HBO Effects on Blood Count Recovery and Post-transplant Outcomes Following High-dose Therapy and Autologous HSPC Transplantation for Multiple Myeloma
Phase: PHASE2
Conditions: Myeloma
Sponsor: Omar Aljitawi

 
Protocol Title: 2017-Phase II HBO in MM             Page 1 of 47 
Version Date: 20Apr2022 
 
Investigator Initiated Trial 
Phase II HBO Auto-HSPC for MM 
HBO effects on blood count recovery and post-transplant outcomes following high-dose 
therapy and autologous HSPC transplantation for multiple myeloma 
PRINCIPAL INVESTIGATOR 
Omar Aljitawi, MD 
University of Rochester Medical Center 
  601 Elmwood Avenue 
Rochester, NY 
Phone:  585-276-6259 
Fax:     585-276-2596 
     Omar_aljitawi@urmc.rochester.edu 
Protocol Number:     2017-Phase II HBO in MM 
 
Study Drug: 
Hyperbaric Oxygen (HBO) 
 
IND Number: 
17479 
           Clinical Trials.gov#: NCT03398200 
 
IND Holder Name: 
Omar Aljitawi, MD 
 
Initial Version:  
05Sept2017 
Version 2:                  07Mar2018 
 
Version 3:  
06Jun2018 
 
Version 4:  
14Jan2019 
Version 5:                  12Feb2019 
Version 6: 
7Oct2019   
Version 7: 
04Apr2021 
            Version 8:                 26Aug2021   
            Version 9:                   20Apr2022  
 
 
 
 
 
 
 
 
 
 

 
Protocol Title: 2017-Phase II HBO in MM                 Page 2 of 47 
Version Date:20Apr2022 
 
 
             
LIST OF KEY PERSONNEL 
 
PRINCIPAL INVESTIGATOR 
Omar Aljitawi, MD 
SUB-INVESTIGATOR(S) 
Michael Becker, MD 
Jane Liesveld, MD 
Brea Lipe, MD 
Neil Blumberg, MD 
Leyla Shune, MD 
Andrew Evans, MD 
Gerhard Hilderbrandt, MD 
BIOSTATISTICIAN 
Andrea Baran 
Derick Peterson, PhD 
COLLABORATORS 
Howard Langstein, MD 
Dennis Allin, MD 

 
Protocol Title: 2017-Phase II HBO in MM                 Page 3 of 47 
Version Date:20Apr2022 
Signature Page 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
Principal Investigator (PI) Name: _____________________________ 
PI Signature: _____________________________ 
Date: ____________________ 

 
Protocol Title: 2017-Phase II HBO in MM                 Page 4 of 47 
Version Date:20Apr2022 
    
        TABLE OF CONTENTS 
LIST OF ABBREVIATIONS 
6 
STUDY SCHEMA 
7 
STUDY SUMMARY 
8 
1.0 
BACKGROUND AND RATIONALE 
11 
2.0 
STUDY OBJECTIVES 
15 
 
2.1 
PRIMARY OBJECTIVES 
16 
 
2.2 
SECONDARY OBJECTIVES 
16 
 
2.3 
EXPLORATORY OBJECTIVES (CORRELATIVE STUDIES) 
16 
 
2.4 
ENDPOINTS 
16 
3.0 
PATIENT ELIGIBILITY 
17 
 
3.1 
INCLUSION CRITERIA 
17 
 
3.2 
EXCLUSION CRITERIA 
18 
4.0 
TREATMENT PLAN 
18 
 
4.1 
TREATMENT DOSAGE AND ADMINISTRATION 
18 
 
4.2 
HYPERBARIC OXYGEN (HBO) TREATMENT: 
19 
 
4.3 
POST-HBO ASSESSMENT AND MONITORING: 
20 
 
4.4 
TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS 
20 
 
4.5 
CONCOMITANT MEDICATIONS/TREATMENTS 
20 
 
4.6 
DURATION OF THERAPY 
20 
 
4.7 
DURATION OF FOLLOW UP 
20 
 
4.8 
REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
21 
 
4.9 
REDCAP FOR STUDY DATABASE 
21 
 
4.10   PATIENT REPLACEMENT 
21 
21 
5.0 
STUDY PROCEDURES 
21 
 
5.1 
SCREENING/BASELINE PROCEDURES 
22 
 
5.2 
FOLLOW-UP PROCEDURES 
25 
 
5.3 
SCHEDULE OF EVENTS 
26 
 
5.4 
REMOVAL OF SUBJECTS FROM STUDY TREATMENT AND STUDY 
28 

 
Protocol Title: 2017-Phase II HBO in MM                 Page 5 of 47 
Version Date:20Apr2022 
6.0 
ADVERSE EVENTS 
28 
 
6.1 
DEFINITIONS 
29 
 
6.2 
REPORTING REQUIREMENTS FOR ADVERSE EVENTS 
31 
7.0 
DRUG INFORMATION 
33 
 
7.1 
HYPERBARIC OXYGEN 
33 
8.0 
CORRELATIVES/SPECIAL STUDIES 
33 
 
8.1 
ASSAY METHODOLOGY 
34 
 
8.2 
SPECIMEN BANKING 
34 
9.0 
MEASUREMENT OF EFFECT 
34 
 
9.1 
SAFETY / TOLERABILITY 
34 
10.0 
DATA AND SAFETY MONITORING 
34 
 
10.1   OVERSIGHT AND MONITORING PLAN 
35 
      10.2   STOPPING RULES 
35 
11.0 
REGULATORY CONSIDERATIONS 
36 
 
11.1 
PROTOCOL REVIEW AND AMENDMENTS 
36 
 
11.2 
INFORMED CONSENT 
36 
 
11.3 
ETHICS AND GOOD CLINICAL PRACTICE (GCP) 
36 
12.0 
REGISTRATION PROCEDURES 
37 
 
12.1 
GENERAL GUIDELINES FOR URMC AND OTHER PARTICIPATING ORGANIZATION 
37 
 
12.2 
REGISTRATION PROCESS FOR URCC AND OTHER PARTICIPATING CENTERS 
37 
13.0 
STUDY MANAGEMENT 
38 
 
13.1 
OVERALL STUDY ORGANIZATION 
38 
 
13.2 
INVESTIGATOR FILES AND RETENTION OF DOCUMENTS 
38 
 
13.3 
CASE REPORT FORMS 
38 
 
13.4 
STUDY MONITORING 
38 
14.0 
STATISTICAL CONSIDERATIONS 
38 
 
14.1 
STUDY DESIGN/STUDY ENDPOINTS 
38 
 
14.2 
SAMPLE SIZE AND ACCRUAL 
39 
 
14.3 
DATA ANALYSES PLANS 
40 
15.0 
REFERENCES 
40 
16.0 
APPENDICES 
43 

 
Protocol Title: 2017-Phase II HBO in MM                 Page 6 of 47 
Version Date:20Apr2022 
 
APPENDIX A. PERFORMANCE STATUS 
43 
 
APPENDIX B. STOPPING RULES 
44 
     APPENXIX C. DAY +15 SURVEY                                                                                                                                                                      45                                 
LIST OF ABBREVIATIONS 
ATM 
atmospheric pressure 
DLCO 
diffusing capacity of the lung for carbon monoxide 
EPO 
erythropoietin 
FEV1 
forced expiratory volume in one second 
FVC 
forced vital capacity  
G-CSF 
granulocyte-colony stimulating factor 
GVHD 
graft versus host disease  
HBO 
hyperbaric oxygen  
HPCs 
hematopoietic progenitor cells 
HSCs 
 hematopoietic stem cells 
MM                 multiple myeloma  
HSPC 
Peripheral Blood Stem Cell 
SDF-1 
stromal-derived factor 1 
 

 
Protocol Title: 2017-Phase II HBO in MM                 Page 7 of 47 
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STUDY SCHEMA  
 
 
 
Efficacy analysis: 
a. 
Time to neutrophil engraftment and 
ALC>500 recovery. 
b. 
Time to platelet engraftment. 
c. 
Average PRBC and platelet unit 
transfusions. 
d. 
Average days of G-CSF use. 
e. 
Length of hospital stay. 
 
Day +30 
≥Day 
 +100 
Efficacy analysis: 
Day+100 responses. 
a. 
b. 
Toxicity assessment :AEs and SAEs 
c. 
Progression free survival at 1 year 
Enrollment 
Randomization 
Arm A 
Arm B 
  HBO  
Treatment 
HSPC infusion 
High-dose melphalan  
  No HBO  
Treatment 
G-CSF 
Day 0 
 hours 
6- 
Day -1 
7- days 

 
Protocol Title: 2017-Phase II HBO in MM                 Page 8 of 47 
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STUDY SUMMARY 
Title 
HBO effects on blood count recovery and post-transplant outcomes 
following high-dose therapy and autologous HSPC transplantation 
for multiple myeloma 
Short Title 
 2017-IIT-Phase II Eval HBO in AutoHSPC for MM 
Phase 
Phase 2 
Methodology 
Randomized to either HBO therapy or no HBO therapy prior to 
HSPC infusion 
Study Duration 
2 years 
Study Center(s) 
Wilmot Cancer Institute 
University of Kansas Medical Center 
University of Kentucky (UK), Markey Cancer Center (MCC) 
Objectives 
Primary Objective:  Evaluate the effect of HBO on blood count 
recovery following high-dose therapy and autologous 
transplantation for multiple myeloma. 
a) Evaluate time to ANC recovery post-transplant. 
b) Evaluate time to platelet recovery post-transplant. 
c) Evaluate ALC recovery through day 15 post-transplant. 
d) Evaluate the average number of PRBC transfused units 
during the first 30 days of transplant. 
e) Evaluate the average number of platelet units transfused 
during the first 30 days of transplant. 
f) Evaluate the average days of G-CSF use post-transplant. 
Secondary Objective:  Examine the effect of HBO on disease 
response post-autologous transplantation. 
a) Evaluate the effect of HBO on day 100 responses in 
patients undergoing transplant and correlate that to 
early ALC recovery. 
b) Progression free survival at one year post-transplant 
Exploratory Objective (Correlative Studies):  Explore HBO 
effects on plasma/serum EPO and IL-15 post-high dose therapy 
and autologous transplantation. 
a) Explore HBO effects on plasma/serum EPO and IL-15. 
b) Explore HBO effects on NK cell recovery 
c) Evaluate the effects of HBO on IL-15 response post-
transplant (pre-chemo, day 0 pre and post HBO, day 3 
post-transplant, weeks 1 and 2 post-transplant) and 
correlate that to early ALC recovery and disease 
response. 

 
Protocol Title: 2017-Phase II HBO in MM                 Page 9 of 47 
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Number of Subjects 
Up to 115 patients to enroll to reach a 100 evaluable subjects in 
total between URMC, KUMC, and UK-MCC 
Up to 90 patients to enroll over 3.5 years at URMC to reach an 80 
evaluable subjects 
Up to 25 patients to enroll over 3.5 years at KUMC and UK-MCC to 
reach 20 evaluable subjects 
Diagnosis and Main 
Inclusion Criteria 
Patients with multiple myeloma who are considered for high-dose 
therapy and autologous transplant. 
Study Product(s), Dose, 
Route, Regimen 
For subjects that are randomized to the HBO arm, HBO treatment 
will be administered on day 0 of the transplant, around 9:00 am. 
The treatment consists of exposure to hyperbaric oxygen at 2.5 
ATA for a total of 90 minutes, in a single see-through hyperbaric 
chamber, breathing 100% oxygen. During the 90 minutes, there will 
be two breaks for 10 minutes each in which subjects will be 
breathing compressed environmental air (21% oxygen). There will 
be an additional 15 minutes spent during compression at the 
initiation of therapy and 15 minutes spent for decompression at the 
end.  
  
