17-N-Allylamino-17-Demethoxygeldanamycin and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia, Chronic Myelomonocytic Leukemia, or Myelodysplastic Syndromes

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  • user warning: Table './intheclinic/cache_filter' is marked as crashed and should be repaired query: UPDATE cache_filter SET data = '<p>RATIONALE: Drugs used in chemotherapy, such as 17-N-allylamino-17-demethoxygeldanamycin and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. 17-N-allylamino-17-demethoxygeldanamycin may also help cytarabine kill more cancer cells by making cancer cells more sensitive to the drug. Giving 17-N-allylamino-17-demethoxygeldanamycin together with cytarabine may kill more cancer cells. PURPOSE: This phase I trial is studying the side effects and best dose of 17-N-allylamino-17-demethoxygeldanamycin when given with cytarabine in treating patients with relapsed or refractory acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, or myelodysplastic syndromes.</p>\n', created = 1283572104, expire = 1283658504, headers = '', serialized = 0 WHERE cid = '1:e68e768f1cf78504f89efcc3de2dbd27' in /persistent/html/includes/cache.inc on line 109.
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  • user warning: Table './intheclinic/cache_filter' is marked as crashed and should be repaired query: UPDATE cache_filter SET data = '<p>A Phase I And Pharmacological Trial Of 17-Allylamino -17-Demethoxygeldanamycin (17-AAG) And Cytarabine In Refractory Leukemia And Myelodysplastic Syndrome</p>\n', created = 1283572104, expire = 1283658504, headers = '', serialized = 0 WHERE cid = '1:4ff6c517382353afc2f6da8806b85a68' in /persistent/html/includes/cache.inc on line 109.
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  • user warning: Table './intheclinic/cache_filter' is marked as crashed and should be repaired query: UPDATE cache_filter SET data = '<p>OBJECTIVES:\n<ul>\n<li>Determine the maximum tolerated dose of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) 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.</li>\n<li>Determine the toxic effects of this regimen in these patients.</li>\n<li>Determine, preliminarily, the activity of this regimen in these patients.</li>\n<li>Correlate the pharmacokinetics of this regimen with cytochrome p450 3A5 genotype in these patients.</li>\n<li>Determine the effect of this regimen on client proteins in vivo and ex vivo using leukemic blasts from patients treated with this regimen.</li>\n</ul>\n</p><p> OUTLINE: This is a multicenter, dose-escalation study of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG). Patients receive induction therapy comprising cytarabine IV continuously on days 1-5 and 17-AAG 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 17-AAG. 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 &#8805; 6 months may be retreated with cytarabine and 17-AAG (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 17-AAG 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. PROJECTED ACCRUAL: A total of 3-42 patients will be accrued for this study within 2.1 years.</p>\n', created = 1283572104, expire = 1283658504, headers = '', serialized = 0 WHERE cid = '1:ae9943969a1916ae0c27d6dec4b2e349' in /persistent/html/includes/cache.inc on line 109.
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  • user warning: Table './intheclinic/cache_filter' is marked as crashed and should be repaired query: UPDATE cache_filter SET data = '<p>DISEASE CHARACTERISTICS:\n<ul>\n<li>Diagnosis of 1 of the following:\n<ul>\n<li>Acute myeloid leukemia, except acute promyelocytic leukemia (M3 disease), meeting 1 of the following criteria:\n<ul>\n<li>Failed to achieve complete remission (CR) after initial induction therapy regimen* NOTE: *Patients receiving 7+3 as induction chemotherapy may be eligible provided the day 14 bone marrow shows a blast index &gt; 0.25 times the initial baseline value. Patients not meeting this criteria may be re-treated with 5+2 re-induction therapy at the discretion of the treating physician</li>\n<li>First relapse within 1 year of initial CR</li>\n<li>Failed re-induction therapy at first or second relapse</li>\n<li>Second or third relapse after completing &#8804; 3 different induction therapy regimens</li>\n<li>Antecedent hematologic disorder (myelodysplastic syndromes [MDS], chronic myeloproliferative disease, or chronic myelomonocytic leukemia [CMML])</li>\n<li>Received prior chemotherapy for a non-hematologic malignancy</li>\n<li>High-risk cytogenetic abnormalities (abnormalities of chromosome 5, 7, 8, or 11 OR &#8805; 3 karyotypic abnormalities)</li>\n</ul>\n</li>\n<li>Acute lymphoblastic leukemia, meeting 1 of the following criteria:\n<ul>\n<li>Failed to achieve CR after initial induction therapy regimen</li>\n<li>First relapse within 1 year of initial CR</li>\n<li>Failed re-induction therapy at first or second relapse</li>\n<li>Second or third relapse after completing &#8804; 3 different induction therapy regimens</li>\n</ul>\n</li>\n<li>Chronic myelogenous leukemia, meeting the following