observed for at least 14 (+/-3) days after Cycle 
2 radiation is completed before the second subject can be treated. If no DLT is observed within 
that period, the second patient can enroll. An interval of 14 (+/-3) days without a DLT must pass 
before treatment of the next patient, i.e. before treating patients within each dose cohort.  
As of Amendment version date 12/15/2022, up to 3 patients may be enrolled in each remaining 
dose cohort (3 and 4).  DLT observation periods noted in above paragraph are no longer required 
prior to enrolling subsequent patients. 
A safety assessment for each dose cohort will be conducted 14 days (+/- 3  days) after the last 

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patient of each dose cohort has completed treatment. If no DLTs are observed for the specific 
dose cohort, enrollment in the next dose cohort can proceed, following approval by the Medical 
Monitor.  
The study team will meet weekly to review the ongoing results of the trial during the dose 
escalation portion of the study. 
Dose levels are defined in the table below. Starting dose will be 5.6 mg/m2. If >1/6 patients 
develop a DLT at level 1 dose and a maximum 1/6 patients develop a DLT at the level -1 dose, 
the latter will be determined as the MTD. 
Table 1: Dose Escalation Schedule 
Dose Level 
Birinapant (mg/m2)  
Level -1 
2.8 
Level 1 
5.6 
Level 2 
11 
Level 3 
17 
Level 4 
24 
 
6.1.2 Radiation Therapy 
x Start Date: All patients with remaining teeth will have a pre-radiotherapy dental 
evaluation. Feeding tube will be placed in patient at the discretion of the radiation 
oncologist and medical oncologist. Radiation therapy will begin on Day 1.  
x Immobilization: Immobilization should include neck and shoulders utilizing the standard 
practice of Aquaplast mask. 
x Treatment Planning CT: will be obtained with standard 0.3 cm slices through the regions 
that include the target volumes. PET/CT and/or MR scans may be used to assist in the 
definition of the target volumes, especially when the targets extend near the base of skull.  
6.1.2.1 Target Volumes:  
The treatment volume will include the gross tumor volume with an organ at risk (OAR) adapted 
margin of 0.1-1.5 cm to the planning target volume. Elective nodal coverage will not be 
included. 
The definition of volumes will be in accordance with The International Commission on 
Radiation Units and Measurements (ICRU) Report # 50 and 62.  
x Gross Tumor Volume (GTV) is the gross palpable or visible/demonstrable extent and 
location of the malignant growth. The GTV will be determining utilizing a combination 
of clinical examination (including endoscopy) and radiographic exams (utilizing CT, 
PET/CT or MRI).  
x Clinical Target Volume (CTV) is a tissue volume that contains a demonstrable GTV 
and/or is considered to contain microscopic, subclinical extensions at a certain probability 
level. This volume thus has to be treated adequately in order to achieve the aim of 

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therapy. In the re-irradiation setting we will at most treat 1-2 nodal levels in addition to 
the gross tumor volume and the margin will be 3-5mm.  
x Planning Target Volume (PTV) is a geometrical concept, and it is defined to select 
appropriate beam sizes and beam arrangements, taking into consideration the net effect of 
all the possible geometrical variations and inaccuracies in order to ensure that the 
prescribed dose is actually absorbed in the CTV. A minimum of 3-5 mm around the CTV 
will be utilized, excluding extension into the spinal cord and non-involved normal tissue.  
x Spinal Cord: The spinal cord will be defined based upon CT scan. A spinal cord 
“planning” volume (PRV) also will be defined by adding a symmetrical margin of at least 
0.5 cm in all dimensions around the cord. 
x Mandible: The mandible includes the entire bony structure from TMJ through the 
symphysis. 
x Brainstem: The brainstem will be defined based upon the CT scan. A brainstem 
“planning” volume (PRV) also will be defined by adding a symmetrical margin of at least 
0.3 cm in all directions around the brainstem. 
x Larynx: The larynx will be defined as the portion of the larynx from the top of the thyroid 
cartilage to the bottom of the cricoid cartilage that does not include any portion of the 
PTV. No additional margin will be added around the larynx. 
x Brachial Plexus: defined per RTOG atlas 
(https://www.rtog.org/CoreLab/ContouringAtlases.aspx) 
x Cervical Esophagus: This is defined as a tubular structure that starts at the bottom of 
pharynx and extends to the thoracic inlet.  
6.1.2.2 Lymph Node Regions and Normal Tissues:  
The lymph node groups at risk will be determined and their volumes (CTVs) will be outlined on 
the treatment planning CT according to image-based nodal classifications (RTOG online nodal 
atlas can be used as a reference; www.rtog.org). In the re-irradiation setting the patients will not 
receive elective nodal irradiation, however 1-2 lymph nodal levels may be added at the discretion 
of the radiation oncologist based on imaging and other clinical factors.  
The normal tissue volumes to be contoured will include the brainstem, brain stem + 0.3 cm 
margin, spinal cord, spinal cord + 0.5 cm margin, mandible, larynx, parotid glands, cochlea, oral 
cavity, optic nerves, optic chiasm, globes, brachial plexus.  
6.1.2.3 Dosimetric Planning:  
Intensity Modulated Radiation Therapy (IMRT) and/or Volumetric Modulate Arc Therapy 
(VMAT) planning and delivery will be performed in all cases. The treatment plan used for each 
patient will be based on an analysis of the volumetric dose, including DVH analyses of the PTV 
and critical normal structures. The treatment aim will be the delivery of radiation to the PTVs 
and exclusion of noninvolved tissue as much as feasible.  
6.1.2.4  Dose Specification:  
The dose prescription is to be based on a dose distribution corrected for heterogeneities. 

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A list of the approved Treatment Planning Systems (TPS) and algorithm for dose calculation can 
be found on the IROC Houston web site. 
The prescription dose will be normalized to the isodose which encompasses at least 95% of the 
planning target volume (PTV).  
No more than 20% of the PTV will receive > 110% of its prescribed dose.  
No more than 1% of any planning target volume will receive < 93% of its prescribed dose.  
No more than 1% or 1 cc of tissue outside the PTV will receive > 110% of the dose prescribed to 
the PTV.  
The dose prescription will be based on dose distribution corrected for tissue inhomogeneity. 
PTV 60 Gy will include the primary tumor and involved nodal regions if adjacent nodal regions 
have disease or are at high risk. 1-2 levels of lymph nodal levels can be treated at the discretion 
of the radiation oncologist and based on imaging data (CT, PET/CT and/or MRI). The dose in 
this region can go as high as 66 Gy as long as the normal structure tolerances are met.  
6.1.2.5  Suggested Dose restraints for critical normal structures 
For CNS structures, Brainstem, Optic nerve and Optic chiasm: No more than 0.03 cc can exceed 
60 Gy (from current AND previous radiation therapy treatments combined). Mandible: There are 
no specific requirements for brachial plexus dose, but if it is not grossly involved with or 
immediately adjacent to tumor, the dose should be kept as low as reasonably possible. Minimize 
hot spots. 
Brachial plexus: There are no specific requirements for brachial plexus dose, but if it is not 
grossly involved with or immediately adjacent to tumor, the dose should be kept as low as 
reasonably possible. Minimize hot spots. 
Larynx: There are no specific requirements for larynx dose, but if it is not grossly involved with 
or immediately adjacent to tumor, the dose should be kept as low as reasonably possible. 
Minimize hot spots.  
6.1.2.6 Treatment Delivery/ Equipment:  
Megavoltage equipment capable of delivering static-gantry intensity modulation beams with a 
multi-leaf collimator or dynamic intensity modulation (using a multi-leaf collimator or 
tomotherapy) is required. Other techniques are acceptable as long as dose specifications and 
constraints are satisfied. This includes tomotherapy and Volumetric Modulated Arc Therapy 
(VMAT) techniques. It is expected that the entire treatment of definitive irradiation will be 
completed in approximately seven weeks. Radiation course should be continuous (Monday-
Friday) for 5 days. However, if an interruption is required for radiation reaction, it should be kept 
to a minimum, recorded, and justified.   
6.2 
Definition of Dose-Limiting Toxicity 
Dose-limiting toxicity (DLT) will be defined as any one of the following adverse events, 
possibly attributable to the combination of birinapant and radiotherapy, that occur within 42 days 
of the start of therapy:  
x Any grade 5 toxicities. 