HSPC infusion: 6-hours from the start of HBO therapy, HBO 
patients will receive HSPC unit infusion approximately at 3pm. 
Non-HBO patients will receive HSPC infusion at 3pm. Institutional 
guidelines will also be followed in terms of pre-medications and  
Auto HSPC unit infusions for both cohorts 
Duration of  
Administration 
120 minutes (90 minutes actual HBO)) 
Reference Therapy 
Standard reference is no HBO therapy 
Interim Monitoring 
The study will be monitored bi-annually by DSMC at Wilmot 
Cancer Institute and interim monitoring will include safety. The 
study will be approved by the IRB at each institution prior to 
enrollment. Local IRB guidelines will be followed for AE and SAE 
reporting.  

 
Protocol Title: 2017-Phase II HBO in MM                 Page 10 of 47 
Version Date:20Apr2022 
Statistical Methodology 
Primary Objective:  The primary endpoint of the study is time from 
transplant to neutrophil recovery. We expect no loss to follow-up or 
death prior to neutrophil recovery, and expect to observe neutrophil 
recoveries in all patients. Our assumptions are based largely on a 
recent single-arm study of hyperbaric oxygen in ASCT (REF). We 
hypothesize that HBO will increase the relative hazard of neutrophil 
recovery by 80%, corresponding to a hazard ratio (HR) of 1.8. This 
corresponds with a decrease in proportion who have not had a 
neutrophil recovery at 10 days from 81% to 68%, or alternatively, 
an increase in 10 day neutrophil recovery from 19% to 32%. 100 
subjects (50 per arm) provides 81% power to detect HR=1.8 at a 
two-sided α=0.05 level of significance.  Subjects will be 1:1 block-
randomized, with random block sizes of 4 and 6.The primary 
analysis will be based on a 1- degree of freedom (1-df) likelihood 
ratio test (LRT) of HBO treatment in the actually infused cell dose-
stratified Cox model. As we expect many ties in recovery time, the 
exact method will be used to handle ties in the Cox model. The HR 
for HBO will be reported along with a 95% confidence interval (CI) 
and associated LRT p-value. Time to neutrophil recovery by HBO 
group will be summarized graphically via the Kaplan-Meier method.  
Secondary Objective:  Secondary endpoints will include time to 
platelet recovery, time to absolute lymphocyte count recovery, 
days of G-CSF use, PRBC units received, platelet units received, 
length of hospital stay, and disease response at 100 days 
posttransplant. Time to event outcomes will be analyzed using 
methods detailed above. Continuous outcomes will be compared 
between groups using the non-parametric Wilcoxon rank-sum test, 
and binary outcomes will be compared using Fisher’s exact test.  
Exploratory Objective (Correlative Studies): To explore HBO 
effects on IL-15 and EPO responses, we will use a linear mixed 
model (and model diagnostics described above for assessment) 
with treatment group as the explanatory measure of interest 
1.0 
BACKGROUND AND RATIONALE 
 
High-dose chemotherapy with or without radiation combined with autologous peripheral blood 
stem cell (HSPC) transplantation is considered a curative option for patients with a myriad of 
hematological malignancies including Hodgkin’s disease1 and non-Hodgkin’s lymphoma (NHL).2 
Data also supports improved survival in patients with relapsed follicular lymphoma who receive 
autologous HSPC transplantation.3 Additionally, it is considered part of standard of care 
treatment strategy in patients with multiple myeloma (MM)4. Though high-dose chemotherapy 
and HSPC transplantation is considered a curative procedure, patients who undergo this 
treatment regimen suffer from multiple morbidities and potential mortality due to complications 
that arise as a result of chemo/radiation therapy-induced bone marrow suppression. 
Morbidity and mortality related to high-dose chemotherapy and autologous HSPC 
transplantation. 

 
Protocol Title: 2017-Phase II HBO in MM                 Page 11 of 47 
Version Date:20Apr2022 
High-dose chemotherapy/radiation-related complications include: mucositis, neutropenia, and 
neutropenic fever. In one prospective study, the incidence of severe oral mucositis (World 
Health Organization (WHO) grades 3 to 4) was 46% in patients with MM and 42% in patients 
with NHL,5 with a mean duration of severe mucositis of 5.3 days in MM patients and 5.5 days in 
NHL patients. This complication seems to be associated with higher chemotherapy dose per 
kilogram of body weight.5 Depending on the severity of mucositis, some patients will require 
tube feeding for nutritional support and opioid analgesics for pain control.6 Additionally, oral 
ulcers increase the risk of febrile neutropenia and infection risk.6,7 These complications, 
obviously, negatively impact the clinical of the transplant and increase the economic burden of 
the transplant.6 However, infectious complications remain the most common cause of early 
mortality post-autologous HSPC transplantation. In a retrospective study 83% of autologous 
HSPC transplantation patients developed at least one neutropenic fever episode; 5% developed 
severe sepsis, and 3% developed severe sepsis requiring intensive care unit admission.8 In that 
study, the duration of neutropenia was a risk factor for severe sepsis. In addition, 
thrombocytopenia necessitates platelet transfusions, adding to potential complications and to 
increased cost of transplant. For example, the average 60-day platelet transfusion cost per 
patient undergoing autologous HSPC transplantation was estimated to be around $4,000.9 
Interventions to help reduce post-transplant complications and economic impact. The 
use of colony-stimulating factors post-transplant clearly results in shortened neutropenia, 
hospitalization and reduced overall cost.10,11  Also, growth factor use might be associated with 
reduced mucositis.12 The move to performing Auto-HSPC transplantation as an outpatient 
procedure is another way to help reduce the overall transplant cost.13 However, a substantial 
percentage of those transplanted as outpatient will be eventually admitted to the hospital; in one 
series of studies, this percentage was 60%.14 The major side effects that trigger hospital 
admission include neutropenic fever and mucositis necessitating narcotic usage. These two 
complications are related to the direct effect of chemotherapy and/or radiation on hematopoietic 
tissue and the gastrointestinal tract, but are reversible upon neutrophil recovery. 
Statement of need for further interventions to help with post-transplant complications. 
Interventions are warranted to further help shorten neutropenia post-high-dose chemotherapy 
and Auto-HSPC transplantation. Such interventions will ultimately help reduce the 
transplantrelated mortality and morbidity related to infectious complications and mucositis. 
Additionally, such interventions will potentially reduce days of hospitalization, transfusions, 
antibiotic use, and narcotic use for mucositis. As such, it will reduce the overall cost of Auto-
HSPC transplantation.  
 
Blood count recovery following HSPC transplantation: Relationship to erythropoietin. 
Earlier observations implicated erythropoietin (EPO) in HSPC homing, in which circulating  
Table-1: Time to count recovery in HBO and historic 
cohorts. 
 
HBO  
Cohort 
(n=20) 
Historic  
Cohort 
(n=225) 
P-value 

 
Protocol Title: 2017-Phase II HBO in MM                 Page 12 of 47 
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HSPCs actively cross the blood/bone 
marrow endothelium barrier and lodge 
(at least transiently) in the bone marrow 
compartment.15  HSPC homing to bone 
marrow is a step that precedes 
engraftment, which corresponds to the 
proliferation and differentiation of 
HSPCs to produce mature, functional 
hematopoietic cells within the bone 
marrow.16 Gonzalez et al. demonstrated that in utero, circulating HSPCs rapidly decline after 
birth. 17 Interestingly, the  
decline in HSPCs correlated with low EPO blood concentration. The authors speculated that the 
decline in HSPCs was explained by HSPC bone marrow homing. These observations 
suggested a possible role for EPO in bone marrow homing process. Intrigued by this 
observation, we investigated the role of EPO in UCB HSPC homing and engraftment as UCB 
HSPCs experience defects in bone marrow homing.18 We demonstrated that a large HSPC 
population of UCB HSPCs (~46%) express cell surface EPO receptor (EPOR), and that their 
exposure to EPO inhibits UCB CD34+ cell in vitro transmigration.18 The effect of such inhibited 
migration was reversed by either depleting EPOR expression on UCB CD34+ cells, or through 
blocking EPO or EPOR by neutralizing antibodies.  Recognizing the negative effects of EPO on  
Table-2: HBO effects on high-dose therapy and auto HSPC transplant outcomes. 
 
HBO Cohort 
(n=19) 
Historic Cohort 
(n=118) 
P-value 
Days G-CSF use 
6.21 (4-9) 
9.16 (5-19) 
0.0007 
Mucositis incidence 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
5 (26.3%) 
0 
4 (21.1%) 
1 (5.2%) 
0 
70 (59.3%) 
14 (12.2%) 
44 (37%) 
12 (10.1%) 
0 
0.008 
PRBC units 
transfused 
2.1(1-7) 
2.58(1-7) 
0.22 
Platelet units 
transfused 
2.5 (1-12) 
3.2(1-21) 
0.17 
Neutropenic fever 
9 (47%) 
77 (65%) 
0.11 
HSPC transmigration and possibly homing, we investigated hyperbaric conditions as an 
intervention to lower EPO to improve HSPC homing, as hyperbaric oxygen (HBO) is known to 
reduce EPO in healthy volunteers.19 HBO therapy involves inhalation of 100% oxygen 
intermittently under a pressure greater than 1 atmosphere (ATM), which results in both 
mechanical effects related to increased pressure and physiologic effects related to hyperoxia46. 
Our in vivo studies showed that HBO conditions promoted homing of transplanted UCB HSPC 
to the bone marrow by reducing systemic EPO levels in the recipient.18 We also evaluated the 
impact of HBO on UCB HSPC homing in a murine transplant model. In these experiments, 
irradiated mice that received HBO treatment prior to UCB cell infusion, showed significantly 
improved myeloid, B-cell and T cell engraftment in comparison to non-treated mice. 20 In a pilot 
clinical trial, we also have demonstrated that HBO therapy given as a single treatment 6 hours 
prior to UCB transplantation was well-tolerated and resulted in significant reduction in median 
EPO level from baseline. Compared to historic controls, median time to neutrophil recovery was 
shorter in HBO- treated patients (14 vs 20.5 days). Also, all HBO patients had complete platelet 
Time to neutrophil 
recovery, mean in 
days (Range) 
10.7 (9- 
13) 
11.3 (7- 
18) 
0.04 
Time to platelet 
recovery, mean in 
days (Range) 
16.2  
(14-21) 
19.8 (11- 
86) 
0.04 

 
Protocol Title: 2017-Phase II HBO in MM                 Page 13 of 47 
Version Date:20Apr2022 
recovery as compared to only 69% of controls (p=0.013) and these HBO-treated patients 
achieved transfusion independency (TTI) earlier than the controls.  
Pilot clinical trial indicate safety and feasibility of HBO in autologous HSPC 
transplantation. 
 