criteria:\n<ul>\n<li>Accelerated OR blast phase (&gt; 10% increase in the blast percentage in bone marrow)</li>\n<li>Failed prior imatinib mesylate\n<ul>\n<li>No more than 1 prior chemotherapy regimen in addition to imatinib mesylate</li>\n</ul>\n</li>\n</ul>\n</li>\n<li>CMML, meeting the following criteria:\n<ul>\n<li>More than 10% increase in blast percentage AND organ infiltration OR impending marrow failure as evidenced by cytopenia</li>\n<li>No t(5;12) by cytogenetics (unless failed prior trial of imatinib mesylate)</li>\n</ul>\n</li>\n<li>High-grade MDS, defined as &gt; 10% blasts on marrow cellularity (refractory anemia with excess blasts in transformation) OR International Prognostic Scoring System MDS prognostic score &gt; 1.5</li>\n</ul>\n</li>\n<li>Not a candidate for allogenic bone marrow transplantation* from a related sibling donor (i.e., HLA-identical sibling) NOTE: *Patients with prior pulmonary aspergillus and inadequate pulmonary, cardiac, renal, and hepatic functions are not considered candidates for transplantation</li>\n<li>No known standard or potentially curative therapy exists or is capable of extending life expectancy</li>\n<li>No clinical symptoms suggesting CNS leukemia</li>\n</ul>\n</p><p> PATIENT CHARACTERISTICS: Age\n<ul>\n<li>18 and over</li>\n</ul>\n</p><p> Performance status\n<ul>\n<li>ECOG 0-2</li>\n</ul>\n</p><p> Life expectancy\n<ul>\n<li>At least 60 days</li>\n</ul>\n</p><p> Hematopoietic\n<ul>\n<li>See Disease Characteristics</li>\n</ul>\n</p><p> Hepatic\n<ul>\n<li>Bilirubin &#8804; 1.5 times upper limit of normal (unless attributed to underlying disease)</li>\n</ul>\n</p><p> Renal\n<ul>\n<li>Creatinine clearance &#8805; 60 mL/min</li>\n</ul>\n</p><p> Cardiovascular\n<ul>\n<li>No New York Heart Association class III-IV heart failure</li>\n<li>No myocardial infarction within the past year</li>\n<li>LVEF &#8805; 40% by MUGA</li>\n<li>No cardiac symptoms &#8805; grade 2</li>\n<li>No uncontrolled dysrhythmia requiring medication</li>\n<li>No poorly controlled angina</li>\n<li>QTc &#8804; 450 msec for men and &#8804; 470 msec for women</li>\n<li>No congenital long QT syndrome</li>\n<li>No left bundle branch block</li>\n<li>No ischemic heart disease within the past 6 months</li>\n<li>No history of cardiac toxicity after treatment with anthracyclines (e.g., doxorubicin hydrochloride, daunorubicin hydrochloride, mitoxantrone hydrochloride, bleomycin, or carmustine</li>\n<li>No other significant cardiac disease</li>\n</ul>\n</p><p> Immunologic\n<ul>\n<li>No active uncontrolled infection</li>\n<li>No history of serious allergic reaction to eggs</li>\n<li>No known HIV infection or AIDS (with or without highly active antiretroviral treatment)</li>\n</ul>\n</p><p> Pulmonary\n<ul>\n<li>DLCO &gt; 80%</li>\n<li>No pulmonary symptoms &#8805; grade 2</li>\n<li>No symptomatic pulmonary disease requiring medication including any of the following:\n<ul>\n<li>Dyspnea on or off exertion</li>\n<li>Paroxysmal nocturnal dyspnea</li>\n<li>Significant pulmonary disease (e.g., chronic obstruction/restrictive pulmonary disease)</li>\n</ul>\n</li>\n<li>No oxygen requirement\n<ul>\n<li>No home oxygen that meets the medicare requirement</li>\n</ul>\n</li>\n<li>No history of pulmonary toxicity after treatment with anthracyclines (e.g., doxorubicin hydrochloride, daunorubicin hydrochloride, mitoxantrone hydrochloride, bleomycin, or carmustine</li>\n</ul>\n</p><p> Other\n<ul>\n<li>Not pregnant or nursing</li>\n<li>Negative pregnancy test</li>\n<li>Fertile patients must use effective contraception</li>\n<li>No psychosis</li>\n<li>No other serious underlying medical condition that would preclude study participation</li>\n</ul>\n</p><p> PRIOR CONCURRENT THERAPY: Biologic therapy\n<ul>\n<li>No prior allogeneic or autologous bone marrow transplantation</li>\n<li>No concurrent immunotherapy</li>\n<li>No concurrent biologic agents</li>\n<li>No concurrent gene therapy</li>\n</ul>\n</p><p> Chemotherapy\n<ul>\n<li>See Disease Characteristics</li>\n<li>Recovered from prior chemotherapy</li>\n<li>At least 48 hours since prior hydroxyurea for prevention of leukostasis</li>\n<li>No other concurrent chemotherapy</li>\n</ul>\n</p><p> Endocrine therapy\n<ul>\n<li>At least 48 hours since prior glucocorticoids for prevention of leukostasis</li>\n</ul>\n</p><p> Radiotherapy\n<ul>\n<li>No prior radiotherapy that included the heart in the field (e.g., mantle) or chest</li>\n<li>No concurrent radiotherapy</li>\n</ul>\n</p><p> Surgery\n<ul>\n<li>Not specified</li>\n</ul>\n</p><p> Other\n<ul>\n<li>No concurrent drugs that may cause QTc prolongation</li>\n<li>No concurrent participation in another clinical trial involving a pharmacologic agent for symptom control or therapeutic intent</li>\n<li>No other concurrent investigational drugs or therapy</li>\n</ul>\n</p>', created = 1283572104, expire = 1283658504, headers = '', serialized = 0 WHERE cid = '1:082338c1917c795db84cff6cb356b100' in /persistent/html/includes/cache.inc on line 109.
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Trial phase: 
Phase I
Recruitment status: 
Completed

