Clinical trial NCT02356159
Conditions: Myelodysplastic Syndromes Hodgkin's Lymphoma Non-Hodgkin's Lymphoma Acute Leukemia Multiple Myeloma
Keywords: Hematopoietic Stem Cell Transplant Lymphoma Leukemia Unrelated Donors
Sponsor: National Cancer Institute (NCI)
Start date: 2015-09-24; Completion date: 2025-03-25
Enrollment: 34 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Background:

\- In allogeneic stem cell transplantation (SCT), stem cells are taken from a donor and given to a recipient. Sometimes the recipient's immune system destroys the donors' cells. Or donor immune cells attack the recipient's tissues, called graft-versus-host disease (GVHD). This is less likely when the recipient and donor have similar human leukocyte antigens (HLA). Researchers want to see if the drug palifermin improves the results of allogeneic SCT from HLA-matched unrelated donors.

Objective:

\- To see if high doses of palifermin before chemotherapy are safe, prevent chronic GVHD, and improve immune function after transplant.

Eligibility:

\- Adults 18 years of age or older with blood or bone marrow cancer with no HLA-matched sibling donor, but with a HLA-matched unrelated donor.

Description of Research Study:

* Participants will be screened with medical history, physical exam, and blood and urine tests. They will have scans and heart and lung exams.
* Before transplant, participants will:
* Have many tests and exams. These include blood tests throughout the study and bone marrow biopsy.
* Get a central line catheter if they do not have one.
* Have 1-3 rounds of chemotherapy.
* Have more tests to make sure they can have the transplant, including medical history, physical exam, blood tests, disease specific restaging.
* Get palifermin by intravenous (IV) and conditioning chemotherapy to prepare for hematopoietic stem cell transplantation (HSCT). They will get other drugs; some they will take at least 6 months.
* Participants will get the HSCT.
* After transplant, participants will:
* Be hospitalized at least 3-4 weeks.
* Monitored at least weekly for the first 100 days.
* Stay near District of Columbia (D.C). for approximately 100 days post-transplant.
* After 100 days post-transplant - visit National Institutes of Health (NIH) 5 times the first 2 years, then yearly until 5 years post-transplant.
* Additional tests/procedures may be performed to monitor safety, response to transplant, side effects.

Detailed description:
Background:

* Graft versus host disease (GVHD) and impaired immune reconstitution are major transplant complications and barriers to improving outcomes after allogeneic hematopoietic stem cell transplantation (alloHSCT) for hematologic malignancies. GVHD is initiated when donor T-cells become alloreactive against recipient major or minor histocompatibility antigens. This process may be exacerbated during the transplantation process by exposure of tissue antigens to donor T-lymphocytes after chemotherapy-induced injury.
* Palifermin, a recombinant keratinocyte growth factor-1 (KGF-1), imitates the actions of intrinsic KGF and binds to the Fibroblast growth factor (FGF) receptor 2b, which is expressed in the epidermis, oral mucosa, gastrointestinal (GI) mucosa and urothelium, thereby increasing the regenerative capacity of these tissues. Palifermin has been shown to reduce the duration and severity of oral mucositis after intensive chemo-radiotherapy and autologous HSCT for hematologic cancers and is Food and Drug Administration (FDA) approved. In pre-clinical studies, palifermin has been shown to have an effect on control of acute or chronic GVHD and immune reconstitution after alloHSCT. However, subsequent clinical studies in alloHSCT indicate that the dose and schedule of palifermin as currently

used in humans does not optimize its activity in terms of prevention of GVHD or thymus recovery following alloHSCT.

\- We hypothesize that higher doses of palifermin in the immediate pre alloHSCT conditioning setting will lead to enhanced thymopoiesis, decreased chronic GVHD, and improved immune reconstitution. A dose escalation study is necessary to determine safe dosing levels in persons undergoing alloHSCT.

Objectives:

* The primary objective of the phase I portion is to assess the safety and tolerability of the administration of the recombinant keratinocyte growth factor (KGF) palifermin in alloHSCT using unrelated donor peripheral blood stem cells.
* The primary objective of the phase II portion is to determine the incidence of severe chronic GVHD after the addition of palifermin to TMS (tacrolimus, methotrexate and sirolimus) based GVHD prophylaxis delivered in the identical fashion to the NCI 07-C-0195 study.

Eligibility:

* Adults (greater than or equal to 18 years) with advanced or high-risk hematologic malignancies (including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), chronic myeloid leukemia (CML), multiple myeloma, and myeloproliferative neoplasm (MPN) who lack a suitable human leukocyte antigens (HLA)-matched sibling donor.
* An unrelated donor matched at a minimum of 8 alleles (HLA-A,-B,-C, and major histocompatibility complex, class II, DR beta 1 (DRB1) by high-resolution typing, identified through the National Marrow Donor Program.
* Karnofsky greater than or equal to 60 and acceptable organ functions.

Design:

* Patients will receive disease-specific induction chemotherapy etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride with fludarabine and rituximab (EPOCH-F/R or fludararbine, ara-c, granulocyte colony-stimulating factor (FLAG) prior to transplant as needed for disease control and immune depletion.
* All patients will receive an identical conditioning regimen consisting of cyclophosphamide 1200 mg/m\^2/day intravenous (IV) for 4 days and fludarabine 30 mg/m\^2/day for 4 days (transplant days -6 to -3).
* All patients will receive a peripheral blood stem cell product from an unrelated donor matched at HLA-A, -B, -C, -DRB1 (8/8) by high-resolution typing.
* Palifermin will be administered in a phase 1, open label design with the following proposed schedule:

  * Dose level 1: 180 mcg/kg on day -7
  * Dose level 2: 360 mcg/kg on day -7
  * Dose level 3: 540 mcg/kg on day -7
  * Dose level 4: 720 mcg/kg on day -7
* The phase I portion will be conducted in a standard 3+3 design; the maximum possible number of patients accrued to this portion will be 24.
* The maximum tolerated dose (MTD) from the phase I portion of the study will be used to conduct a phase II study. Total accrual on the phase II study will be 27 patients, including 3-6 patients treated at the MTD in the phase I portion of the study

Arms: arm 1: Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. arm 2: Induction chemotherapy, then palifermin at the recommended phase 2 dose determined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression.
Interventions: intervention 1: Rituximab intervention 2: Conditioning chemotherapy intervention 3: TMS intervention 4: FLAG intervention 5: EPOCH-F intervention 6: Hematopoietic stem cell transplant intervention 7: Palifermin intervention 8: Acetaminophen intervention 9: Diphenhydramine intervention 10: Prednisone intervention 11: Epinephrine intervention 12: IV Saline intervention 13: ECG intervention 14: ECHO intervention 15: MUGA intervention 16: DEXA intervention 17: CT chest intervention 18: PET intervention 19: MRI intervention 20: BM aspirate intervention 21: BM biopsy intervention 22: Lumbar puncture
Intervention descriptions: intervention 1: Rituximab: 375 mg/m\^2 intravenous (IV) day 1 for patients with cluster of differentiation 20 (CD20)-positive disease. intervention 2: Fludarabine:30 mg/m\^2 per day intravenous (IV) infusion over 30 minutes, daily on days -6, -5, -4, and -3; Cyclophosphamide:1200 mg/m\^2 per day IV infusion over 2 hours on Days 6, -5, -4, -3. Mesna: 1200 mg/m\^2 per day IV infusion, daily on days 6, -5, -4, and -3 Furosemide: 20 mg IV flat dose on days -6, -5, -4, -3; Furosemide: 20 mg IV flat dose on days -6, -5, -4, -3. intervention 3: Tacrolimus: 0.02 mg/kg, start day 3. Continue intravenous (IV) or by mouth (PO). Taper will begin at day +60 if no acute graft-versus-host disease (GVHD) then at day +100 and discontinue at day +180 as tolerated. Methotrexate: 5 mg/m\^2 IV over 15 minutes on days 1, 3, 6, and 11. Sirolimus: 12 mg PO on days -3 to 60, followed by a taper if GVHD does not develop. intervention 4: Fludarabine: 25 mg/m\^2 per day intravenous (IV) over 30 minutes, daily on days 1-5 Cytarabine: 2,000 mg/m\^2 IV over 4 hours, on Days 1, 2, 3, 4, 5. Filgrastim: 5 mcg/kg per day subcutaneous (SC) beginning 24 hours PRIOR to initiation of chemotherapy. intervention 5: Fludarabine: 25 mg/m\^2 per day intravenous (IV) infusion over 30 minutes, daily on days 1-4. Etoposide: 50 mg/m\^2 per day continuous IV infusion over 24 hours on days 1-4. Doxorubicin: 10 mg/m\^2/day continuous intravenous (CIV), days 1-4. Vincristine: 0.4 mg/m\^2 per day continuous IV infusion over 24 hours daily on days 1-4.

Cyclophosphamide: 750 mg/m\^2 IV infusion over 30 minutes on day 5. Prednisone: 60 mg/m\^2 per day by mouth (PO) daily on days 1-5. Filgrastim: 5 mcg/kg per day SC or IV. intervention 6: Hematopoietic stem cell transplant intervention 7: Escalating doses of palifermin given during transplant phase. intervention 8: Before each infusion of rituximab as indicated. intervention 9: Before each infusion of rituximab as indicated. intervention 10: For engraftment syndrome. intervention 11: Emergency medication as indicated. intervention 12: Before each infusion of rituximab as indicated. intervention 13: As indicated. intervention 14: As indicated. intervention 15: As indicated. intervention 16: As indicated. intervention 17: As indicated. intervention 18: As indicated. intervention 19: As indicated. intervention 20: As indicated. intervention 21: As indicated. intervention 22: As indicated.

Protocol documents:
Prot_SAP_000.pdf: 
Abbreviated title: Palifermin dose escalation
Version date: 4/7/2022
                                                                                                                   1
Abbreviated Title: Palifermin dose escalation 
NIH Protocol #: 15C0067 
NCT #:  NCT02356159
Version Date:  4/7/2022
Title: A Phase I/II Open Label, Dose Escalation Study of Palifermin (Kepivance) in 
Persons Undergoing Unrelated Donor Allogeneic Hematopoietic Cell Transplantation 
NCI Principal Investigator: Steven Z. Pavletic, MD, MS, 
Immune Deficiency Cellular Therapy Program (IDCTP)
National Cancer Institute (NCI)
National Institutes of Health (NIH)
10 Center Drive, CRC 4-3130
Phone: 240-760-6174
E-mail: pavletis@mail.nih.gov 
Investigational/Commercial Agents:
Drug Name:
Palifermin
Cyclophosphamide, Mesna, Filgrastim, Fludarabine, 
Etoposide, Doxorubicin, Vincristine, Prednisone, 
Rituximab, Cytarabine, Methotrexate, Sirolimus, 
Tacrolimus
IND Number:
124506
124506
Sponsor:
Center for Cancer 
Research
Center for Cancer Research
Manufacturer:
Swedish Orphan 
Biovitrum (Sobi) AB 
Generic
Supplier:
Swedish Orphan 
Biovitrum (Sobi) AB
CC Pharmacy


Abbreviated title: Palifermin dose escalation
Version date: 4/7/2022
                                                                                                                   2
PRÉCIS:
Background:

Graft versus host disease (GVHD) and impaired immune reconstitution are major 
transplant complications and barriers to improving outcomes after allogeneic 
hematopoietic stem cell transplantation (alloHSCT) for hematologic 
malignancies. GVHD is initiated when donor T-cells become alloreactive against 
recipient major or minor histocompatibility antigens. This process may be 
exacerbated during the transplantation process by exposure of tissue antigens to 
donor T-lymphocytes after chemotherapy-induced injury. 

Palifermin, a recombinant keratinocyte growth factor-1 (KGF-1), imitates the 
actions of intrinsic KGF and binds to the FGF receptor 2b, which is expressed in 
the epidermis, oral mucosa, GI mucosa and urothelium, thereby increasing the 
regenerative capacity of these tissues. Palifermin has been shown to reduce the 
duration and severity of oral mucositis after intensive chemo-radiotherapy and 
autologous HSCT for hematologic cancers and is FDA approved. In pre-clinical 
studies, palifermin has been shown to have an effect on control of acute or 
chronic GVHD and immune reconstitution after alloHSCT. However, subsequent 
clinical studies in alloHSCT indicate that the dose and schedule of palifermin as 
currently used in humans does not optimize its activity in terms of prevention of 
GVHD or thymus recovery following alloHSCT.

We hypothesize that higher doses of palifermin in the immediate pre alloHSCT 
conditioning setting will lead to enhanced thymopoiesis, decreased chronic 
GVHD, and improved immune reconstitution. A dose escalation study is 
necessary to determine safe dosing levels in persons undergoing alloHSCT. 
Objectives:

The primary objective of the phase I portion is to assess the safety and 
tolerability of the administration of the recombinant keratinocyte growth factor 
(KGF) palifermin in alloHSCT using unrelated donor peripheral blood stem 
cells.

The primary objective of the phase II portion is to determine the incidence of 
severe chronic GVHD after the addition of palifermin to TMS (tacrolimus, 
methotrexate and sirolimus) based GVHD prophylaxis delivered in the identical 
fashion to the NCI 07C0195 study.
Eligibility:

Adults (≥18 years) with advanced or high risk hematologic malignancies 
(including AML, ALL, MDS, CLL, NHL, HL, CML, multiple myeloma, and MPN) 
who lack a suitable HLA-matched sibling donor.

An unrelated donor matched at a minimum of 8 alleles (HLA-A, -B, -C, and 
DRB1) by high-resolution typing, identified through the National Marrow Donor 
Program.

Karnofsky ≥60 and acceptable organ functions.


Abbreviated title: Palifermin dose escalation
Version date: 4/7/2022
                                                                                                                   3
Design:

Patients will receive disease-specific induction chemotherapy (EPOCH-F/R or 
FLAG) prior to transplant as needed for disease control and immune depletion. 

All patients will receive an identical conditioning regimen consisting of 
cyclophosphamide 1200 mg/m2/day IV for 4 days and fludarabine 30 mg/m2/day 
for 4 days (transplant days -6 to -3).

All patients will receive a peripheral blood stem cell product from an unrelated 
donor matched at HLA-A, -B, -C, -DRB1 (8/8) by high-resolution typing.

Palifermin will be administered in a phase 1, open label design with the following 
proposed schedule: 
o
Dose level 1: 180 mcg/kg on day -7
o
Dose level 2: 360 mcg/kg on day -7
o
Dose level 3: 540 mcg/kg on day -7
o
Dose level 4: 720 mcg/kg on day -7

The phase I portion will be conducted in a standard 3+3 design; the maximum 
possible number of patients accrued to this portion will be 24.

The maximum tolerated dose (MTD) from the phase I portion of the study will be 
used to conduct a phase II study. Total accrual on the phase II study will be 27 
patients, including 3-6 patients treated at the MTD in the phase I portion of the 
study.


Abbreviated title: Palifermin dose escalation
Version date: 4/7/2022
                                                                                                                   4
TABLE OF CONTENTS
PRÉCIS: ...........................................................................................................................2
TABLE OF CONTENTS....................................................................................................4
STATEMENT OF COMPLIANCE .....................................................................................7
1
INTRODUCTION..................................................................................................7
1.1
Study Objectives...............................................................................................7
1.2
Background ......................................................................................................8
1.3
Summary and Rationale for the Study............................................................23
2
ELIGIBILITY ASSESSMENT & ENROLLMENT.................................................24
2.1
Eligibility Criteria .............................................................................................24
2.2
Screening Evaluation......................................................................................30
2.3
Participant Registration and Status Update Procedures ................................31
2.4
Baseline Evaluation ........................................................................................32
3
STUDY IMPLEMENTATION ..............................................................................33
3.1
Study Schema ................................................................................................33
3.2
Induction Phase..............................................................................................34
3.3
Research Phase .............................................................................................37
3.4
Cost and Compensation .................................................................................46
3.5
Telehealth.......................................................................................................46
3.6
Criteria for Removal from Protocol Therapy and Off Study Criteria ...............47
4
CONCOMITANT MEDICATIONS/MEASURES..................................................48
4.1
Infection Prophylaxis ......................................................................................48
4.2
Blood Product Support ...................................................................................49
4.3
Menses Suppression ......................................................................................49
4.4
Engraftment Syndrome...................................................................................49
4.5
Graft Versus Host Disease (GVHD) ...............................................................49
4.6
Donor Lymphocyte Infusions (DLI) .................................................................50
4.7
Other Therapies..............................................................................................50
5
CORRELATIVE STUDIES FOR RESEARCH....................................................51
5.1
Research Studies of Transplant Biology ........................................................51
5.2
Sample Processing.........................................................................................54
5.3
Sample Storage, Tracking and Disposition ....................................................54


Abbreviated title: Palifermin dose escalation
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                                                                                                                   5
6
DATA COLLECTION AND EVALUATION..........................................................56
6.1
Data Collection Procedures............................................................................56
6.2
Record Keeping..............................................................................................58
6.3
Genomic Data Sharing Plan ...........................................................................58
6.4
Response Criteria...........................................................................................58
6.5
Toxicity Criteria...............................................................................................59
7
NIH REPORTING REQUIREMENTS/DATA SAFETY MONITORING PLAN.....59
7.1
Definitions.......................................................................................................59
7.2
OHSRP Office of Compliance and Training / IRB Reporting..........................59
7.3
NCI Clinical Director Reporting.......................................................................59
7.4
National Marrow Donor Program Reporting Criteria.......................................60
7.5
NIH Required Data and Safety Monitoring Plan .............................................60
8
SPONSOR PROTOCOL/SAFETY REPORTING...............................................60
8.1
Definitions.......................................................................................................60
8.2
Assessment of Safety Events.........................................................................61
8.3
Reporting of Serious Adverse Events.............................................................62
8.4
Waiver of Expedited Reporting to CCR ..........................................................62
8.5
Reporting Pregnancy......................................................................................63
8.6
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND....64
8.7
Sponsor Protocol Deviation Reporting ...........................................................64
9
CLINICAL MONITORING...................................................................................64
10
STATISTICAL CONSIDERATIONS ...................................................................65
11
HUMAN SUBJECTS PROTECTION..................................................................68
11.1
Rationale for Subject Selection ......................................................................68
11.2
Risk/Benefit Assessment................................................................................69
11.3
Informed Consent Process and Documentation.............................................70
12
REGULATORY AND OPERATIONAL CONSIDERATIONS ..............................72
12.1
Study Discontinuation and Closure ................................................................72
12.2
Quality Assurance and Quality Control...........................................................72
12.3
Conflict of Interest Policy ................................................................................73
12.4
Confidentiality and Privacy .............................................................................73
13
PHARMACEUTICAL INFORMATION ................................................................74
13.1
Cyclophosphamide (CTX, Cytoxan) ...............................................................74


Abbreviated title: Palifermin dose escalation
Version date: 4/7/2022
                                                                                                                   6
13.2
Mesna (Sodium 2-Mercapoethanesulfonate, Mesnum, Mesnex) ...................75
13.3
Filgrastim (G-CSF, Neupogen®) ....................................................................76
13.4
Fludarabine.....................................................................................................77
13.5
Etoposide, Doxorubicin, and Vincristine (in EPOCH) .....................................78
13.6
Prednisone .....................................................................................................80
13.7
Rituximab (Rituxan) ........................................................................................81
13.8
Cytarabine (Cytosine Arabinoside, Cytosar, ARA-C) .....................................84
13.9
Methotrexate (Methotrexate Sodium, MTX, NSC-740)...................................85
13.10
Sirolimus (Rapamycin, Rapamune®, Wyeth-Ayerst Laboratories).................85
13.11
Tacrolimus (KF-506, Prograf®) ......................................................................86
13.12
Palifermin (Kepivance®, Sobi Pharmaceuticals) IND # 124506.....................87
13.13
Peripheral Blood Stem Cells...........................................................................87
14
REFERENCES...................................................................................................89
15
APPENDICES ....................................................................................................92
15.1
Appendix A: Definitions / Glossary .................................................................92
15.2
Appendix B: Malignancy Response Assessment ...........................................93
15.3
Appendix C: Acute Graft Versus Host Disease Evaluation (Worksheet)........94
15.4
Appendix D: Chronic Graft Versus Host Disease Evaluation (Worksheet).....96
15.5
Appendix E: NMDP Standard Protocol, 22nd ................................................101
15.6
Appendix F: Immunizations ..........................................................................102
15.7
Appendix G: Variables/Guidance forData Collection in C3D........................103
15.8
Appendix H: Study Calendar ........................................................................107
15.9
Appendix I:  Processing Checklist:  DTM-FORM-5086 ................................110
15.10
Appendix J: Infections graded by the Cordonnier scale. ..............................111
15.11
Appendix K: Sample Processing ..................................................................113


Abbreviated title: Palifermin dose escalation
Version date: 4/7/2022
                                                                                                                   7
STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Conference on 
Harmonisation Good Clinical Practice (ICH GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical 
studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, 
and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who 
are responsible for the conduct, management, or oversight of NIH-funded clinical trials 
have completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant 
materials will be submitted to the Institutional Review Board (IRB) for review and 
approval.  Approval of both the protocol and the consent form must be obtained before 
any participant is enrolled.  Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study.  In addition, all 
changes to the consent form will be IRB-approved; an IRB determination will be made 
regarding whether a new consent needs to be obtained from participants who provided 
consent, using a previously approved consent form.
1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1 Primary objectives
o
The primary objective of the phase I portion is to assess the safety and 
tolerability of administration of the recombinant keratinocyte growth factor 
(KGF) palifermin in alloHSCT using unrelated donor peripheral blood stem 
cells.
o
The primary objective of the phase II portion is to determine the incidence 
of severe chronic GVHD after the addition of palifermin to TMS 
(tacrolimus, methotrexate, sirolimus) based GVHD prophylaxis delivered 
in the identical fashion of the NCI 07C0195 study.
1.1.2
Exploratory objectives
o
Assess the effects of palifermin on immune reconstitution in persons 
undergoing alloHSCT.
o
Monitor the effects of palifermin on thymic function in persons undergoing 
alloHSCT. 
o
Assess for post-transplant outcomes including: 
o
overall survival
o
failure-free survival
o
non-relapse mortality (death in clinical remission)
o
relapse-related mortality (death without clinical remission)
o
GVHD related mortality
o
rate of achieving remission, malignancy relapse (recurrence after 
remission)/progression


Abbreviated title: Palifermin dose escalation
Version date: 4/7/2022
                                                                                                                   8
o
incidence of infections
o
engraftment of neutrophils and platelets, graft failure
o
incidence of starting steroids and steroids administration AUC
o
rate of starting secondary therapy for acute and chronic GVHD 
separately
o
time to permanent (>6 months) interruption of immunosuppression
o
malignancy remission
o
chronic (cGVHD) severity at last yearly follow-up.
o
Assess the fraction of patients who experience grade II-IV acute GVHD 
(aGVHD) and compare it to the fraction from the TMS arm of the NCI 
07C0195 study.
1.2
BACKGROUND 
Allogeneic hematopoietic stem cell transplantation (alloHSCT) is capable of producing 
sustained remissions in patients with hematologic malignancies. Less than one-third of 
transplant candidates have an HLA-matched sibling donor (MSD) available. For these 
persons, HLA-matched adult unrelated donors (URD) have become the preferred stem 
cell source for alloHSCT and is currently a most prevalent and rapidly growing source of 
stem cells for alloHSCT [1, 2]. The use of URDs has expanded the number of persons 
who proceed to alloHSCT but has led to a greater risk of transplant related toxicity, 
principally GVHD and infections [3]. While advances in HLA typing and supportive care 
have decreased transplant-related mortality, the problem of higher rates of late 
complications, especially chronic GVHD after URD alloHSCT, became a major source 
of morbidity and mortality in hematologic cancer patients who are survivors of this 
procedure [3, 4].
Multiple methods to reduce the incidence of chronic GVHD in persons undergoing URD 
alloBMT have been tested in clinical trials. Functionally, these studies have focused on 
reduction in the T-lymphocyte content of the donor stem cell product or administration of 
anti-thymocyte globulin in order to reduce alloreactivity.[5-8] These studies remain 
inconclusive in terms of ultimate benefit for patients in terms of GVHD reduction and 
survival and major concerns remain relative to malignancy control especially in the 
reduced intensity conditioning setting[9]. In order to test the hypothesis that T-
lymphocyte depletion results in decreased chronic GVHD, we conducted a randomized 
phase 2 study (NCI 07C0195) whereby persons with hematologic malignancies 
received an unmodified HLA-matched or single antigen mismatched URD alloHSCT 
graft. Subjects were randomized to GVHD prophylaxis with alemtuzumab (humanized 
anti-CD52 antibody) based in vivo lymphodepletion followed by cyclosporine 
monotherapy (AC arm) versus tacrolimus, sirolimus, and methotrexate (TMS arm). 
Seventy-eight persons have been transplanted at the time of the most recent analysis 
(January 2014). 69 individuals had survived >100 days post-transplant. The 24-month 
overall survival (OS) in AC and TMS were similar but favored TMS (69.8% versus 
49.6%, p=0.052 by Gray test). The most recent analysis of 78 randomized patients 
showed no difference in the rate of grade 2-4 acute GVHD (6 month probability: TMS = 
50.5%, AC = 44.7%; p=0.74). The cumulative incidence of chronic GVHD at 24 months 
was 57.5% in TMS arm vs. 21.8% in AC arm (P=0.0004). Persons receiving AC had 
lower numbers of T- and B-lymphocytes during the first 12 months post alloHSCT 


Abbreviated title: Palifermin dose escalation
Version date: 4/7/2022
                                                                                                                   9
(Figure 1, Gress lab), higher rates of total infections and especially CMV. Finally, there 
was a trend for lower probability of incidence of progressive disease in TMS versus AC 
at 24 months, 27.6% versus 49.6% (P = 0.052 by Gray test). In summary, these results 
indicate that in vivo T-cell depletion is effective at reducing chronic GVHD but does not 
improve overall survival likely due to effects related to impaired recipient immune 
reconstitution. 
Figure 1: Peripheral blood lymphocytes (log-10 scale) following URD allogeneic 
transplantation using AC (grey line) versus TMS (dark line)
One hypothetical approach to reduce acute and chronic GVHD after alloHSCT is 
cytoprotection of target tissues such as skin, mouth, eye, gut and thymus. Injury to 
these tissues during conditioning chemotherapy may result in exposure to alloantigens 
or pathogen antigens that trigger the GVHD cascade or disrupt thymic function in 
establishing immune tolerance [10-12]. The advantage of such an approach is that it is 
GVHD specific, hypothetically sparing anti-tumor or anti-pathogen immunity. One 
pharmacologic mechanism to test this hypothesis is via use of epithelial cell 
cytoprotectants in the context of URD alloBMT. Of available agents, recombinant 
human keratinocyte growth factor-1 has accumulated the most preclinical and clinical 
efficacy.
1.2.1 Recombinant Human Keratinocyte Growth Factor (Palifermin) 
Keratinocyte growth factor-1 (KGF) is a 28 kDa endogenous fibroblast growth factor that 
binds to FGF receptor 2b (FGFR). FGFR is widely expressed on epithelial cell tissues 
including the oral mucosa, gastrointestinal tract, bladder, skin, salivary gland, and 
thymus. Binding of KGF to KGFR induces proliferation and anti-apoptosis in target 
tissues. Hematopoietic cells do not express FGFR and are thus unaffected by KGF. 
Palifermin (Swedish Orphan Biovitrium AB, Stockholm, Sweden) is a recombinant 
human KGF-1 that differs from the endogenous human form by a 23 amino acid 
deletion at the N-terminus to increase stability. 


Abbreviated title: Palifermin dose escalation
Version date: 4/7/2022
                                                                                                                   10
1.2.2 Palifermin Pre-Clinical Studies
1.2.2.1 Effect of Palifermin on Acute GVHD in allogeneic HSCT mouse models
Because palifermin induces cytoprotection of GVHD target tissues, murine studies were 
performed to determine if peri-transplant palifermin would reduce the incidence of 
GVHD. Krijanovski and colleagues administered KGF in a murine allo-HSCT transplant 
model on days -3 to 0 or days -3 to +7. The administration of KGF resulted in decreased 
mortality (p<0.01) in both treatment schedules. There were also decreased levels of 
inflammatory mediators (lipopolysaccharide [LPS] and TNF-alpha), reduced acute 
GVHD, and longer leukemia-free survival. The authors found the incidence of recipient 
alloantigen specific cytotoxic T-lymphocytes was unaffected by KGF, thus suggesting 
that GVL was not affected by KGF in this model [13]. Panoskaltsis-Mortari and 
colleagues administered KGF at a dose of 5 mg/kg on Day -6, -5, -4 pre-transplant in a 
murine allo HSCT model with and without conditioning therapy. The authors noted a 
beneficial effect on 80 days survival and incidence of acute GVHD independent of the 
use of conditioning treatment [14]. 
1.2.2.2 Effect of Palifermin on the Thymus, Chronic GVHD and Immune Reconstitution 
in allogeneic HSCT mouse models
Min and colleagues tested palifermin at a dose of 5 mg/kg/day for 3 days pre-cytotoxic 
treatment vs. placebo, and found that KGF-treated mice had improved thymic cellularity, 
normalized thymic subpopulation and increased peripheral naive T cells [15].  In an 
allogeneic, non-irradiated allo HSCT mouse model for acute GVHD, Rossi and 
colleagues administered palifermin 5 mg/kg/day vs. placebo on days -3 to +3. Although 
the administration of palifermin failed to modulate the incidence of splenic acute GVHD, 
it was found to be associated with preserved, normal thymic size and cellularity 2 weeks 
after HSCT [16]. 
Using a minor antigen mismatch model of chronic graft versus host disease in mice, it 
was found that KGF protected mice from lethality in a dose dependent pattern (Gress 
laboratory murine transplant model B10.D2 to BALB/c with or without thymectomy [17]. 
Mice were lethally irradiated (850 cGy on day 0) using KGF at 5, 10, 50, 100 µg/day on 
days -4, -3 and -2 prior to total-body irradiation. Cumulative doses were 15, 30, 150 and 
300 µg, respectively. There was an effect on immune reconstitution at the latter two 
doses (150 and 300 µg cumulative dose). At the highest dose (300 µg), 100 day 
survival in thymus bearing mice receiving KGF was 90% versus 0% survival in carrier 
treated animals.  In thymectomized mice, those receiving KGF had a survival at 100 
days of 65% versus 0% in control animals.  The difference of enhanced survival 
between thymus bearing and thymectomized animals (25%) was associated with 
enhanced thymus activity.  While specific dose per kilogram of KGF and attendant 
toxicities may not translate from mouse to man, the concept that dose may matter in 
preventing chronic graft versus host disease is potentially of great importance and has 
not been explored in any rigorous fashion (Figure 2). 


Abbreviated title: Palifermin dose escalation
Version date: 4/7/2022
                                                                                                                   11
Figure 2: Survival of mice undergoing transplantation with or without palifermin 
pretreatment.
Recovery of immune function is an important predictor of survival in persons undergoing 
alloHSCT [18-21]. Pre-clinical models suggest that palifermin may augment immune 
reconstitution in this setting. For example, Alpdogan and colleagues found that KGF 
knockout mice demonstrated defective thymopoiesis and peripheral T-lymphocyte 
reconstitution after sub-lethal radiation, with increased donor derived CD8 and naïve 
CD4 T-cells [22]. Volk and colleagues found that KGF enhanced tumor specific 
cytotoxic T-lymphocytes in a murine post-transplant tumor vaccine model. [23] Finally, 
Gress and colleagues (unpublished data) demonstrated improved reconstitution of 
CD4+, CD8+, and double positive T-lymphocyte populations after administration of KGF 
in a murine transplant model (Figure 3).


Abbreviated title: Palifermin dose escalation
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                                                                                                                   12
Figure 3: Improved reconstitution of major T-lymphocyte subpopulations after 
syngeneic (blue), allogeneic with diluent (red) or allogeneic with KGF (orange) 
transplantation in mice.
In a non-human primate study published by Suggewiss R. et al [24], rhesus macaque 
monkeys received palifermin 250 µg/kg/day on Day – 5 (n=4) or on days -5, -4, -3, 0, 
+1, +2 (n=2) of TBI and autologous HSCT rescue. The goal of the study was to 
determine the effect of palifermin on immune reconstitution, and found that CD4 and 
CD8 naïve T cell frequencies in lymph nodes were higher in KGF treated animals vs. 
untreated animals. Animals who had received 6 doses of KGF had higher T-cell 
receptor excision circle (TREC) levels in CD4 and CD8 T cells at >= 5 month post-
transplant. In addition, all 6 KGF treated animals had no or little thymic atrophy, 
whereas 3 out of the 5 control animals had severe thymic atrophy. This is the only non-
human primate study to show the effect of palifermin on thymic function in an 
autologous transplant setting.   
1.2.3 Clinical Experience: Pharmacokinetics, Pharmacodynamics, Safety
The toxicity and pharmacokinetics of palifermin has been extensively studied in humans 
for prevention of chemo or radiotherapy induced mucositis. Meropol and colleagues 
tested various doses and administration schedules of palifermin in metastatic colon and 
rectal cancer patients receiving fluorouracil for 5 days (day +4 to +8) [25]. Palifermin 
was administered on Day +1 to +3 at escalating doses, starting at 1 to 80 µg/kg/day IV 
(3 to 240 µg/kg, cumulative dose). Patients receiving palifermin had reduced incidence 
of grade 2 to 4 mucositis (43% KGF group vs. 67% placebo). The patients who received 
20 µg/kg/day or more had the largest decreases in mucositis incidence compared to 
placebo (25% to 35% decrease in mucositis). Maximum tolerated dose was defined as 
the highest dose tested for which <=33% of patients received that dose experienced a 
dose limiting toxicity, defined by grade 3 or greater adverse event or grade 2 adverse 
event that the subject found intolerable. Twelve subjects were planned per dose level. 
Three adverse events involving the skin occurred in the 18 patients who received 60 or 
* p< 0.05 for all Syn vs. Allo-Dil 
and Allo-KGF Groups


Abbreviated title: Palifermin dose escalation
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                                                                                                                   13
80 µg/kg/day. Although the predefined definition of maximum tolerated dose was not 
met, dose escalation beyond 80 µg/kg/day was halted since there appeared to be 
evidence of biologic activity based on the reduction in the frequency of grade 2 to 4 
mucositis in these two group of patients (60 µg/kg/day: -25% and 80 µg/kg/day: -30%). 
As for other skin and oral toxicities associated with KGF, they were generally mild to 
moderate with onset 36 hours after administration and resolution after 7-10 days. 
Zia-Amirhosseini and colleagues assessed the pharmacokinetics, pharmacodynamics 
and safety of palifermin in healthy volunteers after single, escalating doses starting at 
60 µg/kg and administered as IV boluses [26]. The pharmacodynamic endpoint selected 
for this study was a 3-fold or greater increase in oral mucosal epithelial Ki67-stained 
area per millimeter, as compared to baseline at 48 and 72 hours post-palifermin 
administration. The t1/2 ranged from 4.5 hours at a 60 μg/kg dose to 6.1 hours at 250 
μg/kg, and the AUC was approximately linear across this dose range. Results from Ki67 
staining showed that 13 out of 16 patients who received doses of 120, 160, 210 or 250 
µg/kg achieved the primary endpoint of a 3 fold increase in Ki67-stained area per 
millimeter, and a greater dose response was observed at 48 hours than at 72 hours. 
The drug was well tolerated at these dose levels, and all adverse events (AE) recorded 
were transient and resolved without intervention. No serious AEs were reported and no 
subject discontinued because of an AE. Erythema, warm sensation, elevated amylase 
level were more frequently noted at 210 – 250 µg/kg than lower dose levels. Since there 
was a sufficient pharmacodynamic response at 120 µg/kg and higher doses, as well as 
in an effort to minimize AEs (erythema, warm sensation), a single dose of 120 to 180 
µg/kg was selected for further studies.
A follow-up study by Zia- Amirhosseini and colleagues tested whether a collapsed dose 
of 180 mcg/kg/day was as effective as 60 µg/kg/day in patients with hematological 
malignancies [27]. Patients in the 60 µg/kg/day arm received palifermin for 3 
consecutive days before and 3 consecutive days after chemoradiotherapy and 
autologous HSCT. Patients in the 180 µg/kg/day arm received palifermin once before 
(72 hours before starting conditioning) and once after myeloablative treatment). They 
found that there was similar overall exposure to palifermin in both groups with 
approximately dose-linear pharmacokinetics, and both dosing regimens were well 
tolerated.  
1.2.4 Clinical Experience: Autologous HSCT
Palifermin was approved by the Food and Drug Administration for prevention of 
chemotherapy induced mucositis based on a large, randomized study demonstrating a 
35% reduction in persons undergoing a total body irradiation based autologous HSCT. 
[28]. In this double-blind, randomized study, 212 patients with various hematologic 
cancers were randomized to palifermin vs. placebo, comparing the development of oral 
mucositis which was evaluated daily up until day 28 post-autologous HSCT. The dose 
of palifermin administered was 60 µg/kg/day for three consecutive days pre-conditioning 
and three days post- autologous HSCT. AEs included rash, pruritus, erythema, mouth 
and tongue disorders, and taste alterations.  All AEs were transient (occurring three 
days after the third dose of palifermin and lasting approximately three days), and mild to 
moderate in severity. 