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x $Q\JUDGHKHPDWRORJLFWR[LFLW\ except for lymphopenia.  
x $Q\JUDGHQRQ-hematologic toxicity, except for any of the following: 
¾ nausea and vomiting that can be managed with standard supportive care over 2 weeks  
¾ alopecia,  
¾ drug-related fever,  
¾ radiation-induced in-field related side effects, including but not limited to dermatitis, 
oral mucositis and related pain, dysphagia, dysgeusia, esophagitis, xerostomia, weight 
loss, thickened oral secretions that can be managed with standard supportive care 
over 2 weeks 
¾ isolated laboratory abnormalities without clinical sequelae 
x JUDGHSURORQJHG!GD\VVHUXPDP\ODVHRUOLSDVHHOHYDWLRQ* 
x JUDGHSURORQJHG!GD\VDVSDUWDWHDPLQRWUDQVIHUDVH$67elevation* 
x JUDGHSURORQJHG!GD\VDODQLQHDPLQRWUDQVIHUDVH$/7HOHYDWLRQ*  
x Concurrent elevation of AST/ALT >3 times the upper limit of normal and bilirubin > 2 
times the upper limit of normal (i.e., Hy’s law) 
x Any grade toxicity that mandates discontinuation of birinapant treatment for more than 2 
weeks 
* all of which will be considered to be dose limiting. 
Grade 5 AEs are unacceptable, though the chances of their occurrence are considered to be quite 
low.  The probability of DLTs with birinapant in combination with radiotherapy at the specified 
dose levels are expected not to exceed 30% of patients. All $(VJUDGH are considered 
acceptable in terms of risk, given that the median overall survival of patients with locoregionally 
recurrent head and neck cancer who have received 1 or 2 lines of standard of care treatment is 
very short (approximately 3-6 months). 
Criteria are based on the NCI Common Terminology Criteria for Adverse Events, Version 5.0.   
Dose escalation will proceed within each dose level according to the following scheme. Dose-
limiting toxicity (DLT) is defined above. 
Number of Patients with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
 
Dose escalation will be stopped. This dose level will be 
declared the maximally administered dose (highest dose 
administered). Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients 
were treated previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
x If 0 of these 3 patients experience DLT, proceed to 

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the next dose level. 
x If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose. Three (3) additional 
patients will be entered at the next lowest dose level 
if only 3 patients were treated previously at that dose. 
RXWRIDWKLJKHVWGRVHOHYHO
below the maximally administered 
dose 
This is generally the MTD. At least 6 patients must be 
entered at the MTD. 
This dose escalation plan, on average, will select a maximum tolerated dose with the specified 
acceptable probabilities of DLT. 
6.3 
Dose Expansion Cohort 
Birinapant will be administered IV over 30 minutes on days 2 and 9 of every cycle at the MTD 
estimated during dose escalation part of the study. 
IMRRT will be administered starting on Day 1 at 2Gy/day x 5 days/week/M-F for 2 cycles (6 
weeks) to a total of 60-66Gy.  
IMRRT will start within 1-4h after the infusion of birinapant. 
The study team will meet weekly to review the ongoing results of the trial and will continue to 
monitor and record AEs during the dose expansion portion of the study.   
An expansion cohort of 10 additional patients will be treated at the MTD and the results 
combined with those of patients at the MTD to obtain improved estimates of safety and toxicity 
as well as to perform analyses to address secondary objectives. 
6.4 
General Concomitant Medication and Supportive Care Guidelines 
Because there is a potential for interaction of birinapant with other concomitantly administered 
drugs, the case report form must capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies. The Principal Investigator should be alerted if the patient is 
taking any agent known to affect or with the potential for drug interactions. A Patient Drug 
Information Handout/Wallet Card is provided (Appendix B). 
6.5 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue for 2 cycles 
or until one of the following criteria applies: 
x Disease progression 
x Intercurrent illness that prevents further administration of treatment 
x Unacceptable adverse event(s) as described in Sections 6.2 and 7.  
x Patient decides to withdraw from the study 
x General or specific changes in the patient's condition that render the patient unacceptable 
for further treatment in the judgment of the investigator 

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x Clinical progression 
x Patient experiences a grade 4 non-hematologic toxicity or any grade 3 toxicity not 
returning to JUDGHafter 2 weeks of supportive care.  The patient may continue with 
IMRRT but will be taken off birinapant. 
x Patient non-compliance with <80% of birinapant doses (less than 3 out of the 4 total 
doses) or with scheduled appointments for investigational treatment that may affect 
treatment outcome, per PI discretion. 
x Pregnancy 
o All women of child bearing potential will be instructed to contact the investigator 
immediately if they suspect they might be pregnant (e.g., missed or late menstrual 
period) at any time during study participation. 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
x Termination of the study by sponsor 
x The drug manufacturer can no longer provide the study agent 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
6.6 
Duration of Follow Up 
Patients will be evaluated for safety with follow up visits approximately 14 (+ 7) days and 28 
(+/- 7) days after completion of, or removal from treatment. Patients removed from treatment for 
unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse 
event.  
Patients will be evaluated at 3 (+/- 2 weeks), 6 (+/- 4 weeks), 9 (+/- 4 weeks), 12 (+/- 4 weeks), 
18 (+/- 4 weeks) and 24 (+/- 4 weeks) months after completion of treatment for tumor 
evaluations. These visits will be stopped after confirmation of disease progression.  
If patients are unable or unwilling to come to these visits, they will be contacted by phone or e-
mail. 
7 
DOSING DELAYS/DOSE MODIFICATIONS 
General guidelines for treatment modifications at the time of re-treatment:  
Adverse Events: All adverse events in this trial will be graded using the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0.  A complete listing is available 
at the CTEP website: http://ctep.cancer.gov/forms/CTCAEv5.pdf.  
7.1 
Birinapant 
7.1.1 Safety Consideration When Administering Birinapant 
7.1.2 Dose Adjustments 
Dose adjustments are allowed during both the dose escalation and the expansion phase of the 
study. Patients that have a DLT as defined in Section 6.2 may have their treatment held or will 

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incur up to 2 dose level reductions, as indicated in Section 7.1.3.  If an AE that fulfills DLT 
criteria recurs, treatment will be held as noted below and resumed at 1 dose level lower.  If a 
third AE fulfilling DLT criteria occurs, treatment with birinapant will be permanently 
discontinued, but IMRRT may be continued, provided in-field radiation toxicity is not limiting. 
Patients that are retreated at a lower dose level than initially assigned will not be included in the 
assessment of DLTs for that lower dose level (with the exception of level -1 dose) but will be 
included in the analysis of secondary endpoints.  
In case of grade 4 non-hematologic toxicity or any grade 3 toxicity not returning to grade 1 
after 2 weeks of supportive care, patients will be taken off birinapant treatment and may continue 
with IMRRT only.  Patients who experience a DLT related to the combination at a specific dose 
level will have both their treatments held (both birinapant and IMRRT) for up to 2 weeks and 
supportive measures will be implemented to ameliorate the AE. Once the AE is  grade 1, 
treatment with birinapant will be resumed at 1 dose level lower. In case of concurrent elevation 
of AST/ALT > 3 times the upper limit of normal and bilirubin > 2 times the upper limit of 
normal (i.e., Hy’s law), study treatment will be permanently discontinued. 
Dose adjustments are allowed during the expansion part of the study according to the guidelines 
below, with dose levels defined as follows: 
Dose Level 
Birinapant (mg/m2) 
-1 
2.8 
1 
5.6  
2 
11 
3 
17 
4 
24 
  
7.1.3 Dose Modifications for Hematologic Toxicity 
7.1.3.1 Dose Modification Guidelines for Birinapant-related Neutropenia 
Event Name 
Neutropenia 
Grade of Event 
Management/Next Dose for Birinapant 
*UDGH 
No change in dose 
Grade 2 
+ROGXQWLO*UDGH Resume at same dose level. 
Grade 3 
First occurrence: 
Hold* birinapant XQWLOUHWXUQWR1500/mm3; restart therapy at 1 dose 
level lower. Use of cytokine growth factor (G-CSF or GM-CSF) 
supportive care may be implemented. 
Second occurrence: 
Hold* birinapant XQWLOUHWXUQWRPP3; restart therapy at 1 dose 
level lower **. Use of cytokine growth factor (G-CSF or GM-CSF) 

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supportive care may be implemented based on the judgment of the 
investigator for continued treatment. 
Third occurrence: 
The study participant will not receive additional birinapant and will 
stop further birinapant but continue on study for follow up. 
Grade 4 
First occurrence: 
Hold* birinapant XQWLOUHWXUQWRPP3; restart therapy at 1 dose 
level lower. Use of cytokine growth factor (G-CSF or GM-CSF) 
supportive care may be implemented based on the judgment of the 
investigator for continued treatment.  
Second occurrence: 
Hold* XQWLOUHWXUQWRPP3; restart therapy at 1 dose level 
lower **. Use of cytokine growth factor (G-CSF or GM-CSF) 
supportive care may be implemented.  
Third occurrence: 
The study participant will not receive additional birinapant and will 
stop further birinapant but continue on study for follow up as 
described in Section 6  
*Participants requiring a delay of consecutive days must stop birinapant 
**Participants requiring > two dose reductions must stop birinapant. 
 
