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A Phase 1 Study of UCN-01 in Combination With Perifosine in Patients With Relapsed and Refractory Acute Leukemias and High Risk MDS


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Accelerated Phase Chronic Myelogenous Leukemia, Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Minimally Differentiated Myeloid Leukemia (M0), Adult Acute Monoblastic Leukemia (M5a), Adult Acute Monocytic Leukemia (M5b), Adult Acute Myeloblastic Leukemia With Maturation (M2), Adult Acute Myeloblastic Leukemia Without Maturation (M1), Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Adult Acute Myelomonocytic Leukemia (M4), Adult Acute Promyelocytic Leukemia (M3), Adult Erythroleukemia (M6a), Adult Pure Erythroid Leukemia (M6b), Blastic Phase Chronic Myelogenous Leukemia, Myelodysplastic/Myeloproliferative Neoplasms, Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Relapsing Chronic Myelogenous Leukemia, Secondary Acute Myeloid Leukemia, T-cell Adult Acute Lymphoblastic Leukemia, Untreated Adult Acute Lymphoblastic Leukemia, Untreated Adult Acute Myeloid Leukemia

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Trial Information

A Phase 1 Study of UCN-01 in Combination With Perifosine in Patients With Relapsed and Refractory Acute Leukemias and High Risk MDS


PRIMARY OBJECTIVES:

I. Define the maximum tolerated dose and recommended phase II dose of UCN-01
(7-hydroxystaurosporine) administered after perifosine in patients with relapsed or
refractory acute leukemia, chronic myelogenous leukemia, or high risk myelodysplastic
disorders.

SECONDARY OBJECTIVES:

I. Evaluate the safety and toxicity of UCN-01 administered after perifosine in these
patients.

II. Evaluate the safety and toxicity of perifosine administered after UCN-01 in these
patients.

III. Document responses in patients treated with this regimen. IV. Observe the
pharmacokinetics of both perifosine and UCN-01 when administered in combination.

V. Study the pharmacodynamics of perifosine alone, UCN-01 alone, and in combination in
leukemic blast cells.

OUTLINE: This is a multicenter, dose-escalation study of 7-hydroxystaurosporine. The first
patients enrolled in the study are assigned to arm 1. Once the maximum tolerated dose (MTD)
is determined in arm 1, subsequent patients are enrolled in arm 2.

ARM 1: Patients receive a loading dose of oral perifosine every 6 hours on day 1 followed by
a maintenance dose once daily on days 2-28 of course 1 and then once daily on days 1-28 in
all subsequent courses. Patients also receive 7-hydroxystaurosporine intravenously (IV) over
3 hours on day 4. Cohorts of 3-6 patients receive escalating doses of 7-hydroxystaurosporine
until the MTD is determined. The MTD is defined as the dose preceding that at which 2 of 6
patients experience dose-limiting toxicity.

ARM 2: Patients receive 7-hydroxystaurosporine IV over 3 hours on day 1 at the MTD
determined in group I. Patients also receive oral perifosine as a loading dose every 6 hours
on day 4 followed by a maintenance dose once daily on days 5-28 of course 1 and then once
daily on days 1-28 in all subsequent courses. In both groups, treatment repeats every 28
days for ≥ 2 courses in the absence of disease progression or unacceptable toxicity.
Patients who achieve a complete remission (CR) or a CR with incomplete hematologic recovery
receive 4 additional courses beyond documentation of CR. Patients who achieve a partial
remission or hematologic improvement may continue treatment in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed for 30 days and then periodically
thereafter.


Inclusion Criteria:



- Histologically or cytologically confirmed hematologic malignancy of 1 of the
following types:

- Relapsed or refractory acute myelogenous leukemia (AML)

- Patients with acute promyelocytic leukemia t(15;17) are eligible provided
they failed a prior tretinoin and arsenic-containing regimen

- Patients should be either refractory to both agents (absence of
durable hematologic response) OR relapsed after a complete response
duration of < 6 months

- Relapsed or refractory pre-B-cell or T-cell acute lymphoblastic leukemia (ALL)

- Chronic myelogenous leukemia (CML) in accelerated or blastic phase that is
refractory to imatinib mesylate

- Must have evidence of disease progression despite continued treatment with
imatinib mesylate

- AML arising in the setting of underlying myelodysplastic syndromes (MDS) and/or
myeloproliferative disorders (MPD)

- Secondary or therapy-related AML

- De novo AML or pre-B-cell or T-cell ALL in adults > 60 years of age with
poor-risk features, such as complex (≥ 3) or adverse cytogenetics

- The following are considered adverse cytogenetic abnormalities for AML:

- -5q

- 7q-

- 9q-

- 20q-

- abn12p

- +21

- +8

- t(6;9)

- t(6;11)

- t(11;19)

- -7

- -5

- inv3/t(3;3)

- abn11q23

- abn17p

- abn21q

- t(9;22) refractory to imatinib mesylate

- The following are considered adverse cytogenetic abnormalities for ALL:

- t(9;22) refractory to imatinib mesylate

- Hypodiploidy

- t(4;11)

- t(1;19)

- Myelodysplastic Syndromes (MDS) meeting 1 of the following criteria:

- Intermediate and high risk (i.e., International Prognostic Scoring System
[IPSS] ≥ 1.5) MDS that is refractory or has progressed after treatment
with azacitidine and/or decitabine

- Intermediate and high risk (i.e., IPSS ≥ 1.5) MDS with a 5q- cytogenetic
abnormality that is refractory or has progressed after treatment with
lenalidomide, azacitidine, or decitabine

- Intermediate 2 and high risk MDS without 5q- cytogenetic abnormality that
is refractory or has progressed after azacitidine or decitabine

- Original 5q must also be refractory to lenalidomide

- Received OR ineligible for established curative regimens, including stem cell
transplantation

- No active CNS leukemia

- ECOG performance status (PS) 0-2 OR Karnofsky PS ≥ 60%

- Total or direct bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST/ALT ≤ 2.5 times ULN

- Creatinine ≤ 2 mg/dL

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 3 months after
completion of study treatment

- No hyperleukocytosis (i.e., WBC > 30,000/mm^3) (recent treatment with hydroxyurea to
prevent impending leukostasis allowed provided there has been no dose increase for ≥
1 week)

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to UCN-01 or perifosine

- No intrinsic impaired organ function

- No active, uncontrolled infection

- Infection that is controlled with antibiotics allowed

- No symptomatic cardiac disease

- No active ischemia on EKG

- LVEF ≥ 40% by echocardiogram or MUGA

- Patients with a history of cardiac disease or mediastinal radiation should
undergo testing of ventricular function

- No poorly controlled diabetes mellitus

- No psychiatric illness or social situation that would preclude giving informed
consent or complying with study requirements

- No HIV positivity

- See Disease Characteristics

- At least 4 weeks since prior cytotoxic chemotherapy (6 weeks for carmustine or
mitomycin C) and recovered

- At least 4 weeks since prior radiotherapy and recovered

- At least 4 weeks since prior autologous stem cell transplantation (SCT)

- At least 90 days since prior allogeneic SCT

- No evidence of graft vs host disease

- At least 2 weeks since prior immunosuppressive therapy

- No concurrent hematopoietic growth factors or biologic agents

- No other concurrent investigational agents, chemotherapy, radiotherapy, or
immunotherapy

- No other concurrent anticancer therapy

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Maximum tolerated dose of 7-hydroxystaurosporine administered after perifosine

Outcome Description:

Evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The highest dose with none or one DLT observed in six patients will be declared as MTD. To ensure the toxicity at the MTD is acceptable, additional 6 patients will be accrued at the MTD.

Outcome Time Frame:

Course 1 (first 28 days)

Safety Issue:

Yes

Principal Investigator

Ivana Gojo

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Maryland Greenebaum Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00149

NCT ID:

NCT00301938

Start Date:

March 2006

Completion Date:

Related Keywords:

  • Accelerated Phase Chronic Myelogenous Leukemia
  • Adult Acute Megakaryoblastic Leukemia (M7)
  • Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
  • Adult Acute Monoblastic Leukemia (M5a)
  • Adult Acute Monocytic Leukemia (M5b)
  • Adult Acute Myeloblastic Leukemia With Maturation (M2)
  • Adult Acute Myeloblastic Leukemia Without Maturation (M1)
  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
  • Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
  • Adult Acute Myelomonocytic Leukemia (M4)
  • Adult Acute Promyelocytic Leukemia (M3)
  • Adult Erythroleukemia (M6a)
  • Adult Pure Erythroid Leukemia (M6b)
  • Blastic Phase Chronic Myelogenous Leukemia
  • Myelodysplastic/Myeloproliferative Neoplasms
  • Previously Treated Myelodysplastic Syndromes
  • Recurrent Adult Acute Lymphoblastic Leukemia
  • Recurrent Adult Acute Myeloid Leukemia
  • Relapsing Chronic Myelogenous Leukemia
  • Secondary Acute Myeloid Leukemia
  • T-cell Adult Acute Lymphoblastic Leukemia
  • Untreated Adult Acute Lymphoblastic Leukemia
  • Untreated Adult Acute Myeloid Leukemia
  • Congenital Abnormalities
  • Blast Crisis
  • Neoplasms
  • Leukemia
  • Leukemia, Erythroblastic, Acute
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Megakaryoblastic, Acute
  • Leukemia, Monocytic, Acute
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myeloid, Accelerated Phase
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Leukemia, Myelomonocytic, Acute
  • Leukemia, Promyelocytic, Acute
  • Myelodysplastic Syndromes
  • Preleukemia
  • Leukemia, Myelomonocytic, Chronic
  • Myeloproliferative Disorders
  • Myelodysplastic-Myeloproliferative Diseases

Name

Location

University of Maryland Greenebaum Cancer CenterBaltimore, Maryland  21201