Abbreviated title: Palifermin dose escalation
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                                                                                                                   14
1.2.5 Clinical Experience: Allogeneic HSCT
Based on pre-clinical GVHD models Blazar and colleagues conducted a phase I/II 
randomized, placebo-controlled study examining the effect of palifermin on development 
of acute GVHD in humans undergoing alloBMT [29]. One-hundred persons were 
randomized 2:1 to receive palifermin 40-60 µg/kg/day x 3 doses pre-transplant followed 
by a dose escalation of 60 µg/kg/day up to 9 doses post-transplant. At the highest dose 
level (60 µg/kg/day x 12 doses total), 65% of persons completed the prescribed 
treatment regimen. The most common reason for discontinuing palifermin was 
erythematous skin reaction (3 patients). Other AEs related to palifermin vs. placebo 
were edema (78% vs. 65%), local pain (88% vs. 77%), and infection (11% vs. 0%). 
These events did not result in serious injury to any patient and resolved after drug 
removal.  The rate of acute GVHD was not different between the placebo and palifermin 
arm. Similarly the rate of relapse was not different between the placebo and palifermin 
arms. A subsequent follow-up study did not show any impact on chronic GVHD either 
[30]. Thus, the authors concluded that palifermin was tolerated post-transplant but did 
not result in meaningful benefit at these doses; however, more prolonged palifermin 
administration was associated with highest incidence of side – effects.  
In 2012, Jagasia and colleagues published the results of a phase 3, double-blind, 
randomized trial in which patient undergoing related donor or unrelated 6/6 matched allo 
HSCT received either palifermin (n=77) or placebo (n=78) with a primary aim to explore 
the role of palifermin in reducing the incidence of severe (grade 3-4) acute GVHD [31]. 
All patients underwent myeloablative conditioning, and the palifermin or placebo dose 
was 60 µg/kg/day on three days before the start of conditioning and then a single dose 
of palifermin 180 µg/kg or placebo at least 24 hours after the last dose of conditioning 
chemotherapy or radiation therapy. No significant difference was noted in the palifermin 
arm vs. placebo arm in terms of severe acute GVHD incidence (17% vs. 16&), and rates 
of mucositis were also similar (grade 3-4 mucositis was 73% in palifermin arm vs. 62% 
in placebo arm). AEs attributed to palifermin were tongue disorders, rash and pruritus, 
but all AEs were mild to moderate as well as transient. 
Unfortunately these results are difficult to interpret in terms of GVHD prevention due to 
the doses selected in each study. While similar to that approved by the Food and Drug 
administration for mucositis prevention in the autologous HSCT setting, palifermin dose 
was comparatively much lower than that used in murine models where a benefit in 
GVHD, thymic function and immune reconstitution was observed. 
1.2.6 Palifermin dose effects in patients undergoing chemotherapy +/- radiation for 
solid tumors
Palifermin has been tested in cancer patients using larger doses. Two studies tested 
palifermin at a dose of 180 µg/kg/week x 8 weeks in persons undergoing 
chemoradiotherapy for head/neck squamous cell carcinoma. The first, conducted by Le 
and colleagues, was a randomized, placebo controlled study in 188 persons receiving 
70 Gy of radiotherapy in combination with cisplatin 100 mg/m2 on days 1, 22, and 43. 
[32]. Palifermin was administered weekly at 180 mcg/kg/week for 7 weeks, for a 
cumulative dose of 1260 µg/kg. The drug was tolerated well, with the most common 
grade 3-4 adverse events (AE) reported in the palifermin group being skin rash (9%), 


Abbreviated title: Palifermin dose escalation
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                                                                                                                   15
flushing (5%) and dysguesia (5%). One episode of severe pancreatitis was observed. A 
reduction in grade 3-4 mucositis was observed in the palifermin group compared to 
placebo (54% vs. 69%, p=0.041). 
The second study, conducted by Henke and colleagues, randomized 186 persons 
undergoing 60-66 Gy of radiotherapy plus a similar dose of cisplatin to placebo versus 
palifermin 180 μg/kg/week for up to 8 weeks, for a total cumulative dose of 840 – 1440 
µg/kg [33]. Total adverse events in the palifermin versus control arms included 
dysphagia (35% versus 21%), diarrhea (12% versus 5%), and leukopenia (5% versus 
13%). Elevations in amylase and/or lipase were noted in about 50% of persons 
receiving palifermin but these abnormalities resolved spontaneously in the first three 
weeks of treatment. In both trials greater than 75% of persons completed the study 
drug. A reduction was seen in the incidence of grade 3-4 mucositis in the palifermin vs. 
placebo group (51% vs. 67%, p = 0.027). The authors of these studies conclude that 
this dose of palifermin is tolerable in persons undergoing chemoradiotherapy. 
A summary of the clinical experience with palifermin described in this section, in 
addition to several other prospective and retrospective studies involving the use of 
palifermin in the allogeneic setting are detailed in Table 1 (please see below).
 


Abbreviated title: Palifermin dose escalation
Version date: 4/7/2022
                                                                                                                   16
Table 1: Summary of the clinical studies carried out in humans
Ref.
No. of 
Persons
Conditioning 
/chemothera
py
Dosing
Cumulative 
dose
Toxicities 
aGVHD
Survival
Mucositis
Immune 
reconstit.
Phase 1
Meropol, N. 
2003  [25]
Metastatic 
colon or 
rectal 
cancer
N = 54 
KGF
N=27 
placebo
FU for 5 
days (day +4 
to +8)
Palifermin 
IV mcg/kg/ 
day on Day 
+1 to +3. 
Dosing: 1, 
10, 20, 40, 
60, 80 
mcg/kg/ day
3, 30, 60, 
120, 180, 
240 mcg/kg 
(over 3 
days)
18 rash, 6 
flushing, 13 
pruritus, 2 
edema, 43 
oral 
symptoms, 
19 nausea, 
48 pts 
Amylase 
and lipase 
elevated 
18 DLT skin 
Grade 2-4: 
43% KGF 
vs 67% 
placebo
Decrease in 
OM 
incidence in 
KGF vs. 
placebo:    
10mcg:12% 
20mcg:35%
40mcg:35%
60mcg:25%
80mcg:30% 
Zia-
Amirhossein
i, P et al  
2006 [26]
Healthy 
volunteers
Initially age 
18 to 55
none
Single dose 
IV 
palifermin, 
randomized, 
double blind
Starting at 
60 mcg N= 
63 
palifermin
N=16 
placebo
Max 
tolerated 
dose 250 
mcg/kg.
Majority of 
palifermin 
exposure in 
first 24 
hours, 
>95% AUC 
0-inf i
AUC 3x 
from 60 to 
250 (4x)
1 midcycle 
abd pain, 
Asymptoma
tic elevated 
lipase levels 
(pts > 30 
yo, non-
doses 
related), 
16erythema
, 10warm 
sensation, 
21 access 
pain, 17 
amylase, 8 
lipase


Abbreviated title: Palifermin dose escalation
Version date: 4/7/2022
                                                                                                                   17
Ref.
No. of 
Persons
Conditioning 
/chemothera
py
Dosing
Cumulative 
dose
Toxicities 
aGVHD
Survival
Mucositis
Immune 
reconstit.
Zia-
Amirhossein
i, P et al.  
2007 [27]
Auto 
HSCT
N = 13 
standard 
dose group
N=12 
collapsed 
dose group
TBI 12 Gy 
Day -8 to -5,
Etoposide 
Day -4 
Cyclophosph
amide Day -2
Standard 
dose group: 
palifermin 
60 mcg/kg/d 
IV on Day -
11, -10, -9, 
0, +1, +2).
Collapsed 
dose group: 
180 mcg/kg 
IV on day -
11 and 0 
Standard 
dose: 
360 mcg/kg
Collapsed 
dose: 
360 mcg/kg
Mean AUC 
on D-11 and 
D0 were 4 
fold higher 
for 
collapsed-
dose 
Standard 
vs. 
collapsed:  
Rash 9vs.8, 
Diarrhea 13 
vs.12, 
nausea 13 
vs.12, 
pruritus 9 
vs.5, abd 
pain 9 vs.2, 
vomiting 8 
vs.6, 
anxiety 7 
vs.2, 
increase  
amylase/ 
lipase.
Srinivasan 
A, et al. 
2012 [34]
N = 12, 
pediatric 
undergoing 
allogeneic 
HSCT
Cy/TBI
Or 
TBI/Cy/ATG
GVHD 
prophylaxis 
MMF or TMS 
or 
calcineurin/p
entostatin
IV bolus: 
Day -9 to -7 
or Day -11 
to -9 pre-
conditioning 
and Day +1, 
+2, +3
3 dose 
levels: 40, 
60, 
90mcg/kg/d
ay
dose levels:
240 mcg/kg   
360 mcg/kg    
540 mcg/kg
8 Rash, 1 
facial 
edema, 2 
abd pain, 1 
vomiting, 1 
diarrhea, 1 
headache, 4 
elevated 
AST, 2 
elevated 
ALT. No 
lipase 
/amylase 
changes.
83% 
survival at 
median 
follow-up 
27%, 75% 
without 
progression 
of disease
(25%) 
mucositis. 
Phase 2


Abbreviated title: Palifermin dose escalation
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                                                                                                                   18
Ref.
No. of 
Persons
Conditioning 
/chemothera
py
Dosing
Cumulative 
dose
Toxicities 
aGVHD
Survival
Mucositis
Immune 
reconstit.
Blazar et al. 
2006 [29]
Follow-up 
report: 
Levine/Blaz
ar, BBMT 
2008
UMinn, 
UMich
Palifermin: 
N=69
Control:
N=31
Allogeneic  
6/6 HLA 
matched 
sibling 
donor
Cy/TBI 
or
Bu/Cy
GVHD 
prophylaxis:
MTX (D+1, 3, 
6, 11)+ 
calcineurin 
Pre-
conditioning 
(D-11,-10 ,-
9)
Cohort 1: 
40-60 
mcg/kg/d) 
(D 0, +1, + 
2)
Cohort 2: 60 
mcg/kg 
/day)(D0, 
+1, +2 and 
D+7 to 9)
Cohort 3: 60 
mcg/kg 
/day)(D0, 
+1, +2 and 
D+7 to 9,  
D+14to 16
Cohort 1: 
240 – 360 
mcg/kg
Cohort 2: 
540 mcg/kg
Cohort 3:
720 mcg/kg
patients 
with DLT: 2 
resp event, 
3 skin 
reaction, 1 
cardiac 
event, 1 
hepatic 
enzyme 
elevation 
AEs 
palifermin 
vs. placebo: 
edema 
78%vs65%, 
infection 
11%vs.0%, 
local pain 
88%vs77%, 
rash  
94%vs68%
No 
difference in 
incidence or 
severity 
aGVHD 
Follow-up: 
cGVHD at 2 
years (55 
vs. 53%)
No 
difference in 
survival (84 
vs. 82% at 
day 100) or 
Day 100 
relapse
Follow-up: 
long term 
survival at 2 
yrs. 
(palifermin 
46% vs. 
placebo 
58%, p = 
0.42).
Overall 
severity 2.8 
vs. 2.3, 
p=0.01
Cy/TBI had 
grade 3-4 
mucositis    
(100% 
placebo to 
81% 
palifermin, 
p=0.05) 
No 
difference in 
Bu/Cy 
group (50% 
vs 
44%mean 
severity 2.4 
vs. 2.0) 
Follow-up: 
no 
difference in 
CMV or 
invasive 
fungal 
infections at 
1 year
Median ALC 
at day 30, 
60, 100, 
after 
transplant 
did not 
significantly 
differ 
Rosen, LS 
et al. 2006 
[35]
Colo-
rectal, 
metastatic
N = 28 
palifermin
N= 36 
placebo
FU/
leucovorin
40 mcg/kg 
IV for 3 
consecutive 
days
120 mcg/kg 
Palifermin 
vs. placebo: 
skin rash 67 
vs 54%,  
tongue 
issues 64%  
vs. 44%, 
Amylase 
39% vs. 6%  
lipase 64% 
vs. 17%
Grade 2-4: 
29% 
palifermin 
vs. 61% 
placebo in 
cycle 1, 11 
vs. 47% 
cycle 2


Abbreviated title: Palifermin dose escalation
Version date: 4/7/2022
                                                                                                                   19
Ref.
No. of 
Persons
Conditioning 
/chemothera
py
Dosing
Cumulative 
dose
Toxicities 
aGVHD
Survival
Mucositis
Immune 
reconstit.
Nasilowska-
Adamska, B 
et al 2007 
[36]
Follow-up: 
Nasilowska-
Adamska, B 
et al  2011 
[37] 
N = 53 
palifermin 
(n=29 
auto,    n = 
24 allo)
N= 53 
control, 
(retrospecti
ve,  n=29 
auto, n=24 
allo)
Myeloablativ
e regimens
No T 
depleted 
grafts
60 mcg/kg/d 
IV for 3 
days pre-
conditioning 
and 3 days 
post 
conditioning 
(total 6 
doses)
360 mcg/kg
15 rash, 15 
taste 
change, 
14pruritus, 
13 
erythema, 
10 general 
edema,   13 
white film 
on tongue
Palifermin 
vs. control 
group: 25 % 
vs. 50% 
control 
group 
(p=0.14)
Liver 
aGVHD 
8.3% vs. 
37.5%, 
p=0.036
cGvHD: 
41% vs. 
53.8% 
(p=0.70)
OS at 36 
months f/u: 
62.3% 
palifermin 
vs. 72.8% 
control, 
p=0.13
Auto: Grade 
1-4 45% 
palifermin 
vs. 96% 
control 
(p<0.001),      
Grade 3-4  
(7% 
palifermin 
vs. 28% 
control, 
p=0.037)
Allo: Grade 
1-4:  75% 
palifermin 
vs. 92% 
control 
(p=0.04),        
Grade 3-4 
21% 
palifermin 
vs. 63% 
control 
(p=0.003)
Retrospective 
Langner 
S,et al 2008 
[38]
N = 30 
palifermin
alloHSCT 
Myeloablativ
e transplant  
Cy/TBI or 
Bu/Cy
GVHD 
prophylaxis 
CYA and 
60 mcg/kg/d 
for 3 
consecutive 
days before 
initiation of 
conditioning 
therapy, 
and three 
days after 
10 Rash, 10 
erythema, 5 
white 
coating on 
tongue, 4 
taste 
alteration, 1 
painful 
swelling 
gum, 
Grade 2-4 
aGVHD 
31% vs. 
30%, grade 
3-4 aGVHD: 
17 vs. 20%
OS day 100 
similar: 90 
vs. 86%
Grade 2-4: 
60% 
palifermin 
group, 86% 
control 
group 
(p=0.04)
Grade 3-4: 
37% 


Abbreviated title: Palifermin dose escalation
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                                                                                                                   20
Ref.
No. of 
Persons
Conditioning 
/chemothera
py
Dosing
Cumulative 
dose
Toxicities 
aGVHD
Survival
Mucositis
Immune 
reconstit.
MTX, +/- 
ATG
graft 
infusion
tongue, lips, 
mammary
palifermin 
vs. 53% 
control 
(p=0.19)
Goldberg 
JD, et al 
2013 [39]
N = 251, 
allo HSCT
(n=154 
receiving 
peri-
transplant 
palifermin)
N=121 TBI 
based, 64% 
received 
palifermin
N=130 
chemo 
based, 59% 
received 
palifermin
60 mcg/kg/d 
in three 
daily doses 
pre-
transplant, 
and then 3 
additional 
daily doses 
60 mcg/kg/d 
starting 6 
hours after 
PSCT 
64 rash,  22 
oral 
hyperplasia/
discoloratio
n, 11 
edema of 
hands or 
feet
No effect on 
aGVHD or 
cGVHD
No effect on 
relapse.
No effect on 
OS or EFS
If TBI, PCA 
(palifermin 7 
vs. control 
12 days, 
p=0.023),  
TPN (7 
palifermin 
vs. control 
13 , 
p=0.0002). 
For non-
TBI:   no 
benefit 
observed 
Phase 3
Spielberger 
R. et al 
2004 [28]
Auto 
HSCT
N = 106 
palifermin
N= 106 
placebo
TBI 1200 
cGy,
Etoposide 
60mg/kg on 
Day-4, and 
cyclophosph
amide 100 
mg/kg on 
Day -2 
60 mcg/ 
kg/day IV 
for 3 days 
pre-
conditioning 
(i.e. starting 
3 days 
before 
initiation of 
TBI)
180 mcg/kg  
(over 3 
days)
Palifermin 
vs placebo: 
Rash 55vs 
46%, 
pruritus 
50vs32%, 
erythema 
33vs.30%, 
edema 
27vs.17%, 
taste 
change 
22vs9%
Grade 3-4, 
63% vs. 
98% 
(p<0.001)
Grade 4 
(20% vs. 
62%, 
P<0.001)
Incidence 
febrile 
neutropenia 
(72 vs. 
95%, 
p<0.001)


Abbreviated title: Palifermin dose escalation
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                                                                                                                   21
Ref.
No. of 
Persons
Conditioning 
/chemothera
py
Dosing
Cumulative 
dose
Toxicities 
aGVHD
Survival
Mucositis
Immune 
reconstit.
Vadhan-Raj 
S, et al 
2010 [40]
Sarcoma 
patients, 
multi-cycle 
chemo
N= 32 
palifermin 
N=16 
placebo 
Doxorubicin-
based 
chemotherap
y (90mg/m2 
over 3 days)
Max 6 cycles
180 mcg/kg 
as single 
dose IV 3 
days before 
each chemo 
cycle
180 mcg/kg
Palifermin 
vs. placebo: 
thickness 
oral mucosa 
72vs.31%, 
altered taste 
44 vs. 19%, 
flushing 38 
vs.13%, film 
in mouth 34 
vs. 13%, 
gum 
sensitivity 
28 vs. 6%
Grade 2-4: 
44% 
palifermin 
vs. 88% 
placebo 
(p<0.001).
Grade 3-4: 
13% 
palifermin 
vs. 51% 
placebo 
(p=0.002)
Henke M, et 
al 2011 [33]
Stage II to 
VIB ENT 
cancer 
with post-
op CRT
N=92 
palifermin
N=94 
placebo
60 or 66 
cGY, with 
cisplatin 100 
mg/m2 Day 
1, 22, 43
120 mcg/kg 
or placebo 
once weekly 
from - 3 
days and  
throughout 
radio/chemo
therapy
840 mcg/kg 
– 960 
mcg/kg
Palifermin 
vs. placebo: 
dysphagia 
35 vs. 21%, 
diarrhea 12 
vs. 5%, 
asthenia 14 
vs. 8%, 
headache 
10 vs. 4%, 
Grade 3 or 
4 amylase 
levels 50% 
vs. 42%  
25% deaths 
overall, 
disease 
relapse 
27% 
palifermin 
vs.  24%  
placebo 
Grade 3-4: 
51% 
palifermin 
vs. 67% 
placebo 
(p=0.027)
Decreased 
duration 
(median 4.5 
vs. 22 days) 
Le QT, et al 
2011 [32]
Stage III to 
IVb ENT 
cancer, 
definitive 
CRT
N= 94 
palifermin, 
70 Gy + 
Cisplatin 
(mean 
duration of 
radiation 50 
days)
180 mcg/kg 
IV or 
placebo 
before  
radio/chemo 
and  weekly 
for 7 weeks
1440 
mcg/kg
Palifermin 
vs placebo: 
rash 9 vs. 
2%, flushing 
5 vs. 0%, 
dysgeusia 
5vs1%, 
Grade 3-4: 
54% 
palifermin 
vs. 69% 
placebo arm 
(p=0.041)


Abbreviated title: Palifermin dose escalation
Version date: 4/7/2022
                                                                                                                   22
Ref.
No. of 
Persons
Conditioning 
/chemothera
py
Dosing
Cumulative 
dose
Toxicities 
aGVHD
Survival
Mucositis
Immune 
reconstit.
N= 94 
placebo
100 mg/m2 
on Day 1, 22, 
43
nausea 
4vs1%.  1 
necrotic 
pancreatitis
Jagasia 
MH. Et al 
2012 [31]
Related 
donor or 
unrelated 
6/6 
matched 
allo HSCT
N=77 
palifermin
N = 78 
placebo
Myeloablativ
e: D-11 to -2.
Cy + TBI +/- 
etoposide, 
TBI + 
etoposide
Melphalan + 
TBI
Bu/Cy
Busufan/ 
melphalan or 
fludarabine 
melphalan
GVHD: MTX 
day 1, 3, 6, 
11 + 
calcineurin 
Placebo or 
Palifermin 
60 mcg/kg/d 
IV on 3 
days pre-
condition
+ palifermin 
180 mcg/kg 
IV or 
placebo 24h 
post-
myeloablati
ve Tx 
360 mcg/kg
Palifermin 
vs. placebo 
AEs:  
tongue 
disorders, 6 
vs. 0 
Rash, 11 
vs. 6 
Pruritus in 
10 vs. 4 
Erythema 4 
vs. 3 
Grade 3-4 
aGvHD 
similar, 17% 
vs. 16%
Grade 3-4 
mucositis 
no 
difference 
(73% vs. 
62%)
Grade 2-4 
mucositis 
88 vs.90%
TPN 49 vs 
69%


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23
1.3
SUMMARY AND RATIONALE FOR THE STUDY
In numerous pre-clinical studies, palifermin has been shown to have an effect on control 
of GVHD and immune reconstitution after alloHSCT. Palifermin has been FDA approved 
in the autologous HSCT setting after being found to decrease the incidence of 
mucositis, but in the allogeneic HSCT setting the two prospective studies completed 
thus far have not shown any improvement in the incidence of acute or chronic GVHD or 
clinical immune recovery although thorough clinical immunology studies were lacking. 
One possibility is that these studies with palifermin in the allogeneic HSCT setting 
yielded no clinical effect on GVHD or immune reconstitution due to the fact that the 
doses of palifermin were much lower than those used in animal models. The doses of 
palifermin in these human studies were selected based on different pharmacodynamic 
endpoints, namely the effect on mucosal protection through the epithelial protection 
mechanism, and not based on thymic or immunologic protection. In human studies, the 
AUC of palifermin linearly increases with collapsed dosing, increasing exposure to the 
drug in target tissues such as the thymus. In non-human primate autologous HSCT 
setting, doses of 1500 µg/kg given over the course of a week in 250 µg/kg single doses 
peri-transplant were well tolerated and there was a cumulative dose-effect on 
immunological reconstitution and thymic protection. In addition, the animal chronic 
GVHD mouse model by Chu et al [17] showed better survival and better lymphocyte 
recovery which was dose dependent. Single doses of 180 µg/kg in the allogeneic HSCT 
setting and cumulative doses of 720 µg/kg over 1-2 weeks or 1440 µg/kg over 8 weeks 
have been given in the chemoradiotherapy solid tumor setting with good tolerance.     
We hypothesize that there is a dose effect of palifermin on control of GVHD and 
immune reconstitution after alloHSCT and low dose administration of palifermin is not 
effective at reaching these endpoints.  Therefore we propose to administer higher dose 
palifermin in the pre alloHSCT setting. A single dose of 180 μg/kg is well tolerated in 
humans, therefore we propose to start at this dose level and increase palifermin in a 
stepwise fashion in the pre-conditioning chemotherapy administration period. The 
primary endpoint of the phase I study is to establish a safe and well-tolerated dose of 
palifermin. We will then expand the study in a phase II portion to test the hypothesis that 
the higher dosing schema will result in an improved rate of chronic GVHD in this study 
population. Results of this study will be compared to those of our previous study (NCI-
07C0195), where an identical conditioning (Flu/Cy) and GVHD prophylaxis (TMS) 
regimen was used without palifermin, to instruct the rationale for a larger, multicenter 
study outside of the NIH. Exploratory endpoints of this study include the examination of 
the effects of palifermin on acute GVHD and donor allograft immune reconstitution.


Abbreviated title: Palifermin dose escalation
Version date: 4/7/2022
24
2
ELIGIBILITY ASSESSMENT & ENROLLMENT
2.1
ELIGIBILITY CRITERIA
2.1.1 Induction Phase Inclusion Criteria
Patients meeting below eligibility criteria are eligible to receive suitable disease specific 
therapy for the purposes of disease control while the donor search takes place
2.1.1.1 The patient is ≥18 years of age.  
2.1.1.2 Ability of subject to understand and the willingness to sign a written informed 
consent document.
2.1.1.3 Karnofsky performance score > 60. 
2.1.1.4 No suitable HLA matched sibling donor is available and the patient has one or 
more potentially suitable HLA matched unrelated donor(s) in the National 
Marrow Donor Registry or other available registry. 

The evaluation of donors shall be in accordance with existing NMDP 
Standard Policies and Procedures (See Appendix E)

HLA-matched donors are defined by allele matching at HLA-A, -B, -C, and 
DRB1 (8/8). 
2.1.1.5 There is a high likelihood that the patient, in the opinion of the PI or LAI, will 
meet the research phase eligibility criteria and proceed to transplant after 
induction phase therapy is completed. 
2.1.1.6 Diagnosis of hematologic malignancy meeting at least one of the disease 
status criteria outlined in the table below. Diagnosis must be confirmed by the 
NCI laboratory of pathology. 
Table 2: Disease Status Criteria in HSCT Recipients
Disease
Disease Status
B-Chronic Lymphocytic Leukemia (CLL)
o
Relapse/progression after two previous 
regimens.
o
No response or progression ≤6 months 
after fludarabine or bendamustine 
based regimen.
o
Progression within 24 months of a 
fludarabine and alkylator combination 
regimen.
o
Progression after any regimen in the 
presence of del17p or mutated TP53.
o
Persons with high grade lymphoma 
transformation.


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25
Disease
Disease Status
Prolymphocytic Leukemia (PLL) T-CLL
o
T-PLL:  Treatment failure after 
Campath-1H and at least one other 
regimen
o
B-PLL:  Treatment failure after 
fludarabine and at least one other 
salvage regimen
Hodgkin Lymphoma
o
Primary treatment failure ineligible for 
autologous HSCT.
o
Relapse/progression after autologous 
HSCT.
Follicular Lymphoma, Marginal Zone 
Lymphomas (splenic, nodal, or 
extranodal/MALT type)
o
Primary refractory disease.
o
Relapse after > 2 prior regimens.
o
Relapse/progression after autologous 
HSCT.
Burkitt or Lymphoblastic Lymphomas
o
High-risk disease in remission.
o
Progression after ≥1 previous regimen.
o
Non-CR after salvage regimen.
Diffuse Large B-cell Lymphoma, 
Follicular Large cell Lymphoma, Mantle 
cell Lymphoma, Anaplastic Large Cell 
Lymphoma
o
Primary refractory disease.
o
Relapse/progression after autologous 
HSCT.
o
Non-CR after salvage regimen.
o
Cutaneous T-cell Lymphomas (Mycosis 
Fungoides, Sézary Syndrome)
o
≥Stage III
o
Disease progression > 2 prior regimens, 
including at least one systemic therapy.
Multiple Myeloma*
o
Relapse/progression after autologous 
HSCT
o
Plasma cell leukemia
o
Adverse cytogenetics: e.g. del(13q) or 
11q translocation.
o
*at the time of enrollment, MM must be 
in complete remission, see section 
2.1.1.11 for details
Acute Myelogenous Leukemia
o
In first complete remission (CR1) in 
addition to one of the criteria outlined in 
section 2.1.1.7.
o
Second or greater complete remission.
o
Secondary AML from antecedent 
myeloid neoplasm, myelodysplasia, or 
previous chemo or radiotherapy.
Acute Lymphocytic Leukemia
o
In complete first remission (CR1) in 
addition to one of the criteria outlined in 
section 2.1.1.8.
o
Second or greater complete remission.


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26
Disease
Disease Status
Myelodysplastic Syndrome
o
RAEB I or II
o
Intermediate, high or very-high risk per 
RIPSS
o
Secondary MDS
Myeloproliferative neoplasms (MPN) 
and myelodysplastic/myeloproliferative 
overlap neoplasms
o
Myelofibrosis with adverse-risk features 
as outlined in section 2.1.1.9
o
Polycythemia vera
o
Essential thrombocythemia
o
Chronic myelomonocytic leukemia
Chronic Myelogenous Leukemia
o
Chronic phase CML having progressed 
after treatment with BCR-ABL kinase 
inhibitor or with evidence of T315I BCR-
ABL mutation.
o
Accelerated or blast phase CML.
o
Not eligible for myeloablative allogeneic 
HSCT.
NK Cell Neoplasms
o
First CR for patients with high risk 
natural killer cell neoplasms including 
myeloid/NK cell precursor acute 
leukemia, blastic NK-cell lymphoma, 
aggressive NK-cell leukemia and nasal-
type extranodal NK-cell lymphoma in 
first complete remission.
o
Second or greater CR.
Mature T-cell Non-Hodgkin Lymphoma 
(see WHO for specific malignancies)
o
First CR
o
Relapse after greater than or equal to 1 
prior regimen
2.1.1.7 Recipients with AML in CR1 must have one of the following:
2.1.1.7.1 Adverse cytogenetics (as evaluated by history) as defined as complex 
karyotype (> 3 abnormalities); inv(3) or t(3;3); t(6;9); t(6;11); monosomy 7; 
trisomy 8, alone or with an abnormality other than t(8;21), t(9;11), inv(16) or 
t(16;16); or t(11;19)(q23;p13.1) or adverse-risk per European LeukemiaNet 
(ELN) 2017 criteria. [41, 42]
2.1.1.7.2 Intermediate-risk disease, such as cytogenetically normal AML (CN-AML) with 
mutations in FMS-like tyrosine kinase 3 (FLT3), DNA methyl transferase 3A 
(DMNT3A), or additional sex coombs like 1 (ASXL1) or per ELN 2017 criteria. 
[42-45]
2.1.1.7.3 Primary induction failure, defined as failure to achieve CR with primary 
induction chemotherapy. [46]
2.1.1.7.4 Secondary AML, defined as AML related to antecedent myeloid neoplasm or 
cytotoxic chemotherapy.
2.1.1.7.5 Hyperleukocytosis, WBC > 100,000, at diagnosis.


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27
2.1.1.8 Recipients with ALL in CR1 must have one of the following:
2.1.1.8.1 Adverse cytogenetics defined as translocations involving t(4;11), t(1;19), 
t(8;14), 11q23, t(9;22) or bcr-abl rearrangement, Philadelphia chromosome-
like (Ph-like ALL),  or complex cytogenetic abnormalities. 
2.1.1.8.2 Presence of minimal residual disease using multicolor flow cytometry or other 
analytic technique after primary induction chemotherapy. 
2.1.1.8.3 Primary induction failure, defined as failure to achieve CR with primary 
induction chemotherapy [47].
2.1.1.9 Recipients with myelofibrosis must have at least 2 of the following features, or 
be DIPSS intermediate-2 or high risk [48-50]:
2.1.1.9.1
Hemoglobin < 10 g/dl, or > 10 g/dl with transfusion dependence.
2.1.1.9.2
WBC < 4,000 or > 30,000/mm3 or requires cytoreductive therapy to 
maintain WBC < 30,000/mm3.
2.1.1.9.3
Abnormal cytogenetics.
2.1.1.10
Patients with lymphoma must ideally have at least stable disease from last 
therapy, however if the PI or LAI believes there is a high likelihood of response 
to induction chemotherapy (EPOCH-F+/-R), then the patient may be enrolled on 
the induction phase arm. For enrollment on the research phase arm, the patient 
must have at least stable disease which is defined as:
2.1.1.10.1
absence of disease progression for at least 8 weeks after previous therapy 
or 12 weeks after autologous transplantation.
2.1.1.10.2
Patients who are less than 8 weeks from previous therapy or 12 weeks 
from autologous transplantation may participate in the study at the discretion 
of the PI or LAI as long as they do not have progressive disease.
2.1.1.11
Multiple myeloma in complete remission is defined as per Durie BG et al. 
[51]:
2.1.1.11.1
Negative immunofixation on the serum and urine and disappearance of 
any soft tissue plasmacytomas and <=5% plasma cells in the bone marrow. 
CR requires two consecutive assessments by serum and urine immunofixation 
made at any time prior to enrollment. CR also requires no known evidence of 
progressive or new bone lesions if radiographic studies are performed. 
Confirmation with repeat bone marrow is not needed. 
2.1.1.12
The recipient has acceptable end organ function as defined by:
2.1.1.12.1
DLCO > 50% of the expected value (using USA-ITS-NIH equation) when 
corrected for Hgb (DLCO Adj.) 
2.1.1.12.2
24 hour creatinine clearance or calculated (using the Cockcroft-Gault 
formula) creatinine clearance > 60 mL/min/1.73 m2 (induction phase only)
2.1.1.12.3
Left ventricular ejection fraction > 45% 
2.1.1.12.4
Serum total bilirubin less than 2.5 mg/dl, and serum ALT and AST values 
less than or equal to 2.5 times the upper limit of normal. Patients with 
elevations of serum total bilirubin up to 10 mg/dl and/or ALT or AST up to 10 


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28
times the upper limit of normal may be considered for participation if such 
elevations are thought to be due to liver involvement by malignancy.  
However, in these latter patients, if the BR level does not decrease to less 
than or equal to 2.5 mg/dl, or AST/ALT do not decrease to less than or equal 
to 2.5 times the upper limit of normal after induction chemotherapy, eligibility 
for the transplant (research) phase will be at the discretion of the PI.
2.1.1.13
Patients who are hepatitis B core antibody positive and or have positive 
hepatitis B surface antigen will require hepatology consultation. The risk/benefit 
profile of transplant and hepatitis B will be discussed with the patient and 
eligibility determined by the PI or the LAI.
2.1.1.14
Patient may have a hepatitis C infection. However, each patient will 
require a hepatology consultation. The risk/benefit profile of transplant and 
hepatitis C will be discussed with the patient and eligibility determined by the PI 
or the LAI.
2.1.1.15
Palifermin has had embryotoxic and fetotoxic effects in animal studies. For 
this reason and because the other therapeutic agents used in this trial are 
known to be teratogenic, women of child-bearing potential and men must agree 
to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of active study therapy. 
Should a woman become pregnant or suspect she is pregnant while she or her 
partner is participating in this study, she should inform her treating physician 
immediately.
2.1.2 Research Phase Inclusion Criteria
2.1.2.1 Verification of donor eligibility (clearance must be received from the NMDP)

Donors are evaluated by NMDP affiliated donor centers per NMDP 
Standards (see Appendix E).
o
Donors who are medically suitable, but ineligible by FDA 
guidelines may still donate PBSC with documentation of urgent 
medical need by the PI.
o
Patients who receive stem cell products from ineligible donors 
will be informed of any increase in risk of transfusion-related 
diseases prior to initiation of conditioning chemotherapy.