Based on these results, we initiated a pilot study in autologous HSPC transplantation. A total of 
20 patients were treated on the autologous HSPC transplant study. HBO therapy was very well 
tolerated as 19 completed full therapy. In terms of blood count recovery, our preliminary data 
indicate an average time to neutrophil count recovery of 10.7 days compared to 11.3 days 
(P=0.04) and average time to platelet count recovery of 16.2 days compared to 19.8 historically 
(p=0.04). In a separate analysis, we evaluated HBO effects on other outcomes post- autologous 
transplantation. In this analysis, we compared our HBO cohort patients who completed HBO 
therapy (n=19) with our historic patients (n=118). We found that the average days of GCSF use 
was 6.2 days in the HBO cohort compared to 9.16 days in controls (P=0.0007). HBO patients 
had significantly less mucositis (26.3% vs 53.3%, p=0.008). The average number of transfused 
packed red cell units was 2.1 and 2.58 units (P=0.22), while platelet units transfused was 2.5 
and 3.2 (P=0.17) in the HBO and historic cohorts, respectively. Biologically, a positive 
correlation between HBO mediated reduction in EPO levels and time to neutrophil recovery was 
observed in our HBO cohort (p = 0.05).  
HBO and ALC recovery in Auto-HSPC pilot clinical incorporating HBO. 
We also evaluated ALC recovery post Auto-HSPC in our HBO study, as early ALC recovery is 
another sign of early HSCP engraftment and early ALC recovery was found to be associated 
with improved survival post-transplant. This effect was seen in patients with mantle cell 
lymphoma21, multiple myeloma (MM) 22’ 23, amyloidosis24, Non-Hodgkin lymphoma (NHL) 25, 
Hodgkin’s disease (HD)26 and even acute myeloid leukemia27. Though the definition of early 
ALC varies between studies, most of these studies define early ALC recovery as recovery of 
lymphocyte count to 500 cells/microL on day 15.23 Applying this definition, a study showed that 
the median overall survival (OS) for MM patients was 33 months in patients with early ALC 
recovery compared to 12 months in patient with late ALC recovery (P <.0001). Similarly, 
progression free survival (PFS) was longer in patients with early versus late ALC recovery (16 
vs 8 months, P <.0003). Also, for patients with NHL, the PFS time was significantly longer in 
patients with early ALC recovery than later ALC (not reached vs 4 months, P <.0001). In that 
study, multivariate analysis demonstrated that early ALC recovery was an independent 
prognostic indicator for PFS for both patients with MM and NHL. In our HBO experience, early 
ALC recovery was observed in 13/17 (76%) of assessable patients with all patients achieving 
ALC of 500 by day 18 post-transplant. In our preliminary data, the median time to achievement 
of early ALC was 12 (8-18) days. These data are encouraging as early ALC is seen in 
approximately 50% of patients with MM or NHL receiving high-dose therapy and autologous 
transplant.23  
IL-15 and early ALC recovery following high-dose therapy and autologous 
Transplantation. 
Though the basic mechanism for such improvement in OS and PFS in patients with early ALC 
recovery has not been deeply investigated, evidence suggests that it is related to early recovery 
of Natural Killer (NK) cell subset28’29 mediated by interluken-15 (IL-15).28 The role of NK cells in 
improving survival post autologous transplant has led to several clinical trials utilizing NK 

 
Protocol Title: 2017-Phase II HBO in MM                 Page 14 of 47 
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cellbased mechanisms to reduce disease relapse. For example, the use of FLT-3 ligand was 
found to induce dendritic cells and subsequently NK cells post-transplant.30 In another study, IL-
2 and interferon-α combination was investigated as a modality to increase NK cells post 
autologous transplant.31 Others also investigated the use of NK cells for ex vivo purging of 
autologous graft.32 These approaches are costly and are associated with graft manipulation. 
Simpler approaches are warranted to increase early NK and ALC recovery to reduce relapse 
postautologous transplantation. In this application, we propose the use of hyperbaric oxygen 
(HBO) as a modality to facilitate early ALC recovery post-transplant.     
HBO and IL-15 in autologous HSPC pilot clinical incorporating HBO. 
As NK subset recovery has been shown to be mediated by interluken-15 (IL-15), 28 we 
evaluated IL-15 blood levels in patient who underwent autologous HSPC transplantation on our 
pilot HBO study. We evaluated plasma IL-15 levels at different time points; the day of starting 
preparative regimen (day -6 for lymphoma subjects and day -3 for myeloma subjects), the 
morning of HBO treatment (day 0), and 6, 24, and 
48 hours after starting HBO treatment. We also 
evaluated Il-15 level at the third day of 
engraftment (Figure-1). In preliminary data we 
have observed the following: a.IL-15 level was 
significantly higher on day 0 prior to HBO therapy 
compared to baseline level; b.IL-15 level was 
significantly higher 48-hours following HBO 
therapy compared to day 0, pre-HBO levels, c. 
third day of engraftment IL-15 levels were 
significantly higher than baseline levels.  To add, 
on the third day of engraftment (on average day 
13 post-transplant), average IL-15 levels was 
2.87X the baseline value. In one published study, 
day 14 IL-15 was almost 2X its baseline level in a 
study that utilizes co-stimulated T cells to  
facilitate immune recovery.33 Accordingly, our 
preliminary data suggest that IL-15 might be higher 
in our study cohort than historic data (2.87X vs 2X) 
and suggests a possible role for HBO in inducing 
higher IL-15 blood levels. On  
other hand, there is no published data examining the effects of HBO on IL-15 and such studies 
are warranted. This is especially important since IL-15 blood level was found to correlate with 
patient survival following high-dose therapy and autologous transplantation.28 The effect might 
be even more profound, as data suggest that in a subset of patients with follicular lymphoma 
and MM, autologous HSPC transplantation might be associated with prolonged PFS or might be 
even curative. 34’35   
Hypothesis: 
Based on our preliminary data, our central hypothesize is that HBO therapy significantly reduces 
post-transplant EPO and as a result improves HSPC engraftment evident by improved time to 
neutrophil, platelet, and early ALC recovery in MM patients undergoing high-dose therapy and 
autologous transplantation (Figure-2). We also hypothesize that HBO therapy up-regulates IL- 
Figure-1: HBO effects on IL-15 in 
our pilot study in autologous  

 
Protocol Title: 2017-Phase II HBO in MM                 Page 15 of 47 
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Figure-2: The effects of low EPO environment induced by HBO on HSPC 
engraftment potential. (RBC: red blood cells and IL-15: interleukin-15)  
15 day 15 post-transplant and as a result further enhances ALC recovery in MM patients 
undergoing HSPC transplantation (Figure-2). 
Innovation: 
The use of HBO to improve blood count recovery and to reduce growth factor use, transfusion 
needs, and to shorten hospital stay in MM patients undergoing high-dose therapy and 
AutoHSPC transplantation represents an innovative approach as it targets the host 
microenvironment without manipulating the graft or use of pharmaceuticals, cell therapy or 
immune-modulators. Given the simplicity of the approach, it has the potential to result in a 
paradigm shift in how we deliver high-dose therapy and autologous transplantation. The result 
of this simple and well-tolerated intervention can be far reaching as it has the potential to 
improve ALC recovery and consequently the outcome of high-dose therapy and autologous 
transplantation by reducing disease relapse and improving survival of patients. This approach 
will have a major impact on multiple malignancies beside MM, like NHL and HD.  
2.0 
STUDY OBJECTIVES 
 
In this phase II randomized clinical trial study, we will estimate the effect sizes of HBO therapy in 
improving neutrophil count recovery (primary), platelet count recovery and ALC recovery, and 
growth factor use, transfusion requirements, and hospital stay post high-dose therapy and 
autologous transplantation for MM.  
Briefly, half of the participants in this study will be receiving one HBO therapy session prior to 
HSPC infusion and will be followed closely until day+100 with final assessment at 1 year. Our 
primary end point is time to neutrophil recovery in HBO treated subjects and in control subjects 

 
Protocol Title: 2017-Phase II HBO in MM                 Page 16 of 47 
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not receiving HBO. As secondary end points we will determine platelet count recovery and ALC 
recovery, growth factor use, transfusion requirements, and hospital stay post high-dose therapy 
and autologous transplantation for MM. In addition, we will evaluate day 100 disease responses 
and 1 year PFS and explore the HBO effects on EPO  and IL-15 cytokine levels post-transplant 
in both the HBO treated and control subjects.  
2.1 
Primary Objectives 
2.1.1 Evaluate the effect of HBO on blood count recovery following high-dose 
therapy and autologous transplantation. 
a. Evaluate ANC recovery post-transplant. 
b. Evaluate platelet count recovery post-transplant. 
c. Evaluate ALC recovery day 15 post-transplant. 
d. Evaluate the average number of PRBC transfusions post-transplant. 
e. Evaluate the average number of platelet transfusions post-transplant. 
f. 
Evaluate the number of days of G-CSF use post-transplant. 
g. Evaluate the length of hospital stay.  
   
2.2 
Secondary Objectives  
2.2.1 Examine the effect of HBO on disease response post-autologous 
transplantation. 
a. 
Evaluate the effect of HBO on day 100 responses and 1 year PFS in patients 
undergoing transplant. 
2.3 
Exploratory Objectives (Correlative Studies) 
2.3.1 Explore HBO effects on plasma/serum EPO and IL-15 and NK cell recovery 
posthigh dose therapy and autologous transplantation. 
2.3.2 Evaluate the effects of HBO on plasma/serum EPO and IL-15 response 
posttransplant  
(pre-chemo, day 0 pre and post HBO, day 3 post-transplant, weeks 1 and 2 
posttransplant) and correlate that to early ALC recovery and disease response. 
2.4 
Endpoints 
Primary Endpoint: 
Our primary end point is time to neutrophil count recovery in HBO treated subjects and in control 
subjects not receiving HBO. 
Secondary Endpoints: 

 
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As secondary end points we will determine time to platelet count recovery, time to ALC 
recovery, PRBC and platelet transfusions, days of G-CSF use, lengthy of hospital stay, day 100 
disease responses, and 1-year PFS. We will explore HBO effects on EPO and IL-15 cytokine 
levels and NK cell recovery post-transplant in both the HBO treated and control subjects.  
3.0 
PATIENT ELIGIBILITY 
 
3.1 
Inclusion Criteria 
Subjects must meet all of the inclusion criteria to participate in this study. 
Primary Objective Study population: Patients with MM who are considered for high-dose 
therapy and autologous transplantation at the bone marrow transplant clinic at the Wilmot 
Cancer Institute (WCI) will be screened for eligibility to enroll in this study and if eligible will be 
approached to participate. Eligible patients will have the chance to tour the hyperbaric oxygen 
facility prior to signing the consent form. Patients who agree to proceed will sign a written 
consent. The inclusion and exclusion criteria are listed below: 
 
3.1.1 Voluntary written informed consent 
3.1.2 Multiple myeloma diagnosis applying the latest criteria by IWG 36. Patients should 
have received myeloma-directed induction therapy with appropriate response 
(PR or better) in newly diagnosed myeloma patients. Multiple myeloma patients 
who relapse following induction therapy or following prior Auto-HCT are also 
eligible as far as remission following their first Auto-HCT lasted 12 months or 
more.  
3.1.3 Patients who are considered for high-dose therapy and autologous 
transplantation at the bone marrow transplant clinic at WCI will be screened for 
eligibility to enroll in this study and if eligible will be approached to participate. 
Eligible patients will have the chance to tour the hyperbaric oxygen facility prior to 
signing the consent form.  
 