RATIONALE: Drugs used in chemotherapy, such as 17-N-allylamino-17-demethoxygeldanamycin and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. 17-N-allylamino-17-demethoxygeldanamycin may also help cytarabine kill more cancer cells by making cancer cells more sensitive to the drug. Giving 17-N-allylamino-17-demethoxygeldanamycin together with cytarabine may kill more cancer cells. PURPOSE: This phase I trial is studying the side effects and best dose of 17-N-allylamino-17-demethoxygeldanamycin when given with cytarabine in treating patients with relapsed or refractory acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, or myelodysplastic syndromes.

Background information
Trial ID: 
NCT00098423
Other unique IDs: 
CDR0000401509
MAYO-MC0313
NCI-6383
Official title: 

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

Detailed description: 

OBJECTIVES:

  • Determine the maximum tolerated dose of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) 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.
  • Determine the toxic effects of this regimen in these patients.
  • Determine, preliminarily, the activity of this regimen in these patients.
  • Correlate the pharmacokinetics of this regimen with cytochrome p450 3A5 genotype in these patients.
  • 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 17-N-allylamino-17-demethoxygeldanamycin (17-AAG). Patients receive induction therapy comprising cytarabine IV continuously on days 1-5 and 17-AAG 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 17-AAG. 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 17-AAG (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 17-AAG 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. PROJECTED ACCRUAL: A total of 3-42 patients will be accrued for this study within 2.1 years.

Number to be enrolled: 
42 patients
Clinical information
Age groups: 
Adult
Senior
Gender: 
Both
Eligibility criteria: 

DISEASE CHARACTERISTICS:

  • 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* NOTE: *Patients receiving 7+3 as induction chemotherapy may be eligible provided the day 14 bone marrow shows a blast index > 0.25 times the initial baseline value. Patients not meeting this criteria may be re-treated with 5+2 re-induction therapy at the discretion of the treating physician
      • 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) NOTE: *Patients with prior pulmonary aspergillus and inadequate pulmonary, cardiac, renal, and hepatic functions are not considered candidates for transplantation
  • No known standard or potentially curative therapy exists or is capable of extending life expectancy
  • No clinical symptoms suggesting CNS leukemia

PATIENT CHARACTERISTICS: Age

  • 18 and over

Performance status

  • ECOG 0-2

Life expectancy

  • At least 60 days

Hematopoietic

  • See Disease Characteristics

Hepatic

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

Renal

  • Creatinine clearance ≥ 60 mL/min

Cardiovascular

  • 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

Immunologic

  • 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)

Pulmonary

  • 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

Other

  • 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

PRIOR CONCURRENT THERAPY: Biologic therapy

  • No prior allogeneic or autologous bone marrow transplantation
  • No concurrent immunotherapy
  • No concurrent biologic agents
  • No concurrent gene therapy

Chemotherapy

  • See Disease Characteristics
  • Recovered from prior chemotherapy
  • At least 48 hours since prior hydroxyurea for prevention of leukostasis
  • No other concurrent chemotherapy

Endocrine therapy

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

Radiotherapy

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

Surgery

  • Not specified

Other

  • 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

Study design: 
Treatment
Interventions: 
cytarabine
tanespimycin
Conditions treated: 
Leukemia
Myelodysplastic Syndromes
Outcome measurements: 

Remission rate as measured by standard published criteria based on bone marrow and peripheral blood examination at day 63 [ Designated as safety issue: No ]

Remission duration at months 2-24 [ Designated as safety issue: No ]

Funding
Funding types: 
NIH
OTHER
Sponsor: 
National Cancer Institute (NCI)
Mayo Clinic
Dates
Date the data was first received: 
Tue, 2004-12-07
Trial start date: 
Mon, 2004-11-01
Trial completion date: 
Wed, 1969-12-31
Trial last updated: 
Wed, 2009-05-20