Donors who are ineligible or unwilling to donate bone marrow will not 
be eligible to donate to study recipients.  However, in the event that the 
patient has already begun conditioning chemotherapy and a donor 
PBSC collection is terminated early for donor-related medical 
concerns, a bone marrow graft may be infused.  Should this occur, the 
recipient will continue to be managed on this protocol for all transplant-
related care and complications. Patient will stay on study but clinical 
outcomes will not be eligible for the statistics and end point 
calculations. 


Abbreviated title: Palifermin dose escalation
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29

Inadequate stem cell collection from the selected donor is defined as 
less than or equal to 2 x 106 CD34+ cells/kg. In most cases, donor cell 
collections are infused fresh.  If a fresh collection is found to have an 
inadequate cell count, the cells will still be infused, but the recipient will 
be removed from the study, and managed clinically for all transplant-
related care and complications on this protocol.  If the patient fails to 
engraft, the donor may be requested for a second collection or an 
emergency bone marrow harvest at the discretion of the PI and NMDP 
Medical Director.  In the event of an inadequate collection obtained 
prior to patient conditioning, the donor may be asked to donate a 
second time, or another eligible donor may be requested.
2.1.2.2 Renal and hepatic function continues to meet eligibility criteria, reassessed as 
follows: 

24 hour creatinine clearance or calculated (using the Cockcroft-Gault 
formula) creatinine clearance > 60 mL/min/1.73 m2 (induction phase 
only)

(140 ― age) ∗mass(kg)
72 ∗serum creatinine(
mg
dL)  x 1.73 m2/ patients BSA

If the patient is female, multiply the above by 0.85

In patients with suspected liver disease, bilirubin must be ≤ 2.5 mg/dL, 
AST and ALT must be ≤ 2.5 times institutional ULN
2.1.2.3 The malignancy must be restaged prior to research phase and must not have 
progressed during induction chemotherapy (stable disease or better). Persons 
with acute leukemia, MDS/RAEB-I or –II or CML with previous accelerated or 
blast phase must have <5% blasts in the bone marrow. Persons with chronic 
phase CML may have up to 10% blasts in the bone marrow. 
2.1.3
Exclusion Criteria 
(applies to all phases of this protocol)
2.1.3.1 Active infection that is not responding to antimicrobial therapy.
2.1.3.2 Active CNS involvement by malignancy (patients with known positive CSF 
cytology or parenchymal lesions visible by CT or MRI).
2.1.3.3 Previous other malignancies unless they have undergone curative intent 
therapy for that malignancy and (1) have had no evidence of that disease for 5 
years, and/or (2) be deemed at low risk for recurrence (less than or equal to 
20% at 5 years).
2.1.3.4 HIV positive patients are ineligible as allogeneic stem cell transplant is not yet a 
proven approach in this patient population, and patients are at increased risk of 
lethal infections when treated with marrow suppressive therapy. [52]
2.1.3.5 Pregnant women are excluded from this study because palifermin has been 
shown to be embryotoxic and fetotoxic in animal studies. Because there is an 


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30
unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with palifermin, breastfeeding should be discontinued 
for the duration of active study therapy.  These potential risks may also apply to 
other agents used in this study. 
2.1.3.6 History of psychiatric disorder or any other condition which may compromise 
compliance with transplant protocol or expose patient to unnecessary risk as 
determined by principal investigator or lead associate investigator.
2.1.4 Recruitment Strategies
This protocol may be abstracted into a plain language announcement posted on NIH 
websites (i.e., clinicaltrials.gov) and on NIH social media platforms. 
2.2
SCREENING EVALUATION
The following clinical, laboratory and radiologic assessments will be performed within 30 
days of enrollment unless otherwise specified. Patients will be screened on protocol 
01C0129 (Eligibility Screening and Tissue Procurement for the NIH Intramural Research 
Program Clinical Protocols):

Complete medical history (including Karnofsky performance status 
assessment) and physical examination.

Antibody screen for hepatitis A, B, and C; HIV. 

CBC with differential, acute care panel, hepatic panel, mineral panel, PT, PTT, 
and ABO typing

Urine or serum HCG in women of childbearing potential

Gonadal Assessment: Female: FSH/LH, and Estrogen. Male: Testosterone 
(free and total)

Urinalysis and urine protein creatinine (UPC)

Creatinine clearance by 24 hour urine collection or calculated creatinine 
clearance by Cockcroft Gault formula.

Risk of relapse documentation (Kahl scale) [53] 

Comorbidity index HCT-CI documentation [54]

Unilateral bone marrow aspirate and biopsy as clinically indicated based on 
underlying disease type and patient history.  Flow cytometry, cytogenetics, and 
molecular testing via polymerase chain reaction (PCR) should be performed on 
marrow aspirates as deemed clinically appropriate for specific diseases. Each 
patient will have a MRD (minimal residual disease) marker documented at 
study entry designated as: “flow cytometry”, “cytogenetics”, “molecular” or 
“other (specify)”. If bone marrow biopsies are done within the last 4 months 
outside of NIH (by the referring physician), then these slides will be requested 
and the bone marrow biopsy does not need to be repeated based on clinical 
judgment. Disease status assessments, which must be done at least 18 days 
beyond the start of cycle of therapy prior to enrollment: 


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31
o
CT scans of the chest, abdomen, pelvis +/- neck in order to evaluate 
disease status (with or without IV contrast depending on disease type and 
patient’s renal function). Brain imaging (CT or MRI) may also be 
performed if clinically indicated. 
o
FDG-PET scan for recipients with lymphomas or if clinically indicated to 
evaluate disease status. 
o
Skeletal survey (for multiple myeloma patients only). 
o
Recipients with multiple myeloma will also be tested for Blood: Total 
serum protein, serum protein electrophoresis (with immunofixation), CRP, 
immunoglobulin free light chains, and beta-2 microglobulin; Urine: 24 hour 
urine protein electrophoresis (with immunofixation). 

Electrocardiogram and 2D ECHO or MUGA scan to evaluate cardiac function

Pulmonary function tests including DLCO adjusted for Hemoglobin (USA-ITS-
NIH score)

Hepatology consult in patients with chronic active Hepatitis B and/or Hepatitis C 
infection

Optional lumbar puncture and CSF analysis (patient and disease specific) may 
be performed at the discretion of the principal investigator.

Tests of DNA mini-satellite regions for STR chimerism profile.
2.3
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
2.3.1 Protocol Entry
The patient's entry date on protocol is considered to be the day that consent form has 
been signed by the recipient.  The treatment start date is considered to be the day the 
recipient begins his/her initial induction cycle. Donors are not enrolled on the CCR 
protocol.
2.3.2 Registration
Registration and status updates (e.g., when a participant is taken off protocol therapy 
and when a participant is taken off-study) will take place per CCR SOP ADCR-2, CCR 
Participant Registration & Status Updates found here.
2.3.3 Treatment Assignment and Randomization/Stratification Procedures for 
Registration Purposes:
Cohorts
Number
Name
Description
1
Phase I: Dose escalation 
cohort
Up to 24 evaluable patients requiring an allogeneic stem cell 
transplant for hematologic malignancy enrolled to determine 
the MTD of palifermin
2
Phase II cohort
Patients requiring an allogeneic stem cell transplant for 
hematologic malignancy enrolled after the MTD of palifermin 
has been determined


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32
Arms
Number
Name
Description
1
Phase I:  Dose escalation 
arm 
Induction chemotherapy, then palifermin at escalating doses, 
then conditioning chemotherapy, then allogeneic stem cell 
transplant, then immunosuppression 
2
Phase II arm
Induction chemotherapy, then palifermin at the MTD 
determined in Phase 1, then conditioning chemotherapy, then 
allogeneic stem cell transplant, then immunosuppression 
Stratifications
Not applicable to this study.
Randomization and Arm Assignment
This protocol does not utilize randomization.  Patients in cohort 1 will be directly 
assigned to arm 1, and patients in cohort 2 will be directly assigned to arm 2.
2.4
BASELINE EVALUATION
The following clinical, laboratory and radiologic assessments will be performed on the 
patient (recipient) within 30 days before the initiation of Induction chemotherapy and the 
research phase (Day-7) unless otherwise specified. These tests can also be performed 
during screening.  It will be at the PI’s discretion not to repeat the test if he feels there 
has been no change in the patient’s condition. In addition, all screening tests should be 
repeated if done > 30 days from Day-7. See Section 2.2
Antibody screen for T. Cruzi, HTLV-I/II, HSV, toxoplasma, varicella (VZV), West Nile 
Virus, Syphilis screen (RPR) and 

CMV and EBV PCR testing

QuantiFERON-TB Gold or PPD test

Amylase, lipase

Serum ferritin, TSH, T3 (Triiodothyronine) and T4 (Thyroxine, Free), Lipid 
profile

Flow cytometric analysis of peripheral blood CD3, CD4, CD8, and CD56 
positive lymphocyte populations (TBNK). 

Serum immunoglobulins, quantitative (IgG, IgM, IgA)

Nutritional assessment 

Dental consultation to assess need for teeth cleaning or removal (valid for 90 
days)

Social work consultation

Ophthalmology consultation (valid for 90 days)

Gynecology consultation (for pre-and peri-menopausal women) (valid for 90 
days)


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33

Chemosensitivity status as previously defined by Salit R. et al [55]: 
chemotherapy-sensitive disease, defined by as CR or PR to their most recent 
prior regimen, chemo-refractory disease: SD or PD to their most recent prior 
regimen.
3
STUDY IMPLEMENTATION
3.1
STUDY SCHEMA 


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3.2
INDUCTION PHASE

The following items should be obtained within 48 hours before starting 
induction chemotherapy. The tests need not be repeated if obtained in the 
appropriate timeframe at screening or baseline: 
o
Adequate central venous access is required for all patients 
undergoing transplantation on this protocol.
o
CBC with differential
o
Acute care, hepatic, and mineral panel.
o
Urine or serum beta-HCG in women of childbearing potential.

The purpose of induction chemotherapy prior to transplant conditioning is 
to establish host immune depletion. Individuals who meet the following 
criteria secondary to previous treatment will not require further immune 
depletion and may proceed directly to the research phase.
o
≤100 CD4 cells/l of blood assessed at least 18 days beyond the 
start of last cycle of prior therapy. The investigator may allow 
proceeding without induction if the CD4 count is within the 
statistical margin of error (≤115 cells/μL) or if dictated by the patient 
best interest (such excessive risk of infection, toxicity or malignancy 
relapse), at the discretion of the PI.
o
Demonstration of disease response/control that is at least 28 days 
beyond the start of cycle of therapy prior to enrollment.

Induction Chemotherapy - After study enrollment, recipients will typically 
receive either EPOCH-F/R (every 21 days, maximum 3 cycles) or FLAG 
(every 28 days, maximum 2 cycles) according to the underlying diagnosis, 
as indicated in the following table. If other therapy is found more 
appropriate for disease, this will be allowed per the discretion of PI or LAI. 

Number of cycles of induction chemotherapy will be determined by the 
quantity of host immune CD4 cells/μL remaining after each cycle or if 
maximum cycles have been completed or if dictated by the patient best 
interest (such excessive risk of infection, toxicity or malignancy relapse).

The CD4 count must be measured at least 48 hours after the cycle’s last 
dose of filgrastim and within three days before the next scheduled cycle. 

Recipients will undergo a CBC two times per week (typically at least 3 
days apart) to determine the absolute neutrophil count (ANC) during the 
neutrophil nadir post EPOCH-F/R or FLAG.

Recipients with progressive malignancy between the final cycle treatment 
and transplantation (Research phase) may be removed from study per PI 
discretion.


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35
FLAG
EPOCH-F/R
Acute myelogenous leukemia (AML)
Secondary AML
Acute lymphocytic leukemia (ALL)
Lymphoblastic lymphoma
Myelodysplastic syndrome
Myeloproliferative disorder (MPD)
Chronic myelogenous leukemia 
(CML)
Hodgkin lymphoma
Non-Hodgkin lymphoma (NHL)
(except lymphoblastic lymphoma)
Chronic lymphocytic leukemia (CLL)
Prolymphocytic leukemia (PLL)
Multiple myeloma
3.2.1 EPOCH-F/R
3.2.1.1 Drug Administration
Drug
Dose
Days
Rituximab+*
375 mg/m2 IV infusion (Patients 
with CD20+ malignancies only)
Day 1 only
Fludarabine
25 mg/m2 per day IV infusion over 
30 minutes, daily for 4 days
Days 1, 2, 3, 4
Etoposide
50 mg/m2 per day continuous IV 
infusion over 24 hours daily for 4 
days
Days 1, 2, 3, 4
Doxorubicin
10 mg/m2 per day continuous IV 
infusion over 24 hours daily for 4 
days
Days 1, 2, 3, 4
Vincristine
0.4 mg/m2 per day continuous IV
infusion over 24 hours daily for 4 
days
Days 1, 2, 3, 4
Cyclophosphamide
750 mg/m2 IV infusion over 30 
minutes
Day 5 only
Prednisone
60 mg/m2 per day PO daily for 5 
days
Days 1, 2, 3, 4, 5
Filgrastim
5 g/kg per day SC or IV (see 
section 13.3.4) 
Daily from day 6 until ANC 
> 1000/l x 2 or > 5000/μL 
x 1 following nadir.
*Recipients with a malignancy that does not express CD20 will not receive Rituximab.
+Subjects will be premedicated 30 -60 minutes prior to rituximab infusion. Please see section 13.7.4
3.2.1.2 Dose modifications to EPOCH-F/R
The above table describes dose level 1. For cycles 2 and 3 patients may 
receive dose adjustment according to the following guidelines:


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
Cyclophosphamide, doxorubicin, etoposide dose adjustments
Dose Level
-2
-1
1
2
3
Doxorubicin (mg/m2/day)
10
10
10
12
14.4
Etoposide (mg/m2/day)
50
50
50
60
72
Cyclophosphamide 
(mg/m2/day)
480
600
750
900
1080
o
Drug doses are based on the duration of ANC nadir during the previous 
cycles (as determined by consecutive twice weekly CBC/differential tests).
If ANC < 500/l on 1 or fewer 
measurements AND there is no other 
grade 3+ non-hematologic toxicity 

Increase cyclophosphamide, 
doxorubicin, and etoposide 1 dose 
level above previous cycle.
If ANC < 500/l on 2 measurements

Same dose level as previous cycle.
If ANC < 500/l on 3 measurements or if 
there is a grade 4 non-hematologic toxicity 
Decrease cyclophosphamide, 
doxorubicin, and etoposide 1 dose 
level below previous cycle.

Vincristine Dose Adjustment (for EPOCH-F/R):
a) For grade 2 sensory or motor neuropathy reduce vincristine to 50%
b) For grade 3 sensory or motor neuropathy omit vincristine

Fludarabine will be reduced by 20% in recipients with a 24 hour or calculated 
creatinine clearance of < 70 mL/min/1.73 m2 (Cockcroft-Gault formula).

There are no dose modifications for rituximab; however adverse events may 
be managed by changes in the infusion rate as described in section 13.7.4.
All other patients will continue at the same dose of EPOCH-F/R for the 
subsequent cycle.


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3.2.2 FLAG
3.2.2.1 Drug Administration
Drug
Dose
Days
Fludarabine
25 mg/m2 per day IV
infusion over 30 
minutes,
Daily for 5 days
Days 1, 2, 3, 4, 5
Cytarabine
2,000 mg/m2 IV
infusion over 4 hours,
Daily for 5 days
Days 1, 2, 3, 4, 5
Filgrastim
5 g/kg per day SC
beginning 24 hours 
PRIOR to initiation of 
chemotherapy
Daily from day 0
until ANC >1000/l x 2
following nadir

Corticosteroid ophthalmic drops will be administered every 6 hours starting 
the day before and continuing until the day after cytarabine therapy.

In the event of signs of CNS toxicity the cytarabine infusion will be 
discontinued. No cytarabine will be administered in recipients with history of 
cytarabine neurotoxicity.
3.2.2.2 FLAG dose modification for cycle 2:
o
If the first cycle of FLAG is associated with a grade 4 non-hematologic 
toxicity the second cycle of FLAG will be dose reduced by eliminating the 
fifth day of drug infusion to the above regimen.
o
Fludarabine will be reduced by 20% for recipients with 24 hour or 
calculated creatinine clearance < 70 mL/min/1.73 m2 (Cockcroft-Gault 
formula – section 2.1.2.2).
o
Patients with malignancies positive for BCR-ABL mutation may continue 
use of BCR-ABL tyrosine kinase inhibitors during therapy as deemed 
appropriate by the investigator.
3.3
RESEARCH PHASE
3.3.1 Palifermin / Conditioning chemotherapy / HSCT

Recipients may begin the research phase (administration of palifermin 
followed by conditioning and peripheral blood hematopoietic stem cell 
transplant) 22 or 28 days after the most recent cycle of EPOCH-F/R or FLAG 
induction therapy, respectively. 

Disease restaging must be done no more than 28 days before initiation of 
research phase, with testing done per patient’s primary disease and 
investigator discretion:


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38
o
Unilateral bone marrow aspirate and biopsy.  Flow cytometry, 
cytogenetics, and molecular testing via polymerase chain reaction (PCR) 
should be performed on marrow aspirates as deemed clinically 
appropriate for specific diseases. Each patient will have a MRD (minimal 
residual disease) marker documented at study entry designated as: “flow 
cytometry”, “cytogenetics”, “molecular” or “other (specify)”
o
 CT scans of the chest, abdomen, pelvis +/- neck in order to evaluate 
disease status in Lymphoma patients (with or without IV contrast 
depending on disease type and patient’s renal function) 
o
Brain imaging (CT or MRI) may also be performed if clinically indicated.
o
FDG-PET scan if clinically indicated to evaluate disease status (e.g., some 
lymphoma patients).
o
Recipients with multiple myeloma will also have the following tests: Total 
serum protein, serum protein electrophoresis (with immunofixation), 
immunoglobulin free light chains; 24 hour urine protein electrophoresis 
(with immunofixation).
o
Persons with acute leukemia, MDS/RAEB-I or –II or CML with previous 
accelerated or blast phase must have peripheral blood flow cytometry for 
determination of blast count performed.

CT scan of the chest without IV contrast to determine baseline thymus 
measurements. (If CT chest with IV contrast is being done to determine 
disease status, this may be used instead for thymus measurement.) 

GI consultation prior to administration of palifermin (to document any pre-
existing conditions) within 30 days

Collection of Dental Research Samples (See Section 5.1.3.1)

The following studies will be obtained from the recipient within 7 days prior to 
starting palifermin:
o
CBC with differential, acute care panel, mineral panel, and hepatic panel, 
serum amylase and lipase, urine or serum beta-HCG in women of 
childbearing potential.
o
Recording of baseline symptoms prior to administration of palifermin.
3.3.1.1 Palifermin Administration

Palifermin will be administered as a single intravenous bolus injection at the 
appropriate dose levels on day -7 relative to HSCT. Co-administration with 
heparin should be avoided.
3.3.1.2 Phase 1
3.3.1.2.1 Dose Escalation


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
The initial phase I study will incorporate a 3+3 type design using the following 
dose levels:
Dose Level
Dose palifermin (mcg/kg) IV on day -7
1
180
2
360
3
540
4
720

Three patients will be enrolled on each dose level. If no dose limiting toxicities 
occur in the first cohort after three patients (and they have reached the 30 day 
post-transplant time point), subsequent patients will be enrolled in the next 
dose level.

If one patient experiences a dose limiting toxicity, an additional three patients 
will be enrolled on this dose level. If no further dose limiting toxicities occur, 
subsequent patients will be enrolled in the next dose level.

If a second dose limiting toxicity (DLT) occurs, this dose level will be closed 
and the previous dose level dosing will be selected as the maximum tolerated 
dose (MTD).

In summary: The MTD is the dose level at which no more than 1 (of ≤ 6) 
patients who experience DLT, and the dose below that at which at least 2 (of 
≤6) patients have DLT as a result of the drug.
3.3.1.2.2 Dose Limiting Toxicity
The following events are considered dose limiting toxicities secondary to palifermin 
administration:

Non-relapse mortality (see Section 8 for definition) before day 30 post 
transplantation regardless of attribution to palifermin. Persons who expire 
from malignancy related causes are not considered DLTs.

Non-hematologic CTCAE ≥ grade 4 adverse events (AEs), occurring within 14 
days after administration of palifermin that are determined by the investigator 
to be at least possibly related to the study drug. An isolated laboratory value 
is not considered an AE unless it meets the guidelines described in section 8.
Note: Patients will not be removed from study therapy due to palifermin toxicity as only 
1 dose is administered. DLT criteria are established only to determine dose levels for 
subsequent patients.
3.3.1.3 Phase 2 Guidelines 

The maximum tolerated dose (MTD) from the phase I portion of the study will 
be used to conduct a phase II study. If no MTD is reached, the highest dose 
level will be used for the phase II portion of the study

The maximum number of individuals enrolled on the phase II study portion is 
27 (see section 8). Individuals treated at the MTD in the phase I portion are 
included in the phase II portion.


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
The phase II portion of the study will be conducted with a stopping rule based 
on treatment related mortality as described in section 8.
3.3.2 Conditioning Chemotherapy
The conditioning chemotherapy will consist of:

Hydration and dose modifications associated with conditioning chemotherapy 
include:
o
Hydration will consist of 0.9% Sodium Chloride at a rate of 100 
mL/hour starting 12 hours prior to initiation of cyclophosphamide 
and continuing until 24 hours post the final dose of 
cyclophosphamide.
o
Furosemide may be increased at the investigators’ discretion.
o
Fludarabine will be reduced by 20% in recipients with 24 hour or 
calculated creatinine clearance < 70 mL/min/1.73 m2 (Cockcroft-
Gault formula – section 2.1.2.2).

Filgrastim will be administered at a dose of 10 mcg/kg recipient body weight 
beginning one day after donor cell infusion and continuing until the recipient 
has an ANC of >1000/mcL for at least two days or > 5000/mcL once.
3.3.3 Graft versus Host Disease (GVHD) prophylaxis 
3.3.3.1 Tacrolimus

Tacrolimus will be initiated on day -3 before the transplant. Tacrolimus will be 
administered continuous intravenous infusion at 0.02 mg/kg/day.  Tacrolimus 
dose will be adjusted to achieve a therapeutic goal of 5 to 10 ng/ml according 
to trough levels monitored at least two times per week and/or upon symptoms 
or alterations in renal function.  Trough levels may be monitored more 
frequently if clinically indicated.  
Drug
Dose
Days
Fludarabine
30 mg/m2 per day
IV infusion over 30 minutes,
daily for 4 days
Transplant Days –6, -5, 
-4, -3
Cyclophosphamide
1200 mg/m2 per day
IV infusion over 2 hours,
daily for 4 days
Transplant Days –6, -5, 
-4, -3
Mesna
1200 mg/m2 per day
Continuous IV infusion,
Daily for 4 days
Concurrent with 
cyclophosphamide
Transplant Days –6, -5, 
-4, -3
Furosemide
20 mg IV flat dose
Transplant days -6, -5, -4, 
-3


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
When the recipient is able to take oral medications (typically 10 to 21 days 
after transplantation), tacrolimus will be converted to an equivalent oral dose.  
The total daily dose will be divided into two equal doses, one dose given 
approximately every 12 hours.

This dose of tacrolimus will continue until day +60 (+/- 7 days), and then 
reduced by one-third as long as the severity of GVHD is at minimum less than 
grade 2 and patient is not requiring systemic steroids. Tacrolimus will be 
subsequently reduced by one third on day +100 (+/- 7 days). Tacrolimus will 
then be completely discontinued by day +180 (i.e. 6 months) if there are no 
signs of GVHD or as clinically indicated.
3.3.3.2 Methotrexate

Methotrexate will be given at 5 mg/m2 IV on days +1, +3, +6, and +11.  Each 
day’s dose of methotrexate will not be administered until approved that day by 
the transplant attending after the transplant team has evaluated the patient.  

Doses will be withheld for the development of grade III or IV mucositis or 
clinical evidence of veno-occlusive disease. Administration of the combination 
of trimethoprim and sulfamethoxazole (i.e., Bactrim) or non-steroidal anti-
inflammatory drugs is contraindicated during methotrexate administration.  

Methotrexate administration will be assessed on each planned day of 
administration, and dose adjustments will be guided by the following criteria, 
however can be adjusted based on the discretion of the attending physician, 
P.I., and/or LAI:

Methotrexate may also be held or dose adjusted at the discretion of attending 
physician, P.I., and/or LAI for severe mucositis, third space fluid collection 
(e.g. pleural effusion, ascites, or edema). 

Leucovorin (folinic acid) rescue may be considered under the direction of the 
attending physician or PI. The recommended dose regimen of leucovorin is 
10mg IV or PO every 6 hours starting 24 hours after methotrexate 
administration and continued until undetectable methotrexate levels or upon 
the discretion of the attending physician, P.I., and/or LAI. 

Leucovorin should be held 12 hours prior to the any subsequent methotrexate 
dose and not resumed (if indicated) for 24 hours after a methotrexate dose.
Creatinine
Total Bilirubin
Methotrexate 
Dose
< 2.0 mg/dL
<5.0 mg/dL
100%
2.0 – 3.0 mg/dL
----
50%
> 3.0 mg/dL
> 5.0 mg/dL
Hold Dose


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3.3.3.3 Sirolimus

Sirolimus will be initiated on day –3 before the transplant procedure. Sirolimus 
will be administered by mouth as sirolimus tablets at an initial “loading dose” 
of 6 mg, p.o., on day –3 of transplantation.

Subsequently, sirolimus dosing will be 2 mg, p.o., each day.

Sirolimus dose will be adjusted to achieve a therapeutic goal of 3 to 12 ng/ml 
according to trough levels monitored at least two times a week and/or upon 
symptoms or alterations in renal function.  Trough levels may be monitored 
more frequently if clinically indicated.  

This dose of sirolimus will continue until day +60 (+/- 7 days), and then 
reduced by one-third as long as the severity of GVHD is at minimum less than 
grade 2 and patient is not requiring systemic steroids.  Sirolimus will be 
subsequently reduced by one third on day +100 (+/- 14 days). Sirolimus will 
then be completely discontinued by day +180 (+/-14 days) if there are no 
signs of GVHD or as clinically indicated.
3.3.4 Hematopoietic Stem Cell Transplant
Hematopoietic stem cell transplant will be performed per the standards of the NIH CC 
Department of Transfusion Medicine.  Please see section 13.13 for protocol specific 
donor cell processing procedures. 
3.3.5 Evaluation Post Transplant
3.3.5.1 Clinical Response

The following studies and clinical response evaluations will be obtained in the 
recipient during post transplantation:
o
CBC and differential count daily during transplant hospitalization, then as 
clinically indicated. 

Persons with minor ABO mismatch will have their CBC checked 
twice daily from Day +4 to Day +14 post-transplant and transfused 
for a goal hemoglobin level of ≥ 9.5 g/dL.
o
Acute care, mineral panel and hepatic panel, daily during transplant 
hospitalization, then as clinically indicated. 
o
GGT twice a week through day 100 and then as clinically indicated.  
o
Amylase, lipase daily during transplant hospitalization until Day +6, then 
twice weekly until day +28.  After Day +28, amylase and lipase will be 
drawn weekly until Day +100, then at each timepoint.
o
CMV weekly through day +180 post-transplant, then as clinically indicated 
(monitoring will continue longer if patients are continued on 
immunosuppression). 
o
EBV weekly until day +180 post-transplant, then as clinically indicated 
(longer if patient deemed high risk).


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o
Type and screen every 4 days during transplant hospitalization, then as 
clinically indicated. 
o
Toxoplasmosis weekly on positive patients during inpatient hospitalization, 
then as clinically needed. 
o
Tacrolimus and sirolimus trough level at least twice weekly, for first 100 
days, or as clinically indicated. Sirolimus trough level will need to be 
collected on day -2 (one day after loading dose).
o
Of note,  all lab tests done between day +100 and Day +180 (namely 
CBC, acute care panel, mineral panel, hepatic panel, CMV, EBV, 
tacrolimus and sirolimus levels) can be obtained at patient’s home 
institution since beyond Day +100 as patients are usually stable enough to 
go home and no longer require all lab testing to be obtained at NIH.  The 
frequency of the labs will be at the discretion of the patient’s home 
physician.
o
TBNK at day +14 +/-7 days, +28(+/- 7 days), +60 (+/- 7 days), +100(+/- 14 
days), +180(+/- 14 days), +270(+/-14 days), +365(+/-  30 days), 18 
months (+/- 30 days) and 24 months (+/- 30 days) then yearly until year 5 
in follow-up.
o
Recipient peripheral blood lymphoid, myeloid, and total chimerism on day 
+14 (+/- 7 days), +28(+/- 7 days), +60 (+/- 7 days), +100 (+/-  14 days), 
+180(+/- 14 days). Chimerism may be measured at other time-points if 
clinically indicated (e.g., to determine effect of manipulating immune 
suppression in order to increase donor chimerism).
o
Peripheral blood or bone marrow flow cytometry, cytogenetics, and/or 
molecular studies to determine minimal residual disease as is clinically 
indicated day +28 (+/- 7 days), +100(+/- 14 days), +180(+/- 14 days), 
+365(+/-  30 days), 24 months (+/- 30 days) and yearly thereafter as 
clinically indicated. 
o
Bone marrow biopsy and aspiration (including cytogenetics and molecular 
studies) on day +28 (+/- 7 days), +100(+/- 14 days), +180(+/- 14 days), 
+365(+/-  30 days) and yearly thereafter in patients with prior bone marrow 
disease up until year three post-transplant. Confirm with the PI if 
cytogenetics and/or molecular studies are needed. Bone marrow biopsy 
and aspirates can also be done at any time if clinically indicated.
o
Recipient bone marrow chimerism on days +28 (+/-7 days), +100(+/- 14 
days), and +180 (+/- 14 days).  Lymphoid & myeloid subset chimerism will 
also be measured at these time-points if donor chimerism was < 95% on 
the previous study. Chimerism may be measured at other time-points if 
clinically indicated.
o
Optional lumbar puncture and CSF analysis (patient and disease specific)  
if the principal investigator determines it is needed on day +28 (+/- 7 
days), +100(+/- 14 days), +180(+/- 14 days), +365(+/- 30 days) and yearly 
thereafter in patients with prior CNS disease up until year three post-


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44
transplant. Confirm with the PI for the appropriateness and need for 
concurrent intrathecal chemotherapy administration (see section 4.7).
o
CT scan of the chest (without IV contrast) at day +28(+/- 7 days), +180 
days (+/- 14 days), +365 days (+/-  30  days), 24 months (+/- 30 days) and 
36 months (+/- 60 days) post -transplant for determination of palifermin 
effect on thymus measurements [15, 24, 56-59] . At each timepoint the 
thymus volume (cm3), thymus size grading score (Score 0-5, ref: McCune 
et al [56]) and thymic density grading score (Score 1 to 5, ref: Simanovsky 
[59]). If a CT chest is being done with IV contrast for other reasons, then 
this scan can be used to evaluate thymus measurements as well. 
o
For assessment of disease, CT scans (with contrast if medically 
appropriate) of chest, abdomen, and pelvis (neck included if measurable 
disease is present), and/or PET and/or cranial imaging will be performed 
at the discretion of the PI or LAI at day 28(+/-7 days), day 100 (+/- 14 
days), day 180(+/- 14 Days) , and yearly  (+/- 30 Days) thereafter as 
clinically indicated. 
o
For multiple myeloma patients, repeat MM workup at 28 days (+/- 7 days), 
+100(+/- 14 days), +180(+/- 14 days), +365(+/- 30 days), 24 months (+/- 
30 days) and yearly thereafter as clinically indicated. 

Evaluation and documentation for acute GVHD at time point clinic visits at 
days +28, +100, and +180. The date of acute GVHD diagnosis and 
stage/grade will be recorded at diagnosis (+/-30 days from time point, due to 
clinic schedule).

Evaluation and documentation for chronic GVHD at time-point clinic visits at 
days +28, +100, +180, +270, +365, +18 months, 24 months and every year 
thereafter up until 5 years (+/-30 days from time point, due to clinic schedule).

The recipient will be seen in follow-up at the Clinical Center at Day+28 (+/- 7 
days, if Outpatient) this visit will count as a 30 day post palifermin safety visit , 
Day +60 (+/- 7 days), Day +100 (+/- 14 days), Day +180 (+/- 14 days), Day 
+270 (+/- 14 days), 12 months (+/-  30 days), 18 months (+/-  30 days), 24 
months (+/- 30 days) and then annually post-transplant until 5 years, unless 
an earlier evaluation is clinically indicated. Evaluations beyond 5 years will be 
done only if clinically indicated.
3.3.5.2 Other Studies

Other studies: Patients may obtain these studies within 2 months of desired 
date unless otherwise specified and these may be done in other institutions 
than NIH with documentation.  Please note that the following can be 
performed either as part of this protocol or at an outside clinic.

PFTs on day +100 (+/- 14 days), +180 (+/- 14 days), +270 (+/- 14 days), 
+365 (+/- 30 days), 18 months (+/-  30 days), and 24 months (+/- 30 days) 
then yearly until 5 years.


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
Serum immunoglobulins (IgG, IgM, IgA) at day +28 (+/- 7 days), +60 (+/- 7 
days), +100 (+/-  14 days), +180 (+/- 14 days), +270 (+/- 14 days), +365 
(+/-  30 days), 18 (+/-  30 days) and 24 months (+/- 30 days) then yearly 
until 5 year follow-up

Eye clinical exam at 1 year and later if clinically indicated

Dental evaluation at day 60 (+/- 7 days), +180 (+/- 14 days), +365 (+/- 30 
days), and later if clinically indicated. Buccal biopsy, saliva collection and 
clinical oral photo series at day 60 (+/- 7 days) and +180 (+/- 14 days). 
Note:  Dental consult and biopsies/saliva collection/photo series will be 
obtained only if the patient’s medical status allows for these outpatient 
evaluations to take place.  The buccal biopsy is an elective procedure and 
is not required for this protocol.

Dermatology evaluation and skin biopsy at day +60 (+/- 7 days) and +180 
(+/- 14 days). Additional dermatology evaluations if clinically indicated. 
Dermatology consult will be obtained if the patient’s medical status allows 
for these outpatient evaluations to take place.  Additional skin biopsies will 
be taken at the time of suspected GVHD for diagnosis and/or research. 
Skin biopsy is an elective procedure and is not required for this protocol.

Serum ferritin measured in patient’s day +365 (+/-  30 days) then as 
clinically indicated

DEXA scan at day +365 (+/-  30 days) post-transplant then as clinically 
indicated

Thyroid function test (TSH, T3 (Triiodothyronine), T4 (Thyroxine, Free)) at 
1 year (+/-  30 days) and then yearly thereafter until 5 years or as clinically 
indicated.

Echocardiogram at day +100 (+/- 14 days), then as clinically indicated.

Clinical and gonadal assessment of women 1 year after transplant then 
yearly until 5-year follow-up if clinically indicated (GYN consult, FSH, LH, 
estrogen levels)

Clinical and gonadal assessment of men at 1 year after transplant then 
yearly until 5- year follow-up if clinically indicated (testosterone)

Urinalysis day +180 (+/- 14 days), +365 (+/- 30 days), then yearly until 5 
years. 
3.3.5.3 Relapse or malignancy progression:
If a patient relapses they will be followed clinically for survival and occurrence of Graft 
versus Host Disease; no research blood or protocol-directed tests or procedures are 
planned. Patients will continue to be evaluated as close as possible to protocol driven 
timepoints, these evaluations can occur at NIH or at home (via medical records review 
and/or phone call).  Further clinical evaluation will be at the discretion of the PI.