3.1.4 Subjects must be ≥ 18 years old and ≤ 75 years old 
 
3.1.5 Karnofsky performance status (KPS) of ≥ 70% (Appendix A). 
3.1.6 Adequate hepatic, cardiac and pulmonary function to be eligible for transplant. 
Minimum criteria include: 
- ALT, AST: < 4x IULN  
- Total bilirubin: ≤ 2.0 mg/dL 
- EF measured by 2D-ECHO or MUGA scan of ≥ 45% 
- FEV1, FVC and DLCD ≥ 50% of predicted value (corrected to serum hemoglobin) - 
EKG with no clinically significant arrhythmia.  
3.1.7 Patients should have New York Heart Association (NYHA) Functional 
Classification, classI(ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain)or Class II (ordinary physical activity results 
in fatigue, palpitation, dyspnea, or anginal pain). 

 
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3.1.8 Patients should be evaluated for fitness for HBO by a hyperbaric oxygen trained 
medical professional who is not part of the study team prior to starting 
preparative regimen. 
3.1.9 Women of child-bearing potential should have a negative urine or serum 
pregnancy test within 4 weeks of starting preparative regimen. 
3.1.10 Women of child-bearing potential and men with partners of child-bearing potential 
must agree to use adequate contraception (hormonal or barrier method of birth 
control; abstinence) prior to study entry, for the duration of study participation, and 
for 30 days following completion of therapy.  Should a woman or partner become 
pregnant or suspect she is pregnant while participating in this study, she should 
inform her treating physician and the investigator immediately. 
3.1.10.1 A woman of child-bearing potential is any female (regardless of sexual 
orientation, having undergone a tubal ligation, or remaining celibate by choice) who 
meets the following criteria: 
• 
Has not undergone a hysterectomy or bilateral oophorectomy; or 
• 
Has not been naturally postmenopausal for at least 12 consecutive months (i.e., 
has had menses at any time in the preceding 12 consecutive months) 
 
3.2 
Exclusion Criteria 
Subjects meeting any of the exclusion criteria at baseline will be excluded from study 
participation. 
 
3.2.1 Pregnant or breastfeeding 
 
3.2.2 
Severe chronic obstructive pulmonary disease requiring oxygen supplementation 
 
3.2.3 History of spontaneous pneumothorax 
3.2.4 Active ear/sinus infection. Patients with hronic sinusitis or sinus headaches are 
excluded unless cleared by ear,nose,throat consult 
3.2.5 Recent sinus surgery (within the last 5 years) or ear surgery, excluding 
myringotomy or ear tubes 
 
3.2.6 Claustrophobia 
 
3.2.7    History of seizures  
3.2.8 Evidence of pneumothorax or significant pulmonary fibrosis on chest imaging 
within 60 days of transplant. 
 
3.2.9 
Prior chest surgery that involved thoracotomy or prior direct irradiation to the lungs 
3.2.10 Patients who had intrathecal chemotherapy within 2 weeks of starting preparative 
regimen or cranial irradiation within 4 weeks of starting preparative regimen 
3.2.11 Active infection (viral, fungal, and/or bacterial) 
3.2.12 Positive screening for Hepatitis A, B, or C indicating an ongoing infection 
3.2.13 No active tobacco use 72 hours prior to transplant until complete transplant 
recovery. 

 
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4.0 
TREATMENT PLAN 
 
4.1 
Treatment Dosage and Administration 
Preparative regimens prior to HBO therapy: 
Melphalan 200mg/M2 given intravenously (IV) on day -1. For patients 70 years or older and/or 
those with serum creatinine ≤ 2.0 mg/dL, a lower melphalan dose of 140 mg/M2 can be given 
intravenously (IV) on day -1, under the discretion of the treating physician.  
4.2 
Hyperbaric oxygen (HBO) treatment:  
HBO treatment will be administered as either outpatient (WCI and KUCC patients) or inpatient 
(KUCC patients) on the morning of the stem cell transplant (Day 0), around 9am. The treatment 
consists of exposure to hyperbaric oxygen at 2.5 ATA for a total of 2 hours, in a single see-through 
hyperbaric chamber, breathing 100% oxygen while subjects are resting in supine position. During 
the 2 hours, there will be compression and decompression phases for 15 minutes each in which 
subjects will be breathing compressed environmental air (21% oxygen). Subjects will be able to 
communicate with the treating nurse and treatment will be stopped immediately, temporarily or 
permanently, in the event the treated subject develops any acute complications, or upon his/her 
request. For WCI patients, the treatment will be conducted as outpatient in the hyperbaric 
medicine unit at the Strong Wound Healing Center; University of Rochester Medical Center, 160 
Sawgrass Drive, Rochester, NY 14620. WCI patients are responsible for transporting themselves 
to and from this location and given instructions on where to go before and after HBO therapy.  In 
the case of using sedatives prior to outpatient HBO therapy, the patient will be asked to arrange 
for someone else to drive them to and from the Strong Wound Healing Center.  The HBO device 
and the duration and specifications (pressure and % FiO2) of HBO therapy are the same as 
described in IND#17373.The unit is directed by Howard Langstein, M.D, who is a collaborator in 
this study. Patients will be admitted following HBO therapy to WCI for HSPC infusion and 
posttransplant care.  For KUCC patients, the HBO treatment will be done as inpatient or outpatient 
using Sechrist Industries model 3200/3200R at KUMC’s Hyperbaric Medicine unit. If HBO therapy 
is performed outpatient at KUMC, patients are responsible for transporting themselves to and from 
the outpatient location and given instructions on where to go before and after HBO therapy. 
Similarly, for UK-MCC, patients will receive HBO therapy inpatient our outpatient using Sechrist 
Industries model 4100 located adjacent to the Emergency Department in the hospital. The HBO 
therapy will be monitored by a hyperbaric oxygen trained nurse. Following HBO therapy, all 
subjects will be admitted as inpatient and recommended to shower with chlorhexidine (CHG) 
soap, however, this is not required. The choice of these treatment parameters is based on our 
two recently conducted pilot studies indicating the safety and efficacy of these treatment 
paremeters.18,37 In our pilot studies we chose standard HBO treatment conditions that have been 
adequately explored previously with good track record of safety and tolerance. Our pilot studies 
data showed that standard HBO conditions were safe in UCB transplant as well as in autologous 
HSPC transplantation setting. Additionally, the current treatment schedule did result in reducing 
erythropoietin levels significantly in both studies, which is the biologic marker of effectiveness of 
HBO therapy in improving engraftment in our studies. Since the use of HBO in hematopoietic stem 
cell transplant setting is novel, we will stagger enrollment for the first 5 patients randomized to the 
HBO arm. We plan to monitor the first 5 subjects receiving HBO for 30 days after HBO therapy 
prior to enrolling subsequent patients to the HBO arm. To minimize ear discomfort during HBO 
therapy, Bone Marrow Transplant medical providers should strongly encourage the use of 
supportive medications like over the counter nasal steroids if patients have signs of nasal allergies 
and/or cerumen removal kits for cerumen removal if they have wax upon ear exam at the time of 

 
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patient evaluation on Day -1 or Day 0 prior HBO therapy. Also, HBO staff might recommend these 
over the counter measures upon their independent evaluation. Also, sedatives like short acting 
benzodiazepines might be prescribed by the Bone Marrow Transplant medical providers for mild 
anxiety related to the procedure, which can be prescribed any time prior to Day -1. In the case of 
using sedatives prior to outpatient HBO therapy, the patient will be asked to arrange for someone 
else to drive to and from the Strong Wound Healing Center.   
HSPC infusion:  
All patients participating on this study should have peripherally mobilized and cryopreserved 
autologous HSPC products. Peripheral blood mobilization of autologous HSPCs is achieved by 
using high-dose G-CSF +/- plerixafor +/- high-dose cytoxan according to institutional guidelines. 
Autologous HSPCs are collected by apheresis. Between 6 and 10 hours following the start of  
HBO therapy, patients will receive Auto HSPC stored units. Auto HSPC dose should be ≥ 2x106 
CD34+cells/Kg body weight. Institutional standard operating procedures (SOPs) will be followed 
in terms of pre-medications and infusion. We cross reference IND 17373 for the pertinent 
Chemistry, Manufacturing, and Control (CMC) information.   
4.3 
Post-HBO assessment and monitoring: 
A specific assessment for acute HBO toxicity will be collected within 24-hours of the procedure.  
The assessment is clinical and includes brief history and physical examination, including vitals.   
Enrolled subjects will have daily blood counts checked after transplantation until ANC and ALC 
recovery is documented. Achieving an ALC of >500/mm3 will be considered the day of ALC 
recovery. Additionally, ALC will be determined daily through day 15. Achieving ANC of 
>500/mm3 for three consecutive days is considered day of ANC recovery. Blood counts will be 
checked daily until ANC recovery is documented, following that blood counts will be checked 
less frequently (2-3 times/week) until ANC, ALC, and platelet recovery are documented. Time to 
ANC recovery, ALC recovery, platelet recovery, number of PRBC and platelet transfusions, 
number of days of G-CSF use, and length of hospitalization will be determined for each patient, 
except patients who die prior to that, whose time to recovery measure will be right-censored at 
the date of death. In addition, we will collect the following information: CD34 cell dose and 
infused lymphocyte dose to determine using multivariate analysis if HBO effect on ALC recovery 
is independent of these factors that have been found to impact ALC recovery. 
Patients will have disease assessment prior to and after transplant on day +100 and at 1 year 
using the International Response Criteria for multiple myeloma. Since maintenance therapy 
could potentially affect day +100 responses, it is recommended that maintenance therapy be 
held until after day +100 disease assessment is obtained.  
4.4 
Toxicities and Dosing Delays/Dose Modifications 
Any subject who receives full or partial HBO treatment on this protocol will be evaluable for 
toxicity. Toxicity will be assessed according to the NCI Common Toxicity Criteria for Adverse 
Events (CTCAE), version 4.03. Toxicities will be collected for up to 1-year post transplant. We 
will specifically assess for treatment-limiting toxicities (TLTs) defined as the occurrence of any of 

 
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the following complications within 24 hours of HBO: Seizure disorder, pneumothorax, death, any 
irreversible grade Ill or any grade IV toxicity.    
4.5 
Concomitant Medications/Treatments 
No prohibited medications or treatments. 
4.6 
Duration of Therapy 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study, OR 
• 
General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator”. 
4.7 
Duration of Follow Up 
Patients will be followed for up to day +100 to assess disease response and at 1 year for PFS 
assessment. Patients continuing care at URMC will have disease status collected at the time of 
routine follow up appointments to determine progression free survival (PFS). All these visits are 
considered part of standard of care visits post-transplant. All CTCAE v4.03-defined adverse 
events of grades 1-5 will be recorded and reported to the sponsor, WCI CTO at each study visit. 
Events which are serious, unexpected and suspected adverse reactions to the experimental 
intervention should be reported expeditiously to FDA according to the timeframe noted in 
21CFR312.32. All other AEs can be reported in aggregate in the annual report as described in 
21CFR312.33(b)(1). 
In the event that a patient decides to withdraw from the study treatment, we would like to continue 
to collect information from them for the duration of the study or (up to one year from the patient’s 
transplant date). Patients do not have to agree to the continual optional data collection after 
withdrawal. Any follow-up data collected for this study will be for the purposes of monitoring 
adverse events that may occur as a result of the study or for changes related to disease 
progression.  
4.8 
Removal of Patients from Protocol Therapy 
Subjects can choose to be removed from the protocol at any time. 
Subjects will be removed from therapy when any of the criteria listed in Section 5.5 apply. Notify 
the Principal Investigator, and document the reason for study removal and the date the patient 
was removed in the Case Report Form. The patient should be followed-up per protocol.  
4.9 
REDCap for Study Database 
After consent is obtained and screening procedures are complete, eligible subjects will be 
randomized within 4 weeks of planned study start. Each site will receive access to the 
studyspecific, REDCap database. Site users will enter subject demographic information directly 
into REDCap to receive an assignment in real time as eligible patients are registered. A URMC 
statistician will also have the randomization schema and will be able to communicate urgent 
randomization results to sites in case of REDCap login issues or system failures.  
 Randomization Procedures: Study statisticians will prepare a 1:1 block randomization table 
based on random 4- and 6- blocks. This randomization table will be uploaded into the 
Randomization module in REDCap.  