7.1.3.2 Dose Modification Guidelines for Birinapant-related Thrombocytopenia 
Event Name 
Thrombocytopenia 
Grade of Event Management/Next Dose for Birinapant 
*UDGH 
No change in dose 
Grade 2 
Hold* birinapant XQWLO*UDGH Resume at same dose level. 
Grade 3 
 
First occurrence: 
Hold* ELULQDSDQWXQWLOUHWXUQWRPP3; restart therapy at 1 
dose level lower.  
Second occurrence: 
Hold* ELULQDSDQWXQWLOUHWXUQWRPP3; restart therapy at 1 
dose level lower**.  
Third occurrence: 
The study participant will not receive additional birinapant and will 
stop further birinapant but continue on study for follow up as 
described in Section 6 

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Grade 4 
 
First occurrence: 
Hold* ELULQDSDQWXQWLOUHWXUQWRPP3; restart birinapant at 1 
dose level lower**.  
Second occurrence: 
Hold* ELULQDSDQWXQWLOUHWXUQWRPP3; restart therapy at 1 
dose level lower**. 
Third occurrence: 
The study participant will not receive additional birinapant and will 
stop further birinapant but continue on study for follow up as 
described in Section 6 
*Participants requiring a delay of consecutive days must stop birinapant 
**Participants requiring > two dose reductions must stop birinapant. 
 
7.1.3.3 Dose Modification Guidelines for Birinapant - related Anemia 
Event Name 
Anemia 
Grade of Event Management/Next Dose for Birinapant 
*UDGH 
No change in dose 
Grade 2 
Hold* birinapant XQWLOUHWXUQWR+JEJG/**; transfusion is 
allowed to achieve Hgb >10 g/dL***. No change in dose 
Grade 3 
First occurrence: 
Hold birinapant until UHWXUQWR+JEJG/*; transfusion is allowed 
to achieve Hgb >10 g/dL***. Restart birinapant at 1 dose level lower.  
Second occurrence: 
Hold birinapant XQWLOUHWXUQWR+JEJG/*; transfusion is allowed 
to achieve Hgb >10 g/dL. Restart birinapant at 1 dose level lower****.  
Third occurrence: 
The study participant will not receive additional birinapant and will 
stop further birinapant but continue on study for follow up as 
described in Section 6 
Grade 4 
Transfuse and initiate appropriate supportive therapy. Continuation 
of birinapant is at the discretion of the Investigator depending on the 
attribution assigned to the anemia. 
*Participants requiring a delay of consecutive days must stop birinapant. 
**Transfusion is allowed to achieve Hgb >10 g/dL.  
*** Erythropoiesis stimulating agents are not allowed due to possible increased risk of 
inhibition of apoptosis pathway and disruption of NFNB-mediated tumor cell killing.  
****Participants requiring > two dose reductions must stop birinapant. 

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7.1.4 Dose Modification Guidelines for Birinapant-related Non-hematologic Toxicities 
 
Non-hematologic Toxicities 
Grade of Event Dose Modification 
Grade 1 
Continue at same dose level.  
Grade 2 
Hold* GRVHXQWLOUHFRYHU\WREDVHOLQHRU*UDGHZLWKVWDQGDUG
supportive therapy. Resume at current dose. For second hold for 
Grade 2, hold until recovery to grade 1 and restart at one dose level 
lower. If no recovery to grade 1 within 16 days, the study participant 
will not receive additional birinapant and will stop further birinapant 
administration but continue on study for follow up as described in 
Section 6 
Grade 3 
First occurrence: 
Discontinue further birinapant or withhold birinapant until recovery 
WREDVHOLQHRU*UDGHZLWKVWDQGDUGVXSSRUWLYHWKHUDS\Birinapant 
will be restarted at 1 dose level lower. As an exception, grade 3 non-
hematologic laboratory abnormalities without clinical symptoms that 
resolve to Grade 1 or baseline (if the study participant entered the 
study with existing toxicity) within 7 days will not lead to dose 
modification. 
Second occurrence: 
Discontinue further birinapant or withhold birinapant until recovery 
WREDVHOLQHRU*UDGHZLWKVWDQGDUGVXSSRUWLYHWKHUDS\ Therapy 
will be restarted at 1 dose level lower.  
Third occurrence: 
The study participant will not receive additional birinapant and will 
stop further birinapant but continue on study for follow up as 
described in Section 6. 
Grade 4 
The study participant will stop further birinapant but continue on 
study for follow up as described in Section 6. If a study participant 
experiences a grade 4 toxicity lasting less than 24 hours, re-initiation 
of birinapant at 1 dose level lower may be considered after recovery 
WREDVHOLQHRU*UDGHZLWKVWDQGDUGVXSSRUWLYHWKHUDS\ 
 *Participants requiring a delay of consecutive days must stop birinapant 
**Participants requiring > two dose reductions must stop birinapant. 
 

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7.1.5 Management of Expected Toxicities 
7.1.5.1 Management of Nausea 
Event Name 
Nausea 
Grade of Event Management/Next Dose for Birinapant 
*UDGH 
No change in dose 
Grade 2 
Hold birinapant until d Grade 1. Resume at same dose level. 
Grade 3 
Hold* until d Grade 1. Resume at same dose level.** 
*Participants requiring a delay of consecutive days must stop birinapant 
**Participants requiring > two dose reductions must stop birinapant. 
Recommended management: antiemetics (see Section 6). 
 
7.1.5.2 Management of Vomiting 
Event Name 
Vomiting 
Grade of Event 
Management/Next Dose for Birinapant 
*UDGH 
No change in dose 
Grade 2 
Hold* XQWLO*UDGH Resume at same dose level. 
Grade 3 
Hold* until < Grade 1. Resume at same dose level.** 
Grade 4 
The study participant will stop further birinapant but continue on 
study for follow up as described in Section 6. If a study participant 
experiences grade 4 vomiting lasting less than 24 hours, 
reinitiation of birinapant at 1 dose level lower may be considered 
DIWHUUHFRYHU\WREDVHOLQHRU*UDGHZLWKVWDQGDUGVXSSRUWLYH
therapy. 
*Participants requiring a delay of consecutive days should go off birinapant 
**Participants requiring > two dose reductions should go off birinapant. 
Recommended management: antiemetics. 
 
7.1.5.3 Management of Diarrhea 
Event Name 
Diarrhea 
Grade of Event 
Management/Next Dose for Birinapant 
*UDGH 
No change in dose 
Grade 2 
+ROGXQWLO*UDGH Resume at same dose level. 
Grade 3 
Hold* XQWLO*UDGH Resume at one dose level lower.** 

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Grade 4 
The study participant will stop further birinapant but continue on 
study for follow up as described in Section 6. If a study participant 
experiences grade 4 diarrhea lasting less than 24 hours, re-
initiation of birinapant at 1 dose level lower may be considered 
DIWHUUHFRYHU\WREDVHOLQHRU*UDGHZLWKVWDQGDUGVXSSRUWLYH
therapy. 
*Participants requiring a delay of consecutive days must stop birinapant 
**Participants requiring > two dose reductions must stop birinapant. 
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. 
7.1.5.4  Management of Cranial Nerve Palsies 
Cranial nerve palsies (most frequently Bell’s palsy) have occurred in subjects who have received 
birinapant.  The cranial nerve palsies are typically mild to moderate in severity and in those cases 
treated with corticosteroids, symptoms have either resolved or were resolving at the last follow-
up visit.  Some subjects who reported cranial nerve palsy elected to continue birinapant 
treatment, and of those that continued on treatment, none had a recurrent event.   
The onset of cranial nerve palsy may be preceded by a prodromal syndrome of headache, ear, 
facial pain and/or diplopia. Therefore, it is recommended that subjects should be given non-
steroidal anti-inflammatory agents (NSAIDs) at an appropriate anti-inflammatory dose.  If within 
24 hours symptoms do not resolve a course of steroids should be started.  In addition, sites are 
advised to delay the next dose of birinapant by 1 week. 
7.1.5.5 Management of Inflammatory Reactions 
Subjects have experienced birinapant-related inflammatory reactions of rash, fever, chills, 
hypotension, nausea, headache, and hypophosphatemia. These occurred with first drug exposure 
and resolved without sequelae. This clinical diagnosis of "cytokine release syndrome" may have 
been related to mechanism-based induction of cytokines, but there was no detectable increase in 
serum levels of a panel of cytokines, no significant cardiovascular or pulmonary compromise, 
and no recurrent risk with repeated exposures. Most of these events were reversible and all were 
asymptomatic. Although no information is available as to the amount of drug retained in the skin 
or mechanism of action of the reported skin reactions in pre-clinical studies, until more is known, 
patients should be advised to avoid prolonged periods of unprotected sun exposure. Skin 
reactions can be medically managed as clinically indicated by the type and severity of the skin 
reactions. Other events should be managed with standard medical care, such as anti-
inflammatory agents, diphenhydramine, acetaminophen, IV fluids, analgesics, and anti-emetic 
agents.  
7.2 
Radiation treatment 
In the event of febrile neutropenia or severe radiation related toxicity (grade 4), that in the 
judgement of the PI or local PI would contraindicate continuing radiation, radiation treatment 