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3.4
COST AND COMPENSATION 
3.4.1 Costs
NIH does not bill health insurance companies or participants for any research or related 
clinical care that participants receive at the NIH Clinical Center.  If some tests and 
procedures performed outside the NIH Clinical Center, participants may have to pay for 
these costs if they are not covered by insurance company.  Medicines that are not part 
of the study treatment will not be provided or paid for by the NIH Clinical Center.    
3.4.2 Compensation
Participants will not be compensated on this study.
3.4.3 Reimbursement 
The NCI will cover the costs of some expenses associated with protocol participation.  
Some of these costs may be paid directly by the NIH and some may be reimbursed to 
the participant/guardian as appropriate.  The amount and form of these payments are 
determined by the NCI Travel and Lodging Reimbursement Policy.
3.5
TELEHEALTH
Telemedicine is the use of interactive audio, video, audio-visual, or other 
telecommunications or electronic technology by a licensed health care practitioner to 
deliver clinical services. This protocol will allow the team to practice telemedicine to 
communicate with patients in real time, to be able to monitor and collect data, as well as 
the ability to share the patients’ health information with other health professionals. 
Providers may include primary providers, specialists/consultants and nurses. Other 
members of the healthcare team may also be present to aid with the communication 
devices, scheduling or records management. These visits may include the following: 
patient history, verbal exam, symptom reporting, and education.
The patient or patient’s legal representative will be informed prior to the use of a 
telemedicine encounter and consent will be obtained as outlined in the Consent Process 
and Documentation (section 11.3). 
Telemedicine visits will be arranged through our NIH Clinical Center Health Information 
Management Department and will be scheduled using NIH-approved remote platforms. 
Telemedicine visits may be used for follow-up visits if deemed appropriate by the PI. All 
telemedicine visits must be documented in CRIS like a normal onsite visit and the note 
should indicate that this visit was performed virtually.
Remote visits will be conducted in compliance with NIH guidelines and FDA regulations. 
Local Evaluations
A patient may be asked to come to the NIH CC for an in-person assessment or be 
referred to their local provider or outside lab, at the discretion of the investigator. All 
physical exams, assessments, labs, and imaging used for follow-up or restaging visits 
may also be performed with the patient’s local physician or completed at outside labs. 
For laboratory evaluations conducted with local providers, interlaboratory variability is 
not a concern. In the case of any visits with participants’ local providers or outside labs, 
records will be obtained for the research records. 


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3.6
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from study, effort must be made to have all subjects complete a safety 
visit approximately 30 days following the last dose of Palifermin . 
3.6.1 Criteria for Removal from Protocol Therapy

Failure to meet pre-transplant eligibility criteria after completion of induction 
therapy

Patient requests to be withdrawn from protocol therapy

PI Discretion.

Relapse Disease

Once the post-Palifermin safety follow-up visit has been conducted
3.6.2 Off Study Criteria

Failure to meet pre-transplant eligibility criteria (See section 2.1.2).

The recipient requests to be removed from the study.

Patient lost to follow up

Investigator discretion.

After completing 5 years of follow-up per protocol per discretion of the 
Principal Investigator

Death
3.6.3 Lost to Follow-up
A participant will be considered lost to follow-up if he or she fails to return for 3 
scheduled visits and is unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site will attempt to contact the participant and reschedule the missed visit 3 
times and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain if the participant wishes to and/or should continue in 
the study.

Before a participant is deemed lost to follow-up, the investigator or designee will 
make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, an IRB approved certified letter to the 
participant’s last known mailing address or local equivalent methods). These 
contact attempts should be documented in the participant’s medical record or 
study file. 

Should the participant continue to be unreachable, he or she will be considered 
to have withdrawn from the study with a primary reason of lost to follow-up.


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4
CONCOMITANT MEDICATIONS/MEASURES
4.1
INFECTION PROPHYLAXIS
All Concomitant medications will be listed in the study database with just the start and 
stop dates. See Appendix G for further details.

All infection prophylaxis medications will be administered as per NIH Bone 
Marrow Transplant Consortium guidelines viewed at: 
(http://intranet.cc.nih.gov/bmt/education/supportive-care.shtml) Pneumocystis 
jiroveci pneumonia prophylaxis will be instituted at the time of induction 
chemotherapy (EPOCH-F/R or FLAG) and continue for at minimum six months 
after transplant immunosuppression is discontinued. If 
trimethoprim/sulfamethoxazole is used, it should be held during the engraftment 
period immediately after donor cell infusion.

Trimethoprim/Sulfamethoxazole double strength will be administered twice a day 
starting on the evening of day -7 for 5.5   days for a total of 11 doses (stopping 
with the evening dose on day-2) for gut decontamination pre-transplant. This was 
a strategy used in the 07C0195 patients; thus we will continue this for the current 
protocol for consistency. 

Yeast prophylaxis will begin during induction chemotherapy and continue until at 
least 100 days post transplantation. Typically, during induction chemotherapy, 
fluconazole will be used, except it will be held during EPOCH-F/R infusion due to 
interaction with vincristine. During conditioning chemotherapy, micafungin will be 
used.

Persons on extended schedules (>1 week) of high-dose corticosteroids (>0.5 
prednisone/kg) may be changed to an alternate anti-fungal regimen at the 
investigator’s discretion.

Persons with an absolute neutrophil count of <500/μL post conditioning 
chemotherapy shall receive ceftazidime or appropriate alternative regimen (as 
recommended by infectious disease consultant) until neutrophils have recovered.

All recipients will receive herpes virus prophylaxis starting with induction 
chemotherapy and continuing for at minimum six months until 
immunosuppression is discontinued after transplantation.

All recipients will undergo weekly peripheral blood mononuclear cell DNA 
analysis for CMV and EBV at least until day 100 post transplantation and then as 
clinically indicated thereafter.

Management of CMV viremia is according to the NIH Bone Marrow Transplant 
Consortium guidelines. (http://intranet.cc.nih.gov/bmt/education/supportive-
care.shtml)

Vaccines will be administered on the schedule provided in the appendices, as 
clinically appropriate.


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
Patient on immunosuppression for chronic graft versus host disease should take 
penicillin VK 500 mg twice daily or appropriate alternative regimen (as 
recommended by infectious disease consultant) for prevention of bacterial 
infections. 
4.2
BLOOD PRODUCT SUPPORT

Packed red blood cells will be infused in recipients at any time the serum 
hemoglobin concentration falls below 8.0 g/dL or if symptoms of anemia are 
present.

Platelets may be infused at the investigator’s discretion to prevent bleeding or if 
the platelet count falls below 10,000/μL.

Leukocyte filters and irradiation will be used for all blood and platelet products 
according to the NIH Department of Transfusion Medicine standard policies.
4.3
MENSES SUPPRESSION

All pre- or peri-menopausal women who have not undergone hysterectomy will 
be referred at study entry for gynecology consult to receive counseling about 
menses suppression, contraception and fertility preservation per NIH Blood and 
Marrow Consortium supportive care guidelines.  
(http://intranet.cc.nih.gov/bmt/education/supportive-care.shtml)

Male patients will be advised to use abstinence or barrier methods (condoms) for 
pregnancy prevention for at least one year post transplantation.
4.4
ENGRAFTMENT SYNDROME

Engraftment syndrome is an inflammatory disorder that may occur within 96 
hours of neutrophil recovery after transplantation. [60]

Recipients may receive corticosteroids for engraftment syndrome at a starting 
dose of at least 1 mg/kg/d of prednisone or equivalent. The steroid taper may be 
performed at the investigator’s discretion.
4.5
GRAFT VERSUS HOST DISEASE (GVHD)

Grading and diagnosis:
o
Acute GVHD will be graded according to the 1994 Consensus 
Conference Working Criteria. [61]

Diagnosis of acute GVHD is a clinical diagnosis and is 
therefore at the discretion of the investigator. The 
diagnosis will include review of tissue biopsy whenever 
clinically feasible.
o
Chronic GVHD will be graded according to the 2014 NIH 
Consensus Criteria. [62]

Therapy:


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o
Grade 2 or greater acute GVHD typically requires systemic 
therapy. Corticosteroids will be initiated in these persons at a 
dose and schedule to be determined by the investigator.
o
Persons with more than mild chronic GVHD may be treated with 
systemic therapy at the investigator’s discretion. 
o
If the patient is eligible for a therapeutic study that is available at 
the NIH for either acute or chronic GVHD this is the preferred 
treatment option.
4.6
DONOR LYMPHOCYTE INFUSIONS (DLI)

Persons with relapsed primary malignancy, development of EBV related 
lymphoproliferative disorder (EBV-PTLD), or those who fail to achieve full 
donor derived hematopoietic cell engraftment (mixed chimerism) are 
eligible for a DLI.

Mobilized, cryopreserved donor lymphocytes may be used if there are 
remaining samples from the original donor collection; otherwise, a request 
will be made to NMDP for subsequent lymphocyte collection from the 
original donor. 

Donor and recipient hematopoiesis (chimerism) will be assessed after DLI 
infusion if deemed necessary. 

Withdraw of immune suppression should be attempted before DLI if the 
donor lymphoid chimerism is >50%. However, DLI may be performed 
before withdrawal of immune suppression at the investigator’s discretion

Recipients with declining donor chimerism despite withdrawal of immune 
suppression or with donor lymphoid chimerism <50% are eligible for a DLI.

The initial dose of the DLI is at the discretion of the investigator.

Persons must have < grade 2 acute GVHD or < moderate chronic GVHD 
in order to receive a DLI.

DLIs will not be administered more frequently than every 28 days

Subsequent DLIs will be at the discretion of the PI
4.7
OTHER THERAPIES

Chemotherapy, cytokines, radiotherapy, monoclonal antibodies, or any 
other available therapy may be administered to persons with progressive 
primary malignancy,  or EBV-PTLD post-allogeneic transplant in order to 
establish a remission. These therapies are administered at the discretion 
of the investigator. If the patient is eligible for another study ongoing at the 
NIH, this approach is preferred.

Intrathecal chemotherapy may be administered as deemed clinically 
appropriate per PI. 


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5
CORRELATIVE STUDIES FOR RESEARCH
Note: Once a patient is taken off “protocol therapy” and the safety follow-up visit has 
been conducted, then no further research samples will be collected.
Please note that tubes and media may be substituted based on availability with the 
permission of the PI or laboratory investigator.
5.1
RESEARCH STUDIES OF TRANSPLANT BIOLOGY
5.1.1 Immune Reconstitution of Blood
5.1.1.1 Recovery of T cell receptor repertoire diversity by CDR3 spectratyping and 
assessment of recent thymic emigrants by TREC PCR. 
5.1.1.1.1 50 mL of blood will be drawn from the recipient at Baseline (pre induction) and, 
following transplant, at 6 months, 12 months and 24 months and placed into 
yellow top ACD tubes. 50 million lymphapheresis cells from the donor PBSC 
product will be sent to the Blood Processing Core (Dr. Figg’s Lab).
This sample permits calculation of spectratype complexity index. (Blood to be 
sent to the Blood Processing Core (Dr. Figg’s Lab).
5.1.1.1.2 Studies performed: Donor and recipient samples will be sorted to separate 
CD4+ and CD8+ T cells and monocytes.  T cell subsets will be divided for 
storage by snap freezing (DNA) or in Trizol (RNA). After completion of patient 
accrual, RNA will be isolated and RT-PCR followed by Vβ spectratype 
analysis will be performed to assess T cell receptor repertoire diversity. DNA 
will be used in PCR assays to assess the frequency of T cell receptor 
rearrangement circles (TREC) relative to total genomic DNA (compared to a 
single gene standard, RNAseP).
5.1.1.2 Phenotypic and functional assessment of lymphocyte reconstitution. (Blood to 
be sent to the Blood Processing Core (Dr. Figg’s Lab).
5.1.1.2.1 Collection

16ml of whole blood, collected in the form of 1 green top (heparin) tube 
and 1 SST (serum) tube will be sent at Day-7 and the day of PBSC 
infusion (Day 0 +/- 1 Day) to the Blood Processing Core (Dr. Figg’s Lab). 
These will be used to track depletion of lymphocyte populations during 
conditioning and as a source of plasma and serum for assessing cytokine 
changes during conditioning.

50 ml of whole blood, collected in the form of 1 SST and 5 red & green 
CPT tubes will be sent at serial time points to the Blood Processing Core 
(Dr. Figg’s Lab). These time points include: baseline (before start of 
respective (EPOCH-F/R or FLAG) induction chemotherapy); days +7(+/- 3 
Days), +14 (+/-  7 Days), +28 (+/- 7 Days), +60 (+/- 7 Days), +100 (+/- 14 
Days); 6 months (+/- 14 Days), 9 months (+/- 14 Days), 12 months (+/-  30 
days), then 18 months (+/-  30  Days), 24 months (+/- 30 Days), annually 
thereafter (+/- 30 days). These will be used to track reconstitution of 
lymphocyte populations following transplant and as a source of plasma 
and serum for assessing cytokine changes after transplant.


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
An additional 50 ml (6 R&G CPT) will be sent at the onset of acute and/or 
chronic GVHD, prior to start of systemic GVHD treatment, whenever 
clinically possible.
5.1.1.2.2 Studies performed

For all recipients, peripheral blood subsets will be serially monitored by 
multiparameter FACS analysis on fresh whole blood, to assess T, B and 
NK subsets. Peripheral blood mononuclear cells (PBMC) will be 
cryopreserved in liquid nitrogen (vapor phase) for later assays by flow 
cytometry of T lineage commitment (based on cytokine production and 
transcription factors) and expression of markers indicative of 
hematopoietic lineage, state of activation and anergy and capacity for 
migration (adhesion and chemokine receptors). Heparinized plasma will 
be separately stored at -80°C as the main source of plasma for assays of 
chemokines, cytokines and other factors relevant to studies of immune 
dysfunction after transplantation.

Cryopreserved PBMC cells may be activated in vitro with a number of 
different stimuli including specific antigens and mitogens which are known 
to activate distinct pathways of T lymphocyte function. Assays may include 
T cell proliferation, cytokine production and gene expression, cytotoxic T 
lymphocyte generation, and antigen presenting cell function.

The specific assays to be used in the on-going data analyses are subject 
to be modified, deleted or replaced as technology and knowledge in the 
field evolve during the course of the study without constituting a change in 
research aims. These assays apply also to those samples received from 
outside institutions.  If a significant departure from this “Immune 
Characterization” is contemplated based on accumulated data, then the 
protocol and consent will be amended accordingly to cover the new line of 
investigation and its potential risks to subjects.
5.1.2 Immune Reconstitution of Bone Marrow
The bone marrow is a critical site in allogeneic transplantation because it is (1) the site 
of hematopoietic progenitors and early differentiation of lymphocyte and myeloid 
lineages, as well as (2) a potential site of persistent or relapsed malignancy. For all 
patients, an additional bone marrow aspirate (up to 5ml in a heparinized syringe) will be 
obtained at the times scheduled for bone marrow examination as per protocol. The 
aspirate will be collected following marrow aspirates required for clinical assessments.
5.1.3 GVHD Pathogenesis
The pathogenesis of chronic GVHD is poorly understood and no studies have rigorously 
evaluated cellular and molecular changes that occur in the target tissues of chronic 
GVHD. Heterogeneity in patient and treatment related factors complicate group 
comparisons. Prospectively designed study with planned sequential sample collection is 
the ideal format that would give the best chance of success in study of this complex 
problem. 


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5.1.3.1 Collection 

We will focus on the skin and oral cavity as the two most common target organs 
of chronic GVHD. Standard 4-6 mm punch biopsies will be performed in the skin 
and buccal mucosa in all patients at the beginning of immunosuppressive taper 
at day 60 (+/- 7 days) and at 6 months (+/- 14 days). A research biopsy may also 
be performed at the onset of clinical chronic GVHD (skin or oral mucosa) at 
additional time points.  Research skin and oral biopsies are optional and will not 
be collected if the patient declines this procedure.  If a patient’s medical status is 
unstable, then these research biopsies will not be collected.
o
Preferably, skin biopsies should be taken from upper back, biceps area or 
mid-abdomen. However, consideration should be that day 60 and day 180 
biopsy will be done of the same anatomical area. 

Whole saliva will be collected at pre- Palifermin (Post induction and before 
Palifermin administration on Day – 7) and at day 60 (+/- 7 days) and at day 180 
(+/- 14 days) to evaluate the changes in the salivary proteome, microbiome and 
cytokine content at the onset of chronic GVHD.

Swabs of the buccal mucosa, tongue and gums will be performed at Pre- 
Palifermin (Post induction and before KGF administration on Day-7) and at Day 
60 (+/- 7 days) and at day 180 (+/- 14 days) to evaluate changes in oral 
microbiome.
5.1.3.2 Studies Performed
Analysis of changes in immune cell populations and molecular events in the target 
tissues of chronic GVHD (Blood Processing Core - Dr. Figg’s Lab). 
The tissue biopsy samples may be analyzed using a variety of methods including 
immunofluorescence and confocal microscopy, gene expression profiles, and protein 
based assays in order to better understand the reconstitution of resident immune cell 
populations following HSCT and how they change with the onset of chronic GVHD.  
5.1.4 Exploring status of Endocannabinoids/CB1R system and iNOS 
5.1.4.1 Background
Endocannabinoids are lipid-signaling molecules that act on the same cannabinoid 
receptors - CB1 and CB2 - that recognize and mediate the effects of marijuana.  
Arachidonoylethanolamide (anandamide) and 2-arachidonlyglycerol (2AG) are the 
major endocannabinoids. Endocannabinoids acting via CB1R promote inflammation and 
fibrosis progression in multiple organs including liver, kidney, heart, lung and skin. 
Blocking CB1R by selective antagonists attenuated the disease progression in animal 
models of organ fibrosis. Therefore, CB1R antagonist identified therapeutic target for 
multiple forms of fibrosis.
Inducible nitric oxide synthase (iNOS), an enzyme that catalyzes the generation of 
proinflammatory reactive nitrogen species involved in cell injury, inflammation and 
oxidative stress, is induced in fibrotic tissues like liver, lung, heart and skin. Recently, 
dual targeting CB1R and iNOS inhibition by a single molecule provided improved anti-
fibrotic efficacy targeting these proteins alone. Currently, a dual-target CB1R and iNOS 


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inhibitor (MRI-1867) is a potential clinical candidate for fibrotic disorders and under 
clinical development.
5.1.4.2 Objective
The laboratory of Dr. Cinar at NIH would like to explore the status of endocannabinoids / 
CB1R system and iNOS in specimens (plasma and skin biopsies) from patients with 
cGVHD. Identifying overactivity of CB1R system and iNOS in cGVHD may suggest 
potential pathologic roles of CB1R and iNOS in cGVHD. Furthermore, it could identify 
CB1R and iNOS as therapeutic targets for cGVHD. 
5.1.4.3 Methods
Liquid chromatography and triple quad mass spectrometry (LC-MS/MS). 
Immunohistochemistry will be performed on plasma (about 200 uL) and frozen and 
parafilm embedded skin biopsies. De-identified and coded samples will be sent from the 
Blood Processing Core (BPC) to Dr. Cinar’s lab for analysis (shipping address: 5625 
Fishers lane room 2S-18 Rockville, MD 20852).  Dr. Cinar will not be given or have 
access to identifiable data or samples from subjects. 
5.2
SAMPLE PROCESSING
See Section Error! Reference source not found., Appendix K for planned sample 
processing details/techniques that may be adjusted as needed. 
Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting 
samples (the Friday before is preferred).
For sample pickup, page 102-11964.
For immediate help, call 240-760-6180 (main blood processing core number) or, if no 
answer, 240-760-6190 (main clinical pharmacology lab number).
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov
The samples will be processed, barcoded, and stored in Dr. Figg’s lab until requested 
by the investigator.
5.3
SAMPLE STORAGE, TRACKING AND DISPOSITION
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management 
system.  Should a CRIS screen not be available, the CRIS downtime procedures will be 
followed.  Samples will not be sent outside NIH without appropriate approvals and/or 
agreements, if required. 
5.3.1 Sample Data Collection
All samples sent to the Blood Processing Core (BPC) will be barcoded, with data 
entered and stored in Labmatrix utilized by the BPC. This is a secure program, with 
access to Labmatrix limited to defined Figg lab personnel, who are issued individual 
user accounts. Installation of Labmatrix is limited to computers specified by Dr. Figg. 
These computers all have a password restricted login screen. 
Labmatrix creates a unique barcode ID for every sample and sample box, which cannot 
be traced back to patients without Labmatrix access. The data recorded for each 


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sample includes the patient ID, name, trial name/protocol number, time drawn, cycle 
time point, dose, material type, as well as box and freezer location. Patient 
demographics associated with the clinical center patient number are provided in the 
system. For each sample, there are notes associated with the processing method (delay 
in sample processing, storage conditions on the ward, etc.).
5.3.2 Future Studies
Blood, fluid and tissue specimens collected in the course of this research project may be 
banked and used in the future to investigate new scientific questions related to this study, 
when patients give consent, in the Optional Studies section of the informed consent 
document, for storage for future use.  However, this research may only be done if the 
risks of the new questions were covered in the consent document. If new risks are 
associated with the research (e.g. analysis of germ line genetic mutations) protocol 
amendment will be required and informed consent will be obtained from all research 
subjects to whom these new studies and risks pertain. 
5.3.3 Protocol Completion/Sample Destruction 
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -
80C according to stability requirements.  These freezers are located onsite in the BPC 
and offsite at NCI Frederick Central Repository Services in Frederick, MD. Visitors to 
the laboratory are required to be accompanied by laboratory staff at all times. 
Access to stored clinical samples is restricted. Samples will be stored until requested by 
a researcher named on the protocol. All requests are monitored and tracked in 
Labmatrix. All researchers are required to sign a form stating that the samples are only 
to be used for research purposes associated with this trial (as per the IRB approved 
protocol) and that any unused samples must be returned to the BPC. It is the 
responsibility of the NCI Principal Investigator to ensure that the samples requested are 
being used in a manner consistent with IRB approval.
Following completion of this study, samples will remain in storage as detailed above. 
Access to these samples will only be granted following IRB approval of an additional 
protocol, granting the rights to use the material. 
If, at any time, a patient withdraws from the study and does not wish for their existing 
samples to be utilized, the individual must provide a written request. Following receipt of 
this request, the samples will be destroyed (or returned to the patient, if so requested).. 
The PI will record any loss or unanticipated destruction of samples as a deviation. 
Reporting will be per the requirements of section Error! Reference source not found..
Sample barcodes are linked to patient demographics and limited clinical information. 
This information will only be provided to investigators listed on this protocol, via 
registered use of the Labmatrix. It is critical that the sample remains linked to patient 
information such as race, age, dates of diagnosis and death, and histological 
information about the tumor, in order to correlate genotype with these variables.
6
DATA COLLECTION AND EVALUATION
The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant 
data capture system provided by the NCI CCR and ensuring data accuracy, consistency 


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and timeliness. The principal investigator, associate investigators/research nurses 
and/or a contracted data manager will assist with the data management efforts. Primary 
and final analyzed data will have identifiers so that research data can be attributed to an 
individual human subject participant.
6.1
DATA COLLECTION PROCEDURES

After obtaining Informed Consent, a file will be created in the database with 
standardized forms. The study database will maintain data for described 
endpoints in the protocol. The medical record will maintain complete records on 
each patient including any pertinent supplementary information obtained from 
outside laboratories, outside hospitals, radiology reports, laboratory reports, or 
other patient records. The study database will serve as the primary source from 
which all research analyses will be performed.

Available data on donor characteristics will be entered into the study database.  
Note: Per NMDP regulations, and to maintain donor confidentiality, unrelated 
donor source documents will not be sent to the NIH. The NMDP will maintain all 
required source documents in accordance with NMDP policies and procedures.

Documentation of data verification will be tracked in the study database.

Please see Appendix G for detailed information to be included in the database

Concurrent medications will not be captured for the duration of the study except 
for GVHD specific systemic immunosuppressive drugs
6.1.1 Adverse Event (AE) Recording:
Grade 1 adverse events will not be recorded.
If a patient has relapsed disease adverse events will no longer be recorded except 
grade 5 events and unanticipated problems. 
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following:

Results in discontinuation from the study

Is associated with clinical signs or symptoms 

Requires treatment or any other therapeutic intervention

Is associated with death or another serious adverse event, including 
hospitalization. 

Is judged by the Investigator to be of significant clinical impact

If any abnormal laboratory result is considered clinically significant, the 
investigator will provide details about the action taken with respect to the test 
drug and about the patient’s outcome.
End of study procedures: Data will be stored according to HHS, FDA regulations and 
NIH Intramural Records Retention Schedule as applicable. 


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Loss or destruction of data: Should we become aware that a major breach in our plan 
to protect subject confidentiality and trial data has occurred, this will be reported 
expeditiously per requirements in section 7.2.1.
As the two induction therapy regimens are standard regimens with well-defined toxicity 
profiles, adverse events will not be collected during induction therapy administered prior 
to the conditioning chemotherapy except grade 5 events and unanticipated problems.  
This also includes any laboratory data before Day -7.
Record adverse events from the first study intervention (i.e. D-7) then as directed below. 

Hematologic events (anemia, neutropenia, etc..) are not considered adverse 
events as they the desired outcome the conditioning chemotherapy

Grade 2-4 AEs will be recorded up to 14 days after palifermin dose (e.g. day 
+6 post-transplant) regardless of attribution to IND.

After day +6 post-transplant, only grade 4 AEs occurring up to 100 days post 
transplantation and infections noted infection 6.1.2will be recorded. After 100 
days post transplantation only infections per section 6.1.2will be recorded up 
to 24 months.

Any grade 5 AE will be recorded.
All adverse events, including clinically significant abnormal findings on laboratory 
evaluations, regardless of severity, will be followed until return to baseline or 
stabilization of event
6.1.2 Infection Recording Requirements  

Any grade 2-4 infection occurring from Day+7 to 24 months will be recorded 
using the Cordonnier scale only (see Section 15.10, appendix J for details).  
These events will not be captured as adverse events unless they meet the 
requirements mentioned in the adverse events recording section of the protocol: 
CMV/EBV 
Results of nasopharyngeal virus panel (Nasal Wash) that may 
include Influenza A, Influenza B, Parainfluenza 1, 2 or 3; 
Adenovirus, Respiratory Syncytial Virus (RSV), Rhinovirus, 
Coronavirus, Meta-pneumovirus, or any other nasopharyngeal 
virus.
Sepsis, Bacteremia, Candidemia, Aspergillus, Varicella Zoster, 
Viral Encephalitis, Pneumocystis jiroveci, Toxoplasmosis gondii, 
and pneumonia
* If a patient has relapse disease infection data will no longer be recorded or reported
6.2
RECORD KEEPING
All patients must have signed an Informed Consent, and on-study eligibility checklist will 
be filled out by the Research RN and faxed to the Central Registration Office (CRO) 
before patient is entered on the study.


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Complete records must be maintained on patients; these will consist of the hospital 
chart with any supplementary information obtained from outside laboratories, radiology 
reports, or physician’s records.  These records will serve as the primary source material 
that forms the basis for the research record.  All relevant data will also be entered on 
the study database from which formal analyses are done.  The primary source 
documentation will assure the following: on-study information, including patient eligibility 
data and patient history; flow-sheets, specialty forms for pathology, radiation, or 
surgery; adverse event assessment; and off-study summary sheet, including a final 
assessment by the treating physician.
6.3
GENOMIC DATA SHARING PLAN
Unlinked genomic data will be deposited in public genomic databases in compliance 
with the NIH Genomic Data Sharing Policy. 
Note: The analyses planned will not generate incidental genomic findings; as indicated 
in Section 5.3.2, the study will be updated for appropriate consent, management, etc., 
added in an amendment if the plan should change.  
6.4
RESPONSE CRITERIA
6.4.1 Definitions 
6.4.1.1 Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of 
their first treatment with palifermin.
6.4.1.2 Evaluable for Disease Response: All patients will be evaluable for disease 
response from Day +0 transplant onwards. Subjects will no longer be followed 
for GVHD endpoint if it is necessary to deviate from original prophylaxis plan 
(e.g. more rapid tapering of immunosuppression for malignancy relapse, any 
anti-malignancy therapy, DLI administration)
6.4.2 GVHD Diagnosis/Grading Criteria
Formal acute GVHD assessment will be performed on days +28 (± 7 days), 
+60 (± 4 days), +100 (+/- 14 days) and +180 (+/- 14 days).  
Formal chronic GVHD assessment will be performed on days +28, +60, +100, 
+ 180, +270, +365, yearly thereafter until 5 years.  
Acute and chronic graft-versus-host disease (GVHD) will be graded according 
to NIH cGVHD staging criteria specified in Appendix C: Acute Graft Versus 
Host Disease Evaluation (Worksheet) and Appendix D respectively
6.4.3 Malignancy Response Criteria
Please see Appendix B.
6.5
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety 
of each patient while on the study.  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will 
be utilized for AE reporting.  All appropriate treatment areas should have access to a 


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copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded 
from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40). 
7
NIH REPORTING REQUIREMENTS/DATA SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found 
here.
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING 
7.2.1 Expedited Reporting
Please refer to the reporting requirements in Policy 801: Reporting Research Events 
and Policy 802 Non-Compliance Human Subjects Research found here. Note: Only IND 
Safety Reports that meet the definition of an unanticipated problem will need to be 
reported per these policies.
7.2.2 IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events 
found here. 
7.3
NCI CLINICAL DIRECTOR REPORTING 
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI 
Clinical Director.  A separate submission is not necessary as reports in iRIS will be 
available to the Clinical Director.
In addition to those reports, all deaths that occur within 30 days after receiving a 
research intervention should be reported via email to the Clinical Director unless they 
are due to progressive disease.  
To report these deaths, please send an email describing the circumstances of the death 
to the Clinical Director/designee at NCICCRQA@mail.nih.gov within one business day 
of learning of the death.
7.4
NATIONAL MARROW DONOR PROGRAM REPORTING CRITERIA
7.4.1 Adverse Events
7.4.1.1 NMDP shall be notified of serious adverse events at possibly, probably or 
definitely related to the product
7.4.1.2 Fatal or potentially life-threatening adverse events possibly, probably or 
definitely related to the product shall be reported to NMDP by close of the next 
business day following determination of the event
Please contact the NMDP research coordinator

Data will also be sent to the Center for International Bone Marrow Transplant 
Research (CIBMTR).


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7.5
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.5.1 Principal Investigator/Research Team
The clinical research team will meet on a weekly basis when patients are being actively 
treated on the trial to discuss each patient. Decisions about dose level enrollment and 
dose escalation if applicable will be made based on the toxicity data from prior patients. 
All data will be collected in a timely manner and reviewed by the principal investigator or 
a lead associate investigator. Events meeting requirements for expedited reporting as 
described in section 7.2.1 will be submitted within the appropriate timelines. 
The principal investigator will review adverse event and response data on each patient 
to ensure safety and data accuracy. The principal investigator will personally conduct or 
supervise the investigation and provide appropriate delegation of responsibilities to 
other members of the research staff.
8
SPONSOR PROTOCOL/SAFETY REPORTING
8.1
DEFINITIONS
8.1.1 Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An adverse event (AE) can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product (ICH E6 (R2))
8.1.2 Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of 
the investigator or the sponsor, it results in any of the following:

Death,

A life-threatening adverse event (see section 8.1.3)

Inpatient hospitalization or prolongation of existing hospitalization
o
A hospitalization/admission that is pre-planned (i.e., elective or scheduled 
surgery arranged prior to the start of the study), a planned hospitalization for 
pre-existing condition, or a procedure required by the protocol, without a 
serious deterioration in health, is not considered a serious adverse event.
o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient or subject convenience) is not considered a serious 
adverse event. 
o
Emergency room visits or stays in observation units that do not result in 
admission to the hospital would not be considered a serious adverse event. 
The reason for seeking medical care should be evaluated for meeting one of 
the other serious criteria.


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
Persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions

A congenital anomaly/birth defect.

Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition.
8.1.3 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 
subject 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. 
(21CFR312.32)
8.1.4 Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 4.0.
8.1.5 Relationship to Study Product
All AEs will have their relationship to study product assessed using the terms:  related 
or not related.  

Related – There is a reasonable possibility that the study product caused the 
adverse event. Reasonable possibility means that there is evidence to suggest a 
causal relationship between the study product and the adverse event.

Not Related – There is not a reasonable possibility that the administration of the 
study product caused the event.
8.2
ASSESSMENT OF SAFETY EVENTS
AE information collected will include event description, date of onset, assessment of 
severity and relationship to study product and alternate etiology (if not related to study 
product), date of resolution of the event, seriousness and outcome. The assessment of 
severity and relationship to the study product will be done only by those with the training 
and authority to make a diagnosis and listed on the Form FDA 1572 as the site principal 
investigator or sub-investigator.  AEs occurring during the collection and reporting 
period will be documented appropriately regardless of relationship.  AEs will be followed 
through resolution.
SAEs will be:

Assessed for severity and relationship to study product and alternate etiology (if 
not related to study product) by a licensed study physician listed on the Form 
FDA 1572 as the site principal investigator or sub-investigator.


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
Recorded on the appropriate SAE report form, the medical record and captured 
in the clinical database.

Followed through resolution by a licensed study physician listed on the Form 
FDA 1572 as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1. All serious 
adverse events recorded from the time of first investigational product administration 
must be reported to the sponsor with the exception of any listed in section 8.4.
8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets  protocol-defined serious criteria or meets the definition of Adverse 
Event of Special Interest that require expedited reporting must be submitted 
immediately (within 24 hours of awareness) to OSRO Safety using the CCR SAE report 
form. Any exceptions to the expedited reporting requirements are found in section 
Error! Reference source not found..
All SAE reporting must include the elements described in section 8.2.
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report 
form and instructions can be found at: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions
Following the assessment of the SAE by OSRO, other supporting documentation of the 
event may be requested by the OSRO Safety and should be provided as soon as 
possible.
8.4
WAIVER OF EXPEDITED REPORTING TO CCR 
8.4.1 Disease progression
Death and hospitalization that are deemed to be due to disease progression, and not 
attributable to the intervention will not be reported as an SAE unless there is evidence 
suggesting a causal relationship between the study intervention and the event (e.g., 
death from anaphylaxis). In that case, the investigator must immediately report the 
event to the sponsor.
The event, and the assessment that it was caused by disease progression will be 
documented in the medical records.
8.4.2 Late occurring SAEs
Any serious adverse event that occurs > 30 days post Palifermin unless possibly, 
probably, or definitely related to IND. 
The PI will submit a summary table of all grade 3-5 events, whether or not considered 
related to the product, every 6 months. The report shall include the number of patients 
treated in the timeframe, the number of events per AE term per grade which occurred in 
the 6-month timeframe and in total since the start of the study, attribution, and 
type/category of serious. 


