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A Phase I And Pharmacological Trial Of 17-Allylamino -17-demethoxygeldanamycin (17-AAG) And Cytarabine In Refractory Leukemia And Myelodysplastic Syndrome


Phase 1
18 Years
N/A
Not Enrolling
Both
Accelerated Phase Chronic Myelogenous Leukemia, Adult Acute Basophilic Leukemia, Adult Acute Eosinophilic 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), Blastic Phase Chronic Myelogenous Leukemia, Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndromes, Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Refractory Anemia With Excess Blasts in Transformation, Relapsing Chronic Myelogenous Leukemia, Secondary Acute Myeloid Leukemia, Secondary Myelodysplastic Syndromes

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Trial Information

A Phase I And Pharmacological Trial Of 17-Allylamino -17-demethoxygeldanamycin (17-AAG) And Cytarabine In Refractory Leukemia And Myelodysplastic Syndrome


OBJECTIVES:

I. Determine the maximum tolerated dose of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG)
(tanespimycin) when administered with cytarabine in patients with relapsed or refractory
acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, chronic
myelomonocytic leukemia, or high-grade myelodysplastic syndromes.

II. Determine the toxic effects of this regimen in these patients. III. Determine,
preliminarily, the activity of this regimen in these patients. IV. Correlate the
pharmacokinetics of this regimen with cytochrome p450 3A5 genotype in these patients.

V. Determine the effect of this regimen on client proteins in vivo and ex vivo using
leukemic blasts from patients treated with this regimen.

OUTLINE: This is a multicenter, dose-escalation study of tanespimycin.

Patients receive induction therapy comprising cytarabine intravenously (IV) continuously on
days 1-5 and tanespimycin IV over 1 hour on days 3 and 6.

Patients achieving a morphologic complete response with incomplete blood count recovery
(CRi) or partial response may be eligible to receive a second induction course of therapy
after day 21 at the discretion of the principal investigator. Patients achieving a complete
response (CR) receive up to 4 courses of consolidation therapy with cytarabine and
tanespimycin. Consolidation therapy repeats approximately every 60 days in the absence of
disease progression or unacceptable toxicity. Patients who achieve CR and remain in
remission for ≥ 6 months may be retreated with cytarabine and tanespimycin (at the current
dose level or the maximum tolerated dose [MTD]) at the time of relapse. Cohorts of 3-6
patients receive escalating doses of tanespimycin until the MTD is determined. The MTD is
defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience
dose-limiting toxicity. Patients are followed at 3 months.


Inclusion Criteria:



- Diagnosis of 1 of the following:

- Acute myeloid leukemia, except acute promyelocytic leukemia (M3 disease),
meeting 1 of the following criteria:

- Failed to achieve complete remission (CR) after initial induction therapy
regimen*

- First relapse within 1 year of initial CR

- Failed re-induction therapy at first or second relapse

- Second or third relapse after completing ≤ 3 different induction therapy
regimens

- Antecedent hematologic disorder (myelodysplastic syndromes [MDS], chronic
myeloproliferative disease, or chronic myelomonocytic leukemia [CMML])

- Received prior chemotherapy for a non-hematologic malignancy

- High-risk cytogenetic abnormalities (abnormalities of chromosome 5, 7, 8,
or 11 OR ≥ 3 karyotypic abnormalities)

- Acute lymphoblastic leukemia, meeting 1 of the following criteria:

- Failed to achieve CR after initial induction therapy regimen

- First relapse within 1 year of initial CR

- Failed re-induction therapy at first or second relapse

- Second or third relapse after completing ≤ 3 different induction therapy
regimens

- Chronic myelogenous leukemia, meeting the following criteria:

- Accelerated OR blast phase (> 10% increase in the blast percentage in bone
marrow)

- Failed prior imatinib mesylate

- No more than 1 prior chemotherapy regimen in addition to imatinib
mesylate

- CMML, meeting the following criteria:

- More than 10% increase in blast percentage AND organ infiltration OR
impending marrow failure as evidenced by cytopenia

- No t(5;12) by cytogenetics (unless failed prior trial of imatinib mesylate)

- High-grade MDS, defined as > 10% blasts on marrow cellularity (refractory anemia
with excess blasts in transformation) OR International Prognostic Scoring System
MDS prognostic score > 1.5