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may be held temporarily. Similarly, medical events that require hospitalization or would interfere 
with patient setup, alignment, or delivery of radiation may also result in a temporary treatment 
break. If a patient requires a cumulative treatment break for 10 business days (2 weeks) they will 
be removed from protocol therapy. 
If IMRRT is held temporarily, birinapant will be held too and restarted with IMRRT.  
If IMRT is discontinued, birinapant will be stopped and patient will be taken off study treatment. 
8 
PHARMACEUTICAL INFORMATION 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 10.1. 
8.1 
CTEP AGENT BIRINAPANT (NSC 756502) 
Chemical Name: Propanamide, N,N'-[(6,6'-difluoro[2,2'-bi-1H-indole]-3,3'- 
diyl)bis[methylene[(2R,4S)-4- hydroxy-2,1-pyrrolidinediyl][(1S)-1- ethyl-2-oxo-2,1-
ethanediyl]]]bis[2-(methylamino)-, (2S,2'S)- 
Classification: SMAC mimetic selective IAP antagonist 
Other names: TL32711 
Molecular Formula:  C42H56F2N8O6  
Molecular Weight: 806.9 g/mol as free base 
Approximate Solubility: 6ROXELOLW\LQP0FLWUDWHEXIIHUS+LVPJP/ 
Mode of Action: Birinapant is a potent and selective small molecule peptidomimetic of SMAC 
that binds to multiple members of the IAP family. SMAC (secondary mitochondrial activator of 
caspase) is a natural IAP antagonist that rapidly antagonizes IAPs resulting in caspase activation 
and apoptosis. Members of the Inhibitors of Apoptotic Proteins (IAPs) family can block cell 
death by directly binding to and suppressing caspase activity. The activity of the IAPs is 
regulated by SMAC. 
How Supplied: IGM Biosciences supplies and CTEP, DCTD, NCI distributes birinapant in 
single-use 10 mL amber-glass vials containing sterile-filtered liquid in 50 mM citrate buffer 
solution pH 5. Each vial contains 10 mg (1 mg/mL, 10 mL) of birinapant as a clear, colorless to 
pale yellow drug solution. Excipients include citric acid monohydrate, sodium citrate dihydrate, 
sodium chloride, citric acid and sodium citrate. 
Each vial is packaged in a secondary carton to further protect the product from potential 
photodegradation on exposure to UV/visible light. 
Preparation:  Thaw birinapant at ambient temperature for approximately 2.5 hours (or at 2-8 °C 
for 16-64 hours) while protected from light. Invert the vials several times to mix.  
Aseptically remove desired dose from the vial and inject into an intravenous bag containing 
sterile 250 mL 0.9% sodium chloride injection USP. Invert several times to mix. Inspect bag for 
particulates. If particulates are present, do not use and repeat the preparation process using new 
vials. If particulates are present for a second time, report the finding to PMB. Do not use a filter.  
If preparing a large dose, remove a sufficient amount of normal saline from the IV bag 
beforehand to accommodate the birinapant volume. There is no specific final concentration range 

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required by the manufacturer. 
The manufacturer conducted compatibility studies with latex-free materials only. Only latex-free 
infusion bags, administration sets and syringes may be used to prepare birinapant doses. 
Vials are for single use only and must be discarded after preparation. 
Storage: Store birinapant in the freezer (-10 to -30° C) in the carton that is provided by the 
manufacturer. The agent is potentially light sensitive. 
If a storage temperature excursion is identified, promptly return birinapant to between -10 to -
30°C 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 studies of intact vials are ongoing. The prepared solution is stable for up to 4 
hours at -room temperature in ambient light. The dose must be administered within 4 hours after 
preparation. Only store prepared solution at room temperature. 
Route and Method of Administration: Intravenous over 30 minutes. Solution must be diluted 
prior to administration and should not be filtered at any point.  
Potential Drug Interactions: The drug-drug interaction potential of birinapant has not been 
fully assessed. In vitro studies indicate that birinapant is not a substrate for CYP450-mediated 
metabolism. Birinapant is not an inhibitor of CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 
and 4A11, but some moderate, partially-reversible, time-dependent inhibition of CYP3A4/5 is 
observed. Overall results indicate that birinapant has a low potential for CYP-mediated drug 
interactions.   
Birinapant is not a P-gp substrate; however, P-JSLQKLELWLRQZDVREVHUYHGDWȝ0LQYLWUR)RU
UHIHUHQFHWKHDYHUDJH&PD[REVHUYHGZDVDSSUR[LPDWHO\ȝ0IROORZLQJDGRVHRIPJP
Birinapant is likely a substrate of the OATP1B3 transporter, which may be involved in the 
biliary excretion of birinapant. Birinapant moderately binds to plasma proteins. The excretion of 
the drug is mainly biliary per PK studies in animals.  In humans, a phase I trial (12), has shown 
that the renal excretion of the drug is low. 
Population PK analysis showed that the central volume of distribution increased with body 
surface area (BSA) and a reduction in the central volume of distribution of approximately 60% 
was observed when birinapant was administered in combination with carboplatin/paclitaxel 
relative to birinapant alone and other combination therapies studied. Also, a reduction in 
clearance of birinapant of 65% was observed with the combination of birinapant and 
carboplatin/paclitaxel.  
At present, based on the available clinical data, it is judged that no change of birinapant dosing is 
indicated for the combination with carboplatin/paclitaxel, however awareness of the above PK 
observations in patient studies using this combination is important. 
Patient Care Implications: The pharmaceutical collaborator reports that birinapant synergizes 
ZLWK71)ĮLQYLWUR3DWLHQWVZLWKDVHULRXVDFWLYHLQIHFWLRQZLWKLQZHHNVRIGRVLQJRUZKR
have ongoing autoimmune disease or a recent history (within last 5 years) of autoimmune disease 
should not receive birinapant. Patients receiving anti-TNF therapies should not receive 
birinapant. 

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Birinapant should not be administered to women study participants who are pregnant or nursing. 
Women and men of child-bearing potential must agree to use adequate contraception (hormonal 
or barrier method of birth control; abstinence) prior to study entry and for the duration of study 
participation. The effect of birinapant on male fertility is unknown; however, a 14 week animal 
study indicated that it caused testicular atrophy/degeneration with effects on spermatogenesis 
noted microscopically and reduced sperm count. Due to a long half-life in tissue, male study 
participants should use an additional barrier method of contraception for 30 days following the 
last dose of birinapant. 
8.1.1 Availability 
Birinapant is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 
Birinapant is provided to the NCI under a Collaborative Agreement between the Pharmaceutical 
Collaborator and the DCTD, NCI (see Section 13.3). 
8.1.2 Agent Ordering and Agent Accountability 
8.1.2.1 NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution. The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents. The 
eligible participating investigators at each participating institution must be registered 
with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form 
(FDF). 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 
participating investigator at that institution.  
8.1.2.2 Birinapant clinical supplies may be ordered when a patient is in screening.  
8.1.2.3 Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application. Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account and the maintenance of an “active” account status, a 
“current” password, and active person registration status. For questions about drug 
orders, transfers, returns, or accountability, call or email PMB any time. Refer to the 
PMB’s website for specific policies and guidelines related to agent management.  
8.1.2.4 Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page. Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this protocol. 
8.1.3 Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and 
research staff through the PMB OAOP application. Access to OAOP requires the 
establishment of a CTEP IAM account and the maintenance of an “active” account status 
and a “current” password. Questions about IB access may be directed to the PMB IB 
Coordinator via email. 