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Reports will be submitted to the Center for Cancer Research (CCR) at 
OSROSafety@mail.nih.gov
The Sponsor might request case summaries for those events if, upon review, the 
Sponsor determines that an aggregate safety report is required 
(21CFR312.32(c)(1)(iv)).
8.5
REPORTING PREGNANCY 
All required pregnancy reports/follow-up to OSRO will be submitted to: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  Forms and 
instructions can be found here: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions.
8.5.1 Maternal exposure
If a patient becomes pregnant during the course of the study, the study treatment 
should be discontinued immediately, and the pregnancy reported to the Sponsor no 
later than 24 hours of when the Investigator becomes aware of it. The Investigator 
should notify the Sponsor no later than 24 hours of when the outcome of the Pregnancy 
become known,
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth 
defects and spontaneous miscarriages that meet serious criteria (section 8.1.2) should 
be reported as SAEs. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) should be followed up and 
documented.
8.5.2 Paternal exposure
Male patients should refrain from fathering a child or donating sperm for the duration of 
active study therapy.
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) occurring from the date of the first dose until the 
last dose is administered should, if possible, be followed up and documented.
8.6
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND
Following notification from the investigator, CCR, the IND sponsor, will report any 
suspected adverse reaction that is both serious and unexpected.  CCR will report an AE 
as a suspected adverse reaction only if there is evidence to suggest a causal 
relationship between the study product and the adverse event.  CCR will notify FDA and 
all participating investigators (i.e., all investigators to whom the sponsor is providing 
drug under its INDs or under any investigator’s IND) in an IND safety report of potential 
serious risks from clinical trials or any other source, as soon as possible, in accordance 
to 21 CFR Part 312.32. 
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8.7
SPONSOR PROTOCOL DEVIATION REPORTING
A Protocol Deviation is defined as any non-compliance with the clinical trial Protocol, 
Manual of Operational Procedures (MOP) and other Sponsor approved study related 
documents, GCP, or protocol-specific procedural requirements on the part of the 
participant, the Investigator, or the study site staff inclusive of site personnel performing 
procedures or providing services in support of the clinical trial.
It is the responsibility of the study Staff to document any protocol deviation identified by 
the Staff or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) 
online application. The entries into the PDTS online application should be timely, 
complete, and maintained per CCR PDTS user requirements. 
In addition, any deviation to the protocol should be documented in the participant’s 
source records and reported to the reviewing IRB per their guidelines. OSRO required 
protocol deviation reporting is consistent with E6(R2) GCP: Integrated Addendum to 
ICH E6(R1): 4.5 Compliance with Protocol; 5.18.3 (a), and 5.20 Noncompliance; and 
ICH E3 16.2.2 Protocol deviations.
9
CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure:

that the rights of the participants are protected; 

that the study is implemented per the approved protocol, Good Clinical Practice 
and standard operating procedures; and, 

the quality and integrity of study data and data collection methods are 
maintained.  
Monitoring for this study will be performed by NCI CCR Office of Sponsor and 
Regulatory Oversight (OSRO) Sponsor and Regulatory Oversight Support (SROS) 
Services contractor. Clinical site monitoring activities will be based on OSRO standards, 
FDA Guidance E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) 
March 2018, and applicable regulatory requirements.
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address 
human subject protections and integrity of the study data. OSRO will determine the 
intensity and frequency of monitoring based on several factors, including study type, 
phase, risk, complexity, expected enrollment rate, and any unique attributes of the study 
and the site. The Sponsor will conduct a periodic review of the CMP to confirm the plan's 
continued appropriateness. A change to the protocol, significant or pervasive non-
compliance with GCP, or the protocol may trigger CMP updates.
OSRO SROS Monitoring visits and related activities will be conducted throughout the 
life cycle of each protocol. The first activity is before the study starts to conduct a Site 
Assessment Visit (SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim 
Monitoring Visit(s) (IMVs), and a study Close-Out Visit (COV).
Some monitoring activities may be performed remotely, while others will occur at the 
study site(s). Monitoring visit reports will describe visit activities, observations, and 
associated action items or follow-up required for resolution of any issues, discrepancies, 


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or deviations. Monitoring reports will be distributed to the study PI, NCI CCR QA, CCR 
Protocol Support Office, coordinating center (if applicable), and the Sponsor regulatory 
file.
The site Monitor will inform the study team of any deviations observed during monitoring 
visits. If unresolved, the Monitor will request that the site Staff enter the deviations in the 
CCR Protocol Deviation Tracking System (PDTS) for deviation reporting to the Sponsor 
and as applicable per institutional and IRB guidance.
10 STATISTICAL CONSIDERATIONS

The primary objectives of this study are to determine a reasonable safe 
maximum dose level of palifermin to use in connection with an alloHSCT regimen 
and to determine in a pilot fashion if adding palifermin to the TMS regimen will 
result in a modest reduction of the incidence of severe chronic GVHD.

In the phase 1 portion of the study, we will use a standard 3+3 design to 
determine maximum dose level of palifermin that could be administered to 
patients receiving a transplant using the TMS regimen. If 4 different increasing 
doses are investigated then up to 24 patients may be needed in this portion of 
the study.

Once the dose to use has been determined, in the phase II portion of the trial 
patients will be treated at that dose of palifermin along with the TMS regimen.  
Patients treated at that dose level in the phase I portion of the trial will be 
included in the phase II portion of the trial.  

Based upon results from the recent 07C0195 trial, when analyzed by cumulative 
incidence curve analysis, the probability of having severe chronic GVHD on the 
TMS regimen was approximately 28% at two years. It would be useful to try to 
see if the 28% rate of severe cGVHD by 2 years as seen on the prior study could 
be substantially improved upon. With 27 patients in arm 4 to be evaluated in the 
phase II (including those who were included in the dose escalation phase), an 
exact binomial test with a 10% one-sided significance level will have 87.3% 
power to detect the difference between 28% with severe chronic GVHD at 2 
years and 10% on the present trial.

In practice, in addition to forming the fractions of patients who have not 
experienced severe cGVHD by 2 years, a Kaplan-Meier curve of the probability 
of avoiding development of severe chronic GVHD will be constructed, and will 
have values at key time points such as 12, 24 and 36 months without severe 
chronic GVHD estimated, along with appropriate 80% and 95% confidence 
intervals to explore whether the present results exceed those from the prior study 
with TMS alone, in an informal comparison without formal statistical testing. As 
death due to any cause is a substantial competing risk, a cumulative incidence 
curve of development of severe chronic GVHD competing with death due to any 
cause will also be constructed. This curve can also be compared informally to the 
corresponding curve from the TMS arm from the 07C0195 study. In addition, as 
exploratory evaluations, Kaplan-Meier and cumulative incidence curves adjusting 
for the competing risk of death from any cause may be constructed moderate 


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and severe chronic GVHD. These curves may also potentially be compared to 
the corresponding curves from the TMS arm from the 07C0195 study.  In 
addition, curves that include patients treated with fewer than the maximum safe 
number of doses may be constructed for exploratory purposes.

This trial is of limited size and intends to establish if a trend toward improvement 
in severe chronic GVHD incidence may occur by the addition of palifermin. 
Should these results appear promising, the palifermin regimen studied in this trial 
may be explored in a subsequent more definitive, multi-institutional study.

The following are stopping rules for patients included in the phase II portion 
(including 3 to 6 at the MTD from the dose escalation phase) based on observing 
non-relapse mortality (NRM) rates which are inconsistent with those identified on 
07C0195: 
o
If anytime within the first 15 patients who are included in the phase II portion, 
there are 5 or more patients who have experienced NRM within 100 days of 
PBSC, no further patients will be accrued to this trial as soon as this is able to 
be determined. This is because the TMS arm of 07C0195 has a 100 day 
NRM cumulative incidence of 10.8%, and 5/15 has a lower one-sided 90% 
confidence interval of 17.2%, which exceeds the rate experienced on the 
07C0195 trial. 4/15 has a lower one-sided 90% CI of 12.2%, and thus this 
could be potentially interpretable as being essentially marginally consistent 
with that of the prior trial and not sufficiently worse to mandate early stopping.
o
Additionally, if anytime within the first 15 patients who are included in the 
phase II portion, there are 6 or more patients who have experienced NRM 
within 6 months of PBSC, no further patients will be accrued to this trial as 
soon as this is able to be determined. This is because the TMS arm of 
07C0195 has a 6 month NRM cumulative incidence of 16.2%, and 6/15 has a 
lower one-sided 90% confidence interval of 22.6%, which exceeds the rate 
experienced on the 07C0195 trial. 5/15 has a lower one-sided 90% CI of 
17.2%, and thus this could be potentially interpretable as being essentially 
marginally consistent with that of the prior trial and not sufficiently worse to 
mandate early stopping.
o
Finally, if anytime within the first 15 patients who are included in the phase II 
portion, there are 7 or more patients who have experienced NRM within 12  
months of PBSC, then no further patients will be accrued to this trial as soon 
as this is able to be determined. This is because the TMS arm of 07C0195 
has a 12 month NRM cumulative incidence of 19.0%, and 7/15 has a lower 
one-sided 90% confidence interval of 28.2%, which exceeds the rate 
experienced on the 07C0195 trial. 6/15 has a lower one-sided 90% CI of 
22.6% and thus this could be potentially interpretable as being essentially 
marginally consistent with that of the prior trial and not sufficiently worse to 
mandate early stopping.

Assuming accrual of 10 patients per year, and assuming that up to 18 
patients are included only in the phase I portion and 27 are included in the 
phase II portion (including 3-6 patients on both the phase I and II portions), 


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the accrual period for the entire trial is expected to be 4-4.5 years. In order to 
allow for non-evaluable patients, the accrual ceiling will be set at 50 patients.

In addition to toxicity, chronic GVHD and immunological endpoints, the study 
may report analysis for additional transplant outcomes supported by the data, 
including: Overall survival, failure-free survival, non-relapse mortality (death in 
clinical remission), relapse-related mortality (death without clinical remission), 
GVHD related mortality, rate of achieving remission, malignancy relapse 
(recurrence after remission)/progression, incidence of severe infections, 
engraftment of neutrophils and platelets, graft failure, incidence of starting 
steroids and steroids administration AUC, rate of starting secondary therapy 
for acute and chronic GVHD separately, time to permanent (>6 months) 
interruption of immunosuppression, malignancy remission and cGVHD 
severity at last yearly follow-up. It will also be of interest to compare the 
fraction of patients with grade II-IV aGVHD among patients included in the 
phase II portion of the present trial to that of patients treated on the TMS arm 
of 07C0195.  An analysis based on 39 patients from the TMS arm of 07C0195 
showed that 21/39 (53.8%) of patients experienced grade II-IV aGVHD. With 
27 patients on the present trial, and 39 from the prior trial, a Fisher's Exact 
Test with a 10% one-sided sided significance level will have 84.3% power to 
detect the difference between a 24% rate of grade II-IV aGVHD on the 
present study 54% on the TMS arm of 07C0195. (Appendix A and Appendix 
B show definitions of hematopoietic engraftment and disease responses).    

Acute and chronic GVHD incidence will be reported in 2 ways:
o
Total incidence across trial independently of other interventions,
o
No longer followed for GVHD endpoint if it is necessary to deviate from 
original prophylaxis plan (e.g. more rapid tapering of immunosuppression 
for malignancy relapse, any anti-malignancy therapy, DLI administration).       
 
11 HUMAN SUBJECTS PROTECTION
11.1 RATIONALE FOR SUBJECT SELECTION
Lymphoid malignancies affect all races and genders.  However, in some instances 
males are more likely than females to be affected, and this will be reflected in the 
gender distribution of this study.  For example, while NHL has a higher incidence in 
African Americans from the mid-to-late teens to mid-50s, the incidence in white 
individuals exceeds African Americans beginning at age 55.  Among women, Hispanics 
of all races have the second highest incidence of NHL after whites.
This trial will use a convenience sample of participants from subjects being screened at 
the NCI.  Therefore, targeted selection by race or gender for equal distribution will not 
be feasible.  Should trends in racial, ethnic or gender differences become evident, 
additional studies may be designed or this trial be amended to further explore those 
differences.


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Patients with high-risk hematologic malignancies will be the subjects for this study.  
Allogeneic HSCT represents a potentially curative treatment for patients with the 
disease characteristics selected for inclusion.  The expected survival of such patients 
with conventional chemotherapy is approximately one year or shorter.  Eligibility in this 
protocol is limited to adults (age > 18 years).
11.1.1 Participation of Children
Children will not be enrolled in this study.  Immune reconstitution is different between 
children and adults, which is an exploratory endpoint of this study.
11.1.2 Unrelated Donors
The National Marrow Donor Program (NMDP) IRB will be responsible for the review 
and continuing oversight of protocol procedures that relate only to NMDP unrelated 
donors.  These donors will not be enrolled on this protocol. 
11.1.3 Participation of Subjects Unable to Give Consent
Adults unable to give consent are excluded from enrolling in the protocol.  However re-
consent may be necessary and there is a possibility, though unlikely, that subjects could 
become decisionally impaired. For this reason and because there is a prospect of direct 
benefit from research participation (section 11.2), all subjects will be offered the 
opportunity to fill in their wishes for research and care, and assign a substitute decision 
maker on the “NIH Advance Directive for Health Care and Medical Research 
Participation” form so that another person can make decisions about their medical care 
in the event that they become incapacitated or cognitively impaired during the course of 
the study. Note: The PI or AI will contact the NIH Ability to Consent Assessment Team 
(ACAT) to assess ongoing capacity of the subjects and to identify an LAR, as needed.
Please see section 11.3.1 for consent procedure.
11.2 RISK/BENEFIT ASSESSMENT
11.2.1 Benefits
There is a potential benefit to the transplant recipient, as demonstrated by the published 
literature documenting long-term disease-free survival for patients with high-risk 
hematologic malignancies following allogeneic HSCT.  This carefully defined patient 
population is a reasonable one in which to explore strategies to improve the results of 
allogeneic HSCT from unrelated donors, which historically has achieved prolonged 
remission and survival for some patients but has been associated with significant 
morbidity and high transplant-related mortality.  The strategies chosen in this protocol 
extend our previous work to develop a platform for consistent engraftment and immune 
reconstitution using unrelated donor products.
11.2.2 Risks
11.2.2.1
Radiation Risks
This research study involves exposure to radiation from up to:

6 CT scans of the chest in order to determine changes in the thymus 
measurements 


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
1 DEXA scan

1 MUGA scan (if performed instead of echocardiogram)
Note:  The 6 CT scans of the chest will be replaced with a CT scan of 
neck/chest/abdomen/pelvis in lymphoma patients (neck may be omitted in follow-up 
if no disease). 
The amount of radiation exposure received from these procedures is equal to 
approximately 1.43 rem (or 8.27 rem in lymphoma patients). These levels of radiation 
may be associated with an increased risk of cancer.      
11.2.2.2
Transplant risks
The potential risks to the transplant recipient have been carefully considered and are 
felt to be potentially less than would otherwise occur with myeloablative allogeneic 
HSCT.  The risks graft rejection, acute and chronic GVHD, infection, and relapse will be 
present, as discussed previously. Other risks related to drugs used in this study are 
found in section 0 and in the informed consent document.
11.2.2.3
Procedure Risks
Stem Cell Infusion: The donor cells will be infused fresh or frozen with a chemical 
called DMSO to protect them from the effects of freezing. Patients receiving thawed 
cells often develop side effects from the DMSO. DMSO side effects may include fever 
and allergic reactions, such as skin rash, itching, difficulty breathing, and low blood 
pressure. These reactions are usually mild and temporary, and they can be easily 
treated with IV fluids and medications. 
Bone Marrow Aspiration and Biopsy: This procedure usually causes only mild pain 
for a short time at the biopsy site. Very rarely, bleeding or an infection may occur at the 
biopsy site.
Blood Draws: Side effects of blood draws include pain and bruising in the area where 
the needle was placed, lightheadedness and rarely, fainting. When a large amount of 
blood is drawn, your red blood cell count may drop causing anemia. Anemia can cause 
a lack of energy and other symptoms. Transfusions of red blood cells are sometimes 
needed to treat anemia. 
Central Venous Catheter: Side effects of placing a central venous line in your chest 
wall include bleeding, bruising, blood clots, or pain in the area of insertion. This line will 
be placed by physicians with experience in this procedure. These physicians will 
discuss the above risks at the time of the line insertion. Rarely, placement of a central 
venous catheter can result in a collapsed lung. If a collapsed lung occurs, it may require 
hospitalization and temporary insertion of a plastic tube in your chest to re-expand the 
lung.
Echocardiogram:  Other than possibly experiencing some minor skin irritation from the 
electrodes there are no anticipated risks related to complete the electrocardiogram 
and/or the echocardiogram.
Pulmonary Function Tests:  PFTs are safe for most participants; however, some may 
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collapsed lung.  In participants with asthma, PFTs may precipitate an asthma attack. 
Lumbar Puncture (Spinal Tap): Though lumbar punctures are generally recognized as 
safe, some risks may include pain or bleeding at the site of needle insertion (the low 
back), infection, and headache.
Skin Biopsies: Whenever possible, we will perform biopsies on covered areas of the 
body. There may be minor bleeding right after the procedure and this can easily be 
controlled by applying pressure on the spot for a few minutes. Rarely, a bruise might 
form and this usually heals on its own. Sometimes a small infection may occur at the 
biopsy site. This can usually be treated with topical antibiotics. On the very rare 
occasion that a larger or deeper infection occurs, oral antibiotics may be needed for 7-
10 days. An infection can be recognized by redness, soreness, and pus at the site. It 
generally starts 2 days or more after the procedure and does not clear up in another 
couple of days. These biopsy/excision sites generally heal very well, leaving red, white, 
dark or skin-colored flat scars. Sometimes, the scar that forms may be a bit thicker than 
usual. Rarely, a keloid (large, painful or itchy scar) may form. Keloids are more likely to 
form on the chin, earlobes, chest and upper backs of Blacks and Asians between 
adolescence and the 30’s.
Oral Mucosa Biopsy: There may be minor bleeding, bruising, numbness and slight 
swelling. There is also the possibility of infection. Mouth sores have occurred in some 
patients, but this is uncommon.
11.3 INFORMED CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document 
to the participant or consent designee(s) as applicable for review prior to consenting. A 
designated study investigator will carefully explain the procedures and tests involved in 
this study, and the associated risks, discomforts and benefits. In order to minimize 
potential coercion, as much time as is needed to review the document will be given, 
including an opportunity to discuss it with friends, family members and/or other advisors, 
and to ask questions of any designated study investigator. A signed informed consent 
document will be obtained prior to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in 
person or remotely (e.g., via telephone or other NIH approved remote platforms used in 
compliance with local policy, including HRPP policy 303) per discretion of the 
designated study investigator and with the agreement of the participant/consent 
designee(s). Whether in person or remote, the privacy of the subject will be maintained. 
Consenting investigators (and participant/consent designee, when in person) will be 
located in a private area (e.g., clinic consult room). When consent is conducted 
remotely, the participant/consent designee will be informed of the private nature of the 
discussion and will be encouraged to relocate to a more private setting if needed. For 
the optional biopsies, the patient will consent at the time of the procedure.  If the patient 
refuses the optional biopsy at that time, the refusal will be documented in the medical 
record and in the research record.  
Consent will be documented with required signatures on the physical document (which 
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below, with a manual (non-electronic) signature on the electronic document. When 
required, witness signature will be obtained similarly as described for the investigator 
and participant.. 
Manual (non-electronic) signature on electronic document:
When a manual signature on an electronic document is used for the documentation 
of consent at the NIH Clinical Center, this study will use the following to obtain the 
required signatures:

Adobe platform (which is not 21 CFR Part 11 compliant); or,  

iMedConsent platform (which is 21 CFR Part 11 compliant)
During the consent process, participants and investigators will view individual copies 
of the approved consent document on screens at their respective locations (if remote 
consent); the same screen may be used when in the same location but is not 
required.  
Both the investigator and the participant will sign the document using a finger, stylus 
or mouse. 
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent 
Process for additional information (e.g., verification of participant identity when 
obtaining consent remotely) found here.
.
11.3.1 Consent Process for Adults Who Lack Capacity to Consent to Research 
Participation
For participants addressed in section Error! Reference source not found., an LAR will 
be identified consistent with Policy 403 and informed consent obtained from the LAR, as 
described in Section Error! Reference source not found.. 
12 REGULATORY AND OPERATIONAL CONSIDERATIONS  
12.1 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study 
participants, investigators, funding agency, the Investigational New Drug (IND) sponsor 
and regulatory authorities. If the study is prematurely terminated or suspended, the 
Principal Investigator (PI) will promptly inform study participants, the Institutional Review 
Board (IRB), and sponsor and will provide the reason(s) for the termination or 
suspension. Study participants will be contacted, as applicable, and be informed of 
changes to study visit schedule.
Circumstances that may warrant termination or suspension include, but are not limited 
to:

Determination of unexpected, significant, or unacceptable risk to participants

Demonstration of efficacy that would warrant stopping   

Insufficient compliance to protocol requirements


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
Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met

Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality 
are addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug 
Administration (FDA).
12.2 QUALITY ASSURANCE AND QUALITY CONTROL
The clinical site will perform internal quality management of study conduct, data and 
biological specimen collection, documentation and completion.  An individualized quality 
management plan will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry 
system and data QC checks that will be run on the database will be generated. Any 
missing data or data anomalies will be communicated to the site(s) for 
clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that 
the clinical trial is conducted and data are generated and biological specimens are 
collected, documented (recorded), and reported in compliance with the protocol, 
International Conference on Harmonisation Good Clinical Practice (ICH GCP), and 
applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, 
and inspection by local and regulatory authorities.
12.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons 
who have a role in the design, conduct, analysis, publication, or any aspect of this trial 
will be disclosed and managed. Furthermore, persons who have a perceived conflict of 
interest will be required to have such conflicts managed in a way that is appropriate to 
their participation in the design and conduct of this trial.  The study leadership in 
conjunction with the National Cancer Institute has established policies and procedures 
for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest.
12.4 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating 
investigators, their staff, and the sponsor(s). This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information 
relating to participants. Therefore, the study protocol, documentation, data, and all other 
information generated will be held in strict confidence. No information concerning the 
study or the data will be released to any unauthorized third party without prior written 
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All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of 
the Institutional Review Board (IRB), and/or regulatory agencies may inspect all 
documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
participants in this study. The clinical study site will permit access to such records.
The study participant’s contact information will be securely stored at the clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept 
in a secure location for as long a period as dictated by the reviewing IRB, Institutional 
policies, or sponsor requirements.
Study participant research data, which is for purposes of statistical analysis and 
scientific reporting, will be stored at the NCI CCR. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data 
will be identified by a unique study identification number. The study data entry and study 
management systems used by the clinical site(s) and by NCI CCR research staff will be 
secured and password protected. At the end of the study, all study databases will be 
archived at the NCI CCR.
To further protect the privacy of study participants, a Certificate of Confidentiality has 
been issued by the National Institutes of Health (NIH). This certificate protects 
identifiable research information from forced disclosure. It allows the investigator and 
others who have access to research records to refuse to disclose identifying information 
on research participation in any civil, criminal, administrative, legislative, or other 
proceeding, whether at the federal, state, or local level. By protecting researchers and 
institutions from being compelled to disclose information that would identify research 
participants, Certificates of Confidentiality help achieve the research objectives and 
promote participation in studies by helping assure confidentiality and privacy to 
participants.
13 PHARMACEUTICAL INFORMATION
13.1 CYCLOPHOSPHAMIDE (CTX, CYTOXAN)
13.1.1 Source  
Cyclophosphamide will be purchased by the NIH Clinical Center Pharmacy Department 
from commercial sources and is supplied as a lyophilized powder in various vial sizes.
13.1.2 Preparation  
Cyclophosphamide will be reconstituted with sterile water for injection to yield a final 
concentration of 20 mg/ml as described in the package insert.
13.1.3 Storage and Stability 
The vials are stored at room temperature.  Following reconstitution as directed, 
solutions of cyclophosphamide are stable for 24 hours at room temperature, or 6 days 
when refrigerated at 2-8 C.
13.1.4 Administration 


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The cyclophosphamide used in this regimen will be mixed in 100 ml 0.9% sodium 
chloride, Inj., and given as an IVPB over 30 minutes in the induction regimen. In the 
preparative regimen it is given over two hours. Patients will be instructed to drink an 
adequate amount of fluids and empty their bladders frequently during 
cyclophosphamide administration.
13.1.5 Toxicities 
Please refer to the package insert for a complete listing of all toxicities.

Nausea and vomiting - variable; symptomatically improved with standard anti-
emetics and/or benzodiazepines [e.g., lorazepam].

Water retention – cyclophosphamide may rarely provoke the syndrome of 
inappropriate antidiuretic hormone secretion and resultant hyponatremia, usually 
manifested 12-48 hours after IV administration, necessitating frequent accurate 
assessment [q 1-2 hours] of intake, urine output and urine specific gravity.  This 
effect can be counteracted by furosemide.  Fluid restriction is not feasible during 
administration of high dose cyclophosphamide.

Cardiomyopathy - cyclophosphamide may cause severe, sometimes lethal, 
hemorrhagic myocardial necrosis or congestive cardiomyopathy.  Patients may 
present with congestive cardiomyopathy as late as 2 weeks after the last dose of 
cyclophosphamide.  The clinical syndrome has been observed in patients 
receiving the dose of cyclophosphamide used in this protocol.  In an attempt to 
minimize this complication, patients with significant cardiac dysfunction are 
excluded from this protocol [see section 2, patient eligibility].  Congestive failure 
is managed according to standard medical therapeutics.

Hemorrhagic cystitis – this is a serious, potentially life-threatening complication 
related to injury of the bladder epithelium by cyclophosphamide metabolites.  
Although sub-clinical hematuria is not uncommon at this dose level, clinically 
significant hematuria or serious hemorrhage can usually be avoided by 
maintaining a high urine volume and frequent voidings and the administration of 
Mesna.  Diuresis is maintained for 24 hours after completion of last dose by 
parenteral infusions of 0.9% Sodium Chloride with potassium chloride. Careful 
monitoring of serum and urine electrolytes is mandated.  Furosemide may be 
required to ensure this diuresis.  Continuous bladder irrigation may be used for 
control of significant hematuria.

Less common but serious complications include pulmonary fibrosis and 
secondary malignancies. Less common but reversible toxicities include alopecia 
and skin rash.
13.1.6 Hydration Guidelines
All patients should receive 0.9%NS at the following volumes (based on 
cyclophosphamide dose levels) and rates with half the specified volume given before 
starting cyclophosphamide administration and half the volume given after completion of 
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Cyclophosphamide
Dosage Levels
Fluid Volume and Administration Rate
1 & 2
1000 mL 0.9%NS @ 300 – 500 mL/h
Levels 3, 4, & 5
2000 mL 0.9%NS @ 300 – 500 mL/h
Levels 6
2500 mL 0.9%NS @ 300 – 500 mL/h
13.2 MESNA (SODIUM 2-MERCAPOETHANESULFONATE, MESNUM, MESNEX) 
13.2.1 Supply 
Mesna will be will be purchased by the NIH Clinical Center Pharmacy Department from 
commercial sources and is supplied as a 100mg/ml solution.
13.2.2 Preparation  
Dilute up to 20 mg Mesna/mL fluid in D5W or 0.9% sodium chloride, Inj.  Mesna should 
be started concurrently with the cyclophosphamide in the preparative regimen. Mesna 
will be given at 1200 mg/m2 in 500 ml by continuous IV infusion over 24 hour infusion 
for four doses (days -6, -5, -4, and -3).
13.2.3 Storage and Stability 
Intact ampules are stored at room temperature.  Diluted solutions (1 to 20 mg/dl) are 
physically and chemically stable for at least 24 hours under refrigeration.  Mesna is 
chemically stable at room temperature for 48-72 hours in D5W, 48-72 hour in 
D5W/0.45% sodium chloride injection, or 24 hours in 0.9% sodium chloride injection.
13.2.4 Administration  
To be administered intravenously as continuous infusion.
13.2.5 Toxicities 
Nausea, vomiting, diarrhea. Please refer to the package insert for a complete listing of 
all toxicities.
13.3 FILGRASTIM (G-CSF, NEUPOGEN®)
13.3.1 Supply 
Commercially available as filgrastim injection in a concentration of 300g/ml in 1ml 
(300g) and 1.6ml (480g) vials.
13.3.2 Preparation  
For subcutaneous administration, the appropriate prescribed dose is drawn up from the 
vial with no further dilution prior to administration.  For intravenous administration, the 
commercial solution for injection should be diluted prior to administration.  It is 
recommended that the prescribed dose be diluted with dextrose 5% in water to a 
concentration greater than 5g/ml.  Dilution of filgrastim to a final concentration of less 
than 5g/ml is not recommended at any time.  Do not dilute with saline at any time; 


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product may precipitate. Filgrastim diluted to concentrations between 5 and 15g/ml 
should be protected from absorption to plastic materials by the addition of Albumin 
(Human) to a final concentration of 2mg/ml.  When diluted in 5% dextrose or 5% 
dextrose plus Albumin (Human), filgrastim is compatible with glass bottles, PVC and 
polyolefin IV bags, and polypropylene syringes.  The dose may be “rounded down” to 
within 10% of patient’s calculated dose to use the drug cost-effectively.
13.3.3 Storage and Stability 
Filgrastim for injection should be stored in the refrigerator at 2o to 8oC (36o to 46oF).  
Avoid shaking.
13.3.4 Administration
Subcutaneous injection is preferred.  If clinically indicated, filgrastim may be 
administered as an intravenous infusion over 15 to 30 minutes.
13.3.5 Toxicities 
Medullary bone or skeletal pain is the most commonly reported toxicity.  In addition, 
reversible elevations in uric acid, lactate dehydrogenase, and alkaline phosphatase are 
common laboratory abnormalities.  Four cases of splenic rupture have been reported in 
healthy donors when given filgrastim or other myeloid growth factors for peripheral 
blood stem cell mobilization; 1 of these cases resulted in fatality.  Five additional cases 
of splenic rupture have been reported in cancer patients undergoing chemotherapy or 
peripheral blood stem cell mobilization; splenic rupture may have contributed to deaths 
in 2 of these cases.  One additional death due to splenic rupture after filgrastim therapy 
was reported to the manufacturer without additional information.  According to the 
manufacturer, the reporting rate for splenic rupture with filgrastim is less than 1 in 
486,000. Please refer to the package insert for a complete listing of all toxicities.
13.4  FLUDARABINE
13.4.1 Supply 
Fludarabine monophosphate will be purchased by the NIH Clinical Center Pharmacy 
Department from commercial sources and is supplied as a white, lyophilized powder.  
Each vial contains 50 mg of fludarabine phosphate, 50 mg of mannitol, and sodium 
hydroxide to adjust pH.  Fludarabine is stored at room temperature.
13.4.2 Preparation 
Fludarabine should be prepared for parenteral use by aseptically adding Sterile Water 
for Injection, USP.  When reconstituted with 2 ml of Sterile Water for Injection, each ml 
of the resulting solution will contain 25 mg of Fludarabine Phosphate, 25 mg of 
mannitol, and sodium hydroxide to adjust the pH to 7–8.5.  Fludarabine will be diluted in 
100 to 125ml of either 5% dextrose in water or 0.9% sodium chloride, and infused IV 
over 30 minutes.
13.4.3 Storage and Stability 
Reconstituted fludarabine is chemically and physically stable for 24 hours at room 
temperature or for 48 hours if refrigerated.  Because reconstituted FLUDARA IV 
contains no antimicrobial preservative, care must be taken to assure the sterility of the 


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prepared solution; for this reason, reconstituted FLUDARA IV should be used or 
discarded within 8 hours.
13.4.4 Administration 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration.
13.4.5 Toxicities 
Fludarabine toxicities include myelosuppression (dose limiting toxicity), fever, nausea, 
vomiting, stomatitis, diarrhea, gastrointestinal bleeding, anorexia, edema, skin rashes, 
myalgia, headache, agitation, hearing loss, transient episodes of somnolence and 
fatigue, auto-immune hemolytic anemia, auto-immune thrombocytopenia, paresthesias, 
peripheral neuropathy, renal, and pulmonary toxicity (interstitial pneumonitis).  Severe 
fatal CNS toxicity presenting with loss of vision and progressive deterioration of mental 
status were encountered almost exclusively after very high doses of fludarabine 
monophosphate.  Such toxicity has only rarely been demonstrated at the 25-30 
mg/m2/day dosage of fludarabine.  Very rarely described complications include 
transfusion-associated graft-versus-host disease, thrombotic thrombocytopenic purpura, 
and liver failure.  Tumor lysis syndrome following fludarabine administration has been 
observed, especially in patients with advanced bulky disease.  Opportunistic infections 
(protozoan, viral, fungal, and bacterial) have been observed post-fludarabine, especially 
in heavily pre-treated individuals, and in individuals receiving fludarabine combined with 
other agents. Please refer to the package insert for a complete listing of all toxicities.
13.5 ETOPOSIDE, DOXORUBICIN, AND VINCRISTINE (IN EPOCH)
13.5.1 Supply  
Etoposide, doxorubicin, and vincristine will be purchased by the NIH Clinical Center 
Pharmacy Department from commercial sources.
13.5.2 Preparation 
For this study, etoposide, doxorubicin, and vincristine comprising a daily dose (a 24-
hour supply) will be diluted in 0.9% Sodium Chloride Injection, USP (0.9%NS). Product 
containers will be replaced every 24 hours to complete the planned duration of 
infusional treatment. Product volumes will be determined by the amount of etoposide 
present in a 24-hour supply of medication. For daily etoposide doses ≤130 mg, 
admixtures will be diluted in approximately 500 mL 0.9%NS.  For daily etoposide doses 
>130 mg, admixtures will be diluted in approximately 1000 mL 0.9%NS.
Etoposide + doxorubicin + vincristine admixtures will be administered by continuous IV 
infusion over 96 hours with a suitable rate controller pump via a central venous access 
device.
All 3-in-1 admixtures dispensed from the Pharmacy will contain a 24-hour supply of 
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proportional amount of drug to compensate for volume lost in parenteral product 
containers and administration set tubing.
Etoposide Dose
Volume of Fluid 
Containing a Daily Dose
Volume of Overfill
(fluid + drug)
Total Volume in the Product
(including overfill)
< 130 mg
528 mL
40 mL
568 mL
> 130 mg
1056 mL
40 mL
1096 mL
Before dispensing 3-in-1 admixtures, Pharmacy staff will:
[1] Purge all air from the drug product container,
[2] Attach an administration set appropriate for use with a portable pump,
[3] The set will be primed close to its distal tip, and
[4] The set will be capped with a Luer-locking cap.
Pre-printed product labeling will identify the ‘Total Volume To Infuse’ and the ‘Volume of 
Overfill (fluid + drug)’.
Bags will be exchanged daily for four consecutive days to complete a 96-hour drug 
infusion (unless treatment is interrupted or discontinued due to un-anticipated events).
13.5.3 Administration
Portable pumps used to administer etoposide + doxorubicin + vincristine admixtures will 
be programmed to deliver one of two fixed volumes at one of two corresponding fixed 
rates based on the amount of etoposide and fluid that is ordered (see the table, below).
Etoposide Dose
Total Volume to 
Infuse per 24 hours
Volume of Overfill
(drug-containing 
fluid)*
Administration Rate
< 130 mg
528 mL
40 mL
22 mL/hour
>130 mg
1056 mL
40 mL
44 mL/hour


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 DO NOT attempt to infuse the overfill
At the end of an infusion, some residual fluid is expected because overfill (excess 
fluid and drug) was added; however, nurses are asked to return to the Pharmacy for 
measurement any drug containers that appear to contain a greater amount of residual 
drug than expected.
Example at right: The amount of fluid remaining in a bag after completing 
a 24-hour infusion (1056 mL delivered).
13.5.4 Storage and Stability 
Stability studies conducted by the Pharmaceutical Development Section, Pharmacy 
Department, NIH Clinical Center, have demonstrated that admixtures of vincristine, 
doxorubicin, and etoposide in 0.9% Sodium Chloride Injection, USP (0.9%NS) at 
concentrations, respectively, of 1, 25, and 125 mcg/mL; 1.4, 35, and 175 mcg/mL; 2, 50, 
and 250 mcg/mL; and 2.8, 70, 350 mcg/mL are stable for at least 36 hours at room 
temperature when protected from light. Also, admixtures containing vincristine, 
doxorubicin, and etoposide concentrations of 1.6, 40, and 200 mcg/mL are stable for at 
least 30 hours at 32°C. [63].
13.5.5 Toxicities
Please refer to the package inserts for a complete listing of all toxicities.