 
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It is the expectation that all eligibility data has source documentation available at the enrolling 
sites. Site personnel will be responsible for entering subject data regularly into this database.  
REDCap will be used to accommodate data entry, data retrieval, and data security.  Access to 
study data and proper back-up procedures will be utilized in REDCap.   
4.10 
Patient Replacement 
Subjects who do not continue therapy on this protocol prior to HBO therapy will be replaced by 
new subjects. 
5.0 
STUDY PROCEDURES 
 
5.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only after 
obtaining informed consent. Assessments performed for clinical indications (not exclusively to 
determine study eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. To help potential patients understand the clinical trial concept, 
we have prepared an animation that will be provided to prospective patients as a link on a 
handout and/or shown to potential subjects on a tablet or computer in clinic when time permits. 
The animation will be made available to potential subjects during the informed consent process 
and/or study screening 
All screening procedures must be performed within 30 days prior to registration unless 
otherwise stated. The screening procedures include: 
 Informed Consent  Medical history 
o Complete medical, surgical and oncology history as well as history of infections 
are obtained at screening.  
 
 
Demographics 
o Demographic profile will include date of birth, gender, race, and zip code. 
o Baseline disease characteristics will be collected including the stage at 
diagnosis, cytogenetic and FISH anomalies, and the treatment medications 
used prior to ASCT 
 
Review subject eligibility criteria o Review of eligibility criteria as 
described in Section 3 to ensure subject qualification for study entry 

 
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Review previous and concomitant medications 
o All prior medication taken by the subject within 7 days before starting the study is 
to be recorded. Concomitant medications taken by the subject during the  
study are to be recorded up until 30-days after last study dose. If a reportable 
adverse event (see Section 7) occurs within 30-days after last study dose, 
recording of concomitant medications should continue until resolution of the 
adverse event 
 
Physical exam including vital signs, height and weight o Vital signs 
(temperature, pulse, respirations, blood pressure), height, weight 
 
 
Performance status 
o Karnofsky Performance Status (KPS) will be evaluated at the time of physical 
exam prior to study entry and possibly during study. Specific criteria for 
assessing KPS can be found in Appendix A 
 
Pregnancy test (for females of child bearing 
potential) o See section 3.1 for definition  
 
 
 
Hematology 
o Hematology to include hemoglobin (Hgb), platelets, total white blood cell count 
(WBC) and differential 
 
 
Serum chemistries 
o   Comprehensive metabolic panel (CMP) to include: albumin, alkaline 
phosphatase, ALT, AST, BUN, creatinine, electrolytes (sodium, potassium, 
calcium, chloride, bicarbonate), glucose, and total bilirubin or BMP to include: 
BUN, creatinine, electrolytes (sodium, potassium, calcium, chloride, 
bicarbonate), glucose  
 
 
EKG 
o      EKG within 60 days of the anticipated transplant date, unless clinically indicated 
 
 
Chest x-ray 
o      Chest x-ray within 60 days of the anticipated transplant date, unless clinically  
indicated 

 
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MUGA or ECHO 
o 2D-ECHO or MUGA scan within 90 days of the anticipated transplant date, 
unless clinically indicated 
 
 
Disease assessment 
o For multiple myeloma, the International Response Criteria for multiple 
myeloma will be applied.38  
 
 
Pulmonary Function Test 
o PFT to be performed within 90 days of the anticipated transplant date, unless 
clinically indicated 
Procedures During Treatment 
 
 
Day  -1 
o Chemotherapy preparative regimens as outlined in Section 4.0. o Blood 
draw for correlative studies prior to chemotherapy administration. 
o Physical exam and vital signs 
 
Day 0, pre-
HBO o CBC 
o Blood draw for correlative studies o 
Physical exam and vital signs 
 
 
Day 0 
o HBO treatment 
 
Day 0, at least 6 hrs, but no more than 10 hours post-
HBO o HSPC unit transplantation 
o Blood draw for correlative studies just prior to HSPC infusion and two hours later.  
 
 
Day 1 
o Physical exam o Vital signs 
o CBC 

 
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o Acute HBO toxicity assessment 
o Blood draw for correlative 
studies 
• 
Days 1 – 14 Every Day Post-Transplant o CBC with diff (daily 
until neutrophil recovery) 
o Correlative lab draws (day 2, 3, and 7 post-transplant, and on first day of 
neutrophil recovery). A window of 3 hours is allowed. If day 7 time point or 
first day of neutrophil recovery sample occurs on a weekend or a holiday, 
the sample is to be collected the first business day after the weekend or 
holiday. o Physical exam and vital signs 
o G-CSF 5 mcg/kg will be given daily subcutaneously, until ANC≥500 for 
three consecutive days or ANC≥1500 for one day 
• 
Day 15  post-transplant (2 day window allowed) o Blood draw 
for CBC with diff and correlative studies. A window of two days is 
allowed for correlative studies. If any of these days occur on a 
weekend or a holiday, the correlative study sample is to be 
collected the first business day after the weekend or holiday 
o Physical exam and vital signs o Study survey to evaluate patient’s HBO 
experience.  
• 
Day 100 post-transplant o CBC with diff o Disease Assessment 
per standard criteria. 
o Blood draw for correlative studies within a 2 week window is allowed to 
accommodate any scheduling issues.  o Physical exam and vital signs 
• 
1- year post-transplant (1 month window is allowed to 
accommodate any scheduling issues)  o Disease Assessment per 
standard criteria o Physical exam and vital signs 

 
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5.2 
Follow-up Procedures 
Patients will be seen daily on the inpatient ward until neutrophil count recovery, then if their 
condition allows will be discharged to outpatient with visits scheduled 2-3 times a week for the 
first 30 days as clinically indicated. Laboratory testing will occur per institutional guidelines.  
Neutrophil recovery is defined as ANC ≥ 500/µL for three consecutive days. Follow up for AEs or 
SAEs will begin from the start of treatment at Day -1 and will continue until day +100 post-
transplant. All CTCAE v4.03-defined adverse events of grades 1-5 will be recorded and reported 
to the sponsor at each study visit. Events which are serious, unexpected and suspected adverse 
reactions to the experimental conditions, i.e: HBO, should be reported expeditiously to FDA 
according to the timeframe noted in 21CFR312.32. All other AEs can be reported in aggregate in 
the annual report as described in 21CFR312.33(b)(1). 

 
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5.3 
Schedule of Events 
HBO+AutoHSPC 
STUDY CALENDAR 
Screening/ 
Baseline 
Day -1 
Day 0, pre- 
HBO 
Day 0 
HBO 
6 hrs 
Post  
HBO 
8 hrs 
Post  
HBO 
Day 1 
(24 hrs 
post  
HBO) 
Day 2 
and 3 
(post  
HBO) 
Every Day -  
Days 1-14  
Each Day  
PostTransplant 
Approximate Visit Time 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Concomitant Medication 
 
 
 
At each clinical encounter 
 
 
 
Physical  
Exam  
(With  
performance status) 
 
 
 
At each clinical encounter 
 
 
 
Adverse Events 
 
At each clinical encounter 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
CBC with diff 
X 
 
X 
 
 
 
X 
X 
X 
MUGA or ECHO 
X 
 
 
 
 
 
 
 
 
Pulmonary Function Tests 
X 
 
 
 
 
 
 
 
 
Disease Assessment 
X 
 
 
 
 
 
 
 
 
High-dose melphalan 
(Preparative Regimen) 
 
X 
 
 
 
 
 
 
 
Correlative Blood Samples 
(EPO, IL-15) 
 
X 
X 
 
X 
X 
X 
X  
 
HBO Treatment 
 
 
 
X 
 
 
 
 
 
HSPC Transplant 
 
 
 
 
X 
 
 
 
 
Acute HBO Toxicity 
Assessment 
 
 
 
 
 
 
X 
 
 
Growth factor use days 
 
 
 
 
 
 
 
 
X 
    

 
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HBO+AutoHSPC Study Calendar - CONTINUED 
HBO+AutoHSPC 
Study Calendar 
Day 7  
Post- 
Trans 
plant 
First day of 
neutrophil  
recovery (+/-  
2 days) 
Day 15 
 Post – 
Transplant  
(+/- 2 days) 
Day 100 Post Transplant 
Long-term follow up for PFS 
1 year post-transplant 
Medical History 
 
Each clinical encounter 
 
Concomitant 
Medication 
 
Each clinical encounter 
 
Physical Exam (with 
performance status) 
 
Each clinical encounter 
 
Vital Signs 
 
Each clinical encounter 
 
Adverse Events 
 
Each clinical encounter 
 
Disease Assessment 
 
 
 
X 
X 
Research Blood  
Samples (CBC with 
diff for ALC Recovery) 
 
 
X 
 
 
Correlative Blood  
Samples (IL-15, NK 
cells, EPO ) 
X** 
X** 
X 
X*** 
 
Study survey 
 
 
X**** 
 
 
Duration of 
hospitalization 
And readmissions 
 
Data will be collected through day +100 
 
Blood product 
transfusions 
 
Data will be collected through day +100 
 
* A window of 3 hours is allowed for post-transplant day 1, 2, and 3 sample collection. If day 7, day 15 or first day of neutrophil 
recovery sample collection days occur on a weekend or a holiday, the sample is to be collected the first business day after the 
weekend or holiday. 
** On day 7 and first day of neutrophil recovery patients will  have blood drawn for IL-15 and EPO. 
*** On day 100 patients will have blood drawn for IL-15. 
**** To be completed by patients who completed HBO therapy.  

