Study of Palifermin (Kepivance) in Persons Undergoing Unrelated Donor Allogeneic Hematopoietic Cell Transplantation

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 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 (18 - 70 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 greater than or equal to 60 and acceptable organ functions.

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/m^2/day 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

- 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

- The patient is 18-70 years of age.

- Ability of subject to understand and the willingness to sign a written informed
consent document.

- Karnofsky performance score >= 60.

- 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

- HLA-matched donors are defined by allele matching at HLA-A, -B, -C,

- 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.

- Diagnosis of hematologic malignancy meeting at least one of the disease status
criteria outlined in the table below. Diagnoses from outside laboratories must be
confirmed by review in the NCI laboratory of pathology.

- Recipients with AML in CR1 must have one of the following:

- 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).

- 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).

- Primary induction failure, defined as failure to achieve CR with primary induction
chemotherapy.

- Secondary AML, defined as AML related to antecedent myeloid neoplasm or cytotoxic
chemotherapy.

- Hyperleukocytosis, WBC > 100,000, at diagnosis.

- Recipients with ALL in CR1 must have one of the following:

- Adverse cytogenetics defined as translocations involving t(4;11), t(1;19), t(8;14),
11q23, t(9;22) or bcr-abl rearrangement or complex cytogenetic abnormalities.

- Presence of minimal residual disease using multicolor flow cytometry or other analytic
technique after primary induction chemotherapy.

- Primary induction failure, defined as failure to achieve CR with primary induction
chemotherapy.

- Recipients with myelofibrosis must have at least 2 of the following features, or be
DIPSS intermediate-2 or high risk:

- Hemoglobin < 10 g/dl, or > 10 g/dl with transfusion dependence.

- WBC < 4,000 or > 30,000/mm3 or requires cytoreductive therapy to maintain WBC <
30,000/mm3.

- Abnormal cytogenetics.

- 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 be rnrolled on the induction phase
arm. For enrollment on the research phase arm, the patient must have at lease stable
disease which is defined as:

- Absence of disease progression for at least 8 weeks after previous therapy or 12 weeks
after autologous transplantation.

- 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.

- Multiple myeloma in complete remission is defined as per Durie BG et al.

- 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.

- The recipient has acceptable end organ function as defined by:

- DLCO > 50% of the expected value (using USA-ITS-NIH equation) when corrected for Hgb
(DLCO Adj.)

- 24hr creatinine clearance or calculated (using the Cockcroft-Gault formula) creatinine
clearance > 60 ml/min/1.73 (induction phase only)

- Left ventricular ejection fraction > 45%

- 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 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 atthe discretion of the PI.

- 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.

- 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.

- 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.

Research Phase Inclusion Criteria:

Verification of donor eligibility (clearance must be received from the NMDP)

- Donors are evaluated by NMDP affiliated donor centers per NMDP Standards .

- Donors who are medically suitable, but ineligible by FDA guidelines may still
donate PBSC with documentation of urgent medical need by the PI.

- 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 be removed from the study, but will continue to be managed on this
protocol for all transplant-related care and complications.

- 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 transplantrelated 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.

- 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)

- In patients with suspected liver disease, bilirubin must be less than or equal to 2.5
mg/dL, AST and ALT must be less than or equal to 2.5 times institutional ULN

- 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.

EXCLUSION CRITERIA (applies to all phases of this protocol) :

- Active infection that is not responding to antimicrobial therapy.

- Active CNS involvement by malignancy (patients with known positive CSF cytology or
parenchymal lesions visible by CT or MRI).

- 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).

- 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.

- Pregnant women are excluded from this study because palifermin has been shown to be
embrytoxic and fetotoxic in animal studies. Because there is an 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.

- 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.