Tanespimycin in Treating Young Patients With Recurrent or Refractory Leukemia or Solid Tumors

Recurrent Childhood Acute Lymphoblastic Leukemia Clinical Trial

Official title:

A Multicenter Phase I Trial of 17-N-allylamino-17-demethoxy Geldanamycin (17-AAG, NSC #330507) in Patients With Recurrent/Refractory Pediatric Solid Tumors (Ewing's Sarcoma, Desmoplastic Small Round Cell Tumor, Osteosarcoma, Neuroblastoma, and Rhabdomyosarcoma) and Leukemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00093821
• Other study ID #: NCI-2012-01456
• Secondary ID: 04-069POETIC-MSK
• Status: Completed
• Phase: Phase 1
• First received: October 6, 2004
• Last updated: June 3, 2013
• Start date: September 2004

Study information

• Verified date: June 2013
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This phase I trial is studying the side effects and best dose of tanespimycin in treating young patients with recurrent or refractory leukemia or selected solid tumors. Drugs used in chemotherapy, such as tanespimycin, work in different ways to stop cancer cells from dividing so they stop growing or die.

Description:

PRIMARY OBJECTIVES:

I. Determine the dose-limiting toxicity and maximum tolerated dose (MTD) of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) in pediatric patients with recurrent or refractory leukemia or selected solid tumors.

II. Determine the levels of key proteins known to influence cancer cell survival and proliferation in patients treated with this drug at the MTD.

SECONDARY OBJECTIVES:

I. Determine the pharmacokinetics of this drug in these patients. II. Evaluate effects of genetic polymorphisms known to alter the activity of enzymes involved in the metabolism of this drug.

III. Correlate the alteration of fludeoxyglucose F18 accumulation with tumor response in patients treated with this drug.

OUTLINE: This is a dose-escalation, multicenter study. Patients are stratified according to diagnosis (leukemia vs solid tumor).

Patients receive tanespimycin IV over 2-6 hours on days 1, 4, 8, and 11 (for patients with solid tumors) OR days 1, 4, 8, 11, 15, and 18 (for patients with leukemia). Courses for all patients repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of tanespimycin until the maximum tolerated dose (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. At least 15 patients are treated at the MTD.

Patients are followed for 30 days.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 70
• Est. primary completion date: August 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 21 Years

Eligibility

Inclusion Criteria:

• Histologically confirmed diagnosis of 1 of the following malignancies:

• Leukemia

• Lymphoid, myeloid, or mixed lineage

• Relapsed (in second or greater relapse) or refractory disease, confirmed by 1 of the following:

• Bone marrow relapse, defined as either M3 bone marrow (> 25% blasts in the bone marrow aspirate) OR M2 bone marrow (5-25% blasts in the bone marrow aspirate) at any time after complete remission is attained

• CNS relapse, defined as at least 5 WBC/mL by cytospin of any cerebrospinal fluid (CSF) specimen OR less than 5 WBC/mL by cytospin of 2 consecutive CSF specimens obtained >= 4 weeks apart and having definitive confirmation that blasts are derived from the original leukemic clone by molecular cytogenetics, multiparameter flow cytometry, or immunostaining of >= 2 antigens

• Patients with underlying chronic myeloid leukemia must have > 25% blasts in the bone marrow aspirate

• Patients with M3 bone marrow AND extramedullary sites of disease, other than leptomeningeal disease, are eligible

• Solid tumor

• One of the following tumor types:

• Neuroblastoma

• Ewing's sarcoma

• Osteosarcoma

• Desmoplastic small round cell tumor

• Rhabdomyosarcoma

• Progressed after prior standard therapy OR no effective standard therapy exists

• Measurable or nonmeasurable disease

• No known brain metastases

• No active leptomeningeal leukemia, defined by the following criteria:

• WBC > 5/mm^3 in cerebrospinal fluid (CSF)

• Unequivocal confirmation of leukemic blasts in CSF by cell morphology

• No symptomatic CNS disease (e.g., cranial nerve abnormalities) without cytologic abnormality in CSF

• Performance status - Karnofsky 70-100% (for patients > 10 years of age)

• Performance status - Lansky 70-100% (for patients =< 10 years of age)