Etoposide:  nausea, vomiting, stomatitis, diarrhea, thrombocytopenia, 
neutropenia, and alopecia.  Secondary AML has been associated with etoposide.  
Bradycardia and hypotension are sometimes observed with etoposide 
administration.

Doxorubicin:  Cardiotoxicity is particularly noted after cumulative doses of greater 
than 550 mg/m2.  Other toxicities include myelosuppression, nausea, vomiting, 
stomatitis, diarrhea, and alopecia.  Skin infiltration of doxorubicin causes tissue 
necrosis.

Vincristine causes neurological toxicities such as paresthesia, jaw pain, ataxia, 
foot-drop, cranial nerve palsies, paralytic ileus, constipation, abdominal pain, and 
loss of deep tendon reflexes.  It is also a vesicant, and occasionally causes 
alopecia and myelosuppression.


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13.6 PREDNISONE
13.6.1 Supply 
Prednisone will be purchased by the NIH Clinical Center Pharmacy Department from 
commercial sources. It is commercially available in a large number of oral dosage 
strengths including pills and liquid formulations.  
13.6.2 Storage and Stability 
Prednisone tablets should be stored in the container provided away from heat.  The 
product labeling bears the manufacturer's expiration dating for stability. Tablets should 
be stored in well-closed containers at temperatures between 15-30oC. 
13.6.3 Administration 
Prednisone will be given on days 1-5 of EPOCH induction therapy. Prednisone 
utilization may be simplified by using only 20- and 50-mg tablets to produce individual 
doses and by stratifying prednisone doses by a patient’s body surface area (BSA), 
according to the chart below. These are recommendations and not requirements.
BSA (m2)
Each Dose
1.25 – 1.49
80 mg
1.5 – 1.83
100 mg
1.84 – 2.16
120 mg
2.17 – 2.41
140 mg
2.42 – 2.6
150 mg
2.61 – 2.69 160 mg
2.7 – 3
170 mg
In patients unable to tolerate oral medication, methylprednisolone can be substituted at 
an equivalent dosage, diluted in a small volume (e.g. 25-50ml) of 5% dextrose in water 
or 0.9% sodium chloride and infused over 15 minutes.  
13.6.4 Toxicities 
Prednisone frequently causes immunosuppression, muscle wasting, fluid retention, 
proximal muscle weakness, glucose intolerance, thinning of skin, redistribution of body 
fat, Cushingoid facies, and propensity to gastrointestinal ulceration. To reduce 
gastrointestinal side effects, prednisone should be taken with food. Please refer to the 
package insert for a complete listing of all toxicities.
13.7 RITUXIMAB (RITUXAN)
13.7.1 Supply 
The NIH Clinical Center Pharmacy Dept. will purchase rituximab from commercial 
sources. Rituximab is provided in pharmaceutical grade glass vials containing 10 mL 


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(100 mg) or 50 mL (500 mg) at a concentration of 10 mg of protein per milliliter. Please 
refer to the FDA-approved package insert for rituximab for product information, 
extensive preparation instructions, and a comprehensive list of adverse events.
13.7.2 Preparation 
Rituximab will be diluted to a final volume of 0.9% Sodium Chloride or 5% Dextrose 
Injection to prepare a standard product with concentration of 2 mg/ml.  Caution should 
be taken during the preparation of the drug, as shaking can cause aggregation and 
precipitation of the antibody
13.7.3 Storage and Stability 
Rituximab for clinical use should be stored in a secure refrigerator at 2 to 8 degrees C. 
After dilution, rituximab is stable at 2-8 degrees C (36-46 degrees F) for 24 hours and at 
room temperature for an additional 12 hours.
13.7.4 Administration 
During rituximab infusion, a patient's vital signs (blood pressure, pulse, respiration, 
temperature) should be monitored according to the standard of care. Medications 
readily available for the emergency management of anaphylactoid reactions should 
include: epinephrine (1:1000, 1 mg/mL) for subcutaneous injection, diphenhydramine 
hydrochloride for intravenous injection, and resuscitation equipment.
Prophylaxis against hypersensitivity and infusion-related reactions associated with 
rituximab will include acetaminophen 650 mg and diphenhydramine hydrochloride 50-
100 mg administered 30 to 60 minutes prior to starting rituximab. Patients will also 
receive their first dose of prednisone 60 mg/m2 (or a glucocorticoid equivalent dose of 
an alternative steroid) at least 60 minutes before rituximab treatment commences.
Rituximab will be administered as an intravenous infusion at 375 mg/m2 on day 1 of 
each cycle of EPOCH, immediately prior to starting etoposide + doxorubicin + vincristine 
administration. Rituximab infusions will be administered to patients primarily in an 
outpatient clinic setting.  
First dose:
The initial dose rate at the time of the first rituximab infusion should be 50mg/hour (25 
mL/hr) for the first 30 minutes. If no toxicity is seen, the dose rate may be escalated 
gradually in 50 mg/hour (25 mL/h) increments at 30 minute intervals) to a maximum of 
400 mg/hour (maximum rate = 200 mL/h). 
Second and Subsequent Doses (select the appropriate administration timing):
90-minute Administration
If the first dose of rituximab was well tolerated, subsequent doses may be administered 
over 90 minutes with 20% of the total dose given in the first 30 minutes, and remaining 
80% of the total dose administered over the subsequent 60 minutes; e.g.:
Two-Step Rate Escalation
Volume to administer (X mL)


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Special Note: The 90-minute infusion scheme is not recommended for patients with 
clinically significant cardiovascular disease or high circulating lymphocyte counts 
(≥5000/mcL).
Standard Administration for Second & Subsequent Infusions
Patients who tolerate initial treatment without experiencing infusion-related adverse 
effects but for whom the 90-minute infusion scheme during subsequent treatments is 
considered inappropriate, may receive subsequent rituximab doses at the Standard 
Rate for Subsequent Infusions, which is as follows:
Begin at an initial rate of 100 mg/hour (50 mL/h) for 30 minutes. If administration is well 
tolerated, the administration rate may be escalated gradually in 100-mg/hour (50-mL/h) 
at 30-minute intervals to a maximum rate of 400 mg/hour (maximum rate = 200 mL/h).
CAUTION:  DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS. 
13.7.5 Toxicities
The most serious adverse reactions caused by rituximab include infusion reactions, 
tumor lysis syndrome, mucocutaneous reactions, hypersensitivity reactions, cardiac 
arrhythmias and angina, and renal failure. Please refer to the package insert for a 
complete listing of all toxicities.

Fatal and Severe Infusion Reactions:  Deaths within 24 hours of rituximab 
infusion have been reported.  Approximately 80% of fatal infusion reactions 
occurred in association with the first infusion.  Severe reactions typically occurred 
during the first infusion with time to onset of 30 to 120 minutes.  Signs and 
symptoms of severe infusion reactions may include hypotension, angioedema, 
hypoxia or bronchospasm, and may require interruption of rituximab 
administration.  The most severe manifestations and sequelae include pulmonary 
infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular 
fibrillation, and cardiogenic shock.  In the reported cases, the following factors 
were more frequently associated with fatal outcomes:  female gender, pulmonary 
infiltrates, and chronic lymphocytic leukemia or mantle cell lymphoma.

Management of severe infusion reactions:  The rituximab infusion should be 
interrupted for severe reactions and supportive care measures instituted as 
medically indicated (e.g., intravenous fluids, vasopressors, oxygen, 
bronchodilators, diphenhydramine, and acetaminophen).  In most cases, the 
infusion can be resumed at a 50% reduction in rate (e.g., from 100 mg/hr to 50 
mg/hr) when symptoms have completely resolved.  Patients requiring close 
monitoring during first and all subsequent infusions include those with pre-
existing cardiac and pulmonary conditions, those with prior clinically significant 
cardiopulmonary adverse events and those with high numbers of circulating 
malignant cells (= 25,000/mm3) with or without evidence of high tumor burden.
1st portion (0 – 30 minutes)
2nd portion (30 – 
90 minutes)
Total Dose (mg)
2
0.2 X mL (over 30 min)
Total Dose (mg)
2
0.8 X mL (over 60 min)


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
Tumor Lysis Syndrome (TLS):  Acute renal failure requiring dialysis with 
instances of fatal outcome has been reported in the setting of TLS following 
treatment with rituximab.  Rapid reduction in tumor volume followed by acute 
renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or 
hyperphosphatemia, have been reported within 12 to 24 hours after the first 
rituximab infusion.  Rare instances of fatal outcome have been reported in the 
setting of TLS following treatment with rituximab.  The risks of TLS appear to be 
greater in patients with high numbers of circulating malignant cells (= 
25,000/mm3) or high tumor burden.  Prophylaxis for TLS should be considered 
for patients at high risk.  Correction of electrolyte abnormalities, monitoring of 
renal function and fluid balance, and administration of supportive care, including 
dialysis, should be initiated as indicated.  Following complete resolution of the 
complications of TLS, rituximab has been tolerated when re-administered in 
conjunction with prophylactic therapy for TLS in a limited number of cases.

Severe Mucocutaneous Reactions:  Mucocutaneous reactions, some with fatal 
outcome, have been reported in patients treated with rituximab.  These reports 
include paraneoplastic pemphigus (an uncommon disorder which is a 
manifestation of the patient’s underlying malignancy), Stevens-Johnson 
syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal 
necrolysis.  The onset of the reaction in the reported cases has varied from 1 to 
13 weeks following rituximab exposure. Patients experiencing a severe 
mucocutaneous reaction should not receive any further infusions and seek 
prompt medical evaluation.  Skin biopsy may help to distinguish among different 
mucocutaneous reactions and guide subsequent treatment.  The safety of re-
administration of RITUXAN to patients with any of these mucocutaneous 
reactions has not been determined.

Infusion reactions and lymphopenia are the most commonly occurring adverse 
reactions.  Mild to moderate infusion reactions consisting of fever and chills/rigors 
occur in the majority of patients during the first rituximab infusion.  Other frequent 
infusion reaction symptoms included nausea, pruritus, angioedema, asthenia, 
hypotension, headache, bronchospasm, throat irritation, rhinitis, urticaria, rash, 
vomiting, myalgia, dizziness, and hypertension.  These reactions generally occur 
within 30 to 120 minutes of beginning the first infusion, and resolved with slowing 
or interruption of the rituximab infusion and with supportive care 
(diphenhydramine, acetaminophen, IV saline, and vasopressors).  In an analysis 
of data from 356 patients with relapsed or refractory, low-grade NHL who 
received 4 (N = 319) or 8 (N = 37) weekly infusions of rituximab, the incidence of 
infusion reactions was highest during the first infusion (77%) and decreased with 
each subsequent infusion (30% with fourth infusion and 14% with eighth 
infusion).
13.8 CYTARABINE (CYTOSINE ARABINOSIDE, CYTOSAR, ARA-C)
13.8.1 Supply 
Cytarabine will be purchased by the NIH Clinical Center Pharmacy Department from 
commercial sources and is supplied as un-reconstituted lyophilized powder (100 mg, 


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500 mg, 1 g, and 2 g vials).  Cytarabine for injection is available for subcutaneous, 
intravenous, and intrathecal administration.
13.8.2 Preparation
To prepare high dose (2 gm/m2) cytarabine intravenous infusions, each vial of drug 
should be reconstituted with sterile water for injection USP (containing no preservative) 
with the diluent volumes listed below.  Note that the manufacturers recommended 
diluent for cytarabine is bacteriostatic water for injection containing benzyl alcohol. For 
preparation of intrathecal injection doses and for high dose intravenous dosing 
regimens, ONLY a preservative-free diluent should be used.  The recommended 
volumes for reconstitution include the following:
Vial Size
Volume of Diluent
Concentration
100 mg
5 ml
20 mg/ml
500 mg
10 ml
50 mg/ml
1 g
10 ml
100 mg/ml
2 g
20 ml
100 mg/ml

The drug will be further diluted in 500 ml of 5% Dextrose Injection or 0.9% 
Sodium Chloride Injection prior to administration.
13.8.3 Storage and Stability 
Vials should be stored at room temperature (25oC or 77oF); excursions permitted to 15-
30o C (59-86oF). [See USP Controlled Room Temperature.]  Once reconstituted with 
sterile water for injection, USP the reconstituted vial should be used within 24 hours. 
After final dilution with 0.9% Sodium Chloride Injection or 5% Dextrose Injection, the 
prepared dose should be used within 24 hours if stored at room temperature or 48 
hours if refrigerated.
13.8.4 Administration 
Begin each cytarabine dose 3.5 hours after completion of the preceding fludarabine 
dose.  Intravenous doses should be infused over at least 2 hours.
13.8.5 Toxicity 
Acute dose-limiting toxicity with IV administration consists of severe leukopenia and 
thrombocytopenia.  Nausea and vomiting may be dose limiting at higher doses.  Other 
adverse reactions include diarrhea, immunosuppression, anorexia, stomatitis, oral 
ulceration, flu-like syndrome, fever, hepatic dysfunction, and alopecia. At high doses, as 
in this protocol, keratoconjunctivitis, dermatitis, and central nervous system toxicity 
(e.g., ataxia, somnolence, coma, dysarthria) may occur. Occasionally, the CNS 
impairment is not fully reversible. Renal impairment will enhance toxicity.  In the event 
that signs of CNS toxicity occur, the cytarabine will be interrupted and the M.D. notified.  
No further cytarabine will be administered if there is CNS toxicity (any grade) deemed 
related to cytarabine.  Please refer to the package insert for a complete listing of all 
toxicities.


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Conjunctivitis Prophylaxis: Corticosteroid ophthalmic drops will be administered 2 drops 
to each eye every 6 hours starting prior to first dose and continuing until 24 hours after 
the last dose of cytarabine has been completed.
13.9 METHOTREXATE (METHOTREXATE SODIUM, MTX, NSC-740)
13.9.1 Supply 
Methotrexate will be obtained commercially and is supplied as a 25 mg/ml preservative-
free isotonic solution for injection.
13.9.2 Preparation 
The desired dose will be diluted in 5% dextrose in water or 0.9% sodium chloride.
13.9.3 Storage and Stability 
 Methotrexate should be stored at room temperature and protected from light.  Once the 
prepared dose is diluted for administration, the solution is stable for 24 hours 
refrigerated or at room temperature when protected from light.
13.9.4 Administration 
Methotrexate will be given as IV infusion over 15 minutes.
13.9.5 Toxicities  
The toxicity associated with methotrexate primarily involves the gastrointestinal tract.  
Severe mucositis can occur, particularly in patients who have received an intensive 
preparative regimen. Other gastrointestinal symptoms include nausea, vomiting and 
diarrhea.  Transient elevations in serum transaminases have been seen. The 
myelosuppression associated with methotrexate often results in delayed engraftment.  
Folinic acid can effectively circumvent the enzymatic block produced by methotrexate. 
Please refer to the package insert for a complete listing of all toxicities.
13.10
SIROLIMUS (RAPAMYCIN, RAPAMUNE®, WYETH-AYERST LABORATORIES)
13.10.1 Supply 
For patient administration, oral tablets will be purchased by the NIH Clinical Center 
Pharmacy Department from commercial sources.
13.10.2 Storage and Stability  
Oral tablets should be stored 20-25 C° (68-77 F°). Oral solution should be refrigerated 
(2-8 C° or 36-46 F°).
13.10.3 Administration
Because food, in particular fatty foods, can decrease the absorption of sirolimus, it is 
suggested the tablets should be administered consistently between meals.
13.10.4 Toxicities
Sirolimus induces immune suppression, which has been associated with opportunistic 
infection and an increased rate of malignancy, particularly skin cancer.


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Some individuals may develop hypersensitivity to sirolimus.  May cause an increase in 
cholesterol and triglycerides, which may be associated with pancreatitis. With long-term 
administration, may result in impaired renal function.  Metabolism is via the cytochrome 
p450 pathway, and as such, co-administration of voriconazole is prohibited with 
sirolimus can result in prolonged blood levels of sirolimus. As such, if the administration 
of voriconazole is required the dose of sirolimus will be reduced by 90% and close 
attention must be given relative to serum sirolimus levels and associated toxicities [98]. 
Please refer to the package insert for a complete listing of all toxicities.
13.11
TACROLIMUS (KF-506, PROGRAF®)
13.11.1 Supply 
Tacrolimus will be obtained by the NIH Clinical Center Pharmacy Department from 
commercial sources and is available for oral administration as capsules (tacrolimus 
capsules) containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus. 
Tacrolimus is also available as a sterile solution (tacrolimus injection) containing the 
equivalent of 5 mg anhydrous tacrolimus in 1 mL for administration by intravenous 
infusion only. Each mL contains polyoxyl 60 hydrogenated castor oil (HCO-60), 200 mg, 
and dehydrated alcohol, USP, 80.0% v/v.
13.11.2 Preparation 
For parenteral doses, tacrolimus injection must be diluted with 0.9% Sodium Chloride 
Injection or 5% Dextrose Injection before use. Parenteral doses of tacrolimus will be 
prepared in non-PVC containers and infused with non-PVC administration sets/tubing.
13.11.3 Storage and Stability 
Capsules, oral solution, and ampules of parenteral concentrate bear expiration dates 
and are stored at room temperature and protected from light.
13.11.4 Administration 
Tacrolimus will be administered as a continuous intravenous infusion over 24 hours or 
given orally in divided doses every 12 hours.
13.11.5 Toxicities 
Tacrolimus can cause neurotoxicity and nephrotoxicity, particularly when used in high 
doses. Mild to severe hyperkalemia has been observed following tacrolimus 
administration. Serum potassium levels should be monitored and potassium-sparing 
diuretics should not be used during tacrolimus therapy. Neurotoxicity, including tremor, 
headache, and other changes in motor function, mental status, and sensory function 
have been reported with tacrolimus administration. Tremor and headache have been 
associated with high whole-blood concentrations of tacrolimus and may respond to 
dosage adjustment. Seizures have occurred in adult and pediatric patients receiving 
tacrolimus. Coma and delirium also have been associated with high plasma 
concentrations of tacrolimus. The most common adverse reactions reported with 
tacrolimus administration include infection, tremor, hypertension, abnormal renal 
function, constipation, diarrhea, headache, abdominal pain and insomnia. Less common 
adverse reactions reported with tacrolimus administration include anorexia, cholangitis, 


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jaundice, diarrhea, dyspepsia, hepatitis, ALT (SGPT) increased, AST (SGOT) 
increased, abnormal ECG, angina pectoris, arrhythmia, acute kidney failure, acidosis, 
alkaline phosphatase increased, alkalosis, bicarbonate decreased, bilirubinemia, BUN 
increased, dehydration, edema, hypercalcemia, , hypocalcemia, hypercholesterolemia, 
hyperlipemia, hyperphosphatemia, hyperuricemiahypoglycemia, hypomagnesemia, 
hyponatremia, hypophosphatemia, hypoproteinemia, lactic dehydrogenase increase, 
peripheral edema, weight gain, Cushing’s syndrome, diabetes mellitus, anemia, allergic 
reaction, and photosensitivity reaction.  Please refer to the package insert for a 
complete listing of all toxicities.
13.12
PALIFERMIN (KEPIVANCE®, SOBI PHARMACEUTICALS) IND # 124506
13.12.1 Supply 
Palifermin is supplied by the manufacturer, Sobi Pharmaceuticals, for the purposes of 
this study to the NIH pharmacy. Palifermin is packaged as a lyophilized powder with 
6.25 mg/vial. 
13.12.2 Preparation 
Palifermin is reconstituted using 1.2 mL sterile water followed by gentle agitation for 1-3 
minutes.
13.12.3 Storage and stability 
Palifermin is stable as a lyophilized powder at room temperature until the expiration 
date provided by the manufacturer. After reconstitution, palifermin is stable at room 
temperature for up to 1 hour or can be kept at 2-8 degrees C up to 24 hours before 
injection.
13.12.4 Administration 
See section 3.3.1.1
13.12.5 Toxicities 
The purpose of this study is to determine toxicities at this dosage and schedule. At 
lower doses, Palifermin led to edema, pain, fever, mouth or tongue thickness, arthralgia, 
erythematous rash, pruritis, dysguesia, dysthesia, paresthesia, and elevated 
lipase/amylase. Please refer to the package insert for a complete listing of all toxicities.
13.13
PERIPHERAL BLOOD STEM CELLS
PBSC Collection of matched unrelated donors will be performed according to NMDP 
Standards, which adhere to the strictest interpretation of AABB and FDA standards.  
(See Appendix E)
13.13.1 PBSC Products will be received by NIH DTM.  Products will be processed 
according to standard DTM operating procedures.
o
Targeted cell infusion dose is greater than or equal to 7 x 106 CD34+ 
cells/kg recipient weight 
o
If recipient BMI (Body Mass Index) is 35 or less, use actual body weight


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o
If recipient BMI is greater than 35, use practical body weight as calculated 
by Cell Processing Services (CPS).  See form DTM-Form-5086 in 
Appendix I
o
If targeted cell dose is exceeded, excess cells may be cryopreserved 
according to CD3+ cell content, in escalating doses of:

1 x 106 CD3+/kg

5 x 106 CD3+/kg

1 x 107 CD3+/kg

5 x 107 CD3+/kg
o
When collected cells dose is 5-7 x 106 CD34+ cells/kg recipient weight, on 
case by case basis DLI aliquots can be stored only after consultation and 
permission of the PI or LAI.  
13.13.2 Upon arrival at NCI, the following tests will be performed on blood samples 
accompanying the stem cell product:

ABO compatibility testing (per AABB Standards). If an ABO incompatibility 
exists between the donor and patient, the graft will be processed in the 
cell processing laboratory, according to standard DTM operating 
procedures.

Hepatitis A, Adenovirus, EBV, and Toxoplasma screens will be performed 
upon receipt of the PBSC product if additional donor blood is available at 
the time of collection.  The results of these tests do not affect eligibility.

PCR test of DNA mini-satellite regions for future determination of 
chimerism
13.13.3 Storage and stability 
Cells may be processed, cryopreserved, and stored in liquid nitrogen until the day of 
transplant upon delivery to the NIH Department of Transfusion Medicine (DTM). In the 
event that cryopreservation is required, special permission will be obtained from NMDP. 
13.13.4 Toxicities
Death occurs in between 15% and 40% of subjects two years after stem cell transplant. 
Subjects may also experience complications that include graft versus host disease, graft 
rejection, veno-occlusive disease and late transplant complications that can affect any 
organ in the body. Rarely, patients may develop a second cancer such as lymphoma, 
leukemia, lung cancer or other tumors.


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Thol, F., et al., Incidence and Prognostic Influence of DNMT3A Mutations in Acute Myeloid Leukemia. 
Journal of Clinical Oncology, 2011. 29(21): p. 2889-2896.
44.
Schnittger, S., et al., ASXL1 exon 12 mutations are frequent in AML with intermediate risk karyotype and 
are independently associated with an adverse outcome. Leukemia, 2013. 27(1): p. 82-91.
45.
Bornhauser, M., et al., Improved outcome after stem-cell transplantation in FLT3/ITD-positive AML. Blood, 
2007. 109(5): p. 2264-5; author reply 2265.
46.
Matthews, J.P., et al., Patterns of failure with increasing intensification of induction chemotherapy for 
acute myeloid leukaemia. Br J Haematol, 2001. 113(3): p. 727-36.
47.
Garcia-Manero, G. and D.A. Thomas, Salvage therapy for refractory or relapsed acute lymphocytic 
leukemia. Hematol Oncol Clin North Am, 2001. 15(1): p. 163-205.
48.
Dupriez, B., et al., Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new 
scoring system. Blood, 1996. 88(3): p. 1013-8.
49.
Tefferi, A., The forgotten myeloproliferative disorder: myeloid metaplasia. Oncologist, 2003. 8(3): p. 225-
31.
50.
Passamonti, F., et al., Dynamic International Prognostic Scoring System (DIPSS) predicts progression to 
acute myeloid leukemia in primary myelofibrosis. Blood, 2010. 116(15): p. 2857-8.
51.
Durie, B.G., et al., International uniform response criteria for multiple myeloma. Leukemia, 2006. 20(9): p. 
1467-73.
52.
Krishnan, A. and S.J. Forman, Hematopoietic stem cell transplantation for AIDS-related malignancies. Curr 
Opin Oncol, 2010. 22(5): p. 456-60.
53.
Kahl, C., et al., Relapse risk in patients with malignant diseases given allogeneic hematopoietic cell 
transplantation after nonmyeloablative conditioning. Blood, 2007. 110(7): p. 2744-8.
54.
Sorror, M.L., et al., Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk 
assessment before allogeneic HCT. Blood, 2005. 106(8): p. 2912-9.
55.
Grkovic, L., et al., Clinical laboratory markers of inflammation as determinants of chronic graft-versus-host 
disease activity and NIH global severity. Leukemia, 2012. 26(4): p. 633-43.
56.
Priola, A.M. and S.M. Priola, Imaging of thymus in myasthenia gravis: from thymic hyperplasia to thymic 
tumor. Clin Radiol, 2014. 69(5): p. e230-45.
57.
Hakim, F.T., et al., Age-dependent incidence, time course, and consequences of thymic renewal in adults. J 
Clin Invest, 2005. 115(4): p. 930-9.
58.
McCune, J.M., et al., High prevalence of thymic tissue in adults with human immunodeficiency virus-1 
infection. J Clin Invest, 1998. 101(11): p. 2301-8.
59.
Simanovsky, N., et al., Normal CT characteristics of the thymus in adults. Eur J Radiol, 2012. 81(11): p. 
3581-6.
60.
TR, S., Engraftment Syndrome Following Hematopoietic Stem Cell Transplantation. Bone Marrow 
Transplantation, 2001. 27(9): p. 893-898.
61.
Przepiorka, D., et al., 1994 Consensus Conference on Acute GVHD Grading. Bone marrow transplantation, 
1995. 15(6): p. 825-828.
62.
Filipovich, A.H., et al., National Institutes of Health consensus development project on criteria for clinical 
trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood 
Marrow Transplant, 2005. 11(12): p. 945-56.
63.
Wolfe, J.L., et al., Compatibility and stability of vincristine sulfate, doxorubicin hydrochloride, and 
etoposide in 0.9% sodium chloride injection. American Journal of Health-System Pharmacy, 1999. 56(10): 
p. 985-9.
64.
Cordonnier, C., et al., A grading system based on severity of infection to predict mortality in allogeneic 
stem cell transplant recipients. Transplantation, 2006. 82(1): p. 86-92.


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15 APPENDICES
15.1 APPENDIX A: DEFINITIONS / GLOSSARY  

Neutrophil Recovery: Designated by the first of 3 consecutive days with an ANC 
above 500/mm3. 

Platelet Recovery: Designated by the first of 7 days where the platelet count 
remains above 20,000/mm3 without transfusion support. 

Lymphocyte Recovery: Designated by the first of 3 consecutive days with ALC 
above 500 /mm3.

Sustained Donor Engraftment: Neutrophil recovery associated with complete 
donor chimerism at day 100. Any patient who dies before day 28 will not be 
evaluated for engraftment but will be evaluable for palifermin.

Primary Graft Failure: Failure to achieve sustained donor engraftment defined as 
ANC >0.5x109/L not reached by day +28 after SCT.   .

Secondary Graft Failure: Documented sustained donor engraftment as defined 
above followed by: 1: severe neutropenia (ANC<500/mm3) and bone marrow 
biopsy revealing a cellularity of less than 25% or 2: absence of donor cells in the 
marrow or blood as demonstrated by a chimerism assay without subsequent 
improvement occurring either spontaneously or after growth factor treatment. 
Improvement is defined as ANC >500mm3 consistently. Severe neutropenia with 
marrow cellularity > 25% is not secondary graft failure. 

Aplasia: Less than 5% marrow cellularity as measured on bone marrow biopsy.


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15.2 APPENDIX B: MALIGNANCY RESPONSE ASSESSMENT
The malignancy response assessments will be done per the CIBMTR post-transplant 
criteria and may be viewed at: https://www.cibmtr.org/manuals/fim/1/en/topic/none .


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15.3 APPENDIX C: ACUTE GRAFT VERSUS HOST DISEASE EVALUATION (WORKSHEET)

Acute GVHD is diagnosed at any time after transplant before or after day 100 providing there are no concurrent 
diagnostic signs of chronic GVHD
Glucksberg Scoring System:
Stage 
Skin 
Liver 
Gut
1
Rash < 25% BSA
Total bilirubin 2-2.9 mg/dl
Diarrhea 500-1000ml/d
2
Rash 25-50% BSA
Total bilirubin 3-6 mg/dl
Diarrhea 1000-1500ml/d
3
Generalized erythoderma 
Total bilirubin 6.1-15 mg/dl 
Diarrhea >1500ml/d
4
Desquamation and bullae 
Total bilirubin > 15 mg/dl 
Diarrhea >2000ml/d & Pain +/- ileus
*BSA = body surface area; use “rule of nines” or burn chart to determine extent of rash

Isolated upper GI symptoms need a biopsy confirmation 

Elevation of transaminase without elevated bilirubin is not graded as acute GVHD (a note should say GVHD if liver biopsy 
proven)
Overall GVHD grading according to Keystone consensus:
Grade
Skin
Liver
Gut
PS**
0 (none)
0
0
0
0
I
+ to ++
0
0
0
II
+ to +++
+
+
+
III
++ to +++
++ to +++
++ to +++
++
IV
+ +to ++++
+ +to ++++
+ +to ++++
+++
*The nominal stage is reduced by 1 if organ is simultaneously and unequivocally affected by a complication other than GVHD
**PS is not used in routine practice acute GVHD grading
+Gut stage 4 has frequent poor outcome and is commonly designated as grade IV especially if more severe symptoms and 
deterioration in performance status
++Designation as grade III would be appropriate for only scattered bullae
Acute GVHD data collection: 
(Patient Label)
(present or absent, date of diagnosis, stage at diagnosis, and max stage during first 6 months) 
Glucksberg Scoring System
Skin
Liver
GI
Stage
1
Rash < 25% BSA
Total bilirubin 2-2.9 
mg/d
Diarrhea 500-1000ml/d
2
Rash 25-50% BSA
Total bilirubin 3-6 
mg/dl
Diarrhea 1000-
1500ml/d
3
Generalized 
erythoderma
Total bilirubin 6.1-15 
mg/dl
Diarrhea >1500ml/d
Date of 
evaluation
Timepoint 
(D28, etc.)
Classic
Vs.
Late 
Acute
4
Desquamation and 
bullae
Total bilirubin > 15 
mg/dl
Diarrhea >2000ml/d 
&Pain +/- ileus
Grade*

Date of initial diagnosis of acute GVHD: _____________________

Grade of acute GvHD at time of initial diagnosis: _______________

Organ involvement at time of initial diagnosis (1= liver only, 2 = skin only, 3 = GI only, 4 = liver + skin, 5 = liver + GI, 6 = skin + GI, 7 
= liver + skin + GI) : _______________

Max aGvHD grade in first 6 months: _______________
*Grade
Skin
Liver
Gut
0
0
0
0
I
+ to ++
0
0
II
+ to +++
+
+
III
++ to +++
++ to +++
++ to +++
IV
++ to ++++
++ to ++++
++ to ++++
LIP Signature_______________________________________
Page ____ of ________


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15.4 APPENDIX D: CHRONIC GRAFT VERSUS HOST DISEASE EVALUATION (WORKSHEET)


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When discrepancy exists between pulmonary symptom or PFT scores the higher value should be 
used for final scoring. Scoring using the Lung Function Score (LFS) is preferred, but if DLCO is not 
available, grading using FEV1 should be used. The percent predicted FEV1 and DLCO (adjusted for 
hematocrit but not alveolar volume) should be converted to a numeric score as follows: >80% = 1; 70-
79% = 2; 60-69% = 3; 50-59% = 4; 40-49% = 5; <40% = 6. The LFS = FEV1 score + DLCO score, 
with a possible range of 2-12. 
Global staging (Mild, Moderate, Severe)
If 1-2 Grade 1=Mild  
If at least 1 Grade 3=severe 
Anything between=Moderate 
EXCEPT if Lung Grade 1=moderate Lung Grade 2=severe


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15.5 APPENDIX E: NMDP STANDARD PROTOCOL, 22ND

A copy of the NMDP Standard Protocol may be viewed at:
http://bethematch.org/About/Who_We_Are/NMDP_Network/Draft_NMDP_Standards_22.aspx


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15.6 APPENDIX F: IMMUNIZATIONS

Immunizations:  All recipients will receive immunizations after transplant, according to the 
following table: (from: http://intranet.cc.nih.gov/bmt/clinicalcare/pdf/Table_II.pdf)


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15.7 APPENDIX G: VARIABLES/GUIDANCE FOR DATA COLLECTION IN THE STUDY DATABASE
Patient (recipient) characteristics at protocol entry  (if available)

Gender (male, female)

Age at enrollment (number)

Ethnicity (white, black, American Indian/Alaskan native, Asian/Pacific islander, Hispanic, other)

Karnofsky performance status 

CMV serology status (positive or negative)

EMV serology status (positive or negative)

ABO (A, B, AB, O)

Diagnosis (B-chronic lymphocytic leukemia (B-CLL), T-chronic lymphocytic leukemia (T-CLL), 
T -prolymphocytic leukemia (T-PLL), B-prolymphocytic leukemia (B-PLL), Hodgkin lymphoma, 
Follicular lymphoma, marginal zone lymphoma, Burkitt lymphoma or lymphoblastic lymphoma, 
diffuse large b-cell lymphoma, follicular large cell lymphoma, peripheral T-cell lymphoma, 
mantle cell lymphoma, anaplastic large cell lymphoma, cutaneous T-cell lymphoma, multiple 
myeloma, acute myelogenous leukemia, acute lymphocytic leukemia, myelodysplastic 
syndrome, myeloproliferative neoplasms, chronic myelogenous leukemia, NK cell neoplasms, 
hypatosplenic T-cell lymphoma, enteropathy associated T-cell lymphoma). 

Date of diagnosis (month, year)

Kahl relapse risk (low, intermediate, high)

Sorror score (number)

Chemosensitivity status: chemosensitive (CR or PR to their most recent chemotherapy 
regimen), chemoresistant (SD or PD to their most recent prior chemotherapy regimen), or not 
evaluable [55]

Number of prior treatment regimens (number) [not number of cycles]

History of prior autologous transplantation (yes/no)

History of prior allogeneic transplantation (yes/no)

Malignancy disease status at time of enrollment: CR (Complete Response), MRD (Minimal 
Residual Disease) or not CR (not Complete Response). 
-IF Minimal residual disease (MRD) present at time of enrollment , what was the method of 
detection of MRD: flow, cytogenetics, molecular/PCR, monoclonal protein spike, kappa/lambda 
ratio, other. 

CD3, CD4, CD8, CD 19, CD56, count at enrollment
Donor characteristics (if available) 

Gender (m/f)

If female, parity (Number of pregnancies)

Age at stem cell donation

Ethnicity (white, black, American Indian/Alaskan native, Asian/pacific islander, Hispanic, other)

CMV serology status (positive or negative)

EBV serology status (positive or negative)

ABO type (A, B, AB, O)

ABO mismatch with recipient (0 = none, 1 = major, 2 = minor, 3 = bidirectional)
Data collection post-induction and prior to transplantation (if available):

Number of EPOCH cycles pre-transplant (number)

Number of FLAG cycles pre-transplant (number)


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
CD3, CD4, CD8, CD 19, CD56 count post-induction therapy and at Day -7

Date of palifermin administration 

Dose of palifermin given (mcg/kg)

Thymus measurements determined by CT scan of chest at baseline (cm3, size grade (0-5), 
density grade (1-5). 
Transplantation infusion variables (if available)

PBSC infusion date /Day 0  

Infused CD3+ cell dose per kg (*10^6)

Infused CD34+ cell dose kg (*10^6)
Post-transplantation variables (if available)

Thymus measurements (cm3, size grade (0-5) and density grade (1-5) determined via CT scan 
chest) post-transplant at day +28(+/- 4 days), +180 days (+/- 14 days), +365 days (+/- 30 
days), 24 months (+/- 2 months) and 36 months (+/- 2 months)

Date of neutrophil recovery (Designated by the first of 3 consecutive days with an ANC above 
500/mm3) and # of days post-transplant that this occurred

Date of platelet recovery (Designated by the first of 7 days where the platelet count remains 
above 20,000/mm3 without transfusion support), and # of days post-transplant that this 
occurred

Date of lymphocyte recovery (designated by first of 3 consecutive days with ALC above 
500/mm3), and # of days post-transplant that this occurred.

