Trial Information

Extended Dose - Total Body Irradiation Followed By Allogeneic Stem Cell Transplantation For The Treatment Of Refractory Acute Leukemia And Advanced Myelodysplastic Syndrome

Study Rationale

1. AML is a bone marrow based malignancy that is rapidly growing and rapidly fatal if left
untreated. Despite therapeutic strategies for up to 70% of patients, 20% are primarily
refractory and another 50% will relapse after first line therapy. Among these
refractory and relapsed patients the only, potentially, effective therapy is an
alloHSCT, however, long-term survival rates range from as low as <10% up to 20%.

2. Increased doses of radiation in the form of TBI to a threshold of 15.75 Gy with
chemotherapy have been demonstrated to reduce the relapse rate significantly; however,
OS is compromised by the high rate of toxicity.

3. Evidence suggests that escalated doses of radiation are possible, which offers the
potential to increase the dose of radiation to as much as 20Gy, safely.

4. Locally, increased doses of radiation without chemotherapy did not demonstrate any
significant toxicity up to a dose of 16Gy.

5. Therefore, as proposed a radiation-only stem cell transplant would allow us to test the
hypothesis that increased doses of radiation will reduce the relapse rate while
minimizing the toxicity in a very high-risk population of patients with AML, resulting
in an improved progression-free and overall survival.

Trial Design

This is a single institution, Phase II study examining the efficacy and toxicity of ED-TBI
followed by an alloHSCT on patients with high risk, refractory acute myeloid leukemia.

Treatment Overview

Patients who have met the inclusion criteria will receive a myeloablative dose of radiation
followed by an alloHSCT. Acute radiation and transplant related toxicity will be evaluated
as the maximum value on the National Cancer Institute Common Terminology Criteria for
Adverse Events, version 4.0 (CTCAE v.4), during the first 30 days following the
transplantation and the LENT-SOMA Radiation Toxicity Scale. The radiation dose to the lungs
and kidneys as well as the total dose received by the other organs will be considered
independently for the purposes of determining the maximum tolerated radiation dose for that
body region.

Eligibility Assessments

Assessments to determine the eligibility to participate in this study will be performed
before enrollment in the study, but after the subject has signed the informed consent.
Subjects who do not meet the eligibility criteria will be considered screening failures and
will not be enrolled.

These assessments will determine:

- Subject eligibility for entry on study,

- Suitability to undergo TBI followed by an alloHSCT.

- Pre-treatment leukemia activity.

The following pre-treatment assessments will be performed within a six-week period prior to
enrollment:

- History and physical examination, including height, weight, vital signs

- ECOG Performance Status and Karnofsky performance status (appendix #3).

- CBC, differential, platelets, and reticulocyte count.

- INR, PTT, fibrinogen

- Serum electrolytes, urea, creatinine, calcium and phosphorus, AST, ALT, ALP, total
bilirubin and LD

- Pre-transplant infectious disease markers:CMV serology, HIV-1 and HIV-2, HTLV-1 and
HTLV-2, HBsAg, Anti-HBs, Anti-HBc, Anti-HCV, Serologic Test for Syphilis (STS)

- Electrocardiogram (ECG).

- Echocardiogram including measurement of LVEF.

- Pulmonary function tests including FEV1, FVC and DLCO.

- Pregnancy test (urine or serum βHCG) on female subjects, unless they have undergone a
surgical procedure for sterilization or are post-menopausal (defined as more than 2
years have elapsed since their last menstruation in the absence of contraceptive use)

- A bone marrow aspirate with cytogenetics with or without biopsy with molecular testing.

Study Evaluations

Baseline Assessment

Patient testing will reflect the routine clinical operating practices of the Ottawa Hospital
Blood and Marrow Transplant and Radiation Oncology Programs. The following measures and
tests will be used to evaluate the status of the leukemia prior to treatment and the
patient's pre-treatment organ function. They will be performed within 2 weeks of the first
fraction of ED-TBI .

- History, physical examination, height and weight upon admission

- Urinalysis

- ECOG performance status

- HCT-specific cd-morbidity index

- CBC, differential

- Serum Creatinine, bilirubin, AST, ALT, ALP.

- INR, PTT, fibrinogen

- TSH

- A bone marrow aspirate with cytogenetics and molecular testing, with or without biopsy.

Post-transplant Assessments

Patient testing in the immediate period during ED-TBI and following alloHSCT will reflect
the clinical operating practices of the Ottawa Hospital Blood and Marrow Transplant Program.
The tests will be used to evaluate the severity of acute radiation toxicity, the time to
engraftment, GVHD etc.

- History and physical exam to assess GVHD and other morbidity weekly until Day 100
post-transplant, then at four months, six months, one year, 18 months and two years
post-transplant.

- Acute GVHD will be evaluated according to the grading system in appendix 8

- Chronic GVHD will be evaluated according to the grading system in appendix 9

- CBC at least three times a week from Day 0 until ANC > 0.5 x 109/L for 3 consecutive
measurements over 3 or more days. Thereafter CBC at least twice per week until Day 28,
then preferably weekly until Day 100, then at 12 months, 18 months and two years
post-transplant

- Creatinine, bilirubin, alkaline phosphatase, ALT, AST, twice a week until Day 28 and
then preferably weekly until 12 weeks, then at four months, six months, one year,
eighteen months and two years post-transplant.

- Tacrolimus levels will be measured at least once weekly until the drug is tapered off.

- Serum CMV-PCR weekly for at least 6 months.

- Bone marrow aspirate and biopsy at Day 100 ±30 days on all patients. Bone marrow
aspirate and biopsy at 12 ±3 months post-transplant is recommended, but not required,
for all patients.

- Treat-related toxicity (RRT) assessments will be conducted weekly until Day 100 and
additional toxicity assessments will be conducted on Day 100, 180, 365 and 730
post-transplant using the CTCAE V.4.

- Weekly urinalysis until discharge and then at 6, 12, 18 and 24 months.

The following tests will be performed at 6 months following treatment and then annually
until 2 years after the transplant

- Bone Mineral Density

- TSH

- Serum Testosterone (males)

- LENT-SOMA Radiation Toxicity Scale

- Pulmonary Function Tests (Flow Rates, Diffusion Capacity, Lung Volumes and O2
Saturation by oximetry.)

The following will be performed at any time to look for relapse, if indicated (i.e. drop in
the platelet count below 100 x 109 cells/L or in the neutrophil count below 1 x 109 cells/L,
circulating blasts >0%, unrelated to treatment) or if there is any other reason to suspect
relapse.

-Bone marrow aspirate +/- biopsy

Other tests may be added and the frequency of the above test may be changed depending on the
clinical scenario during the transplant.

The following summary statistics will be obtained at the time of discharge from the alloHSCT
hospital admission:

- Weight at discharge

- Number of units of blood and platelets administered

- Number of febrile days (t>38oC)

- Documented Infections

- Maximum adverse events according to CTCAE v.4

- Days admitted to the BMT Day hospital unit

- Days admitted to the BMT Inpatient unit

- Days admitted to the ICU

- Length of Hospital admission