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Phase I Dose Escalation Study of ON 01910.Na With Increasing Duration of an Initial 3-Day Continuous Infusion in Patients With Refractory Leukemia or MDS


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Acute Myelocytic Leukemia, Acute Lymphocytic Leukemia, Chronic Myelocytic Leukemia, Chronic Lymphocytic Leukemia, Myelodysplastic Syndromes

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Trial Information

Phase I Dose Escalation Study of ON 01910.Na With Increasing Duration of an Initial 3-Day Continuous Infusion in Patients With Refractory Leukemia or MDS


Patients must have histologically documented or cytologically confirmed diagnosis of acute
myelocytic leukemia refractory to standard induction treatment, or relapsed after standard
therapy; acute lymphocytic leukemia refractory to induction treatment, or relapsed after
effective therapy; chronic myelocytic leukemia refractory to imatinib therapy or second line
tyrosine kinase inhibition, or relapsed after tyrosine kinase inhibition, in chronic,
accelerated, or blastic phase; chronic lymphocytic leukemia refractory to standard therapy,
or relapsed in second relapse; a myelodysplastic syndrome (including chronic myelomonocytic
leukemia) refractory to azacitidine; and an int-2 or high myelodysplastic syndrome relapsed
after a hypomethylating agent. Patients may not be eligible for, or must have declined,
bone marrow transplantation or other chemotherapeutic regimens known to produce consistent
remissions. Because hematopoietic criteria in leukemia and lymphoma are confounded by the
nature of the diseases themselves, there are no hematologic exclusions from treatment. If
leukopenia is clinically determined to be attributable to prior treatment, ON 01910.Na
treatment may start when the leukocyte count increases on two successive determinations
performed at least three days apart. Thrombocytopenia is not a criterion, and patients will
be supported with platelet transfusions as clinically necessary. In the absence of
leukopenia, a failed prior treatment may be succeeded immediately by entry into study of ON
01910.Na if the leukocyte count is stable or rising, on two successive determinations
performed at least three days apart, in the absence of other drug toxicity.

The patient population will involve approximately 12 to 28 patients ≥ 18 years of age in the
dose escalation portion of the protocol. All patients must have relapsed or refractory
leukemia or poor risk MDS (i.e., int-2 or high risk MDS who have failed standard therapy).
They must not be candidates for known regimens or protocol treatments of higher efficacy or
priority. Patients with relapsed/refractory leukemia or poor risk MDS must have an ECOG
Performance Status of 0, 1, or 2. Patients must have an expected survival, in the opinion of
the Investigator, to allow a sufficient observation period for evaluating ON 01910.Na, and
meet the eligibility criteria for patients with leukemia or poor risk MDS. After the
maximally tolerated dose and the Recommended Phase II Dose (RPTD) and duration are
determined, up to 12 additional patients with histologically documented or cytologically
confirmed leukemia or poor risk MDS will be added to confirm the appropriateness of the
RPTD. Inclusion criteria for the dose confirmation phase will be similar to those of the
dose escalation phase of the study, but the ECOG Performance Status must be 0 or 1.

Safety data, including laboratory parameters and adverse events, will be collected for all
patients in order to determine the qualitative and quantitative toxicity, and reversibility
of toxicity, of ON 01910.Na. Leukemic cells and MDS cells in peripheral blood will be
measured on a daily basis during infusion, and at least two times weekly during the
following week. If leukemic cells disappear from the blood or blood counts improve as
defined by IWG criteria in MDS patients, a bone marrow aspiration will be performed to
determine response status in the bone marrow.

All patients may continue therapy for at least six cycles unless rapid disease progression
is documented. Patients with an objective clinical response or stable disease can continue
up to six more cycles. Further continuation will be determined by the clinical judgment of
the Investigator.