 
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5.4 
Removal of Subjects from Study Treatment and Study 
Subject can be taken off the study treatment and/or study at any time at their own request, or 
they may be withdrawn at the discretion of the investigator for safety, behavioral or 
administrative reasons. The reason(s) for discontinuation will be documented and may include: 
 
5.4.1 Subject voluntarily withdraws from treatment (follow-up permitted);  
 
5.4.2 
Subject withdraws consent (termination of treatment and follow-up); 
 
5.4.3 Subject is unable to comply with protocol requirements; 
5.4.4 Subject experiences toxicity that makes continuation in the protocol 
unsafe; 
5.4.5 Treating physician judges continuation on the study would not be in 
the subject’s best interest; 
5.4.6 Subject becomes pregnant (pregnancy to be reported along same 
timelines as a serious adverse event); 
5.4.7 
Development of second malignancy (except for basal cell 
carcinoma or squamous cell carcinoma of the skin) that requires treatment, 
which would interfere with this study; 5.4.8 
Lost to follow-up.  
6.0 
ADVERSE EVENTS 
 
Text below in italics is verbatim from “Guidance for Industry and Investigators. Safety Reporting  
Requirements for INDs and BA/BE Studies”, issued December 2012 by U.S. Department of  
Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and 
Research, and Center for Biologics Evaluation and Research.  The guidance may be retrieved 
from:  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U 
CM227351.pdf?source=govdelivery. 
Potential Risk: The potential risks associated with this study are considered minimal and consist 
of those related to phlebotomy (i.e. rare local infection or rare local bleeding necessitating 
temporary pressure dressing) and possible reactions and adverse events related to hyperbaric 
oxygen (HBO). The more common and less serious complications related to HBO include middle 
ear barotrauma, which occurs at incidence of 13.6% as described in one study. On the other hand, 
seizures have been reported to occur at a rate of.033% in one report, or 1.3 in 10,000 in another 
report. The benefits from this research potentially outweigh these small risks. Based on our pilot 
study findings, this procedure was well-tolerated. 
Procedures to Minimize Potential Risks: Blood samples for study purposes will be obtained by an 
experienced health care professional using standard aseptic techniques. Local pressure will be 
applied at the site of phlebotomy to minimize bleeding or bruising. All results obtained from 
laboratory tests will be provided to the participants upon request. The data collected will be used 
for research purposes only, and participants will be identified by study IDs. To minimize risks 
related to HBO therapy, we will exclude patients who have a history of claustrophobia,  

 
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spontaneous pneumothorax, history of seizures, and sinus surgery five years prior to 
enrollment.The treatment will be stopped immediately, temporarily or permanently, in the event 
the treated subject develops any acute complications, or upon his/her request. Standard operating 
procedures will be followed in case of development of acute complication during therapy. 
Monitoring for All Risks:  All risks have been minimized to the greatest extent possible for this 
study as a prior pilot study indicated the safety of HBO in this setting. URMC, KUMC, or UK-MCC 
will not assume responsibility for any costs related to potential injury from this study, again we do 
not anticipate any injury. If an injury does occur, subjects will be asked to notify the PI immediately, 
and notify the bone marrow transplant providers. All data obtained from subjects will remain 
confidential and be securely maintained by the Clinical Trials Office at each institution. All 
electronic data will be password protected. 
6.1 
Definitions 
 
6.1.1 Adverse Event [21 CFR 312.32(a)]  
An adverse event means any untoward medical occurrence associated with the use of a drug or 
an intervention in humans, whether or not considered drug related. 
An adverse event (also referred to as an adverse experience) can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a drug, and does not imply any judgment about causality.  An adverse 
event can arise with any use of the drug (e.g., off-label use, use in combination with another drug) 
and with any route of administration, formulation, or dose, including an overdose. 
This study will use the descriptions and grading scales from Common Terminology Criteria for  
Adverse Events version 4.03 (CTCAE v 4.03) for hematologic and non-hematologic toxicities.  
Detailed information may be found on the Cancer Therapy Evaluation Program (CTEP) website:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
All 
CTCAE 
v4.03defined adverse events of grades 1-5 will be recorded and reported to the sponsor at each 
study visit. Events which are serious, unexpected and suspected adverse reactions to the 
experimental biologic should be reported expeditiously to FDA according to the timeframe noted 
in 21CFR312.32. All other AEs can be reported in aggregate in the annual report as described in 
21CFR312.33(b)(1). 
Information for adverse events, whether reported by the subject, directly observed, or detected by 
physical examination, laboratory test or other means, will be collected, recorded, followed and 
reported in the CRF as described in the following sections.  
Adverse events experienced by subjects will be collected and reported from time of treatment start 
on Day -1, throughout the study, and within 100 days of the last treatment of protocol therapy.  
Subjects who experience an ongoing adverse event related to a study procedure and/or study 
treatment beyond 100 days will continue to be contacted by a member of the study team until the 
event is resolved, stabilized, or determined to be irreversible by the principal investigator. Study 
subjects should also be instructed to report any new serious post-study event(s) that might 
reasonably be related to participation in this study. 
 

 
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Abnormal laboratory values or test results constitute adverse events only if they induce clinical 
signs or symptoms, or require therapy.  In this case they will be recorded on the Adverse Events 
CRF, along with the associated signs, symptoms or diagnosis. 
As far as possible, each adverse event will also be described by: 
• 
its duration (start and end dates), 
• 
grading of severity, 
• 
its relationship to the study drug, 
• 
the action(s) taken,  
• 
outcome 
 
6.1.2 Suspected Adverse Reaction [21 CFR 312.32(a)] 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug or intervention caused the adverse event. For the purposes of safety reporting, 
‘reasonable possibility’ means there is evidence to suggest a causal relationship between the 
drug/intervention and the adverse event. A suspected adverse reaction implies a lesser degree 
of certainty about causality than adverse reaction, which means any adverse event caused by a 
drug.  
Suspected adverse reactions are the subset of all adverse events for which there is a reasonable 
possibility that the drug/intervention caused the event. Inherent in this definition, and in the 
requirement to report suspected adverse reactions, is the need for the sponsor to evaluate the 
available evidence and make a judgment about the likelihood that the drug/intervention actually 
caused the adverse event.  
Factors to be considered in assessing the relationship of the adverse event to study treatment 
include: 
• 
The temporal sequence from study treatment administration: The event should occur 
after the study treatment is given.  The length of time from study treatment exposure to 
event should be evaluated in the clinical context of the event. 
• 
Recovery on discontinuation (de-challenge): Subject’s response after treatment 
discontinuation (de-challenge) should be considered in the view of the usual clinical 
course of the event in question. 
• 
Underlying, concomitant, intercurrent diseases: Each report should be evaluated in the 
context of the natural history and course of the disease being treated and any other 
disease the subject may have. 
• 
Concomitant medication or treatment: The other drugs the subject is taking or the 
treatment the subject receives should be examined to determine whether any of them 
may be suspected to cause the event in question. 
Attribution is the relationship between an adverse event or serious adverse event and the study 
treatment. Attribution will be assigned as follows: 
• 
Unrelated - The AE is clearly NOT related to the study treatment.  
Unlikely - The 
AE is doubtfully related to the study treatment. 
• 
Possible – The AE may be related to the study treatment.  
Probable – The AE is 
likely related to the study treatment. 
• 
Definite – The AE is clearly related to the study treatment. 
 
6.1.3 Unexpected [21 CFR 312.32(a)] 

 
Protocol Title: 2017-Phase II HBO in MM             Page 32 of 47 
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An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application… 
"Unexpected," as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of 
drugs/intervention or as anticipated from the pharmacological properties of the drug/intervention, 
but are not specifically mentioned as occurring with the Particular drug/intervention under 
investigation. 
This definition relies entirely on a listing of the adverse events or suspected adverse reactions in 
the investigator brochure…as the basis for determining whether newly acquired information 
generated from clinical trials or reported from other sources is unexpected. This means that 
events not listed for the Particular drug under investigation in the investigator brochure are 
considered “unexpected” and those listed are considered “expected.”  When new adverse event 
information is received, it is the sponsor’s responsibility to determine whether the event is 
“unexpected” for safety reporting purposes. 
 
6.1.4 Serious [21 CFR 312.32(a)] 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes: Death, a life-threatening 
adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly/birth defect. Important medical events that may not result in death, be 
lifethreatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or patient and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. 
 
6.1.5 Life-threatening 
An adverse event or suspected adverse reaction is considered “life-threatening” if, in the view of 
either the investigator or sponsor, its occurrence places the patient or patient at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred 
in a more severe form, might have caused death. 
6.2 
Reporting Requirements for Adverse Events 
 
6.2.1 Submitting Serious Adverse Events Reports to IRB 
For serious adverse events, the clinical research site will follow local IRB policies and 
procedures.  
 
6.2.2 Study Investigator Notification of Adverse Events 
All expected and unexpected serious adverse events occurring after the subject has 
signed the Informed Consent and has started protocol treatment must be reported to the 
study principal investigator within 24 hours of becoming aware of the event: 
PI Name: Omar Aljitawi, MD 
Office Phone: 585-276-6259 
Fax: 585-276-2596 
6.2.3 
DSMC Notification of SAEs 
See Section 10.0 

 
Protocol Title: 2017-Phase II HBO in MM             Page 33 of 47 
Version Date: 20Apr2022 
6.2.4 Recording Adverse Events and Documentation in WCI Clinical Trials REDCap 
database  
All expected and unexpected adverse events and serious adverse events occurring 
after the subject has signed the Informed Consent and has started protocol treatment 
must be fully recorded in the subject’s case record form. 
All unexpected SAEs should be reported in the REDCap database within 5 business 
days of learning of the event, while other SAEs should be reported bi-annually to DSMC. 
SAE reports are expected to include sufficient detail so that the WCI DSMB can 
determine the severity, toxicity grade, expectedness and treatment. The report should 
be updated to document resolution or any sequelae. The Coordinating Center, WCI, will 
report an aggregate listing of all AEs and SAEs for review at the regular DSMB 
meetings. The board will review these reports and determine if further action is required. 
SAEs that are determined to be related to study intervention AND unexpected require 
expedited reporting to the REDCap database in addition to notification by email to study 
PI.  
The Coordinating Center will report these events to the WCI DSMB in addition to 
sending a formal notification describing the event to all investigators. Each investigator 
must then notify his or her IRB of the event according to local regulations.  
Documentation must be supported by an entry in the subject’s file.  A laboratory test 
abnormality considered clinically relevant, e.g., causing the subject to withdraw from the 
study, requiring treatment or causing apparent clinical manifestations, or judged relevant 
by the investigator, should be reported as an adverse event.  Each event should be 
described in detail along with start and stop dates, severity, relationship to investigational 
product, action taken and outcome. 
 
6.2.5 Reporting of Unexpected, Related SAEs for Hyperbaric Oxygen (HBO) 
For HBO, all unexpected, related serious adverse experiences will be forwarded to the 
product manufacturer by the investigator using the Voluntary MEDWATCH Form FDA 
3500. 
 
