7-Hydroxystaurosporine and Perifosine in Treating Patients With Relapsed or Refractory Acute Leukemia, Chronic Myelogenous Leukemia or High Risk Myelodysplastic Syndromes

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

This phase I trial is studying the side effects and best dose of 7-hydroxystaurosporine when given together with perifosine in treating patients with relapsed or refractory acute leukemia, chronic myelogenous leukemia, or myelodysplastic syndromes. 7-Hydroxystaurosporine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as perifosine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving 7-hydroxystaurosporine together with perifosine may kill more cancer cells.

Study Overview

• Status: Completed
• Conditions: Recurrent Adult Acute Myeloid 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(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia; Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Promyelocytic Leukemia (M3); Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Relapsing Chronic Myelogenous Leukemia; Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Myelodysplastic/Myeloproliferative Neoplasms; Untreated Adult Acute Lymphoblastic Leukemia; Blastic Phase Chronic Myelogenous Leukemia; T-cell Adult Acute Lymphoblastic Leukemia
• Intervention / Treatment: Other: pharmacological study; Drug: 7-hydroxystaurosporine; Drug: perifosine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21201-1595
      • University of Maryland Greenebaum Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (enzyme inhibitor, chemotherapy); 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 IV over 3 hours on day 4. Cohorts of 3-6 patients receive escalating doses of 7-hydroxystaurosporine until the MTD is determined.	Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Drug: 7-hydroxystaurosporine; Given IV; Other Names: UCN-01; Drug: perifosine; Given orally; Other Names: D21266; octadecylphosphopiperidine
Experimental: Arm 2 (enzyme inhibitor, chemotherapy); 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.	Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Drug: 7-hydroxystaurosporine; Given IV; Other Names: UCN-01; Drug: perifosine; Given orally; Other Names: D21266; octadecylphosphopiperidine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose of 7-hydroxystaurosporine administered after perifosine	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.	Course 1 (first 28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response rate, determined by improvement of blast cell count, degree of marrow infiltration by tumor cells, and improvement in peripheral blood count	For patients with acute leukemias we will use revised International Working Group (IWG) response criteria as published by Cheson et al. For patients with MDS we will use IWG response assessment for MDS. 90% confidence interval (CI) will be provided.	Baseline, at the end of course 1 (day 21-28), and any time that disease progression is suspected
Progression free survival	Estimated using the Kaplan-Meier method.	The time between the study entry and the first date that relapse or progressive disease is objectively documented, or death from any cause occurs
Disease specific survival and survival Rate	Estimated using the Kaplan-Meier method.	1 year
Overall survival	Estimated using the Kaplan-Meier method.	From time of enrollment onto this study to the time of death
Pharmacokinetics and pharmacodynamics of both perifosine and 7-hydroxystaurosporine	Descriptive statistics and confidence intervals will be provided for molecular endpoints of drugs action: total akt, phospho akt, total erk, phospho erk, p21 in peripheral blood and marrow. We will also dichotomize pharmacokinetic levels at the median, and estimate differences in response rates for high versus low levels, using Fisher's exact test at the one-sided 0.05 significance level.	Baseline and at weeks 1, 5, and 9

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Ivana Gojo, University of Maryland Greenebaum Cancer Center

Publications and helpful links

General Publications

• Gojo I, Perl A, Luger S, Baer MR, Norsworthy KJ, Bauer KS, Tidwell M, Fleckinger S, Carroll M, Sausville EA. Phase I study of UCN-01 and perifosine in patients with relapsed and refractory acute leukemias and high-risk myelodysplastic syndrome. Invest New Drugs. 2013 Oct;31(5):1217-27. doi: 10.1007/s10637-013-9937-8. Epub 2013 Feb 27.

Study record dates

Study Major Dates

• Study Start: December 1, 2005
• Primary Completion (Actual): May 1, 2012

Study Registration Dates

• First Submitted: March 9, 2006
• First Submitted That Met QC Criteria: March 9, 2006
• First Posted (Estimate): March 13, 2006

Study Record Updates

• Last Update Posted (Estimate): September 30, 2013
• Last Update Submitted That Met QC Criteria: September 27, 2013
• Last Verified: September 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Disease; Bone Marrow Diseases; Hematologic Diseases; Neoplastic Processes; Precancerous Conditions; Cell Transformation, Neoplastic; Carcinogenesis; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Recurrence; Preleukemia; Leukemia, Myelomonocytic, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Leukemia, Monocytic, Acute; Leukemia, Megakaryoblastic, Acute; Leukemia, Erythroblastic, Acute; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Blast Crisis; Leukemia, Promyelocytic, Acute; Leukemia, Myeloid, Accelerated Phase; Myeloproliferative Disorders; Myelodysplastic-Myeloproliferative Diseases; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; 7-hydroxystaurosporine
• Other Study ID Numbers: NCI-2009-00149 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); 7311 (CTEP); MSGCC-0507; NCI-7311; MSGCC-H-27229-0507; CDR0000465368; GCC 0507 (Other Identifier: University of Maryland Greenebaum Cancer Center)