PRevention Of BLeeding in hEmatological Malignancies With Antifibrinolytic (Epsilon Aminocaproic Acid)

Study Treatments: Epsilon aminocaproic acid (EACA) vs. standard prophylactic platelet
transfusions.

Study Title: Randomized Trial of Epsilon Aminocaproic Acid versus Platelet Transfusions for
the Prevention of Bleeding in Thrombocytopenic Patients with Hematological Malignancies.
(PROBLEMA trial: PRevention Of BLeeding in hEmatological Malignancies with Antifibrinolytic
agents (epsilon aminocaproic acid).

Phase: Randomized Phase 2

Eligible Population: Adult patients with acute or chronic thrombocytopenia in the setting of
hematological malignancies.

Summary and Study Rationale: Compare EACA to standard prophylactic platelet transfusion for
the prevention of bleeding in thrombocytopenic patients with hematological malignancies.

Study Design: prospective, randomized, controlled trial.

Study Endpoints: The primary endpoint is to compare the proportion of patients who develop
major (grades 3-4) bleeding in each arm.

Diagnosis and Main Inclusion Criteria: Age > 18 with hematological malignancies. Acute or
chronic thrombocytopenia with platelet counts < 20 x 10⁹/L.

Number of Patients: 100 patients, 50 patients in each arm

Duration of Patient Participation: 6 months

Approximate Duration of Study: 3 years

Dosage and Administration:1,000 mg twice a day orally

Prohibited Medications/Treatment: Hydroxyurea and procoagulant agents including DDAVP,
recombinant Factor VII or prothrombin complex concentrate are prohibited in patients
receiving EACA.

Safety Evaluations: Clinical assessment once weekly during the first 30 days and then monthly
for 6 months, complete blood count and bleeding score twice weekly the first 30 days, and
then according to standard of care or at discretion of treating physician.

Statistical Analysis

- Population Analysis

- Intention to treat (ITT) population: The ITT population includes all patients who
are randomized to the study. Patients will be stratified and analyzed according to
the treatment to which they were assigned.

- Safety Population: The safety population includes all patients who have received at
least 1 dose of EACA. Patients included in the safety population will be analyzed
according to the treatment they received.

- Per-protocol Population: The per-protocol population includes all patients who are
randomized, receive at least one dose of study drug, and have no major protocol
violations that could be expected to impact response data.

- Study Endpoints

- Primary Endpoint: is to compare at the end of the study, the proportion of patients
with major bleeding during the study period among patients randomized to receive
either EACA or standard of care prophylactic platelet transfusions.

- Secondary Endpoints include:

- Proportion of patients with any bleeding during the study period in each arm

- The total number of units of platelets transfused in each arm at the end of
the study

- Quality of life as measured in each arm before the study and at the end of the
study

- Safety in each arm

- Sample Size: This randomized, open-label phase II study is designed to compare the
proportion of patient with major bleeding ever noted during the study. Patients will be
assigned to receive prophylactic EACA (experimental arm) or prophylactic platelet
(standard of care) in a 1:1 fashion. Previous studies suggest that the proportions of
patients with major bleeding will be expected to be 8% and 30% in experimental arm and
standard of care arm, respectively. With one sided Fisher's exact test, the sample size
of 45 patients in each arm will achieve a power of 80% at the significance level of 5%
to test whether prophylactic EACA can prevent major bleeding better than the standard of
care. After adjusting for a 10% drop out rate, the actual required sample size will be
50 patients per arm. Therefore, the total sample size of the study will be 100 patients.

- Efficacy Analysis

- Primary Endpoint Analysis will be performed using a one-sided Fisher's exact test
to compare the proportions of patients with major bleeding during the whole study
between the two arms. The significance level is set at 0.05. This primary analysis
will be based on the ITT population.

- Secondary Endpoint Analysis: one-sided t-test will be used to compare the total
number of any bleeding episode noted during the study between the two arms.
Two-sided t-test will be employed to compare the total number of units of platelets
transfused at the end of the study between the two arms. Appropriate statistical
tests (Chi-square test, t-test, Wilcoxon's rank sum test, etc.) will be conducted
to compare the each score of the quality of life between the two arms before the
study and at the end of the study, respectively. The change of each score of the
quality of life from before the study to the end of the study will also be compared
between the two arms. The safety in each arm will be also compared with Fisher's
exact test. The analyses of secondary endpoints will be performed on the ITT
population and the significance level will be kept at 0.05 for all tests.