Date of sustained donor engraftment (Neutrophil recovery associated with complete donor 
chimerism (defined as myeloid and lymphoid % donor >=95%) at day 100.)

Graft failure at Day 28 evaluation (yes, no)

DLI administered? (yes, no)

Date of first DLI administered

Reason for DLI administration (mixed chimerism or disease) 

Disease response assessment at Day +28, Day +100, Day +180, +12 months, 2 years, 3 
years, 4 years, 5 year visits per CIBMTR viewed at: 
https://www.cibmtr.org/manuals/fim/1/en/topic/none   

Date of first disease relapse (progressive malignancy after prior remission) 

Date of first disease progression (progressive existing malignancy)

Date of remission (applicable only if disease present at time of transplant)

Date of death

Cause of death: relapse vs. non-relapse mortality (NRM) (definition of relapse mortality: at the 
time of death, primary disease is not in clinical remission. Non-relapse mortality: patient in 
clinical remission at time of death.  

If non-relapse mortality, primary cause of death: a. GVHD, b. infection, c. organ failure, d. other 
– list. 

Second malignancy (including EBV associated lymphoproliferative disease, excluding non-
melanoma skin cancer): yes or no – list. 

Secondary malignancy information: date of diagnosis. 

Date off protocol (no more data collected), reason a. death, b. other - list
Post-transplantation infection data (if available)


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
See Section Error! Reference source not found. and Appendix J for detail.
Acute GVHD data collection 

Acute GvHD date of diagnosis 

aGVHD type at diagnosis: classic versus late acute (if late: a. persistent b. recurrent or c. late 
onset)

Grade of acute GvHD and organ stages (skin, liver, GI) at time of initial diagnosis, and at each 
timepoint evaluation at Day +28, Day +100 and Day +180. 

Organ involvement at time of initial diagnosis (1= liver only, 2 = skin only, 3 = GI only, 4 = liver 
+ skin, 5 = liver + GI, 6 = skin + GI, 7 = liver + skin + GI) and at each time point evaluation at 
Day +28, Day +100 and Day +180.

Max aGVHD grade in first 6 months

Acute GVHD skin (max stage during first 6 months)

Acute GVHD liver (max stage during first 6 months)

Acute GVHD GI (max stage during first 6 months)

Date starting systemic steroids for front line acute GVHD therapy 

Date stopping systemic steroids for acute GVHD (for at least 2 weeks) 

Date starting second line systemic therapy for steroid failure (list agent)

Date stopping all non-steroid immunosuppressive systemic therapy (>4 weeks)
Chronic GVHD data collection

Date of cGVHD diagnosis

Patient off systemic steroids for 2 months at time of diagnosis of cGvHD (yes, no)

Patient off non-steroid systemic immunosuppression or therapy for 2 months at time of 
diagnosis of cGVHD (yes, no)

Onset of chronic GVHD: quiescent (>2 weeks no acute GVHD symptoms), progressive, de 
novo

NIH global score (mild vs. moderate vs. severe) at time of diagnosis and protocol evaluation 
time points at Day +28, Day +100, Day +180, Day +270, 1 year, 2 year, 3 year, 4 year and 5 
year. 

Organ specific cGVHD NIH scores (0-3): at time date of initial diagnosis and protocol 
evaluation time points (skin, oral, eyes, GI, liver, lung, joints/fascia, GU)

Type of systemic immune therapy used to treat cGVHD and starting and stopping dates: 
steroids, tacrolimus, sirolimus, cyclosporine, mycophenolate mofetil, etanercept, rituximab, 
prednisone, ECP, anti-thymocyte globulin, cyclophosphamide, daclizumab, thalidomide, 
pomalidomide, IL-2, other-list

Date off all systemic cGvHD therapy (including steroids) for >3 months

Date off systemic steroids for >6 months 

Steroid dose (prednisone equivalent) at each protocol visit

Patient weight (kg) at each protocol visit 
Ancillary post-transplant biology studies

CD3, CD4, CD8, CD19, C56 count:  at +14, 28, 60, 100, 180, 270, 365 days, 18 and 24 
months. 


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106

Peripheral blood lymphoid, myeloid and whole blood chimerism on Days +14, 28, 60, 100 and 
180 

Bone marrow total chimerism on Day +28, 100, 180 and 12 months Immunoglobulin levels 
IgG, IgM, IgA, at day 28, 60, 100, 180, 270, 365, 18 and 24 months and then yearly until 5 year 
follow-up.
Note:  Please see sections 6.1 and 8 for what Adverse events that are to be collected in the study 
database.


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15.8 APPENDIX H: STUDY CALENDAR
Screening1
Baseline/ Pre-
Induction1
Induction 
therapy
RSH 
Phase
Within 7 
days pre-
palifermin
KGF 
Admin
(Day -7)
Day 0
(+/- 1)
Day +7
(+/- 3)
Day +14
(+/- 7)
Day +2816
(+/- 7)
Day +60
(+/- 7)
Day +100
(+/-  14)
Day +180
(+/- 14)
Day +270
(+/- 14)
1 Yr
(+/- 30)
1.5 Yrs
(+/- 30)
2, 3, 4, 5 Yrs
(+/- 30)
H&P/HSCT timepoint note & 
Karnofsky Status
X
X
X
X
X
X
X
X
X
X
X
Risk of relapse documentation 
(Kahl scale), Comorbidity, and 
Index (HCT-CL)
X
Chemosensitivity
X
STR chimerism Profile
X2
Anti-HAV, HBsAg, anti-HBs, 
anti-HBc, anti-HCV, anti-HIV
X
T. Cruzi, HTLV I/II, HSV, 
Toxoplasma18, Varicella, West 
Nile, Syphilis
X
PPD or QuantiFERON Gold
X
CMV/EBV9
X
Weekly until Day +180, then as clinically indicated.
Tacrolimus and Sirolimus levels9
Tacrolimus and Sirolimus start on D-3. Tacrolimus and Sirolimus trough levels to be drawn at least 2 times per week and/or 
upon symptoms or alterations in renal function. Trough levels may be monitored more frequently if clinically indicated. 
Sirolimus trough level will also be drawn on D-2 (one day after loading dose)
U/A & UPC (UPC at screening 
only)
X
X
X
X
24 hr Urine CrCl (CG formula)
X
Urine or Serum HCG in female 
of childbearing potential
X
X6
X
X
ECG
X
Echo or MUGA scan
X
X3
PFTs
X
X
X
X
X
X
X
Dexa Scan
X
X3
CT chest w/o IV contrast for 
thymus volume measurement
X8
X
X
X
X8
(24m & 36m)
CT NCAP (or other imaging, 
such as PET/MRI, per PI 
discretion as clinically 
indicated)
X2
X3
X3
X3
X3
X3
X3
MM work up4
X2
X2
X3
X3
X3
X3
X3
BM aspirate and biopsy14 (flow, 
cytogenetics, molecular studies, 
research samples to Figg’s lab)
X2
X2
X3
X3
X3
X3
X3
Optional Lumbar Puncture , IT 
MTX Administration, and  CSF 
X
X
X3
X
X
X
X


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108
Screening1
Baseline/ Pre-
Induction1
Induction 
therapy
RSH 
Phase
Within 7 
days pre-
palifermin
KGF 
Admin
(Day -7)
Day 0
(+/- 1)
Day +7
(+/- 3)
Day +14
(+/- 7)
Day +2816
(+/- 7)
Day +60
(+/- 7)
Day +100
(+/-  14)
Day +180
(+/- 14)
Day +270
(+/- 14)
1 Yr
(+/- 30)
1.5 Yrs
(+/- 30)
2, 3, 4, 5 Yrs
(+/- 30)
Analysis (Patient & Disease 
Specific)15
Peripheral blood flow
X
X3
X3
X3
X3
X3
X3
BM chimerism5
X
X
X
X3
X3
Whole blood & WBC 
chimerism5
X
X
X
X
X
X3
X3
X3
ABO type & screen
X
q4 days during transplant hospitalization then as clinically indicated
CBC with differential 9
X
X6
X6
X
x
Daily during transplant hospitalization, then as clinically indicate. If minor ABO mismatch, twice daily from Day+4 until Day+14, then as 
clinically indicated
Acute care, hepatic, & mineral 
panel9
X
X6
X6
X
x
Daily during transplant hospitalization then as clinically indicated
PT/PTT
X
X
Weekly during transplant hospitalization, then as clinically indicated
Amylase/lipase
X
x
Daily during transplant hospitalization until Day +6. Then, twice 
weekly until Day +28 or more often if clinically indicated. After 
Day +28, weekly until Day +100. Then at each timepoint.
X
X
X
X
X
X
TBNK
X
X7
X
X
X
X
X
X
X
X
X
Serum Immunoglobulins
X
X
X
X
X
X
X
X
X
Serum ferritin
X
X
X3
TSH, T3, T4 (Thyroxine, free)
X
X
X
Gonadal Assessment -Females: 
FSH/LH, estrogen
Males: Testosterone (free & 
total)
X
X
X3
Research blood, Section 5.1.1
Additional research samples to 
Figg’s Lab11
1 SST,
5 CPT 
&
5 ACD
1 SST &
1 GTT
1 SST &
1 GTT
1 SST & 5 
CPT
1 SST & 5 
CPT
1 SST & 5 
CPT
1 SST & 5 
CPT
1 SST & 5 
CPT
1 SST, 5 
CPT & 5 
ACD
1 SST &
5 CPT
1 SST,
5 CPT &
5 ACD
1 SST & 5 
CPT
1 SST,
5 CPT &
5 ACD @ 24m
Social Work Consult
X
Nutrition Assessment
X
Dental Consult and/or 
collection
X13
X12
X12
X12
X13
X3
Hepatology Consult in patients 
with chronic active hepatitis B 
and/or Hepatitis C
X
X
Dermatology Consult for 
research collection and new 
diagnosis 
X
X
X3
Ophthalmology Consult
X
X2
X2
GI Consult
X
GYN Consult (pre or peri-
menopausal women)
X
X
NIH Advanced Directives Form10
X


Abbreviated title: Palifermin dose escalation
Version date: 4/7/2022
109
Screening1
Baseline/ Pre-
Induction1
Induction 
therapy
RSH 
Phase
Within 7 
days pre-
palifermin
KGF 
Admin
(Day -7)
Day 0
(+/- 1)
Day +7
(+/- 3)
Day +14
(+/- 7)
Day +2816
(+/- 7)
Day +60
(+/- 7)
Day +100
(+/-  14)
Day +180
(+/- 14)
Day +270
(+/- 14)
1 Yr
(+/- 30)
1.5 Yrs
(+/- 30)
2, 3, 4, 5 Yrs
(+/- 30)
Acute GVHD Assessment
X
X
X
Chronic GVHD Assessment
X
X
X
X
X
X
X
GGT17
X
X
X
X
X
X
X
X
X
X
1. In addition to baseline/pre-induction tests listed, all screening tests should be repeated if done > 45 days prior to start date of induction therapy 
2. Must be done at least 30 days before the start of induction or based on PI Discretion
3. Per Investigator discretion/clinically indicated
4. MM workup – skeletal survey; total serum protein, serum and urine (24 hour) protein electrophoresis with immunofixation, CRP, immunoglobulin free light chains, beta 2 microglobulin 
5. Recipient bone marrow chimerism will be measured on days 28, 100 and 180. Lymphoid and myeloid subset chimerism will also be measured at these points if donor chimerism was < 95% on the 
previous study. Chimerism also measured as clinically indicated
6. Must be performed within 48 hours of pre-induction therapy
7. TBNK should be done at the end of each induction cycle, at least 48 hours after the cycle’s last dose of filgrastim and within three days before the next scheduled cycle. This is done in order to determine 
CD4 count, which helps determine whether to continue administering additional cycles of induction chemotherapy.
8. CT scan of the chest without IV contrast is done at 24 months and 36 months. After the scan at 36 months, no additional scans are done. This does not need to be performed separately if CT obtained for 
other reasons is obtained and can be used to collect this data.
9. Of note, for all lab tests done between day +100 and Day +180 (namely CBC, acute care panel, mineral panel, hepatic panel, CMV, EBV, tacrolimus and sirolimus levels) these labs can be obtained at 
patient’s home institution since beyond Day +100, patients are usually stable enough to go home and no longer require all lab testing to be obtained at NIH.  The frequency of the labs will be at the 
discretion of the patient’s home physician.
10. As indicated in section 11.1.3, all subjects will be offered the opportunity to complete an NIH advanced directives form.  This should be done preferably at baseline but can be done at any time during the 
study as long as the capacity to do so is retained.  The completion of the form is strongly recommended, but is not required.
11. An additional 50 ml (6 R&G CPT) will be sent to Figg’s Lab at the onset of acute and/or chronic GVHD, prior to the start of systemic GVHD treatment, whenever clinically possible, as per protocol section 
5.1.1.2.1. 
12. This is to collect the research dental sample only
13. This is a dental consult only
14. Confirm with the PI if cytogenetics and molecular studies are needed.
15. Confirm with the PI for appropriateness and the need for concurrent intrathecal chemotherapy administration. This will only be completed after protocol consent is signed.
16. This visit is considered the 30 day post-Palifermin safety visit.
17. GGT twice a week through day 100 and then as clinically indicated 
18. Toxoplasmosis weekly on positive patients during inpatient hospitalization, then as clinically needed. 


Abbreviated title: Palifermin dose escalation
Version date: 4/7/2022
110
15.9 APPENDIX I:  PROCESSING CHECKLIST:  DTM-FORM-5086
Protocol #:      
      Date:      
Product Type:      
DIN:  (apply sticker on 
receipt)    
Recipient:  
                          
Diagnosis:      
Donor: 
        
Recipient ABO/Rh:         /      
Donor ABO/Rh:       /      
Recipient Antibody Screen: 
 NEG or  
 POS 
Donor Antibody Screen:  
 NEG or  
 POS 
 ABO Interpretation by MD:     
  
  Autologous donation-recipient ABO/Rh, antibody
        screen and ABO interpretation are not applicable 
    
  
  No ABO or other red cell  incompatibility
  
  Major incompatibility with donor RBCs  
         
  
  Minor incompatibility with donor plasma
Donor TTD & RPR Interpretation:      
  
  Results Within Normal Limits (WNL) for Anti-HBc,
  Anti-HCV,  Anti-HIV-1/2,  Anti-HTLV-I/II,  HBsAg,   
  HIV-1/HCV/HBV NAT,  West Nile NAT, RPR and T. Cruzi
  
   CMV test resulted
  
  Results NOT WNL or incomplete (see CRIS report) 
  
  Result >30 days  (see CRIS report) 
Comments: 
 MD review: Storage of product is 
 routine    
 vapor 
   
 physically quarantine product due to ____________
      MD Review:           
  Process per Protocol       or        
  Process per Med Exception   
               PBW adult recipient:       kg        or       Actual weight pediatric recipient: ___ kg
   Height in CRIS:       cm   Date:                      
Weight in CRIS      kg   Date:      
   Ideal Body Weight (IBW) and Practical Body Weight (PBW) Calculations    or    actual weight is used
   
  Male:   ( 0.91 x      ) - 88 =      kg IBW  
  Female:  ( 0.91 x      ) - 92.5 =      kg IBW
                                height(cm)
                                                                       height(cm)
    (     +       ) =      kg =      kg PBW        
       Actual        IBW               2
% Change in PBW if 2nd or 3rd Collection: PBW current – PBW former     X100 =          
                                                                                     PBW former    
 
  If % change is ≤15 then former PBW is used for calculations          kg   
 
  If % change is >15 then current PBW is used for calculations        kg                                              
Note: % Change in PBW not calculated if 1st collection 
Submitted by:      
Date:      
Service Coordinator Review: ________ / ________
Processing Tech Review: ________ / ________
 
  PSI or Medical Exception reviewed 
   DIN label affixed to form; clerical check of DIN, recipient and 
donor information, product type on label performed
 CRIS Processing order # ________
  CRIS Processing order reviewed 
  CRIS order # verified; entered in StemLab; COMPLETED 
 
 Recipient and Donor in StemLab
Comments:
MD Approved by:        Date:                     MD Approved by:         Date:      
Record Reviewed by:        Date:      
SC-FORM-5086 v10.11 Processing Checklist                                                                                                            Referenced in DTM-SOP-5111


Abbreviated title: Palifermin dose escalation
Version date: 4/7/2022
111
15.10
APPENDIX J: INFECTIONS GRADED BY THE CORDONNIER SCALE.

Certain infection related adverse events (will also be graded by the Cordonnier 
scale from Day+7 to 24 months post-transplant. This will include the following 
information: Date of diagnosis of new infection, Affected organ system (if 
applicable), and the type of infection to be graded. These include:
o
Date of 1st CMV reactivation (defined as CMV > 250 copies/ml or ≥ 3.08 
Log 10 IU/ml by peripheral blood PCR)
o
Date of 1st CMV viremia (defined by viral loads ≥1000 copies/mL (4.12 Log 
10 IU/ml), two consecutive rising values 250-1000 copies/mL (3.08 – 4.12 
Log 10 IU/ml), or in persons with any positive CMV PCR result suspected 
of having CMV disease)
o
Date of initiating treatment for CMV viremia
o
Date of 1st EBV activation (EBV infection was defined as ≥1000 copies/mL  
or ≥ 2.70 Log 10 IU/ml by peripheral blood PCR)
o
Date of 1st nasopharyngeal viral infection (nasal wash)
o
Type of nasopharyngeal viral infection: influenza A, influenza B, 
parainfluenza 1, 2, and 3, adenovirus, respiratory syncytial virus (RSV), 
rhinovirus, coronavirus, metapneumovirus, or any other nasopharyngeal 
virus.
o
bacteremia with severe sepsis or deep organ involvement, and type of 
bacteria
o
candidemia (≥1 positive blood culture) or candida deep tissue infection, 
type of candida 
o
proven or probable Aspergillus pneumonia 
o
severe varicella zoster infection 
o
viral encephalitis, and type of virus 
o
cytomegalovirus (CMV) organ involvement
o
Pneumocystis jiroveci pneumonia 
o
Toxoplasmosis gondii with organ involvement 
o
Any pneumonia with PaO2 ≤65 mmHg, or 
o
Any sepsis syndrome requiring transfer to the intensive care unit (type of 
bacteria)
Cordonnier Grade (see Table 3). [64]  


Abbreviated title: Palifermin dose escalation
Version date: 4/7/2022
112
Table 3 Classification of the severity of infections in three grades, specifically designed for the GREFIG 
study 4 according to the data found in the literature in 1998.              


Abbreviated title: Palifermin dose escalation
Version date: 4/7/2022
113
15.11
APPENDIX K: SAMPLE PROCESSING
Bone marrow
1. Transfer bone marrow from heparinized syringe or GTT to 15-mL conical tube
2. Spin for bone marrow supernatant if required by patient protocol (1300g for 10 
min) and distribute 1 mL into 2 vials each, freeze @ -80C (record volume if less 
than 1 mL)
3. Dilute bone marrow to 10 mL with DPBS without CA and Mg
4. Layer diluted bone marrow on top of 4 mL of LSM in a new tube
5. Spin 30 min @ minimum 400g, room temperature, slow brake
6. Collect cell layer above LSM layer and transfer to 50-mL conical
7. Follow counting and washing procedure
8. After determining correct vials for cells, follow freezing protocol
Saliva
1. Weigh tube to determine saliva volume in grams (subtract weight of tube from 
total weight
2. Aliquot 1mL of saliva into microfuge tubes labeled pellet (decrease tube number 
if low volume)
3. Spin saliva for 5min at 10,000x
4. Transfer supernatant to new microfuge tubes labeled supernatant
5. Resuspend pellet tubes in 300ul of 0.5M EDTA
6. Freeze pellets and supernatants at -80 C
Microbiome Swabs 
1. Place 1 mL of RNAlater in tubes for the swabs
2. The swabs will be taken and put into the tubes and sealed
3. Freeze these tubes directly into -80 C
Sputum
1. Sterilize forceps in ethanol
2. Pre-weigh 50mL conical
3. Empty sputum onto petri dish and separate the plug from the saliva using forceps
4. Transfer plugs to petri dish lid and make small circular movements to condense 
them
5. Transfer the plugs to the weighed conical and record sputum weight
6. Add 8 volumes x sputum weighty of DPBS without CA and Mg
7. Disperse sputum gently
8. Vortex 15sec
9. Place tube in a bag of ice and rock on bench rocker for 15min


Abbreviated title: Palifermin dose escalation
Version date: 4/7/2022
114
10.Centrifuge 790g for 10min @ 4 C, brake off
11.Take half of the added DPBS volume and divide into 4 aliquots for freezing at -80 
C
Biopsies
1. Have a Styrofoam box with dry ice in the bottom
2. Place a metal can of 2-methylbutane in the box
3. Bring OCT and trays, RNAlater filled tubes, pen for labeling
4. Fill OCT tray for fragment to be placed in and flash freeze in the 2-methylbutane
5. Fragments SNAP frozen can be flash frozen in 2-methylbutane as well
6. Store RNAlater tubes at 4 C overnight before freezing at -80 C
7. Wrap frozen OCT in foil and freeze at -80 C
PDCMF Sample Processing SOP
Purpose and Scope
Isolation, collection, and storage of Peripheral Blood Mononuclear Cells, plasma, 
serum, bone marrow supernatant and cells, biopsies, cell products, and stool, from 
clinical trial patient research samples, for cryopreservation, and flow cytometry.


Abbreviated title: Palifermin dose escalation
Version date: 4/7/2022
115
PBMC and CPT plasma
1. Weigh CPT tubes for balancing in centrifuge
2. Spin tubes for 30 min @ 1800g, room temperature, slow brake
3. Collect 1 mL plasma per vial and store @ -80C
4. Collect PBMC layer from top of polymer layer, combining into a 50-mL conical
5. Follow counting and washing procedure
6. After determining correct vials for cells, follow freezing protocol
Counting Cells
1. After placing PBMC layer or bone marrow cells into 50-mL conical, balance tubes 
and spin for 10 min, 1500 rpm, room temperature
2. Aspirate supernatant
3. Resuspend in 1 mL of DPBS without Ca and Mg
4. Add 10 ul of cell suspension to 90 ul ACK lysis buffer in one well of a 96 well 
plate
5. Creates 1:10 dilution
6. Add 10 ul of 1:10 dilution to 10 ul of Trypan Blue in another well
7. Creates 1:20 dilution
8. Aliquot dyed cells (20 ul total) on Cellometer slide (use circles)
9. Count the cells in the Cellometer with dilution indicated (20)
10.After counting, dilute samples again to 10 mL with DPBS
11.Spin 10 min at 1500 rpm, room temperature to pellet
12.Aspirate supernatant and resume with freezing protocol
Freezing Cells
1. Resuspend in a 1:1 ratio of chilled Freeze Mix #1 and Freeze Mix #2
–
Resuspend in Freeze Mix #1, then add Freeze Mix #2 dropwise, mix -> 
final 1 mL per vial
–
Store resuspended cells in aliquots as specified by protocol
2. Aliquot into vials 
3. Place vials in a chilled, but not frozen, cryochamber and put in the -80°C freezer 
overnight
4. Transfer vials to storage boxes (-80°C freezer or liquid nitrogen) and place jars in 
hall refrigerator to chill to 4° for next use
5. Replace isopropanol in bottle after 5 uses (once a week)
Plasma from GTT-heparin
1. Set aside aliquots for FACS (500uL)
2. Balance and spin GTT for 10 min at 1300g, room temperature


Abbreviated title: Palifermin dose escalation
Version date: 4/7/2022
116
3. Take 1 mL aliquots of top plasma layer and freeze @ -80 C
Serum
1. Make sure blood was drawn at least an hour prior to centrifugation for clotting to 
occur
2. Balance and spin RTT or SST for 10 min at 1300g, room temperature
3. Make sure granulocytes have gone through the polymer and then take 1 mL 
aliquots of the top serum layer and freeze @ -80 C

ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 4/7/2022
Page 1 of 24
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:  Steven Pavletic, MD
STUDY TITLE:  A Phase I/II Open Label, Dose Escalation Study of Palifermin (Kepivance) 
In Persons Undergoing Unrelated Donor Allogeneic Hematopoietic Cell 
Transplantation
STUDY SITE:     NIH Clinical Center
Cohort: 
Treatment
Consent Version:
4/7/2022
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator: Steven Pavletic, MD
240-760-6174
pavletis@mail.nih.gov
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
Members of the study team will talk with you about the information described in this document. 
Some people have personal, religious, or ethical beliefs that may limit the kinds of medical or 
research treatments they would want to receive (such as blood transfusions). Take the time needed 
to ask any questions and discuss this study with NIH staff, and with your family, friends, and 
personal health care providers. Taking part in research at the NIH is your choice.
If the individual being asked to participate in this research study is not able to give consent to be 
in this study, you are being asked to give permission for this person as their decision-maker. The 
term “you” refers to you as the decision-maker and/or the individual being asked to participate in 
this research, throughout the remainder of this document. 
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
We are conducting a study of allogeneic stem cell transplantation from HLA-matched unrelated, 
volunteer donors for cancers of the blood and immune system.
“Stem cells” are immature blood cells, like seeds; they grow in the bone marrow and produce all 
of the cells needed for normal blood and immunity. When these stem cells are taken from one 
IRB NUMBER: 15C0067
IRB APPROVAL DATE: 05/24/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
person (called the “donor”) and given to another person (called the “recipient”), it is known as 
“allogeneic” stem cell transplantation (SCT). Originally, stem cells were collected for 
transplantation by taking samples of bone marrow from the donor. This was commonly called 
“bone marrow transplantation.” Now, most allogeneic transplants use stem cells collected from 
the donor’s circulating blood.
Allogeneic stem cell transplantation (SCT) has been used successfully to treat, and sometimes 
cure, many kinds of cancer or pre-cancerous conditions that develop in blood or immune system 
cells. Large doses of chemotherapy drugs and/or radiation have been traditionally used to eliminate 
most of the cancerous or abnormal cells from the recipient’s system, along with most of his or her 
own stem cells and immune cells. Donor stem cells can then replace the recipient’s stem cells in 
the bone marrow, restoring normal blood production and immunity; this process is called 
“engraftment”. In this way, an allogeneic SCT provides not only new blood cells but an entire new 
immune system. Immune cells from the donor are important not only to protect the transplant 
recipient from infections; these transplanted cells can sometimes eliminate the abnormal cells that 
caused the patient’s disease. This type of immune attack is called the “graft- versus-tumor” (GVT) 
effect, and it is thought to be the main reason that allogeneic SCT cures some patients of these 
conditions.
If the recipient’s immune system remains strong enough after large doses of chemotherapy or 
radiation, it may attack and destroy the donor’s cells after the transplant. This is called “graft 
rejection.” When this happens, the transplant recipient’s own stem cells may be so severely 
damaged after chemotherapy or radiation that they cannot produce blood cells, usually leading to 
death. Another serious complication can occur if donor immune cells recognize and attack the 
recipient’s normal tissues, damaging the liver, intestinal tract, and skin. This type of immune attack 
is called “graft-versus-host disease” or GVHD.
Graft rejection or GVHD after allogeneic SCT are less likely when the transplant recipient and 
donor are very similar genetically. To measure how genetically similar a recipient and donor are, 
both persons are tested to identify protein markers on the surface of their blood cells and other 
body tissues. These markers are called “human leukocyte antigens”, or HLA. A person inherits 
half of his or her HLA markers from each parent. Your immune system uses HLA proteins on your 
body’s cells to tell the difference between normal, healthy tissues and foreign organisms like 
bacteria or viruses. Differences in HLA proteins between a donor and recipient make it more likely 
that one person’s immune system will recognize the other person’s cells as foreign, causing graft 
rejection or GVHD. A donor and recipient who share all 8 of their HLA markers are called “HLA-
identical”. A transplant from an HLA-identical sibling (brother or sister) has a lower chance of 
graft rejection or GVHD, compared with other unrelated donors for allogeneic SCT. Many people 
have cancers that could be treated with allogeneic SCT, but only 20-30% of people have HLA-
identical sibling donors. For some people without HLA-identical sibling donors, an HLA-matched 
unrelated donor can be used, but the risk of graft rejection and GVHD is higher.
Severe GVHD is the leading cause of death in patients who receive an allogeneic SCT. Drugs can 
prevent GVHD after allogeneic SCT, but they do not work all the time.
We are trying to improve the results of allogeneic SCT from HLA-matched unrelated donors.
IRB NUMBER: 15C0067
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
The main purpose of this study is to study if high doses of palifermin given just prior to 
chemotherapy conditioning in increasing doses could be administered safely, prevent chronic 
GVHD and improve immunological function after transplant. Palifermin is a drug approved by the 
FDA for the prevention of mouth pain and swelling after transplantation, but is investigational in 
this particular study.
In the first part of the study, the phase 1 portion, we will give palifermin at increasingly higher 
doses in order to find the highest dose that is still safe for patients. The first three subjects enrolled 
(or six if one of the first three has an intolerable side effect) will be given the starting dose of 
palifermin. If 0 of 3 or 1 of 6 subjects has an intolerable side effect, then three (or six) more subjects 
will be enrolled at the next highest dose level. If two or more subjects has an intolerable side effect, 
no other subjects can be enrolled at the dose level. Doses will continue increasing until there are 
two intolerable side effects at a dose level or we have reached the highest dose planned in the 
study.
Once we have determined the highest safe dose, we will proceed to the phase 2 portion of the 
study. In this part of the study, additional subjects will be enrolled at the highest safe dose to test 
whether the higher dose is more effective in preventing chronic GVHD and improving 
immunological function after transplant.
If we are required to stop this study because too many patients have serious side effects, we will 
continue to provide care for you according to the study protocol. 
WHY ARE YOU BEING ASKED TO TAKE PART IN THIS STUDY?
This research study is for patients with a blood or bone marrow cancer that meet transplant 
requirements, but who do not have an HLA-matched sibling and who have had a potential HLA- 
matched (at 8/8 markers) unrelated donor identified through one of the bone marrow donor 
registries such as the National Marrow Donor Program.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
Up to 50 patients will take part in this research study.
DESCRIPTION OF RESEARCH STUDY 
Before you begin the study
We will perform some tests to determine whether you are eligible for the study. These tests will 
be explained on a separate consent. Most of the tests would have been done as part of your standard 
medical care; however, specific to this protocol, about 5 to 10 tablespoons of blood will be drawn 
to check how closely you and your donor are genetically matched. Often this blood test has already 
been performed at your home medical office prior to a visit to the NIH or it will be performed at 
the NIH Clinical Center.
During the study
Once it is determined that you are eligible for the study, you will undergo the following 
tests/exams to help us manage your health and monitor your condition while you are on 
the study. These tests will be done before you undergo your induction therapy.