Inclusion Criteria:



- Patient must have histologically documented or cytologically confirmed diagnosis of
acute myelocytic leukemia refractory to standard induction treatment, or relapsed
after standard therapy

- Acute lymphocytic leukemia refractory to induction treatment, or relapsed after
effective therapy

- Chronic myelocytic leukemia refractory to imatinib therapy or second line tyrosine
kinase inhibition, or relapsed after tyrosine kinase inhibition, in chronic,
accelerated, or blastic phase

- Chronic lymphocytic leukemia refractory to standard therapy, or relapsed in second
relapse

- A myelodysplastic syndrome (including chronic myelomonocytic leukemia) refractory to
a hypomethylating agent

- And a int-2 or high myelodysplastic syndrome relapsed after a hypomethylating agent.

- Patients may not be eligible for, or must have declined, bone marrow transplantation
or other chemotherapeutic regimens known to produce consistent remissions.

- There are no hematologic exclusions from treatment.

- Patients with prior radiotherapy are eligible unless leukopenia is ascribed to prior
radiation treatment, and then entry to study of ON 01910.Na may be initiated when two
successive leukocyte counts are rising.

- ECOG Performance Status of 0, 1, or 2 if patient is in the dose escalation phase or 0
or 1 if patient is in the dose escalation phase.

- Patients may have any hematologic parameters without regard to numbers provided that
transfusional support is available and the Investigator stipulates that leukopenia is
attributable to disease rather than to prior therapy.

- Total bilirubin ≤ 1.5 mg/dL, unless the patient has active hemolysis, or the
elevation is secondary to ineffective erythropoiesis.

- Serum creatinine ≤ 1.5 mg/dL, or a calculated creatinine clearance of ≥ 60
mL/min/1.73 m2.

- Women of childbearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) while in the study. If a
woman becomes pregnant or suspects she is pregnant while on study, her treating
physician should be informed immediately.

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

Exclusion Criteria:

- Patients who have positive blood cultures until they are afebrile for 3 days on
antibiotic therapy which will continue.

- Patients who have leukopenia attributed to prior chemotherapy until two successive
leukocyte counts are increasing. Patients with rapidly rising WBC (e.g. >50% increase
over the previous day for 3 consecutive days) or WBC > 40 x 109/L.

- Patients who have continuing toxicity other than hematologic from prior therapy until
it has resolved to grade 1 or less and will not compromise ON 01910.Na
administration.

- Patients who are receiving any other investigational agents or concurrent
chemotherapy, radiotherapy, or immunotherapy.

- Patients receiving corticosteroids or colony-stimulating factors may continue on
these treatments. These agents will not be introduced if previously not employed.

- Patients with known meningeal infiltration may be included in this clinical trial
only if intrathecal therapy and/or radiation has been completed, and cerebrospinal
fluid cytology is improved.

- Patients with a history of allergic reactions attributable to compounds of similar
chemical or biologic composition to ON 01910.Na.

- Patients should have no major third space fluid accumulation, ascites requiring
active medical management including paracentesis, peripheral bilateral edema, or
hyponatremia (serum sodium value less than 134 Meq/L).

- Patients with uncontrolled intercurrent illness including, but not limited to
uncontrolled ongoing or active infection, symptomatic congestive heart failure,
unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social
situations that would limit compliance with study requirements.

- Pregnant and nursing women are excluded from this study.

- HIV-positive patients receiving combination anti-retroviral therapy are excluded.

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Safety data, including laboratory parameters and adverse events, will be collected for all patients in order to determine the qualitative and quantitative toxicity, and reversibility of toxicity, of ON 01910.Na.

Outcome Time Frame:

2 - 4 months

Safety Issue:

Yes

Principal Investigator

Lewis R. Silverman, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mount Sinai School of Medicine

Authority:

United States: Food and Drug Administration

Study ID:

Onconova 04-05

NCT ID:

NCT00854646

Start Date:

October 2008

Completion Date:

December 2013

Related Keywords:

  • Acute Myelocytic Leukemia
  • Acute Lymphocytic Leukemia
  • Chronic Myelocytic Leukemia
  • Chronic Lymphocytic Leukemia
  • Myelodysplastic Syndromes
  • ON 01910.Na
  • refractory
  • leukemia
  • myelodysplastic
  • cell cycle
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Myelodysplastic Syndromes
  • Preleukemia

Name

Location

Mount Sinai Medical CenterNew York, New York  10029