6.2.6 Summary of Expedited Serious Adverse Event Reporting 
 
Relationship to 
study 
investigational 
therapy 
WCI 
Clinical 
Trials DSMC 
IRB 
PI 
Unexpected  
SAE 
Related 
5 days 
5 days 
24 hrs 
Unexpected  
SAE 
Not-related 
Bi-Annual 
meeting  
Not reportable 
24 hrs 
Expected  
SAE 
Related 
Bi-Annual 
meeting  
Not reportable 
24 hrs 
Expected  
SAE 
Not-related 
Bi-Annual 
meeting  
Not reportable 
24 hrs 
7.0 
DRUG INFORMATION 
 
7.1 
Hyperbaric oxygen 

 
Protocol Title: 2017-Phase II HBO in MM             Page 34 of 47 
Version Date: 20Apr2022 
• 
Agent Classification: Physiologic agent 
• 
Mode of action: Investigators think that HBO alters the recipients’ microenvironment to 
facilitate engraftment of hematopoietic stem and progenitor cells.   
• 
Route of administration for this study: Via monoplace hyperbaric chamber (Model 3300H, 
Sechrist Industries, Inc., USA). The treatment will be given at the Strong Wound Healing 
Center; University of Rochester, Rochester, NY 14620. At KUMC, the treatment will be 
given via Sechrist Industries model 3200/3200R at the Hyperbaric Medicine unit at KUMC. 
At UKMCC, the treatment will be given Sechrist Industries model 4100 located adjacent to 
the Emergency Department in the hospital. 
• 
Availability: This is an FDA approved therapy for several indications. 
Side effects: Administration of HBO is generally considered a safe procedure when standard 
protocols are used. This includes oxygen pressures not exceeding 3 atmospheres and 
treatment sessions limited to a maximum of 120 minutes.46 Adverse events, however, can 
occur. The most common complication is reversible myopia. Cataract formation using 
standard procedures is usually not seen.46 Cavity trauma secondary to pressure change (i.e.,  
sinus trauma or tympanic membrane rupture) has also been observed.47 These complications 
can be minimized by adhering to standard procedures and patient education.48 An example 
of a rare but serious complication is pneumothorax, which usually occurs in patients with 
severe lung disease.47 Seizures have been reported to occur at a rate of 1.3 seizures per 
10,000 treatments, but  are  reversible by reducing the pressure of inspired oxygen.48 HBO 
therapy is considered an effective therapy for decompression sickness and air embolism.47 
Other indications include carbon monoxide poisoning,49 treatment of infections such as gas 
gangrene, necrotizing fasciitis, diabetic foot infections, refractory osteomyelitis, neurosurgical 
infections and fungal infections.50 
8.0 
CORRELATIVES/SPECIAL STUDIES 
 
The goal of the planned laboratory correlative studies is to investigate potential mechanisms by 
which hyperbaric oxygen improves time to ANC, ALC, and platelet recovery, days of G-CSF use, 
PRBC/platelet unit utilization, and length of hospital stay. These correlative studies investigate the 
effect of hyperbaric oxygen on EPO and IL-15 in response to HBO following transplant and 
correlate that with time to ANC, ALC, and platelet recovery, days of G-CSF use, PRBC/platelet 
unit utilization, and length of hospital stay. 
Sample Collection Guidelines: 
Peripheral blood samples will be collected by drawing blood from central venous catheters or 
peripheral vein. Samples will be labeled with the subject’s de-identified study number and 
collection date and processed for plasma/serum isolation and storage by CTO. 
                                   CTO 
                                   WCI, second floor 
University of Rochester Medical Center 
  

 
Protocol Title: 2017-Phase II HBO in MM             Page 35 of 47 
Version Date: 20Apr2022 
Samples will be collected at the following time points (+/- 3 hour window): prior to initiation of 
preparative regimen (day-1), prior to HBO treatment on day 0, and following HBO therapy (6 hrs 
and 8 hrs from start of HBO and days 1, 2, and 3 after starting HBO). Additional sample will be 
collected on the first day of neutrophil recovery, day +15, and day +100. Samples will be collected 
from controls at the same time points. Blood samples collected at KUMC or UK-MCC will be 
processed, stored, and shipped to URMC for storage and for testing by the corresponding 
Biospecimen Repository Core Facility (BRCF). All correlative study testing will occur at URMC.  
8.1 
Assay Methodology 
Enzyme-linked immunosorbent assay (ELISA) will be used to measure EPO and IL-15 in 
plasma/serum samples from enrolled subjects. Flow cytometry will be done to document NK cell 
recovery.  
8.2 
Specimen Banking 
Submission of samples for the correlative studies is mandatory for this study. Subject samples 
collected for this study will be retained by CTO at WCI. Specimens will be stored indefinitely or 
until they are used up.  
With the subject’s permission, any leftover specimens will be stored and used for future research 
studies by the PI or other investigators at URMC for IRB approved research purposes if approved 
by the PI. If the leftover specimen samples for storage and future use is denied or withdrawn by 
the subject (submitted in writing to the investigator), best efforts will be made to stop any additional 
studies and to destroy the specimens.  
9.0 
MEASUREMENT OF EFFECT 
 
9.1 
Safety / Tolerability 
Analyses will be performed for all subjects having received the full or partial hyperbaric oxygen 
treatment for any duration. The study will use the CTCAE version 4.03  
(http://ctep.cancer.gov/reporting/ctc.html) for reporting of hematologic and non-hematologic 
adverse events. 
10.0 
DATA AND SAFETY MONITORING 
 
10.1 
Oversight and Monitoring Plan 
Study Investigators at each institution will conduct continuous review of data and patient safety.  
The Principal Investigator (PI) at each institution will submit bi-annual progress reports of these 
data to the Data Safety Monitoring Committee at the corresponding institution for review.  The 
review will include for each treatment arm:  the number of patients enrolled, withdrawals, 
significant toxicities as described in the protocol, serious adverse events both expected and 
unexpected, dose adjustments, and responses observed.  The PI at each institution maintains a 
database of all adverse events with toxicity grade and information regarding treatment required, 
complications, or sequelae.  The PI at each institution will submit a copy of the AE spreadsheet 
along with a Progress Report to the Data Safety Monitoring Committee (DSMC) at WCI for review. 
Actual review dates will be assigned when the 1st patient is accrued. 

 
Protocol Title: 2017-Phase II HBO in MM             Page 36 of 47 
Version Date: 20Apr2022 
The DSMC at the Wilmot Cancer Institute of the University of Rochester provides oversight of 
study progress and safety by review of accrual and adverse events at bi-annual meetings or more 
often if concerns arise. Any adverse event requiting expedited review per protocol, including those 
occurring at participating sites, will be submitted to the Safety Coordinator of the DSMC at WCI 
for determination as to whether further action is required. When patient safety is of concern, an 
interim meeting may be called in any of the following situations:  
• 
Any serious adverse event that is serious, related AND unexpected must be reported 
within 5 calendar days to both the WCI DSMC Safety Coordinator and the local IRB (see 
institutional IRB guidelines).  The WCI DSMC Chair will determine whether further action 
is required, and when patient safety is of concern. 
• 
Serious adverse events that are related AND expected or unrelated AND unexpected will 
be reported to the WCI DSMC for review at the bi-annual meeting. SAE reports are 
expected to include sufficient detail so that the WCI DSMC can determine the severity, 
toxicity grade, expectedness, treatment required, and a follow up report documenting 
resolution or if there are sequelae.  Serious adverse events that require detailed reports 
(but not necessarily expedited) are expected, related, non-hematologic toxicities of grades 
3, 4 or 5. 
The Safety Coordinator administratively coordinates reports and data collection and prepares 
documents for the WCI DSMC Chair and committee review. The Safety Coordinator will 
administratively monitor adverse event rates utilizing the report from the study database.  If any 
study has had two or more of the same SAE’s reported in a month or more than six of the same 
SAE’s in six months, the WCI DSMC will review the summary of SAEs, discuss events with Study 
Chair, and conduct a more detailed review with the Study Chair. The Data Safety Monitoring Chair 
will determine if further action is required. 
10.2 Stopping Rules  
The study activities will be monitored by the Data and Safety Monitoring committee (DSMC) 
at WCI. Also, SAE and suspected but unexpected SAE will be reported to the FDA 
according to FDA guidance (2012) and 21 CFR312.32.   Any death should be evaluated in 
the context of expected autologous transplant mortality to determine the relationship to 
HBO.  
 

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11.0 
REGULATORY CONSIDERATIONS 
11.1 
Protocol Review and Amendments 
This protocol, the proposed Informed Consent and all forms of participant information 
related to the study (e.g., advertisements used to recruit participants) and any other 
necessary documents must be submitted, reviewed and approved by a properly 
constituted IRB governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be 
approved by the local IRB prior to implementation. Any changes in study conduct must be 
reported to each IRB. The Principal Investigator will disseminate protocol amendment 
information to all participating investigators. All decisions of the IRB concerning the 
conduct of the study must be made in writing. 
11.2 
Informed Consent 
All participants must be provided a consent form describing this study and providing 
sufficient information for participants to make an informed decision about their participation 
in this study. The formal consent of a participant, using the IRB approved consent form, 
must be obtained before the participant is involved in any study-related procedure. The 
consent form must be signed and dated by the participant and by the person obtaining the 
consent. The participant must be given a copy of the signed and dated consent document. 
The original signed copy of the consent document must be retained in the medical record 
or research file. 
11.3 
Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which represent 
good and sound research practice: 
1. 
ICH Consolidated Good Clinical Practice: Guidelines (E6) 
www.fda.gov/cder/guidance/iche6.htm  
2. 
US Code of Federal Regulations (CFR) governing clinical study conduct and ethical 
principles that have their origin in the Declaration of Helsinki 
- 
Title 
21 
Part 
11 
– 
Electronic 
Records; 
Electronic 
Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html 
- 
Title 
21 
Part 
50 
– 
Protection 
of 
Human 
Patients 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
- 
Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
- 
Title 
21 
Part 
56 
– 
Institutional 
Review 
Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  
- 
Title 
21 
Part 
312 
– 
Investigational 
New 
Drug 
Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
3. 
State laws 
4. 
Institutional research policies and procedures  

Protocol Title: 2017-Phase II HBO in MM             Page 38 of 47 
Version Date: 20Apr2022 
It is understood that deviations from the protocol should be avoided, except when necessary to 
eliminate an immediate hazard to a research participant. In such case, the deviation must be 
reported to the institutional IRB according to the local reporting policy.  
12.0 
REGISTRATION PROCEDURES 
12.1 
General Guidelines for URMC and Other Participating Organization 
Participating institutions will register eligible subjects through the WCI Clinical Trials 
Office central registration process.  Registration must occur prior to the initiation of 
therapy, with treatment assignment provided by WCI.  Any subject not registered to the 
protocol before treatment begins will be considered ineligible and registration will be 
denied. Subjects should be registered within 5 working days prior to starting treatment. 
The completed source documentation provided for eligibility verification and registration 
must be kept in the subject binder for monitoring purposes and documentation of subject 
eligibility. 
Issues that would cause treatment delays should be discussed with the Principal 
Investigator. If a subject does not receive protocol therapy following registration, notify 
the WCI BMT/Myeloma Team so that the subject’s status can be changed in REDCap. 
12.2 
Registration Process for URCC and Other Participating Centers 
All ethical, regulatory, technical, and scientific approvals must be in place before study 
registrations will be accepted from a site.  
All subjects will be registered centrally through the coordinating site Clinical Trials Office which 
is located at the:  
James P. Wilmot Cancer Institute 
University of Rochester Medical Center 
Rochester, NY 14642 
The Coordinating Center functions both as a Participating Center and as the Coordinating 
Center.  
Each site will receive access to the study-specific, REDCap database at the University of 
Rochester. It is the expectation that all data has source documentation available at the enrolling 
sites. Site personnel will be responsible for entering their patient data regularly into this 
database.  
At the time of registration, the signed informed consent form and documents that support 
eligibility should be faxed to the Coordinating Center: 585-442-0137, Attn: BMT/Myeloma Team.  
Any question regarding eligibility or that may arise during the conduct of the study should be 
addressed to:  

