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Phase 1 Study of Terameprocol (EM-1421) a Survivin and Cyclin-Dependent Kinase-1 (Cdc2) Inhibitor, in Patients With Leukemia

Phase 1
18 Years
Open (Enrolling)
Leukemias, Acute Myeloid Leukemia (AML), Acute Lymphocytic Leukemia (ALL), Adult T Cell Leukemia (ATL), Chronic Myeloid Leukemia (CML-BP), Chronic Lymphocytic Leukemia (CLL), Myelodysplastic Syndrome (MDS), Chronic Myelomonocytic Leukemia (CMML)

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Trial Information

Phase 1 Study of Terameprocol (EM-1421) a Survivin and Cyclin-Dependent Kinase-1 (Cdc2) Inhibitor, in Patients With Leukemia

The dose of Terameprocol (EM-1421) will be escalated in successive cohorts of 3 patients.
Patients will be entered sequentially on each dose level. If none of the first 3 patients
at a dose level experience first cycle drug related dose-limiting toxicity (DLT), new
patients may be entered at the next higher dose level. If 1 of 3 patients experience first
cycle DLT, up to 3 more patients are started at that same dose level. If 2 or more
experience first cycle DLT, no further patients are started at that dose. The MTD is the
highest dose level in which <2 patients of 6 develop a first cycle DLT. New dose levels may
begin accrual only if all patients at the current dose level have been observed for a
minimum of 3 weeks after the last infusion of Terameprocol (EM-1421). The recommended phase
2 dose (RP2D) will be the MTD unless significant clinical activity is seen below the MTD.

During the observation period of 3 weeks, additional accrual to a previously assessed lower
dose level, with no documented DLTs, will be allowed with sponsor approval.

Patients will be treated three times a week, with at least one day in between infusions, for
two weeks followed by one week of rest. The dose for new cohorts will be escalated from
1000, to 1500 and 2200 mg or de-escalated to 500 mg if 1000 mg exceeds the MTD. The
principal investigator will consult with the sponsor to determine the appropriate dose level
for a new patient. At the MTD, up to 10 additional patients may be accrued in that dose
cohort to further define the toxicities and response of the agent. If the initial dose
level exceeds the MTD, a fallback dose level of 500 mg will be implemented.

Patients are allowed to be treated with subsequent cycles of Terameprocol (EM-1421) until
disease progression or until severe toxicities occur and side effects do not outweigh the
benefit of study drug administration in the assessment of the treating physician.

Intrapatient dose escalation Intrapatient dose escalation by one dose level may be
permitted, but only if at least 3 patients in the next higher dose level have been treated
and have been followed for 21 days without experiencing DLT. Decisions for intrapatient dose
escalation will be made jointly by the Study Sponsor, treating physician and Principal

Terameprocol (EM-1421) as a single agent given intravenously over 6 hours three times a week
for two weeks followed by one week rest (two weeks on, one week off)in the following dose
cohorts starting with 1000 mg dose cohort.

Dose Level -1: 500 mg

Dose Level 1: 1000 mg

Dose Level 2: 1500 mg

Dose Level 3: 2200 mg

Inclusion Criteria:

1. Patients with histological confirmed relapsed or refractory leukemias for which no
standard therapies are available that are expected to result in durable remissions.
Eligible are patients with:

- acute myeloid leukemia (AML) by WHO or FAB classification

- acute lymphocytic leukemia (ALL)

- adult T cell leukemia (ATL)

- chronic myeloid leukemia in blast crisis (CML-BP) having failed Bcr-Abl specific
kinase inhibitors (e.g. imatinib and/or dasatinib)

- chronic lymphocytic leukemia (CLL)

- poor-risk myelodysplastic syndrome (MDS) [by WHO >10% blasts or IPSS groups:
Int-2, high]

- chronic myelomonocytic leukemia (CMML)

2. ECOG performance status of 0-1

3. Negative pregnancy test within 7 days of start of study drug NOTE: Men and women of
child-producing potential must use effective contraceptive methods during the study
(e.g. abstinence, intrauterine device [IUD], oral contraceptive or double barrier

4. Written informed consent

5. In the absence of rapidly progressing disease, the interval from prior therapies to
time of study drug administration should be a minimum of 3 weeks for cytotoxic agents
or at least 5 half-lives for noncytotoxic agents. Persistent chronic toxicities from
prior chemotherapy must not be greater than grade 1

6. Age greater than or equal to 18 years

7. Patients must have the following clinical laboratory values:

- Serum creatinine less than or equal to 2.0 mg/dl or creatinine clearance greater
than 50ml/hr

- Total bilirubin less than or equal to 1.5x the upper limit of normal unless
considered due to Gilbert's syndrome

- Alanine aminotransferase (ALT), or aspartate aminotransferase (AST) less than or
equal to 3x the upper limit of normal unless considered due to organ leukemic

Exclusion Criteria:

Patients with any one of the following criteria will not be eligible for study

1. Uncontrolled intercurrent illness including, but not limited to,

- uncontrolled infection,

- myocardial infarction within previous 3 months,

- symptomatic congestive heart failure (New York Heart Association Class III, IV),

- symptomatic coronary artery disease

- cardiac arrhythmia not controlled by medication NOTE: Patients with controlled
infection on antibiotic or antifungal therapy are eligible

2. Psychiatric illness/social situations that would limit compliance with study
requirements or unwillingness or inability to comply with procedures required in this

3. Patients receiving any other standard or investigational treatment for their leukemia
NOTE: Hydroxyurea is allowed prior to study drug start and for the first 7 days of

4. Pregnant and nursing patients are excluded. NOTE: Women of child-bearing potential
and men must agree to use adequate contraception (hormonal or barrier method of birth
control; or abstinence) prior to study entry and for the duration of study
participation. Should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately.

5. Major surgery, other than diagnostic surgery, within 4 weeks prior to Day 1

6. Patients with known CNS disease

7. History of allergic reactions attributed to compounds of similar chemical or
biological composition to Terameprocol (EM-1421) or excipients

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety, maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of Terameprocol (EM-1421) given as intravenous infusion three times a week in patients with leukemia

Outcome Time Frame:

Adverse events and toxicity will be assessed prior to each cycle of treatment and at times when clinically indicated.

Safety Issue:


Principal Investigator

Neil Frazer, MB, ChB

Investigator Affiliation:

Erimos Pharmaceutical


United States: Food and Drug Administration

Study ID:

EM-1421 #105



Start Date:

August 2007

Completion Date:

April 2009

Related Keywords:

  • Leukemias
  • Acute Myeloid Leukemia (AML)
  • Acute Lymphocytic Leukemia (ALL)
  • Adult T Cell Leukemia (ATL)
  • Chronic Myeloid Leukemia (CML-BP)
  • Chronic Lymphocytic Leukemia (CLL)
  • Myelodysplastic Syndrome (MDS)
  • Chronic Myelomonocytic Leukemia (CMML)
  • Adult
  • Leukemia
  • Terameprocol
  • Survivin
  • AML
  • ALL
  • ATL
  • CML
  • CLL
  • CMML
  • MDS
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Leukemia, Myelomonocytic, Chronic
  • Leukemia, T-Cell
  • Leukemia-Lymphoma, Adult T-Cell
  • Myelodysplastic Syndromes
  • Preleukemia
  • Leukemia, Myelomonocytic, Acute



UNC, Lineberger Comprehensive Cancer Center Chapel Hill, North Carolina  27599