Test for viruses and other infectious organisms
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Consent to Participate in a Clinical Research Study
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

Routine blood tests and urine tests

Pregnancy test (if you are a woman who can have children)

Evaluation for central vein access (described below)

Blood test to assess immune system

Nutritional assessment

Dental exam

Eye exam

Social work assessment

GYN exam (for female subjects)

Gastroenterology consult
The Central Venous Catheter
If you do not already have one before you enroll in this study, you will receive an intravenous 
(I.V.) line placed. This line is called a central venous catheter that can be used throughout your 
transplant procedure and follow-up treatment. If the catheter becomes infected or clogged, it can 
be replaced. It will be flushed once daily to prevent clogging and the dressing changed weekly. 
The nursing staff will teach you or your caregiver how to do this yourself.
The catheter will be used to give you chemotherapy, your transplant, donor lymphocyte infusion 
(DLI) (if needed), blood transfusions (if needed), and other medications such as antibiotics. It can 
also be used for drawing blood samples for tests. Since blood will be drawn often during your 
treatment, the catheter will make it easier and less painful.
Lumbar Puncture (optional)
You may undergo a lumbar puncture (also called a spinal tap) to remove a small amount of spinal 
fluid (about 1-2 teaspoons) that will be used for diagnostic testing. A lumbar puncture can help 
diagnose serious infections and other disorders. A lumbar puncture is done by inserting a small 
sterile needle through the skin and muscle, going between the bones of the spine in the lower back 
until the needle punctures the spinal canal covering. The spinal fluid will then drain out through 
the needle on its own.
Induction Chemotherapy
In this study you will receive one to three cycles of induction chemotherapy (based on the type of 
disease you have) to treat your disease and to weaken your immune system. If the study doctors 
feel your immune system is already weakened and your disease is well controlled you may not 
receive induction chemotherapy.
For patients with chronic lymphocytic leukemia, pro-lymphocytic leukemia, multiple myeloma, 
and most forms of lymphoma, this chemotherapy will include the following drugs: fludarabine, 
cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone (also called: “EPOCH- 
F”). Patients with lymphoblastic lymphoma, acute myelogenous leukemia, acute lymphocytic 
leukemia, chronic myelogenous leukemia, and other “pre-leukemic” diseases will receive 
induction chemotherapy with fludarabine, cytarabine, and filgrastim (also called: “FLAG”).
Patients with certain forms of lymphoma and leukemia may also receive a drug called rituximab. 
Each of these medications has been approved by the Food and Drug Administration (FDA). The 
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
study doctors will test a biopsy specimen from your cancer to help them decide if you should 
receive rituximab with your induction chemotherapy.  To start, you will receive common doses of 
these drugs for five days followed by a 16-day (EPOCH-F) or 23-day (FLAG) rest period (this 
time period is 1 cycle). The EPOCH-F regimen is generally given in outpatient setting. The FLAG 
regimen is given in the hospital, so you will be admitted as an inpatient, and you will remain in 
the hospital until your blood counts recover, usually 3 to 4 weeks. The effect of the chemotherapy 
on your immune system and on your disease will determine how many cycles of induction 
chemotherapy you receive. If blood tests show that your immune system is weakened enough after 
one cycle, you will go directly to the transplant. If your immune system is not very weakened and 
your disease is not growing after one cycle of induction chemotherapy, you will receive one or 
two more cycles (5 days of the same chemotherapy you received for cycle 1, followed by 16 
(EPOCH-F) or 23 (FLAG) days of rest per cycle). If your disease grows in spite of the induction 
chemotherapy then the induction chemotherapy will be stopped, and you will be removed from 
the study. If your white blood cell count remains low for a long time after induction chemotherapy, 
meaning your immune system has weakened, you will go directly to the transplant. At most, you 
will receive 3 cycles of chemotherapy. In the unusual circumstances and/or if necessary, your 
doctors may decide to use some other standard drugs or combination prior your transplant to 
achieve best control of your cancer.
Transplant
Once you have completed your induction chemotherapy (if needed), you will undergo additional 
tests to determine whether you are eligible to proceed with the transplant. This portion of the study 
includes which includes palifermin, the conditioning regimen and the transplant.
These tests/evaluations include:

Medical history/physical exam

Confirmation of a matched unrelated donor

Tests to determine whether your cancer has gotten better or worse or stayed the same

CT scan of chest (for research)

Routine blood tests
After it has been confirmed that you are eligible to proceed to the research phase, you will undergo 
the following.
Pre-transplant
You will receive one dose of palifermin intravenously 7 days before you are scheduled for 
transplant.
On the following day, you will begin 4 days of reduced-intensity transplant chemotherapy, also 
called the “conditioning regimen,” to prepare you for the transplant. This consists of a regimen of 
FDA approved agents, fludarabine, cyclophosphamide, mesna and furosemide. These will be 
administered intravenously.
Beginning three days before you receive the stem cell transplant, you will receive the drugs 
tacrolimus and sirolimus to help prevent GVHD. Sirolimus is given by mouth once a day for 
approximately six months after transplant. Tacrolimus is given either through an I.V. or by mouth 
once a day for approximately six months after transplant. Methotrexate is given for four doses 
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intravenously (through the vein) before you are discharged from the hospital, shortly after the 
transplant.
2 days after completing conditioning chemotherapy, you will receive the transplant with your 
unrelated donor’s stem cells.
Collection of the Blood Stem Cells from Your Donor
Before you begin your induction chemotherapy, your unrelated donor will have had a medical 
examination by a doctor in the National Marrow Donor Program (NMDP) network that includes 
extensive testing to make sure they do not have any of the following: HIV, Hepatitis B, Hepatitis 
C, and possible infectious diseases that may be transmitted by stem cell donation. The donor’s 
exam will also ensure that they remain available and are physically well enough to undergo the 
donation procedure. The NMDP will notify NIH if there are any abnormalities that increase the 
risk of transmitting infectious diseases to you during the transplant. These findings will be 
discussed with you.  The donor’s medical clearance will be verified by the NIH study doctor before 
you begin the research phase of the study.
Unrelated donor transplants are confidential and the identity of the donor will be anonymous. This 
means that you will not know who your donor is or where they are. You will know the age and 
gender of the donor and any history or medical exam findings that could possibly change the risk 
of your transplant. Likewise, the donor will not know who you are or where you are. S/he will 
know your age, gender, and the type of disease that you have. The donor will be given basic 
updates about your condition 30 days, 6 months, and 1 year after your transplant. The only 
information they will receive is whether or not the stem cells “engrafted” (taken hold), and if you 
have been discharged from the hospital. The donor will also be notified in the event of your death.
Depending on the policy of the particular donor center, you may be able to communicate without 
revealing your identities in an anonymous manner with your donor beginning at the time of your 
transplant. In some cases, if both you and the donor agree, you may be able to learn who your 
donor is after one year. There are some cases when a donor and patient may never communicate 
or meet. Your transplant coordinator will tell you the details of if and how you may contact the 
donor once the donor has completed his or her medical exam.
Rarely, a volunteer donor may become unavailable or the donor apheresis center is unable to 
collect enough stem cells to perform the transplant. If this happens, you will be removed from the 
study but we will continue to care for you if you have already received conditioning therapy.
Transplant Procedures
While you are in the hospital for your transplant, you will be monitored very closely for possible 
complications, which are described below. You will receive drugs to help manage these 
complications. Blood will be drawn frequently during your treatment. Your blood will be tested to 
monitor your health during and after the chemotherapy and transplant procedure. In general, 4 to 
10 teaspoons of blood will be drawn an average of 2 to 3 times per week. Some blood will be 
drawn for research purposes. In general, 3 to 4 tablespoons of blood will be drawn for research on 
average of once per week for the first 100 days after transplant. 
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After you have had your transplant
You will be hospitalized approximately 3-4 weeks after your transplant, but it could be longer if 
there are any complications. You will be required to remain in the Washington, D.C. area for 
approximately three months after transplantation so the NIH doctors can monitor you in case of 
any complications. You may require re-admission to the hospital for complications.
After the transplant, if tests show that your blood and immune cells have not fully converted to 
your donor’s type (“mixed chimerism”), then the drugs you are taking to prevent GVHD will be 
lowered to help change your blood and immunity to full donor chimerism. Sometimes additional 
therapies such as DLI may be given to you intravenously (I.V.) to reach a state of full donor 
chimerism, as described above. If your cancer is still present or grows after the transplant, 
tacrolimus may be reduced in an attempt to permit a stronger graft-versus-tumor effect. After this, 
if there are no signs of significant GVHD, then you may receive one or more DLI at increasing 
doses. These DLI are intended to “boost” your new immune system and can enhance the graft-
versus-tumor effect in some, but not all, patients. DLI can sometimes lead to the development of 
GVHD, so we will monitor you very closely for signs of GVHD after these infusions. If you 
experience significant GVHD after a DLI, we will give you treatment for GVHD, but you will not 
receive any further DLI. You may also be eligible to receive chemotherapy or other standard 
therapy (like radiation therapy or immune therapies) after the transplant if your cancer requires 
further treatment. This therapy can be given alone or combined with DLI.
You will continue on medications at home to lower the risk of GVHD and infections.
If you are in good health after the three month period after your transplant, you will then be allowed 
to return home to the care of your primary physician. You will be required to return to a local 
oncologist after transplantation so you can be monitored for late transplant complications including 
GVHD and infection. Thereafter you will be seen at NIH at 6, 9, 12, 18 and 24 months after your 
transplant and then every year following your transplant up to 5 years post-transplant, unless an 
earlier visit is required per the study doctors and more frequent monitoring if medically indicated. 
At each visit when you return to NIH, you will have a physical exam and blood draws 
(approximately 4-10 teaspoons of blood will be taken). During some visits you may have a bone 
marrow aspirate and biopsies, and other appropriate tests (for example: CT scans or other scans if 
you doctor feels it is indicated) to monitor disease status. Study-related medications will be 
provided by the NIH during your hospital stay and after you leave the NIH.
Post-transplant research tests
The skin and mouth are the two organs most commonly affected by chronic GVHD. It is important 
for you to know that these tests are being performed for research purposes to help us with our 
understanding of chronic GVHD. They would not routinely be performed unless they were needed 
to confirm the presence of chronic GVHD. These tests will be performed in all patients 60 days 
post-transplant and 6 months post-transplant. These tests may also be performed at the time of 
chronic GVHD diagnosis.

Pulmonary function test – a noninvasive test to check how well the lungs work. During the 
test, you'll breathe in as much air as you can. Then, you'll quickly blow out as much air as 
you can through a tube connected to a machine called a spirometer.
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
Echocardiogram or MUGA scan to evaluate your heart health 

Oral Photographs: We will take clinical photographs of your mouth and the surrounding 
area. Mirrors and retractors may be used to gently visualize areas of the mouth.

Bone marrow aspiration and biopsy: Your pelvis will be numbed with a local anesthetic 
called lidocaine. A small cut will be made in the skin and a needle will be inserted into the 
pelvis. Liquid samples (aspiration) of the bone marrow will be removed through the needle. 
A small fragment of bone will also be removed with the needle. After the procedure, the 
biopsy site will be covered with a small bandage – stiches are not needed to close the small 
cut. 

Skin Biopsy: This is performed so that a piece of skin may be examined under the 
microscope to get a closer look at what is going on in your skin and for diagnostic purposes. 
After cleaning the skin with alcohol and/or another antiseptic, a local numbing medicine 
(Lidocaine with or without epinephrine)--similar to what a dentist injects to numb your 
gums--is injected into the planned biopsy site. A sharp instrument which looks like a 
miniature cookie-cutter is used to remove a round plug of skin about the size of a pencil 
eraser. The biopsy site may be left open or may be closed by putting in one or two stitches, 
and a small dressing is applied. Sometimes more than one such skin sample may be needed.

You will be expected to keep the dressing over the biopsy site dry for 1 to 2 days. 
Thereafter, the dressing may be changed daily until the suture(s) are ready to come out, 
usually in 7 days. Depending on circumstances, the suture(s) may be removed by one of 
us, by your own doctor and/or your doctor’s assistant. This biopsy is optional; you will be 
asked to sign a separate consent at the time of procedure(s).

Oral mucosa biopsy: The procedure is done in a similar manner as a skin biopsy, except 
that a dressing cannot be applied, because it is not possible to keep the area dry enough to 
keep the dressing on. This biopsy is optional; you will be asked to sign a separate consent 
at the time of procedure(s).

Collection of saliva (natural mouth fluid): Saliva will be collected by spitting into a clean 
plastic tube for 5 minutes at set times after transplant. We will use saliva samples to 
measure your salivary gland function and to study in our laboratory factors that may be 
associated with the development of GVHD including the types of protein in the mouth. 
This is a simple procedure that does not have any risks or discomforts. We will use saliva 
samples to study in our laboratory factors that may be associated with the development of 
GVHD including the types of bacteria that live in the mouth. We believe these studies will 
help us understand more about oral GVHD and lead to better treatments for this painful 
condition.

Oral swab and plaque collection (natural mouth material): We will take swabs of your 
mouth and collect plaque from your teeth. We will not do any cutting or injections to collect 
these samples. We will rub a cotton swab over an area in your mouth. The plaque will be 
collected with a sterile swab/toothpick. The samples will be used to study the microbiome 
(normal bacteria found in your mouth) and other laboratory factors, such as genomic 
analysis, that may be associated with the development of GVHD.
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
Collection of whole blood: Blood will be collected to perform genomic analysis on T-cells, 
a cell in your immune system so that we can learn more about how those cells work. No 
research bloods will be collected after relapse.

Bone Density Scan (DEXA): This test measures the density of your bones (bone 
thickness). The scan checks for possible bone damage from your treatments. 
Relapse/Progression of  disease
If you relapse, we will monitor the status of your occurrence of GVHD. These evaluations can 
occur at NIH Clinical Center ,via telephone, or telemedicine visits. No research bloods or 
procedures will be done and treatment will be stopped after relapse or progression. 
STANDARD OF CARE TREATMENT
Treatments covered under this study may include a single medication or a combination of 
medications, surgery or radiation to treat your cancer. These treatments will not be experimental. 
Your doctors will describe your treatment plan to you in detail before asking you to sign this 
consent form. You may be asked to sign a separate consent form for any treatment procedures not 
outlined in this consent.
BIRTH CONTROL
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
some of the medicines used on this study may be harmful to your baby or your unborn child. If 
you are a woman who can become pregnant, or are the partner of a woman who can become 
pregnant, you will need to practice an effective form of birth control while you are on study 
treatment. If you think that you or your partner is pregnant, you should tell your study doctor or 
nurse at once.
If you are a male, you should not father a child or donate sperm while you are on study treatment. 
You should practice abstinence, or two effective forms of birth control before starting study 
treatment and during study treatment.
Effective forms of birth control include:

abstinence

intrauterine device (IUD)

hormonal [birth control pills, injections, or implants]

tubal ligation

vasectomy
REMOTE ASSESSMENTS
In the first quarter of 2020, a pandemic was announced for COVID-19 (Coronavirus Disease 2019) 
which is caused by the virus SARS-CoV-2. In light of the pandemic, tele-medicine has been used 
as an alternative way to perform assessments without having participants in clinical trials come to 
the clinic. Your study doctor may determine that the risks associated with you visiting the clinic 
during the COVID-19 pandemic may outweigh the benefit from seeing you in person at the clinic. 
Remote assessments may be performed at the discretion of your study doctor via phone, email, or 
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video chat to speak with you directly about the following: patient history, verbal exam, symptom 
reporting, and education. 
RISKS OR DISCOMFORTS OF PARTICIPATION 
Transplant risks
Risk of Death from Allogeneic SCT: Patients undergoing allogeneic SCT are at risk of dying
from the transplant procedure and its possible complications. This risk of death due to transplant 
related complications typically ranges between 15% and 40% in the course of two years post- 
transplant. The risk of death or other complications can vary greatly, depending on the age of the 
patient, other prior and current illnesses, functional status or other factors.
Other risks from allogeneic SCT include:
Veno-Occlusive Disease (VOD) - A severe liver complication known as VOD occurs in less than 
5 percent of allogeneic transplants. VOD is a chemotherapy side effect that causes blood vessels 
in the liver to be blocked. Severe VOD can lead to liver failure and death.
Graft Rejection: There is a chance that you may reject your donor’s stem cells. If that were to 
happen, you would most likely recover your own blood cells. However, there is the rare possibility 
that your own cells may not recover. This may result in prolonged low blood counts, which may 
result in infection or bleeding and may lead to death. In this event, we would attempt to support 
you with transfusions, growth factors and antibiotics until your own blood counts recover. A blood 
test will be performed at 14, 28, 60, and 100 days after your transplant to find out if your body has 
accepted the donor cells. If no donor cells can be found, then we will conclude that you rejected 
them. In that case, your blood counts will probably return to the same levels as before the transplant 
in about 2 to 3 weeks. You will receive the growth factor filgrastim to help the cells engraft. In the 
event that your cells do not engraft, we may ask your donor to donate more cells.
Graft-Versus-Host Disease (GVHD): You will be at risk for the development of GVHD for many 
years after transplantation. Acute GVHD usually occurs within 3 months after transplantation and 
typically affects the liver, intestines, and skin. Symptoms of skin GVHD may be as mild as a rash 
with itching, or as severe as blistering and loss of the skin. Symptoms of intestinal GVHD may be 
as mild as heartburn and mild diarrhea, or as severe as vomiting, cramping abdominal pain and 
bloody diarrhea. Liver GVHD may be as mild as slight disturbances in liver blood tests or as severe 
as jaundice (yellowing of the skin) and liver failure. Mild GVHD (skin rash only) can be treated 
with steroid creams that you apply on your skin.
Severe GVHD can be very dangerous and needs to be treated aggressively. Treatment of severe 
GVHD initially includes weakening of the immune system, usually with intravenous (I.V.) 
steroids. Weakening of the immune system increases the risk of infection.
A delayed form of GVHD, known as chronic GVHD, typically occurs between 3 and 12 months 
post-transplant. Some degree of chronic GVHD affects about half of patients after transplantation. 
It most commonly affects the skin, mouth, eyes, muscle, joints, liver and intestines, but it may also 
affect other organs such as the lungs, genitals and bone marrow.
Symptoms of chronic GVHD may include thickening of the skin, itching, decreased range of 
motion in the joints, dryness of the mouth and eyes, mouth pain and difficulties swallowing, loss 
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of appetite, weakness, hair loss, weight loss, liver damage (including yellowing of the skin), 
painful intercourse and lung damage leading to shortness of breath and cough. Patients with severe 
chronic GVHD are also at increased risk of infection and death. Chronic GVHD is also treated 
with drugs that weaken the immune system such as steroids. Taking steroids may increase your 
risk of infection. Treatments with steroids and other drugs are usually prolonged and last 3-5 years, 
but occasionally longer.
Late Transplant Complications:  There are other potential complications that can occur long after 
transplantation. These complications could affect any organ in the body including the heart, lungs, 
kidneys, liver, muscles, and brain. Rarely, patients who receive an allogeneic SCT are at risk for 
developing a second cancer such as lymphoma, leukemia, lung cancer or other tumors.
Other complications are also possible following your transplant. The most common complications 
are infections. Because you will be receiving drugs (e.g. sirolimus) that weaken the immune 
system, you are at greater risk to develop infections from uncommon organisms. These infections 
can be life-threatening, and could cause death.
There is up to 40 percent chance of death from complications of conventional allogeneic bone 
marrow transplants. Although we will use new/unconventional ways to try to reduce these odds, it 
is possible that our approach may not work or that it may even increase the chances of death. There 
is also the risk of complications that cannot be predicted.
Procedure Risks
Stem Cell Infusion: The donor cells will be infused fresh or frozen with a chemical called DMSO 
to protect them from the effects of freezing. Patients receiving thawed cells often develop side 
effects from the DMSO. DMSO side effects may include fever and allergic reactions, such as skin 
rash, itching, difficulty breathing, and low blood pressure. These reactions are usually mild and 
temporary, and they can be easily treated with IV fluids and medications. 
Bone Marrow Aspiration and Biopsy: This procedure usually causes only mild pain for a short 
time at the biopsy site. Very rarely, bleeding or an infection may occur at the biopsy site.
Blood Draws: Side effects of blood draws include pain and bruising in the area where the needle 
was placed, lightheadedness and rarely, fainting. When a large amount of blood is drawn, your red 
blood cell count may drop causing anemia. Anemia can cause a lack of energy and other symptoms. 
Transfusions of red blood cells are sometimes needed to treat anemia. 
Central Venous Catheter: Side effects of placing a central venous line in your chest wall include 
bleeding, bruising, blood clots, or pain in the area of insertion. This line will be placed by 
physicians with experience in this procedure. These physicians will discuss the above risks at the 
time of the line insertion. Rarely, placement of a central venous catheter can result in a collapsed 
lung. If a collapsed lung occurs, it may require hospitalization and temporary insertion of a plastic 
tube in your chest to re-expand the lung.
Lumbar Puncture (Spinal Tap): Though lumbar punctures are generally recognized as safe, some 
risks may include pain or bleeding at the site of needle insertion (the low back), infection, and 
headache.
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Skin Biopsies: Whenever possible, we will perform biopsies on covered areas of the body. There 
may be minor bleeding right after the procedure and this can easily be controlled by applying 
pressure on the spot for a few minutes. Rarely, a bruise might form and this usually heals on its 
own. Sometimes a small infection may occur at the biopsy site. This can usually be treated with 
topical antibiotics. On the very rare occasion that a larger or deeper infection occurs, oral 
antibiotics may be needed for 7-10 days. An infection can be recognized by redness, soreness, and 
pus at the site. It generally starts 2 days or more after the procedure and does not clear up in another 
couple of days. These biopsy/excision sites generally heal very well, leaving red, white, dark or 
skin-colored flat scars. Sometimes, the scar that forms may be a bit thicker than usual. Rarely, a 
keloid (large, painful or itchy scar) may form. Keloids are more likely to form on the chin, earlobes, 
chest and upper backs of Blacks and Asians between adolescence and the 30’s.
Oral mucosa biopsy: There may be minor bleeding, bruising, numbness and slight swelling. There 
is also the possibility of infection. Mouth sores have occurred in some patients, but this is 
uncommon.
Echocardiogram (ECHO):  An echocardiogram is an ultrasound to evaluate your heart structure 
and function. This test is very safe and is performed using a probe with gel placed on your chest.
Pulmonary (lung) function testing:  These tests measure how well your lungs work. They are 
usually safe for most people. However, because the test may require you to breathe in and out 
quickly, you may feel dizzy. There’s a small risk that you might faint. If you have asthma, this test 
could cause you to have an asthma attack. In very rare cases, pulmonary function tests may cause 
a collapsed lung. If you have asthma or feel lightheaded during the test, tell your doctor.
Urine Tests:  There are no physical risks to collecting urine.
Radiation Risks
In order to measure any changes in your thymus, an important organ in your immune system, we 
plan to get CT scans. The measurement of these changes is one of the ways in which we evaluate 
how the study drug is working.  If you need scans to monitor your disease (such as lymphoma 
patients who may otherwise need CT scans of the neck, chest, abdomen and pelvis), we would not 
do an extra CT scan just for this purpose.  You may also receive radiation from MUGA and DEXA 
scans. 
During your participation in this research study, you may be exposed to radiation from up to 6 CT 
scans, 1 MUGA scan, and 1 DEXA scan. The amount of radiation exposure you may receive from 
these procedures is equal to approximately 1.43 rem.  If you are a patient with lymphoma, the 
amount of radiation exposure you may receive from these procedures is equal to approximately 
8.27 rem. A rem is a unit of absorbed radiation.
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them. The average person in the United States receives a radiation exposure 
of 0.3 rem per year from these sources. This type of radiation is called “background radiation.”  
No one knows for sure whether exposure to these low amounts of radiation is harmful to your 
body.
The scans that you may get in this study will expose you to the roughly the same amount of 
radiation as 4.8 years’ worth of background radiation. Most of the time, this amount of extra 
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radiation is not harmful to you. However, scientists believe that being exposed to too much 
radiation can cause harmful side effects. This could include getting a new cancer. We estimate that 
this could happen in about 1 out of every 1000 people who get a very large amount of extra 
radiation.
For patients with lymphoma, the scans that you may get in this study will expose you to the roughly 
the same amount of radiation as 27.6 years’ worth of background radiation. Being exposed to too 
much radiation can cause harmful side effects such as an increase in the risk of cancer. The risk 
depends on how much radiation you are exposed to. Please be aware that about 40 out of 100 
people (40%) will get cancer during their lifeline, and 20 out of 100 (20%) will die from cancer. 
The risk of getting cancer from the radiation in this study is 0.8 out of 100 (0.8%) and of getting a 
fatal cancer is 0.4 out of 100 (0.4%).  
Please tell your doctor if you have had any radiation exposure in the past year, either from other 
research studies or from medical tests or care, so we can make sure that you will not receive too 
much radiation. Radiation exposure includes x-rays taken in radiology departments, cardiac 
catheterization, and fluoroscopy as well as nuclear medicine scans in which radioactive materials 
were injected into your body.
If you are pregnant you will not be permitted to participate in this research study. If you are breast 
feeding and the protocol involves injection of radioactive material you will not be permitted to 
participate. It is best to avoid radiation exposure to unborn or nursing infants since they are more 
sensitive to radiation than adults.
Risks from Chemotherapy
Induction Chemotherapy:
As described previously, the type of induction chemotherapy you will receive depends on the type 
of disease you have. Some patients will receive fludarabine, cyclophosphamide, etoposide, 
doxorubicin, vincristine, and prednisone (called: EPOCH-F), while others will receive fludarabine, 
cytarabine, and filgrastim (called: FLAG). In addition, some patients will receive rituximab. It is 
important for you to know that this type of induction chemotherapy is likely to reduce your white 
blood cells for many days. This will place you at increased risk of infection. Such infections can 
be very serious and may result in death. For this reason, if you develop a fever higher than 101° F, 
you must see your doctor immediately. If necessary, you will be treated with antibiotics. Also, this 
chemotherapy will likely cause your platelet count to fall.
This may place you at increased risk of bleeding. If your platelet count becomes dangerously low, 
you will receive platelet transfusions. The chemotherapy may also cause you to develop a low red 
blood cell count, called anemia.  Anemia can cause a lack of energy and other symptoms. 
Transfusions of red blood cells are sometimes needed to treat anemia. The following are known 
specific risks of each drug used within the specific regimen that you will receive:
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EPOCH-F (with or without rituximab):
Etoposide:
Likely
Less Likely
Rare:

low blood counts

hair loss

nausea and vomiting

diarrhea

mouth sores

low blood pressure

shortness of breath

secondary leukemia (a 
different type of 
cancer)
Prednisone:
Likely:
Less Likely:
Rare:

weight gain

sodium and water 
retention

mood changes

elevated blood sugar

increased risk of 
infection

stomach or bowel ulcers

high blood pressure

diabetes

thinning of bones with greater 
risk of fracture (long term use)

puffing of the face (long term 
use)

acne

thinning of skin

muscle wasting

none
Vincristine:
Likely:
Less Likely:
Rare:

nerve damage resulting 
in a feeling of “pins and 
needles” in hands and 
feet

constipation

hair loss

loss of reflexes (foot 
drop),

low blood counts

hoarseness and pain in 
the jaw

paralytic ileus (bowel 
function completely 
stops),

water retention
Cyclophosphamide:
Likely:
Less Likely:
Rare:

low blood counts

hair loss

nausea and vomiting,

painful and bloody 
urination

sterility

water retention

heart damage

secondary leukemia (a 
different type of 
cancer)

skin rash
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 4/7/2022
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Doxorubicin:
Likely:
Less Likely:
Rare:

low blood counts

hair loss

Urine colored red for a 
day or two after the 
doxorubicin infusion

nausea and vomiting

diarrhea

mouth & throat sores

heart damage

secondary leukemia (a 
different type of cancer)

tissue damage if the drug 
leaks from the vein into 
surrounding tissue

bleeding bowel or stomach
Fludarabine:
Likely:
Less Likely:
Rare:

low blood counts

lowered level of 
immune cells

increased risk of 
infection

nausea and vomiting

diarrhea

fever

mouth & throat sores

loss of appetite

swelling (edema)

skin rash

muscle aches

headache

agitation

hearing loss

fatigue

weakness

numbness / tingling 
(“pins and needles”)

GI bleeding

lung damage

kidney damage

severe neurologic 
(brain and/or spinal 
cord) toxicity has 
occurred after very 
high doses 
including: 
blindness, 
deterioration of 
mental status, and 
death
IRB NUMBER: 15C0067
IRB APPROVAL DATE: 05/24/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 4/7/2022
Page 16 of 24
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Rituximab:
Likely:
Less Likely:
Rare:

mild infusion reactions 
(fever, chills, nausea)

severe infusion / 
hypersensitivity 
reactions (e.g. lowering 
of blood pressure, 
shortness of breath or 
difficulty breathing)

tumor lysis syndrome 
(metabolic 
complications)

severe skin 
reaction/rash,

kidney failure

death

chest pain

cardiac arrhythmias 
(heart beating 
irregularly)

some other viral 
infections may be 
worsened or reactivated 
from a “sleeping state” 
in patients taking 
rituximab
Filgrastim (G-CSF):
Likely:
Less Likely:
Rare:

bone pain

reversible lab changes in 
your blood test results

headache

pain at the needle site

fevers

tiredness

filgrastim can cause 
rupture of the spleen, 
which can cause 
death
FLAG:
Fludarabine and Filgrastim
As above in EPOCH therapy.
Cytarabine (Ara-C):
Likely:
Less Likely:
Rare:

low blood counts,

lowered level of immune 
cells

nausea and vomiting

mouth sores

hair loss

diarrhea,

loss of appetite,

flu-like symptoms

fevers

liver damage

eye irritation

loss of coordination or 
balance

sleepiness

speech difficulties

coma
IRB NUMBER: 15C0067
IRB APPROVAL DATE: 05/24/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 4/7/2022
Page 17 of 24
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Transplantation Chemotherapy:
The main side effect of fludarabine and cyclophosphamide at these doses is severe bone marrow 
and immune system weakening, which decreases the production of red blood cells, white blood 
cells, and platelets. The doses that will be used could cause longer than normal bone marrow 
weakening, if the transplanted stem cells were rejected. Until the transplanted stem cells start 
to produce adequate numbers of blood cells, you will be at significant risk for infections, 
bleeding and severe fatigue. These conditions will be treated with antibiotics and transfusions. 
Other potential side effects of fludarabine and cyclophosphamide are described above.
Risks of Graft-versus-Host Disease Prevention:
As described above, you will receive tacrolimus, methotrexate, and sirolimus.
Tacrolimus:
Likely:
Less Likely:
Rare:

decrease in kidney 
function

headache

tremors*

high blood pressure

increased infection

gum inflammation

seizures*

high blood potassium 
levels

nausea

diarrhea or constipation

loss of appetite

abdominal pain

insomnia

high blood sugar

increase in blood lipid 
levels,

lowering of body 
magnesium levels 
requiring supplementation

liver damage

numbness or tingling in 
hands or feet

coma

delirium
*Because of the risk of seizures and decreased reflexes while taking this medicine, you should 
not drive a car while taking tacrolimus.
Methotrexate:
Likely:
Less Likely:
Rare:

delay in the return of 
blood cells after 
transplant

mouth sores

minor liver damage

nausea

vomiting

diarrhea
IRB NUMBER: 15C0067
IRB APPROVAL DATE: 05/24/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 4/7/2022
Page 18 of 24
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Sirolimus:
Likely:
Less Likely:
Rare:

your infection risk is 
likely increased. 
Because sirolimus as an 
immune suppression 
drug, it is likely the risk 
for some infections may 
be increased.

diarrhea

nausea

damage to the liver

low blood counts

very high levels of fats 
(triglycerides)

increased cholesterol 
(increased lipid blood 
levels)

mouth ulcers

headache

increased risk of infection

red blood cell lysis with 
associated reduced kidney 
function

severe swelling of the 
pancreas

secondary cancers (a 
different type of 
cancer)
Risks of Palifermin: (Kepivance ®)
Likely:
Less Likely:
Rare:

skin reactions (rash, 
irritation, redness, 
swelling, itching)

fever

tongue thickening or 
discoloration

visible water retention

high blood pressure

numbness

abnormal sensations of 
the skin

joint pain

change in taste

tingling, numbness, 
prickling, or burning 
sensation around the 
mouth or on the skin

rash; hives; difficulty 
breathing

tightness in the chest

swelling of the mouth, 
face, lips, or tongue
Other Medications
You will routinely receive several other drugs to prevent or treat various infections and other 
transplant-related complications. The most common medications used and their common side 
effects are listed as follows:
Ursodeoxycholic acid, also known as ursodiol, can cause nausea, vomiting, “heartburn”, a metallic 
taste, abdominal pain, an inflamed gallbladder, constipation, mouth pain, flatulence, diarrhea, 
itching, rash, dry skin, hives, headache, fatigue, anxiety, depression, and sleep disorders. Less 
common side effects include sweating, thinning of hair, back pain, muscle and joint pains, runny 
noses, and cough.
IRB NUMBER: 15C0067
IRB APPROVAL DATE: 05/24/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 4/7/2022
Page 19 of 24
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Mesna is a drug given with cyclophosphamide during the conditioning regimen to prevent bladder 
injury, and side effects may include: nausea, vomiting, and diarrhea.
Furosemide is a drug given with the cyclophosphamide and IV fluids in order to prevent fluid 
buildup, as well as to prevent bladder injury. Side effects of furosemide may include low potassium 
and low magnesium levels, loss of appetite and low blood pressure. Serious side effects are rare, 
but include low platelets, anaphylaxis and skin rashes.
Diphenhydramine may cause tiredness, dizziness, upset stomach, disturbed coordination, dry 
mouth, flushing, or difficulty urinating.
Acyclovir can cause nausea, vomiting, headache, dizziness, abdominal pain, bone pain, allergic 
reactions, mild liver inflammation, kidney injury, and abnormal nervous system function.
Fluconazole can cause nausea, vomiting, headache, skin rash, abdominal pain, and diarrhea. Rare 
but sometimes serious liver toxicity has also been reported. Fluconazole can increase the blood 
levels of other drugs, which can increase their effectiveness and/or their side effects.
Trimethoprim/sulfamethoxazole (Bactrim) may cause nausea, vomiting, loss of appetite, allergic 
skin rashes, and suppression of bone marrow function. Rare but severe reactions may affect the 
skin and bone marrow; these have sometimes been fatal.
Reproductive Risks: This treatment is likely to result in sterility (the inability to produce 
children). However, we cannot predict for certain that you will become sterile during this 
treatment; therefore you will be asked to use birth control while on the study as discussed above.
POTENTIAL BENEFITS OF PARTICIPATION
Are there benefits to taking part in this study?
The chemotherapy you receive may cause improvement in your cancer, although it is not likely to 
result in a cure by itself. The allogeneic SCT may improve the chance that your disease will enter 
into a long remission and possibly be cured. However, you should understand that this cannot be 
guaranteed. Your participation in this study may contribute to understanding and developing new 
ways of using allogeneic SCT for the treatment of cancer.
ALTERNATIVE APPROACHES OR TREATMENTS
What other choices do I have if I do not take part in this study?
To be eligible for this study, you must have already received the standard treatment for your 
disease, but there are other options other than participating on this trial:

You may consider other treatments such as other forms of chemotherapy, radiation, 
surgery, or immune therapies. In some cases, you may be eligible for an autologous bone 
marrow or stem cell transplant, in which your own stem cells are returned to your body 
following high dose chemotherapy treatment.

Taking part in another research study

Instead of participating in a research study such as this, you may also be eligible to receive 
a standard allogeneic stem cell transplant with high dose chemotherapy and/or radiation 
therapy to completely wipe out your bone marrow before donor cells are transplanted.
IRB NUMBER: 15C0067
IRB APPROVAL DATE: 05/24/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 4/7/2022
Page 20 of 24
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

Getting comfort care, also called palliative care. This type of care helps reduce pain, 
tiredness, appetite problems, and other problems caused by cancer. It does not treat the 
cancer directly, but instead tries to improve how you feel. Comfort care tries to keep you 
as active and comfortable as possible.

Another option is not to receive any further treatment at all.
You should discuss with your referring doctor and your doctors at the NCI whether or not any of 
these other treatments might be a reasonable choice for your disease.
STOPPING THERAPY
Your doctor may decide to stop your therapy for the following reasons:

if s/he believes that it is in your best interest

if your disease comes back before you have had your transplant

if you do not meet the transplant eligibility criteria after you have completed induction 
therapy
In this case, you will be informed of the reason therapy is being stopped.
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. If you withdraw your consent and leave the trial, 
any samples of yours that have been obtained for the study and stored at the NCI can be destroyed 
upon request. However, any samples and data generated from the samples that have already been 
distributed to other researchers or placed in the research databases cannot be recalled and 
destroyed.
CONFLICT OF INTEREST
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest. This process is detailed in a Protocol Review Guide.  You may ask your research team 
for a copy of the Protocol Review Guide or for more information. Members of the research team 
who do not work for NIH are expected to follow these guidelines but they do not need to report 
their personal finances to the NIH.
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study. This is allowed under federal rules and is not a 
conflict of interest.
USE OF SPECIMENS AND DATA FOR FUTURE RESEARCH
To advance science, it is helpful for researchers to share information they get from studying human 
samples. They do this by putting it into one or more scientific databases, where it is stored along 
with information from other studies. A researcher who wants to study the information must apply 
to the database and be approved. Researchers use specimens and data stored in scientific databases 
to advance science and learn about health and disease.
IRB NUMBER: 15C0067
IRB APPROVAL DATE: 05/24/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 4/7/2022
Page 21 of 24
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
We plan to keep some of your specimens and data that we collect and use them for future research 
and share them with other researchers. We will not contact you to ask about each of these future 
uses. These specimens and data will be stripped of identifiers such as name, address or account 
number, so that it may be used for future research on any topic and shared broadly for research 
purposes. Your specimens and data will be used for research purposes only and will not benefit 
you. It is also possible that the stored specimens and data may never be used. Results of research 
done on your specimens and data will not be available to you or your doctor. It might help people 
who have cancer and other diseases in the future.
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data. Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
On this study, the NCI will cover the cost for some of your expenses. Some of these costs may be 
paid directly by the NIH and some may be reimbursed after you have paid. The amount and form 
of these payments are determined by the NCI Travel and Lodging Reimbursement Policy. You 
will be given a summary of the policy which provides more information.
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 

If some tests and procedures are performed outside the NIH Clinical Center, you may have 
to pay for these costs if they are not covered by your insurance company.

Medicines that are not part of the study treatment will not be provided or paid for by the 
NIH Clinical Center.

Once you have completed taking part in the study, medical care will no longer be provided 
by the NIH Clinical Center.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
IRB NUMBER: 15C0067
IRB APPROVAL DATE: 05/24/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 4/7/2022
Page 22 of 24
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Will your medical information be kept private?
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

The study Sponsor (Center for Clinical Research) or their agent(s)

Qualified representatives from Swedish Orphan Biovitrum (Sobi), the 
pharmaceutical company who produces palifermin.
When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any 
information about your research involvement without your written permission.  However, if you 
sign a release of information form, for example, for an insurance company, the NIH will give the 
insurance company information from your medical record.  This information might affect (either 
favorably or unfavorably) the willingness of the insurance company to sell you insurance.
If we share your specimens or data with other researchers, in most circumstances we will remove 
your identifiers before sharing your specimens or data. You should be aware that there is a slight 
possibility that someone could figure out the information is about you. 
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
IRB NUMBER: 15C0067
IRB APPROVAL DATE: 05/24/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 4/7/2022
Page 23 of 24
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy Act 
allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Steven 
Pavletic, MD, 240-760-6174, pavletis@mail.nih.gov. You may also call the NIH Clinical Center 
Patient Representative at 301-496-2626, or the NIH Office of IRB Operations at 301-402-3713, if 
you have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
IRB NUMBER: 15C0067
IRB APPROVAL DATE: 05/24/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 4/7/2022
Page 24 of 24
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness should sign below if either:
1. A short form consent process has been used to enroll a non-English speaking subject or
2.
An oral presentation of the full consent has been used to enroll a blind or illiterate subject
Signature of Witness
Print Name of Witness
Date
NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 15C0067
IRB APPROVAL DATE: 05/24/2022