Protocol Title: 2017-Phase II HBO in MM             Page 39 of 47 
Version Date: 20Apr2022 
Name: Omar Aljitawi, MBBS 
Email: omar_aljitawi@urmc.rochester.edu 
Phone: 585-273-3258 
13.0 
STUDY MANAGEMENT 
13.1 
Overall Study Organization 
For this study, the WCI CTO is considered the Sponsor, the Coordinating Site, and one of the 
sites for study activities. KUCC is considered the second site.  
13.2 
Investigator Files and Retention of Documents 
Each site investigator must prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the study for each research participant. This 
information enables the study to be fully documented and the study data to be subsequently 
verified. Original source documents supporting entries in the case report forms include but are not 
limited to hospital records and clinic charts, laboratory and pharmacy records, ECG, signed ICFs, 
subject diaries and pathology reports. All study-related documents must be retained for the 
maximum period required by applicable federal regulations and guidelines or institutional policies.  
13.3 
Case Report Forms 
Case report forms (CRFs) will be completed for each subject enrolled.  All CRFs will be complete 
and accurate. The medical chart and any other clinical worksheets, procedural reports, etc. are 
the source of verification of the data captured into the study database by each participating 
institution.   
13.4 
Study Monitoring 
The study will be monitored by the coordinating center at yearly intervals to assure compliance 
to GCP and to assess the data quality and study integrity.  
The investigator and staff are expected to cooperate and provide all relevant study documentation 
in detail at each site visit on request for review. The study monitors provided by WCI CTO will 
have direct access to source data for data verification. Data verification will be conducted by 
comparing the data entered into the CRFs with source data. Also, unexpected SAEs and 
unexpected suspected SAEs will be reported to the FDA according to FDA guidance (2012) and 
21 CFR312.32.   Any death should be evaluated in the context of expected UCB mortality to 
determine the relationship to HBO. 
14.0 
STATISTICAL CONSIDERATIONS 
 
14.1 
Study Design/Study Endpoints: 1:1 randomized clinical trial. The primary endpoint of 
the study is time from transplant to neutrophil recovery. Secondary endpoints will include 
time to platelet recovery, time to absolute lymphocyte count recovery, days of G-CSF 
use, PRBC units received, platelet units received, length of hospital stay, disease 
response at 100 days post-transplant and PFS at 1 year. 

Protocol Title: 2017-Phase II HBO in MM             Page 40 of 47 
Version Date: 20Apr2022 
Primary Objective Statistical considerations: The primary endpoint of the study is 
time from transplant to neutrophil recovery. We expect no loss to follow-up or death prior 
to neutrophil recovery, and expect to observe neutrophil recoveries in all patients. Our 
assumptions are based largely on a recent single-arm study of hyperbaric oxygen in 
ASCT (REF). We hypothesize that HBO will increase the relative hazard of neutrophil 
recovery by 80%, corresponding to a hazard ratio (HR) of 1.8. This corresponds with a 
decrease in proportion who have not had a neutrophil recovery at 10 days from 81% to 
68%, or alternatively, an increase in 10 day neutrophil recovery from 19% to 32%. 100 
subjects (50 per arm) provides 81% power to detect HR=1.8 at a two-sided α=0.05 level  

 
Protocol Title: 2017-Phase II HBO in MM             Page 41 of 47 
Version Date: 20Apr2022 
of significance.  Subjects will be 1:1 block-randomized, with random block sizes of 4 and 
6. The primary analysis will be stratified by quartiles of the actual infused cell dose ( 
each stratum will include 25% of the enrolled subjects).The primary analysis will be a 1- 
degree of freedom (1-df) likelihood ratio test (LRT) of HBO treatment in the cell 
dosestratified Cox model. As we expect many ties in recovery time, the exact method 
will be used to handle ties in the Cox model. The HR for HBO will be reported along with 
a 95% confidence interval (CI) and associated LRT p-value. Time to neutrophil recovery 
by HBO group will be summarized graphically via the Kaplan-Meier method.  
Secondary Objective: Statistical Considerations: Secondary endpoints will include 
time to platelet recovery, time to absolute lymphocyte count recovery, days of G-CSF 
use, PRBC units received, platelet units received, length of hospital stay, disease 
response at 100 days post-transplant and PFS at 1 year. Time to event outcomes will be 
analyzed using methods detailed above. Continuous outcomes will be compared 
between groups using the non-parametric Wilcoxon rank-sum test, and binary outcomes 
will be compared using Fisher’s exact test.  
Exploratory Objective Statistical Considerations: To explore HBO effects on IL-15 and EPO 
responses and NK cell recovery, we will use a linear mixed model (and model diagnostics 
described above for assessment) with treatment group as the explanatory measure of interest 
14.2 
Sample Size and Accrual 
Primary Objective Sample size justification: The primary endpoint of the study is time 
from transplant to neutrophil recovery. We hypothesize that HBO will increase the 
relative hazard of neutrophil recovery by 80%, corresponding to a hazard ratio (HR) of 
1.8. This corresponds with a decrease in proportion who have not had a neutrophil 
recovery at 10 days from 81% to 68%, or alternatively, an increase in 10 day neutrophil 
recovery from 19% to 32%. 100 subjects (50 per arm) provides 81% power to detect 
HR=1.8 at a two-sided α=0.05 level of significance.  
14.3 
Data Analyses Plans 
Objective 1: Final analysis will be done after all patients are enrolled and completed 1-year of 
follow up. 
15.0 
REFERENCES 
 
1. 
David KA, Mauro L, Evens AM. Relapsed and refractory Hodgkin lymphoma: transplantation 
strategies and novel therapeutic options. Curr Treat Options Oncol 2007;8:352-74. 
2. 
Villanueva ML, Vose JM. The role of hematopoietic stem cell transplantation in non-Hodgkin 
lymphoma. Clin Adv Hematol Oncol 2006;4:521-30. 
3. 
Barr PM, Lazarus HM. Follicular non-Hodgkin lymphoma: long-term results of stem-cell 
transplantation. Curr Opin Oncol 2008;20:502-8. 

 
Protocol Title: 2017-Phase II HBO in MM             Page 42 of 47 
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4. 
Bensinger WI. Role of autologous and allogeneic stem cell transplantation in myeloma. Leukemia 
2009;23:442-8. 
5. 
Blijlevens N, Schwenkglenks M, Bacon P, et al. Prospective oral mucositis audit: oral mucositis in 
patients receiving high-dose melphalan or BEAM conditioning chemotherapy--European Blood 
and Marrow Transplantation Mucositis Advisory Group. J Clin Oncol 2008;26:1519-25. 
6. 
Sonis ST, Oster G, Fuchs H, et al. Oral mucositis and the clinical and economic outcomes of 
hematopoietic stem-cell transplantation. J Clin Oncol 2001;19:2201-5. 
7. 
Ruescher TJ, Sodeifi A, Scrivani SJ, Kaban LB, Sonis ST. The impact of mucositis on 
alphahemolytic streptococcal infection in patients undergoing autologous bone marrow 
transplantation for hematologic malignancies. Cancer 1998;82:2275-81. 
8. 
Hamalainen S, Kuittinen T, Matinlauri I, Nousiainen T, Koivula I, Jantunen E. Severe sepsis in 
autologous stem cell transplant recipients: microbiological aetiology, risk factors and outcome. 
Scand J Infect Dis 2009;41:14-20. 
9. 
Bernstein SH, Nademanee AP, Vose JM, et al. A multicenter study of platelet recovery and 
utilization in patients after myeloablative therapy and hematopoietic stem cell transplantation. 
Blood 1998;91:3509-17. 
10. 
Freeman M, Vose J, Bennett C, et al. Costs of care associated with high-dose therapy and 
autologous transplantation for non-Hodgkin's lymphoma: results from the University of 
Nebraska Medical Center 1989 to 1995. Bone Marrow Transplant 1999;24:679-84. 
11. 
Luce BR, Singer JW, Weschler JM, et al. Recombinant human granulocyte-macrophage 
colonystimulating factor after autologous bone marrow transplantation for lymphoid cancer: an 
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16.0 
APPENDICES 
 
Appendix A. Performance Status 
 

 
Protocol Title: 2017-Phase II HBO in MM             Page 46 of 47 
Version Date: 20Apr2022 
Appendix B. Stopping Rules High-dose therapy and Auto-HSPC is a well-tolerated procedure 
with low mortality (<5%) typically related to infections, hemorrhage, or organ toxicities from 
chemotherapy including interstitial pneumonitis and veno-occlusive disease of the liver.39 Any 
death will be evaluated in the context of expected Auto-HSPC mortality to determine the 
relationship to HBO. In the event of death within 30 days of study treatment, accrual to study will 
pause pending assessment of the risk. For stopping rules, if HBO patients develop grade III or 
IV TLTs or demonstrate disease progression/relapse at day +100 in 20% or higher frequency 
than the standard arm, accrual to study will be halted until full evaluation by the WCI DSMC. 
Appendix C. Study Survey 

 
Protocol Title: 2017-Phase II HBO in MM             Page 47 of 47 
Version Date: 20Apr2022 
 
Subjects who complete HBO therapy will be asked to complete a quick 5 minute survey (see 
below) regarding their HBO experience on day +15 post-transplant. The study team will analyze 
the data in the future to help understand patient’s experience with HBO in HSPC transplantation 
setting. 
Direction: Check the box that best corresponds to your answer. Use the legend as your guide. 
LEGEND: 
5-Stongly Agree      4-Agree       3-Neither       2-Disagree        1-Strongly 
Disagree 
Question 
5 
4 
3 
2 
1 
I had a good understanding of the hyperbaric 
oxygen study and its’ purpose at the time of 
study consent. 
 
 
 
 
 
The visual slides and the informational 
packet helped me understand the study 
procedures. 
 
 
 
 
 
The assessment appointment at the Strong 
Wound Clinic helped prepare me for my 
hyperbaric oxygen therapy-treatment. 
 
 
 
 
 
The Strong Wound Clinic was easily 
accessible for my hyperbaric oxygen 
treatment 
 
 
 
 
 
The wound clinic staff were very helpful in 
delivering hyperbaric oxygen therapy 
 
 
 
 
 
Participating in the study made the transplant 
process more overwhelming. 
 
 
 
 
 
Scheduling/coordinating study related visits 
was simple. 
 
 
 
 
 
Overall, I feel that hyperbaric oxygen therapy 
assisted in my recovery. 
 
 
 
 
 
I am satisfied with my overall study 
experience. 
 
 
 
 
 
Comments/Suggestions: 
 
 
Subject ID: …………………………….. Date:…………………………………………..  
Initials:………