Bortezomib and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01769209
Recruitment Status : Active, not recruiting
First Posted : January 16, 2013
Last Update Posted : January 23, 2018
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Michaela Liedtke, Stanford University

Brief Summary:
This phase II trial studies how well giving bortezomib together with combination chemotherapy works in treating patients with relapsed or refractory acute lymphoblastic leukemia. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Condition or disease Intervention/treatment Phase
B-cell Adult Acute Lymphoblastic Leukemia Ph Positive Adult Acute Lymphoblastic Leukemia Recurrent Adult Acute Lymphoblastic Leukemia T-cell Adult Acute Lymphoblastic Leukemia Drug: bortezomib Drug: doxorubicin hydrochloride Drug: pegaspargase Drug: vincristine sulfate Drug: dexamethasone Drug: cytarabine Drug: methotrexate Phase 2

Detailed Description:


I. Determine the response rate of bortezomib in combination with a chemotherapy backbone of doxorubicin (doxorubicin hydrochloride), vincristine (vincristine sulfate), PEG-asparaginase (pegaspargase), and dexamethasone in patients with relapsed/refractory acute lymphoblastic leukemia.


I. Determine progression free survival. II. Estimate the rate of complete response (CR) and CR with incomplete platelet recovery (CRp) after this re-induction compared to a historical baseline.

III. Estimate failure-free survival (FFS) and survival percent at 1 year compared to a historical baseline.

IV. Assess safety and tolerability of the study drug. V. Determine whether bortezomib induces reactive oxygen species (ROS) in circulating acute lymphoblastic leukemia (ALL) blast cells.


Patients receive bortezomib subcutaneously (SC) on days 1, 4, 8, and 11; doxorubicin hydrochloride intravenously (IV) on day 1; pegaspargase IV or intramuscularly (IM) on days 5 and 22; vincristine sulfate IV on days 1, 8, 15, and 22; dexamethasone orally (PO) daily on days 1-14; cytarabine intrathecally (IT) on day 1 and methotrexate intrathecally (IT) on day 15. Patients with central nervous system disease receive intrathecal treatment per investigator's discretion.

After completion of study treatment, patients are followed up every 3 months for up to 2 years.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of Subcutaneous Bortezomib in Combination With Chemotherapy in Relapsed/Refractory Adult Acute Lymphoblastic Leukemia
Study Start Date : March 2013
Actual Primary Completion Date : September 30, 2017
Estimated Study Completion Date : September 30, 2018

Arm Intervention/treatment
Experimental: Treatment (bortezomib, chemotherapy)
Patients receive bortezomib SC on days 1, 4, 8, and 11; doxorubicin hydrochloride IV on day 1; pegaspargase IV or IM on days 5 and 22; vincristine sulfate IV on days 1, 8, 15, and 22; dexamethasone PO daily on days 1-14; cytarabine IT on day 1 and methotrexate IT on day 15. Patients with central nervous system disease receive intrathecal treatment per investigator's discretion.
Drug: bortezomib
Given SC
Other Names:
  • LDP 341
  • MLN341

Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF

Drug: pegaspargase
Given IV or IM
Other Names:
  • L-asparaginase with polyethylene glycol
  • Oncaspar
  • PEG-L-asparaginase

Drug: vincristine sulfate
Given IV
Other Names:
  • leurocristine sulfate
  • VCR
  • Vincasar PFS

Drug: dexamethasone
Given PO
Other Names:
  • Aeroseb-Dex
  • Decaderm
  • Decadron
  • DM
  • DXM

Drug: cytarabine
Given IT
Other Names:
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside

Drug: methotrexate
Given IT
Other Name: MTX; amethopterin

Primary Outcome Measures :
  1. CR rate [ Time Frame: On day 29 at the end of induction therapy ]
    Response rates will be evaluated and accompanied by 95% confidence intervals using the binomial distribution. Response rate by categories will be calculated with 95% confidence intervals.

Secondary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: From the start of treatment to disease progression or death, whichever comes first, assessed up to 2 years ]
    Analyzed using Kaplan-Meier survival analysis and accompanied with 95% confidence interval.