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8.1.4 Useful Links and Contacts 
x CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ 
x NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov 
x PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
x PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP/ 
x CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
x CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov  
x IB Coordinator: IBCoordinator@mail.nih.gov  
x PMB email: PMBAfterHours@mail.nih.gov 
x PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
9 
STATISTICAL CONSIDERATIONS 
9.1 
Study Design/Endpoints 
The primary objective is to determine the toxicities and MTD of birinapant administered 
concurrently with IMRRT. 
The secondary objectives are to determine the response rate, local-regional control, PFS and OS; 
to determine if FADD and/or BIRC2/3 copy gain in tumor tissue are associated with improved 
response, locoregional control, progression-free survival and overall survival; and to determine 
the feasibility of detecting effects of birinapant and re-irradiation on pilot pharmacodynamic 
markers in tumor tissue, including microwestern for decrease in drug targets IAP1/2; increase in 
apoptosis/necroptosis markers Caspase 3 and MLKL. 
9.2 
Sample Size/ Accrual Rate 
This trial will initially consist of a 4 dose levels 3+3 escalation phase; with up to 6 patients per 
dose level, up to 24 patients may be required to determine the MTD. Then, at the MTD, an 
additional 10 patients will be treated in order to determine more precise estimates of safety and 
toxicity of patients as well as to address secondary objectives. If there are 16 patients at the MTD 
including the expansion cohort, then there would be approximately 80% power to detect an 
effect size of 2.0 for a given test comparing two groups or comparing pre-treatment values to on-
treatment values with a 1.0 effect size, with a 0.01 two-tailed significance test. This would be 
sufficient to allow for up to 6 tests to be performed while holding the overall significance level to 
0.05, taking into consideration enough patients to allow for a Bonferroni correction. In practice, 
given the exploratory nature of the marker and related analyses, the results may be presented 
without any such formal correction, but in the context of the number of such tests performed. As 
an illustration, if IAP1, CASP3, and MLKL were each obtained pre-treatment and at day 4 on 
treatment, with 16 total patients at the MTD, there would be adequate patients so that the 

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differences could each be tested with at least 80% power with an effect size equal to 1.0 times 
the standard deviation of the difference, with a 0.01 two-tailed significance test. In addition, 
although with less power depending on the fraction of patients who respond, comparisons could 
be made of the changes in these parameters between patients who respond or do not respond.  
If all dose levels are evaluated and 10 additional patients are included at the MTD, we anticipate 
enrolling a minimum of 16 patients and a maximum of 34 patients. It is anticipated that 1-2 
patients/month may be enrolled onto this trial.  
Primary endpoints will be the DLTs and other toxicities, and the MTD for the regimen.  
For DLT and MTD determination, escalation will proceed with the 3+3 dose escalation design 
until either the stopping rule below or the MTD is reached.  
 
The DLT evaluation period between dose levels will be 42 days during drug/radiation treatment 
plus 14 (+/- 3) days of follow-up thereafter.  Patients are considered evaluable for toxicity if they 
have received at least 1 dose of birinapant. Patients that are not evaluable will be replaced. A 
standard “3+3” design, described in the table below, will be followed. 
 
No. of patients with DLT's at 
this dose level 
No. of patients treated at this 
dose level 
Action 
Dose escalation rules 
 0 
3 
Treat 3 patients at the next 
higher dose level (or add 3 
patients if at the highest 
level). 
 1 
3 
Treat 3 additional patients at 
this dose level. 
 1 
6 
Treat 3 patients at the next 
higher dose level (or if at the 
highest level, declare the dose 
at this level to be the MTD). 
>1 
3 or 6 
Stop dose escalation; begin 
dose de-escalation. De-
escalate one dose level. 

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PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
0 
2 
0 
0 
2 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
1 
3 
0 
2 
6 
White 
5 
19 
0 
1 
25 
More Than One Race 
0 
1 
0 
0 
1 
Total 
6 
25 
0 
3 
34 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015)  
OMB No. 0925-0001/0002 
9.3 
Stratification Factors 
There will be no stratification in this study.  
Analysis of primary endpoints 
The toxicity and MTD will be evaluated by reporting the DLTs obtained at each dose level, and 
reporting toxicities noted in tabular form. 
9.4 
Analysis of Secondary Endpoints 
1. Overall Response is the best response by RECIST 1.1 criteria recorded from the start of the 
treatment until response assessment by PET-CT at 3 months post treatment as below. Estimates 
of response rates, local control, PFS and OS will be determined at the MTD level, including the 
expansion cohort. Each of these will be presented along with a 95% two-sided confidence 
interval appropriate to the outcome measure. For example, the PFS and OS will have confidence 
intervals presented for the median times. 
2. FADD/ BIRC2 Copy Number Variation will be evaluated as a secondary endpoint to estimate 
if recurrent HNSCC are enriched for these alterations associated with worse prognosis and 
associated with response to birinapant and IMRRT. A bioinformatics analysis algorithm has been 
established for determination of copy number variation and somatic mutation calling, by 
comparison and validation with DNA from matched blood (13). Archived tumor samples will be 
subjected to exome sequencing to estimate copy number variations, from all evaluable patients. 

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Results will be classified according to whether they have a FADD and/or BIRC2 copy gain 
(more than 2 copies) or not (13), and this classification will be compared between patients who 
respond or do not respond, in a descriptive fashion. A Fisher’s exact test will be used to provide 
a p-value to help interpret the potential importance of any association, but in the context of a 
limited size evaluation. The association between results according to whether or not they have a 
copy gain will be presented for OS and PFS, by comparing Kaplan-Meier curves with a two-
tailed log-rank test. In addition, as exploratory analyses, the association between FADD copy 
gain and BIRC2 copy gain will individually be evaluated for any association with response.  
The feasibility of detecting effects of birinapant and re-irradiation on pilot pharmacodynamic 
markers in fresh frozen tumor biopsies, including micro-western for decrease in drug targets 
IAP1/2; increase in apoptosis/necroptosis markers Caspase 3 and MLKLI will be evaluated. If 
IAP1/2, CASP3, and MLKL were each obtained pre-treatment and at day 4 on treatment, with 16 
total patients at the MTD, there would be adequate patients so that the differences could each be 
tested using a paired t-test (or a Wilcoxon signed rank test if the differences are not normally 
distributed) with at least 80% power with an effect size equal to 1.0 times the standard deviation 
of the difference, with a 0.01 two-tailed significance test. In addition, although with less power 
depending on the fraction of patients who respond, comparisons could be made of the changes in 
these parameters between patients who respond or do not respond.  
9.5 
Analysis of exploratory objectives: 
To determine if mutational load detected with whole exome- sequencing influences response, 
differences in patterns noted can be compared descriptively between responders and non-
responders. 
To determine if PD-L1, CD8 T-cell tumor infiltration, TNFĮ, and other immune related 
biomarkers are associated with response, changes in these parameters from baseline can be 
compared between responders and non-responders using a Wilcoxon rank sum test. Any tests 
performed will be done without adjustment for multiple comparisons but in the context of the 
number of tests performed. 
To determine pharmacokinetic of birinapant, bioanalytical measurements will be conducted on 
an ultra HPLC-MSMS system using a validated assay by the Clinical Pharmacology Program 
(CPP) at the NCI. These data will be used to monitor birinapant plasma concentrations in order 
to assess any PK changes with radiation, as well as to correlate with pharmacodynamic 
endpoints, clinical response, and toxicity. 
10 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 10.1) and the characteristics of an observed AE (Sections 10.2 and 
10.3) will determine whether the event requires expedited reporting via the CTEP Adverse Event 
Reporting System (CTEP-AERS) in addition to routine reporting. 
10.1 Comprehensive Adverse Events and Potential Risks Lists (CAEPR) for 
Birinapant (TL32711, NSC 756502) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 

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presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf  for 
further clarification. The CAEPR does not provide frequency data; refer to the Investigator's 
Brochure for this information. Below is the CAEPR for Birinapant. 
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. 
 
Version 1.2, June 26, 2018(23) 
Adverse Events with Possible Relationship to Birinapant 
(CTCAE 5.0 Term) 
 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
  
Febrile neutropenia 
  
GASTROINTESTINAL DISORDERS 
  
Diarrhea 
  
Nausea 
  
Vomiting 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
  
Fatigue 
 Fatigue (Gr 2) 
Fever 
  
IMMUNE SYSTEM DISORDERS 
  
Cytokine release syndrome 
  
INVESTIGATIONS 
  
Lymphocyte count decreased 
 Lymphocyte count decreased (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
  
NERVOUS SYSTEM DISORDERS 
  
Facial nerve disorder(24)  
  
Headache 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  

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Adverse Events with Possible Relationship to Birinapant 
(CTCAE 5.0 Term) 
 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Rash maculo-papular 
  
VASCULAR DISORDERS 
  
Hypotension 
  
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. 
2Facial nerve disorder may manifest itself as Bell’s palsy possibly secondary to cytokine release syndrome. 
Adverse events reported on birinapant trials, but for which there is insufficient evidence to suggest that 
there was a reasonable possibility that birinapant caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia) 
CARDIAC DISORDERS - Restrictive cardiomyopathy 
EYE DISORDERS - Eye disorders - Other (diplopia) 
GASTROINTESTINAL DISORDERS - Abdominal pain; Constipation; Dyspepsia; Typhlitis 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (V. zoster infection); Lung 
infection; Sepsis; Skin infection 
INVESTIGATIONS - Alanine aminotransferase increased; Aspartate aminotransferase increased; Lipase 
increased; Platelet count decreased; Serum amylase increased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Myalgia 
RENAL AND URINARY DISORDERS - Acute kidney injury 
Note: Birinapant 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. 
10.2 Adverse Event Characteristics  
x CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
x 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 (10.1_CAEPR_for_Birinapant) 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 10.3.3. 

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x 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. 
10.3 Expedited Adverse Event Reporting 
10.3.1 Rave-CTEP-AERS Integration 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) integration enables evaluation of post-baseline AEs entered in Rave to determine 
whether they require expedited reporting and facilitates entry in CTEP-AERS for those 
AEs requiring expedited reporting.    
All AEs that occur after baseline are collected in Medidata Rave using the Adverse Event 
form, which is available for entry at each treatment or reporting period and is used to 
collect AEs that start during the period or persist from the previous reporting period.  
CRA will enter AEs that occur prior to the start of treatment on a baseline form that is not 
included in the Rave-CTEP-AERS integration.  AEs that occur prior to enrollment must 
begin and end on the baseline Adverse Event form and should not be included on the 
standard Adverse Events form that is available at treatment unless there has been an 
increase in grade. 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
x The reporting period (course/cycle) is correct, and 
x AEs are recorded and complete (no missing fields) and the form is query-free.  
The CRA reports AEs in Rave at the time the Investigator learns of the event.  If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form.  Both NCI and 
protocol-specific reporting rules evaluate the AEs submitted for expedited reporting.  A 
report is initiated in CTEP-AERS using information entered in Medidata Rave for AEs 
that meet reporting requirements.  The CRA completes the report by accessing CTEP-
AERS via a direct link on the Medidata Rave Expedited Reporting Evaluation form. 
In the rare occurrence that 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 that was phoned in must be entered immediately into CTEP-AERS 
using the direct link from Medidata Rave. 
Additional information about the CTEP-AERS integration is available on the CTSU 
website: 

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x Study specific documents:  Protocols > Documents > Education and Promotion, 
and   
x Expedited Safety Reporting Rules Evaluation user guide:  Resources > CTSU 
Operations Information > User Guides & Help Topics. 
NCI requirements for SAE reporting are available on the CTEP website:  
x NCI Guidelines for Investigators:  Adverse Event Reporting Requirements is 
available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguid
elines.pdf. 
 
10.3.2 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.  
10.3.3 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 as long as the death occurred within 30 days after the last administration of the 
investigational agent. A death on study more than 30 days after last treatment requires 
both routine and expedited reporting, only if attribution to study intervention is possible, 
probably or definite. Attribution to treatment or other cause must be provided. 
Death due to progressive disease should be reported as Grade 5 “Neoplasms benign, malignant 
and unspecified (incl cysts and polyps) - Other (Progressive Disease)” under the system 
organ class (SOC) of the same name. Evidence that the death was a manifestation of underlying 
disease (e.g., radiological changes suggesting tumor growth or progression: clinical deterioration 
associated with a disease process) should be submitted.  
Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:  
1) 
Death 
2) 
A life-threatening adverse event  
3) 
$QDGYHUVHHYHQWWKDWUHVXOWVLQLQSDWLHQW KRVSLWDOL]DWLRQ RUSURORQJDWLRQRIH[LVWLQJKRVSLWDOL]DWLRQ IRUKRXUV 
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 

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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  
KUV 
10 Calendar Days 
24-Hour 5 Calendar Days 
Not resulting in 
Hospitalization  
KUV 
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, with the exception of expected long-term radiation effects, 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: 
x 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
x 
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 
 
10.3.4 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
No exclusions. 
10.4 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 

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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. 
10.5 Pregnancy 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS. In addition, the Pregnancy Information Form included within 
the NCI Guidelines for Adverse Event Reporting Requirements must be completed and 
submitted to CTEP. Any pregnancy occurring in a patient or patient’s partner from the time of 
consent to 90 days after the last dose of study drug must be reported and then followed for 
outcome. Newborn infants should be followed until 30 days old. Please see the “NCI Guidelines 
for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP 
INDs and IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) for more 
details on how to report pregnancy and its outcome to CTEP.  
10.6 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:  
x Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
x Myelodysplastic syndrome (MDS)  
x Treatment-related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
10.7 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. 
 

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11 STUDY CALENDAR 
A time window of -2 days on treatment days and +/- 2 days on non-treatment days will be permitted for weekly physical exam, 
performance status, routine vital signs, weight and routine labs.  Cycle days will be numbered relative to treatment.   
Procedure/ 
Assessment 
Screening 
 

weeks of 
first 
treatment 
Baseline C1D1  
Wk1 
C1D2  
Wk1 
C1D4 
Wk1 
C1D8  
Wk2 
C1D9  
Wk2 
C1D15 
Wk3 
C2D1  
Wk4 
C2D2  
Wk4 
C2D8  
Wk5 
C2D9  
Wk5 
C2D15  
Wk6 
14 Day 
Post tx 
Safety 
Visit j, l  
 
28 Day 
Post tx 
Safety 
Visit j, l  
 
Long 
term 
Follow  
Up k, l 
Informed consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Birinapanta 
 
 
 
Xc 
 
 
X 
 
 
X 
 
X 
 
 
 
 
Re-IMRTb 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
 
X 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
Xp 
Physical examq 
X 
 
X 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
Vital signs  
X 
 
X 
X d 
 
X 
X d 
X 
X 
X d 
X 
X d 
X 
X 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
 
Performance status 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
 
CBC/diff, platelets 
X 
 
X 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
Serum chemistrye  
X 
 
X 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
PT/PTT/INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECGn 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
 
Adverse events  
 
 
X 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
Xo 
Tumor biopsy f, r 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 

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Procedure/ 
Assessment 
Screening 
 

weeks of 
first 
treatment 
Baseline C1D1  
Wk1 
C1D2  
Wk1 
C1D4 
Wk1 
C1D8  
Wk2 
C1D9  
Wk2 
C1D15 
Wk3 
C2D1  
Wk4 
C2D2  
Wk4 
C2D8  
Wk5 
C2D9  
Wk5 
C2D15  
Wk6 
14 Day 
Post tx 
Safety 
Visit j, l  
 
28 Day 
Post tx 
Safety 
Visit j, l  
 
Long 
term 
Follow  
Up k, l 
Blood (for control 
DNA) r 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine HCG g 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Tumor 
measurements h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Blood for 
Pharmacokinetics  
 
 
 
Xi 
Xm 
 
Xi 
 
 
Xi 
 
Xi 
 
 
 
 
Blood for 
Pharmacogenomics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone call or e-mail 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Dental Evaluation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a:  Birinapant on days 2 and 9 of every cycle. If a patient misses a dose on each of those days, the infusion can be given up to 2 days later, but the C1D4 biopsy will not be 
performed.  
b:  Standard re-IMRT 2GY/day/5 days a week/ M-F for 6 weeks to 60-66Gy. 
c:  Patients will be observed for 30-60 minutes post the first and second infusion of birinapant for adverse events. 
d:  Vital signs will be collected prior to and after every birinapant infusion. 
e:  Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT 
[ALT], sodium, magnesium, uric acid, amylase, lipase. 
f:  All attempts will be made to obtained optional tumor biopsies within 28 days before treatment and on C1D4 for biomarkers studies. A blood sample for control DNA will be 
drawn and sent together with the pre-treatment tumor biopsy.  
g:  Women of childbearing potential only. 
h:  Tumor measurements within 6 weeks pre-treatment (PET/CT and CT or MRI neck/chest/upper abdomen with contrast), at 3 (+/- 2 weeks, PET/CT and CT or MRI with 
contrast), 6 (+/- 4 weeks, CT or MRI with contrast), 9 (+/- 4 weeks, CT or MRI with contrast), 12 (+/- 4 weeks, CT or MRI with contrast), 18 (+/- 4 weeks, CT or MRI with 
contrast), 24 (+/- 4 weeks, CT or MRI with contrast) months post-radiation treatment. Evaluations will be stopped after confirmation of disease progression. MRI neck with 
gadolinium and PET/CT can substitute CT with contrast if patient has contrast allergy. 
i:  Pharmacokinetics samples will be drawn within 60 minutes prior to start of infusion and within 60 minutes after end of infusion of the birinapant. Dates and exact times of start 
and stop of the infusions and sample collection dates and times will be noted in the PK sheet 
j:  Patients will be invited for safety follow up visits approximately 14 (+/- 3) days and 28 (+/-7) days after completion of treatment. Patients removed from treatment for 
unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event.  

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k:  Patients will be clinically evaluated at 3 (+/- 2 weeks), 6 (+/- 4 weeks), 9 (+/- 4 weeks), 12 (+/- 4 weeks), 18 (+/- 4 weeks) and 24 (+/- 4 weeks) months after completion of 
treatment. These visits will be stopped after confirmation of disease progression. After completion of visits, participants will be followed by phone or email every 6 months for 
survival for up to 2 years. 
l:  If patients are unable or unwilling to come to these visits, they will be contacted by phone or e-mail for survival. After progression, participants will be followed every six 
months for survival. 
m:  On C1D4 a PK sample will be collected within +/- 4h of the biopsy. Dates and exact times of start and stop of the infusions and sample collection dates and times will be noted 
in the PK sheet. 
n:   An ECG will be performed within 2 hours of the start of infusion and within 2 hours after infusion completion and QTcF will be evaluated by the PI or clinician AI. 
o:   New AEs will be captured through the first 3-month follow-up visit, with the exception of SAEs considered possibly, probably or definitely related to study agents, which will 
continue to be reported per section 10.3.3.   
p:  Concurrent medications will be captured up through the first 3-month follow up visit. 
q:   Physical exam and clinic evaluation should occur 1-5 working days prior to birinapant infusion. 
r:   Research specimens should be collected only after subject has signed consent and all eligibility criteria have been met.

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12 MEASUREMENT OF EFFECT 
Although the clinical benefit of birinapant has not yet been established, the intent of offering this 
treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully 
monitored for tumor response and symptom relief in addition to safety and tolerability. Patients 
with measurable disease will be assessed by standard criteria. For the purposes of this study, 
patients should be re-evaluated at 3, 6, 9, 12 and 24 months after completion of the protocol 
treatment.  
12.1 Antitumor Effect – Solid Tumors 
Patients will be evaluated at baseline and at 3, 6, 9, 12 and 24 months after completion of the 
protocol treatment.  The details of timing and imaging types are specified in Study Calendar in 
Section 11. 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 
1.1)(25). Changes in the largest diameter (unidimensional measurement) of the tumor lesions and 
the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. 
12.1.1 Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment with birinapant. 
Evaluable for objective response. Only those patients who have measurable disease present 
at baseline, have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for response. These patients will have their response 
classified according to the definitions stated below. (Note: Patients who exhibit objective 
disease progression prior to the end of cycle 1 will also be considered evaluable.) 
Evaluable Non-Target Disease Response. Patients who have lesions present at baseline that 
are evaluable but do not meet the definitions of measurable disease, have received at least 
one cycle of therapy, and have had their disease re-evaluated will be considered evaluable 
for non-target disease. The response assessment is based on the presence, absence, or 
unequivocal progression of the lesions.  
12.1.2 Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be accurately 
PHDVXUHGLQDWOHDVWRQHGLPHQVLRQORQJHVWGLDPHWHUWREHUHFRUGHGDVPPFPby 
chest x-UD\RUDVPP FP with CT scan, MRI, or calipers by clinical exam. All 
tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the protocol. 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph 
QRGHPXVWEHPP FP in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm [0.5 cm]). At baseline and in follow-up, 
only the short axis will be measured and followed. 

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Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm [<1 cm] RUSDWKRORJLFDOO\PSKQRGHVZLWKWRPP >WR
<1.5 cm] short axis), are considered non-measurable disease. Bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory 
breast disease, and abdominal masses (not followed by CT or MRI), are considered as non-
measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline. Target lesions should be selected on the basis of their 
size (lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements. It 
may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters. If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
12.1.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g.VNLQQRGXOHVDQGSDOSDEOHO\PSKQRGHVDQGPP FP diameter as 
assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
Conventional CT: This guideline has defined measurability of lesions on CT scan based on 
the assumption that CT slice thickness is 5 mm (0.5 cm) or less. If CT scans have slice 

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thickness greater than 5 mm (0.5 cm), the minimum size for a measurable lesion should be 
twice the slice thickness.  
Conventional MRI: MRI may be substituted for contrast enhanced CT for some sites, but 
not lung. The minimum size for measurability is the same as for CT (10 mm), as long as the 
scans are performed with slice thickness of 5mm and no gap. In the event the MRI is 
performed with thicker slices, the size of a measurable lesion at baseline should be two 
times the slice thickness. In the event there are inter-slice gaps, this also needs to be 
considered in determining the size of measurable lesions at baseline. 
As with CT, if an MRI is performed, the technical specifications of the scanning sequences 
used should be optimized for the evaluation of the type and site of disease.  Furthermore, as 
with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence.  Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as closely as 
possible to prior scans.  Body scans should be performed with breath-hold scanning 
techniques, if possible. 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-
CT is not always of optimal diagnostic CT quality for use with RECIST measurements. 
However, if the site can document that the CT performed as part of a PET-CT is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the 
PET-CT can be used for RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time. Note, however, that the 
PET portion of the CT introduces additional data which may bias an investigator if it is not 
routinely or serially performed.  
FDG-PET While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 

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greater than twice that of the surrounding tissue on the attenuation corrected image. 
12.1.4 Response Criteria 
12.1.5 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm (<1 
cm). 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm (0.5 cm). (Note: the appearance 
of one or more new lesions is also considered progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
12.1.6  Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (<10 mm [<1 cm] 
short axis). 
Note: If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of overall disease status change, not 
a single lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Principal Investigator). 
12.1.6.1.1  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. 
 

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For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once 4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** Only for non-randomized trials with response as primary endpoint. 
*** In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 

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For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
12.1.7 Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
12.1.8 Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
12.1.9 Response Review 
Radiographic response evaluation will be conducted by the Department of Radiology at the NIH.  
13 STUDY OVERSIGHT AND DATA REPORTING / REGULATORY REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 10 
(Adverse Events: List and Reporting Requirements). 
13.1 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(s). The Protocol Principal Investigator and statistician have 
access to the data at all times through the CTMS web-based reporting portal.  
All decisions regarding dose escalation/expansion/de-escalation require sign-off by the Protocol 

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Principal Investigator through the CTMS/IWRS. In addition, for the dose escalation part of the 
study the Protocol Principal Investigator will have at least monthly, or more frequently, conference 
calls with the Study Investigators and the CTEP Medical Officer(s) to review accrual, progress, and 
adverse events and unanticipated problems.  
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. 
This protocol is monitored at several levels, as described elsewhere in this section. The Protocol 
Principal Investigator is responsible for monitoring the conduct and progress of the clinical trial, 
including the ongoing review of accrual, patient-specific clinical and laboratory data, and routine 
and serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s). The Protocol Principal Investigator and 
statistician have access to the data at all times. 
13.2 Data Reporting 
Data collection for this study will be done exclusively through Medidata Rave. Access to the trial in 
Rave is controlled through the CTEP-IAM system and role assignments.   
Requirements to access Rave via iMedidata: 
 
x 
A valid account, and  
x 
Assigned a Rave role on the LPO or PO roster at the enrolling site of:  Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.   
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role, must have a minimum of an Associate 
Plus (AP) registration type, 
o Rave Investigator role, must be registered as an Non-Physician Investigator 
(NPIVR) or Investigator (IVR), and 
o Rave Read Only role, site staff must have at a minimum an Associates (A) 
registration type. 
x 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
 
If the study has a DTL, individuals requiring write access to Rave must also be assigned the 
appropriate Rave tasks on the DTL. 
 
Upon initial site registration approval for the study in Regulatory Support System (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 staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password, and click 
on the accept link in the upper right-corner of the iMedidata page.  Site staff 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 

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by clicking on the link in the upper right pane of the iMedidata screen.  If an eLearning is required 
and has not yet been taken, the link to the eLearning will appear under the study name in iMedidata 
instead of the Rave EDC link; once the successful completion of the eLearning has been recorded, 
access to the study in Rave will be granted, and a Rave EDC link will display under the study name.  
 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will receive a separate invitation from iMedidata to 
activate their account.  Account activation instructions are located on the CTSU website in the Data 
Management section under the Rave resource materials (Medidata Account Activation and Study 
Invitation Acceptance).  Additional information on iMedidata/Rave is available on the CTSU 
members’ website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.   
 
13.2.1 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 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. 
13.2.2 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. 
CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository 

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(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. 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by the 
CTMS contractor, Theradex. CDUS submissions are performed by Theradex on a monthly basis. 
The trial’s lead institution is responsible for timely submission to CTMS via Rave, as above. 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm ). 
13.3 Collaborative Agreements Language 
The agent birinapant 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. 

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3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will 
be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human 
subjects, including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, 
who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, 
or PI for other studies) of Collaborator's wish to contact them. 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-Cooperative 
Group studies for immediate delivery to Collaborator(s) for advisory review and comment prior 
to submission for publication. Collaborator(s) will have 30 days from the date of receipt for 
review. Collaborator shall have the right to request that publication be delayed for up to an 
additional 30 days in order to ensure that Collaborator’s confidential and proprietary data, in 
addition to Collaborator(s)’s intellectual property rights, are protected. Copies of abstracts must 
be provided to CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible 
and preferably at least three (3) days prior to submission, but in any case, prior to presentation 
at the meeting or publication in the proceedings. Press releases and other media presentations 
must also be forwarded to CTEP prior to release. Copies of any manuscript, abstract and/or 
press release/ media presentation should be sent to: 
Email: ncicteppubs@mail.nih.gov  
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
13.4 Genomic Data Sharing Plan 
The investigators and statistician and/or bioinformaticians for a study will have access to all data on 
mutations and variants stored in the Theradex Data Base and the GDC. This information will be 
sequestered from access throughout the study until it is analyzed for purposes of reporting and 
publishing of the study results. As specified in the CRADA for the agents used in the clinical study, 
the pharmaceutical collaborator will have at least 6 months, longer if needed for a regulatory filing, 
to review the data and or receive copies of the data once the study is completed and analyzed, or 
sooner, if specified for purposes of generating Intellectual Property. Once these timeframes have 
been exceeded, the data will be available through a Data Access Committee (DAC) in the GDC 
following NCI and Collaborator review of the proposals.  
13.4.1 Incidental/Secondary Findings Disclosure Procedure 
Given the potential clinical implications conferred by detecting a germline and/or somatic mutation 
in one of the proven cancer susceptibility genes, this protocol will use the following disclosure 

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procedure, consistent with the recommendations of the American College of Medical and Genomics 
(ACMG) (26), (27):  
The NCI Molecular Characterization Laboratory will review the mutations/variants once at the time 
of initial specimen evaluation according to the most recent version of the ACMG guidance on 
variants. The NCI Molecular Characterization Laboratory will not re-review all specimens received 
if a new version of the ACMG guidance is published after the initial review. 
For each participant with a pathogenic or likely pathogenic germline and/or somatic variant 
detected in the WES of blood (as defined in the ACMG guidance), the NCI Molecular 
Characterization Laboratory will report to the Program Director or Scientific Officer the UPID and 
variant(s) identified. The Program Director or Scientific Officer will contact Theradex to obtain the 
name of the protocol, investigator treating the patient, and the Principal Investigator of the grant. 
The treating physician will be contacted by phone and in writing to ask the patient whether he or 
she is interested in learning more about the finding. 
If the patient wants to know more, the physician should contact the Program Director for more 
information about the mutation/variant. The treating physician and a medical genetics counselor 
should meet with the patient to discuss the importance and meaning of the finding, but not the 
finding itself, and notify the patient that this research finding must be confirmed by Sanger 
sequencing at the patient’s/patient insurer’s expense in a Clinical Laboratory Improvement 
Amendments (CLIA)-approved laboratory. The treating physician and genetic counselor should 
inform the patient of the confirmed result and its meaning and significance to the patient. If desired, 
the patient may elect to undergo genetic counseling and confirmatory CLIA-approved clinical 
testing on his or her own. Neither the research laboratory nor the National Cancer Institute will be 
responsible for the costs incurred for any confirmatory genetic testing or counseling 
 
 
 

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Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, et al. ACMG 
recommendations for reporting of incidental findings in clinical exome and genome sequencing. 
Genet Med. 2013;15(7):565-74. 
27. 
Kalia SS, Adelman K, Bale SJ, Chung WK, Eng C, Evans JP, et al. Recommendations 

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for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG 
SF v2.0): a policy statement of the American College of Medical Genetics and Genomics (vol 19, 
pg 249, 2016). Genet Med. 2017;19(4):484-5. 
 
 
 

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15 APPENDICES 
15.1 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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15.2 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, birinapant.  This clinical trial is sponsored by the National Cancer Institute.  This form 
is addressed to the patient but includes important information for others who care for this patient.  
These are the things that you as a healthcare provider need to know: 
Birinapant interacts with certain specific enzymes in your liver.  
x The enzymes in question are CYP3A4 and 3A5. Birinapant may moderately inhibit these 
enzymes and affect other drugs that are broken down by them.   
x The transport proteins in question are P-glycoprotein (P-gp) and OATP1B3. Birinapant can 
inhibit P-glycoprotein which may affect how other drugs are transported in and out of cells. 
Birinapant is a substrate of OATP1B3 and its clearance from the body may be affected by 
other drugs that inhibit OATP1B3.  
To the patient: Take this paper with you to your medical appointments and keep the attached 
information card in your wallet.   
Birinapant may interact with other drugs which can cause side effects. For this reason, it is very 
important to tell your study doctors of any medicines you are taking before you enroll onto this 
clinical trial.  It is also very important to tell your doctors if you stop taking any regular medicines, 
or if you start taking a new medicine while you take part in this study.  When you talk about your 
current medications with your doctors, include medicine you buy without a prescription (over-the-
counter remedy), or any herbal supplements such as St. John’s Wort.  It is helpful to bring your 
medication bottles or an updated medication list with you. 
Many health care providers can write prescriptions.  You must tell all of your health care providers 
(doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a clinical trial.  
These are the things that you and they need to know:  
Birinapant must be used very carefully with other medicines that use certain liver enzymes or 
transport proteins to be effective or to be cleared from your system.  Before you enroll onto the 
clinical trial, your study doctor will work with your regular health care providers to review any 
medicines and herbal supplements that are considered strong inhibitors of OATP1B3 or sensitive 
substrates of CYP3A4/5 or P-gp. 
x 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.  
x 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.   
  
 
 

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STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the experimental study drug 
birinapant.  This clinical trial is sponsored by the NCI.  Birinapant 
may interact with drugs that are processed by your liver or use certain 
transport proteins in your body.  Because of this, it is very important 
to: 
¾ Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
¾ Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) that you are taking part in a 
clinical trial. 
¾ Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
 
 
 
Birinapant interacts with a specific liver enzyme called CYP3A4/5 
and transport proteins called P-gp and OATP1B3, and must be used 
very carefully with other medicines that interact with CYP3A4/5, P-
gp and OATP1B3. 
¾ Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines and herbal supplements that are considered “strong 
inhibitors of OATP1B3 or sensitive substrates of CYP3A4/5 or P-
gp.”  
¾ 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.   
¾ Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  

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15.3 Appendix C: Tissue Biopsy Verification 
A copy of the diagnostic pathology report must be shipped with all tissue specimens sent to the 
EET Biobank. 
If the corresponding pathology report is not available for the biopsy, then a copy of the radiology 
report or operative report from the biopsy procedure and the diagnostic pathology report must be 
sent to the EET Biobank. A completed copy of this Appendix (i.e., Tissue Biopsy Verification) must 
also be submitted to the EET Biobank. 
Note: If this information is not provided with the biopsy specimen, then it will not be accepted by the 
EET Biobank. 
 
Please have the Clinician* responsible for signing out this patient’s case complete the following: 
ETCTN Universal Patient ID:  
 
 
ETCTN Patient Study ID:   
 
 
Date of Procedure (mm/dd/yyyy):   
 
 
Tissue Type (circle one): 
Locoregionally recurrent site 
Distant Metastatic Site 
Time point (circle one):         Ba se line                
 
 C1D4 
 
 
 
Site Tissue Taken From:   
 
 
Diagnosis:   
 
 
I agree that this tissue may be released for research purposes only and that the release of this tissue will not 
have any impact on the patient’s care. 
 
 
Clinician Signature 
Date 
 
 
Clinician Printed Name 
 
*Note: For the purposes of this form, Clinician could include the Nurse Practitioner, Registered Nurse, Pathologist, 
Radiologist, Interventional Radiologist, Surgeon, Oncologist, Internist, or other medical professional responsible for the 
patient’s care.  
Version: 1 
Effective Date: 9/2019