• More than 8 weeks

• Absolute neutrophil count >= 750/mm^3

• Platelet count >= 75,000/mm^3 (transfusion independent)

• Hemoglobin >= 8.5 g/dL (transfusion allowed)

• Bilirubin < 1.5 mg/dL

• ALT and AST =< 2.5 times upper limit of normal (ULN)

• INR =< 1.5 times ULN

• Albumin > 2.0 g/dL

• Creatinine =< 1.5 times ULN for age

• Creatinine clearance or radioisotope glomerular filtration rate > 60 mL/min

• Ejection fraction >= 50%

• Shortening fraction >= 28%

• QTc < 450 msec for men (470 msec for women)

• No congenital long QT syndrome

• LVEF > 40% by MUGA

• No symptomatic congestive heart failure

• No cardiac arrhythmia

• No New York Heart Association class III or IV heart failure

• No myocardial infarction within the past year

• No uncontrolled dysrhythmias

• No poorly controlled angina

• More than 12 months since active ischemic heart disease

• No history of serious ventricular arrhythmia (ventricular tachycardia or ventricular fibrillation >= 3 beats in a row)

• No left bundle branch block

• No other significant cardiac disease

• No pulmonary fibrosis by radiography

• No ongoing or active bacterial or fungal infection

• No other uncontrolled illness

• No psychiatric illness or social situation that would preclude study compliance

• No history of serious allergic reaction attributed to eggs or dimethyl sulfoxide

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• Recovered from all immunotherapy

• At least 6 months since prior allogeneic stem cell transplantation

• At least 3 months since prior autologous stem cell transplantation

• At least 2 weeks since prior biologic agents (e.g., monoclonal antibodies)

• At least 1 week since prior filgrastim (G-CSF) or sargramostim (GM-CSF)

• Recovered from all prior chemotherapy

• At least 2 weeks since prior chemotherapy (for patients with leukemia only)

• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) (for patients with solid tumors)

• No prior oxaliplatin

• No concurrent corticosteroids except for the treatment of adrenal crises in patients with suppressed hypothalamic-pituitary-adrenal axis response OR for treatment of allergic reactions to medications or blood products

• Recovered from all prior radiotherapy

• At least 6 months since prior radiotherapy to >= 50% of the pelvis

• At least 6 months since prior radiotherapy to substantial bone marrow, including total body irradiation

• At least 4 weeks since prior local (small port) radiotherapy

• No prior radiotherapy to the heart

• At least 1 week since prior retinoids

• No concurrent antiretroviral therapy for HIV-positive patients

• No concurrent medication to control arrhythmias

• No concurrent medications that prolong or may prolong QTc interval

• No other concurrent investigational agents

• No other concurrent anticancer therapy

Study Design

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

Related Conditions & MeSH terms

• Childhood Chronic Myelogenous Leukemia
• Childhood Desmoplastic Small Round Cell Tumor
• Desmoplastic Small Round Cell Tumor
• Disseminated Neuroblastoma
• Leukemia
• Leukemia, Lymphoid
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Metastatic Childhood Soft Tissue Sarcoma
• Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor
• Metastatic Osteosarcoma
• Neoplasms
• Neuroblastoma
• Neuroectodermal Tumors
• Neuroectodermal Tumors, Primitive
• Neuroectodermal Tumors, Primitive, Peripheral
• Osteosarcoma
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Previously Treated Childhood Rhabdomyosarcoma
• Recurrent Childhood Acute Lymphoblastic Leukemia
• Recurrent Childhood Acute Myeloid Leukemia
• Recurrent Childhood Rhabdomyosarcoma
• Recurrent Childhood Soft Tissue Sarcoma
• Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor
• Recurrent Neuroblastoma
• Recurrent Osteosarcoma
• Rhabdomyosarcoma
• Sarcoma
• Sarcoma, Ewing

Intervention

Drug:
• tanespimycin
Given IV

Other:
• pharmacological study
Correlative studies
• laboratory biomarker analysis
Correlative studies

Locations

Country	Name	City	State
United States	Memorial Sloan-Kettering Cancer Center	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	MTD, defined as the highest dose level with an observed incidence of DLT in no more than 1 out of 6 patients treated at a particular dose level		21 days	Yes
Secondary	Change in Hsp90 client protein levels in relation to dose of tanespimycin		Baseline to 21 days	No