- Safety Analysis: All patients receiving at least 1 dose of study drug will be considered
evaluable for safety. Patients will be analyzed for safety according to the treatment
which they received. Listings of laboratory test results will also be generated, and
descriptive statistics summarizing the changes in laboratory tests over time will be
presented. Exposure to study drug over time will also be summarized. The adverse events
incidence rates, as well as the frequency of occurrence of overall toxicity, categorized
by toxicity grades (severity) will be described for each treatment arm and be compared
between two arms using two-sided Chi-square test or t-test.

- Quality of Life Analysis: Quality of life and health outcomes measures are being
collected using EuroQoL instruments before the study and at the end of the study. Means
and medians of raw scores of these questionnaires will be summarized for each treatment
group for each domain and be compared between the two arms with t-test or Wilcoxon ranks
sum test.

- Interim Analysis: Three interim analyses are planned after 11 patients in each arm have
been randomized and their results have been obtained. Each interim analysis will focus
on the primary endpoint, the proportion of patients with major bleeding ever noted
during the study. To maintain an overall Type I error rate of 0.05 (1-sided), an O'Brien
Fleming approach will be used which requires a 1-sided p-value < 0.001 at the first
interim analysis (at 25% of total sample size). If this boundary is not crossed, then
the study will continue and the second interim analysis will be conducted at 50% of the
total sample side which requires a 1-sided significance level of 0.004. If this boundary
is not crossed at the second interim analysis then, the study will continue and a third
interim analysis will be conducted at 75% of the total sample side which requires a
1-sided significance level of 0.019. If this boundary is not crossed, the final primary
analysis will be performed after completing 100% of the sample size using a 0.043
one-sided significance level.

Inclusion Criteria:

- Age > 18 with a hematological malignancy

- Informed consent

- Thrombocytopenia with untransfused platelet counts < 20 x 10⁹/L in the out-patient or
in the in-patient setting and one of the following criteria:

- Acute thrombocytopenia in patients with hematological malignancies who are in
remission and are receiving myelosuppressive consolidation chemotherapy that is
expected to induce marrow aplasia for at least 2 weeks; or

- Acute or chronic thrombocytopenia in patients with acute leukemia (myeloblastic
or lymphoblastic) receiving induction or re-induction chemotherapy that is
expected to induce marrow aplasia for at least 2 weeks; or

- Expected chronic thrombocytopenia in patients with newly diagnosed marrow failure
syndromes, myelodysplastic syndromes, aplastic anemia, chronic myelomonocytic
leukemia or myelofibrosis; or

- Expected chronic thrombocytopenia in patients with relapsed or refractory
hematological malignancies; or

- Hematopoietic stem cell transplant recipients with chronic thrombocytopenia due
to chronic graft-versus-host disease (GVHD) or other causes

Exclusion Criteria:

- Acute promyelocytic leukemia

- Patient receiving anticoagulation

- Patient receiving antiplatelet agents

- Patient treated with antifibrinolytic agents (including EACA) within 14 days prior to
screening

- Subjects receiving procoagulant agent including DDAVP, recombinant factor VII or
prothrombin complex concentrate within 24 hours of enrollment

- Subject with known congenital bleeding disorders or platelet dysfunction

- Disseminated intravascular coagulation

- Fibrinogen level < 150 mg/dl

- Patients with known lupus anticoagulant or positive antiphospholipid antibody

- History of arterial or venous thromboembolic disease 6 months prior to screening

- Patient requiring platelet transfusion threshold of > 20 x 10⁹/L

- Active grade ≥ 2 bleeding at the time of randomization, including hematuria

- History of grade 4 bleeding

- Hematopoietic stem cell transplant recipient within 100 days post-transplant

- Pregnancy

- Known allergy to EACA

- History of veno-occlusive disease of the liver

- Myocardial infarction 6 months prior to screening

- Unstable angina

- Grade 2 renal dysfunction: creatinine > 2-3 times the upper limit of normal