- Not a candidate for allogenic bone marrow transplantation* from a related sibling
donor (i.e., HLA-identical sibling)

- No known standard or potentially curative therapy exists or is capable of extending
life expectancy

- No clinical symptoms suggesting CNS leukemia

- Performance status - ECOG 0-2

- At least 60 days

- See Disease Characteristics

- Bilirubin ≤ 1.5 times upper limit of normal (unless attributed to underlying disease)

- Creatinine clearance ≥ 60 mL/min

- No New York Heart Association class III-IV heart failure

- No myocardial infarction within the past year

- LVEF ≥ 40% by MUGA

- No cardiac symptoms ≥ grade 2

- No uncontrolled dysrhythmia requiring medication

- No poorly controlled angina

- QTc ≤ 450 msec for men and ≤ 470 msec for women

- No congenital long QT syndrome

- No left bundle branch block

- No ischemic heart disease within the past 6 months

- No history of cardiac toxicity after treatment with anthracyclines (e.g., doxorubicin
hydrochloride, daunorubicin hydrochloride, mitoxantrone hydrochloride, bleomycin, or
carmustine

- No other significant cardiac disease

- No active uncontrolled infection

- No history of serious allergic reaction to eggs

- No known HIV infection or AIDS (with or without highly active antiretroviral
treatment)

- DLCO > 80%

- No pulmonary symptoms ≥ grade 2

- No symptomatic pulmonary disease requiring medication including any of the following:

- Dyspnea on or off exertion

- Paroxysmal nocturnal dyspnea

- Significant pulmonary disease (e.g., chronic obstruction/restrictive pulmonary
disease)

- No oxygen requirement

- No home oxygen that meets the medicare requirement

- No history of pulmonary toxicity after treatment with anthracyclines (e.g.,
doxorubicin hydrochloride, daunorubicin hydrochloride, mitoxantrone hydrochloride,
bleomycin, or carmustine

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No psychosis

- No other serious underlying medical condition that would preclude study participation

- No prior allogeneic or autologous bone marrow transplantation

- No concurrent immunotherapy

- No concurrent biologic agents

- No concurrent gene therapy

- See Disease Characteristics

- Recovered from prior chemotherapy

- At least 48 hours since prior hydroxyurea for prevention of leukostasis

- No other concurrent chemotherapy

- At least 48 hours since prior glucocorticoids for prevention of leukostasis

- No prior radiotherapy that included the heart in the field (e.g., mantle) or chest

- No concurrent radiotherapy

- No concurrent drugs that may cause QTc prolongation

- No concurrent participation in another clinical trial involving a pharmacologic agent
for symptom control or therapeutic intent

- No other concurrent investigational drugs or therapy

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Tolerability of tanespimycin with cytarabine in patients with relapsed or refractory acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, or high-grade myelodysplastic syndromes

Outcome Description:

Evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 standard toxicity grading.

Outcome Time Frame:

Day 21

Safety Issue:

Yes

Principal Investigator

Scott Kaufmann

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00056

NCT ID:

NCT00098423

Start Date:

November 2004

Completion Date:

Related Keywords:

  • Accelerated Phase Chronic Myelogenous Leukemia
  • Adult Acute Basophilic Leukemia
  • Adult Acute Eosinophilic 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)
  • Blastic Phase Chronic Myelogenous Leukemia
  • Chronic Myelomonocytic Leukemia
  • de Novo Myelodysplastic Syndromes
  • Previously Treated Myelodysplastic Syndromes
  • Recurrent Adult Acute Lymphoblastic Leukemia
  • Recurrent Adult Acute Myeloid Leukemia
  • Refractory Anemia With Excess Blasts in Transformation
  • Relapsing Chronic Myelogenous Leukemia
  • Secondary Acute Myeloid Leukemia
  • Secondary Myelodysplastic Syndromes
  • Congenital Abnormalities
  • Anemia
  • Anemia, Refractory
  • Anemia, Refractory, with Excess of Blasts
  • Blast Crisis
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Basophilic, Acute
  • Leukemia, Eosinophilic, Acute
  • 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, Myelomonocytic, Chronic
  • Myelodysplastic Syndromes
  • Preleukemia
  • Hypereosinophilic Syndrome
  • Anemia, Aplastic

Name

Location

Mayo ClinicRochester, Minnesota  55905