  2. CR and CRp rate after re-induction [ Time Frame: Up to 2 years ]
    Compared to a historical baseline.

  3. Failure-free survival (FFS) [ Time Frame: At 1 year ]
    Analyzed by the Kaplan Meier method. Compared to a historical baseline.

  4. Survival percent [ Time Frame: At 1 year ]
    Compared to a historical baseline.

  5. Incidence of adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 45 days after completion of treatment ]
    Toxicity profile will be presented by rate of overall toxicity and rates of grade 3 or 4 toxicities analyzed separately and combined. Adverse events will be summarized and accompanied by 95% confidence intervals using binomial distribution.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care
  • Female subjects who:

    • Are postmenopausal for at least 1 year before the screening visit, OR
    • Are surgically sterile, OR
    • If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 30 days after the last dose of bortezomib, or agree to completely abstain from heterosexual intercourse
  • Male subjects, even if surgically sterilized (i.e., status post vasectomy) who:

    • Agree to practice effective barrier contraception during the entire study treatment period and through a minimum of 30 days after the last dose of study drug, OR
    • Agree to completely abstain from heterosexual intercourse
  • • The patient has relapsed or refractory B or T cell acute lymphoblastic leukemia that has progressed following at least one prior therapy. Ph+ patients are eligible. Relapsed ALL is defined in patients as the reappearance of leukemia cells in the peripheral blood or bone marrow or appearance of extramedullary disease after a complete remission. Refractory ALL is defined in patients as failure to achieve a complete remission after induction therapy. Complete remission is defined by <5% leukemia cells in the bone marrow with recovery of peripheral blood counts. Relapsed disease can be documented by bone marrow biopsy (>5% cells in the bone marrow) or by flow cytometry in the peripheral blood or biopsy of extramedullary disease.
  • Must have received at least one (1) line of prior systemic therapy that may NOT have included VELCADE (bortezomib); patients who have undergone autologous/allogeneic stem cell transplantation are eligible
  • Transplant eligible patients are eligible
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • No poorly controlled intercurrent illness including, but not limited to, ongoing or active infection, poorly controlled diabetes, symptomatic congestive heart failure, or psychiatric illness that in the opinion of the investigator would limit compliance with study requirements
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x upper limit of normal
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) unless elevation is deemed due to leukemia infiltration. In these patients, dose modifications may be required based on standard guidelines.
  • Patients must have adequate renal function defined as creatinine clearance of >= 30 ml/minute (Cockcroft-Gault)

Exclusion Criteria:

  • Patient has > 1.5 x ULN total bilirubin
  • Patient has >= grade 2 peripheral neuropathy
  • Patient had myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevant
  • Patient has hypersensitivity to bortezomib, boron, or mannitol
  • Female subject is pregnant or lactating
  • Serious medical or psychiatric illness likely to interfere with participation in this clinical study
  • Diagnosed or treated for another malignancy within 2 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy
  • Participation in clinical trials with other investigational agents not included in this trial throughout the duration of this trial
  • Radiation therapy within 3 weeks before randomization; enrollment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy
  • The patient has been exposed to >= 350mg/m^2 of anthracycline (doxorubicin equivalent)
  • The patient has a left ventricular ejection fraction of < 40%

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01769209

United States, California
Stanford University, School of Medicine
Stanford, California, United States, 94305
Sponsors and Collaborators
Stanford University
National Cancer Institute (NCI)
Principal Investigator: Michaela Liedtke Stanford University

Responsible Party: Michaela Liedtke, Assistant Professor of Medicine, Stanford University Identifier: NCT01769209     History of Changes
Other Study ID Numbers: HEMALL0008
NCI-2012-03094 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
First Posted: January 16, 2013    Key Record Dates
Last Update Posted: January 23, 2018
Last Verified: January 2018

Additional relevant MeSH terms:
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone acetate
Liposomal doxorubicin
BB 1101
Anti-Inflammatory Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal