Bortezomib, Vorinostat and Dexamethasone for Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL)

NCT ID: NCT01312818

Last Updated: 2017-12-28

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 2 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-06-30
• Study Completion Date: 2013-01-31

Brief Summary

Both of bortezomib and vorinostat have identified Phase II doses for pediatric and adult patients of which no grade 4 dose limiting toxicities have been observed in prior studies. The pre-clinical synergy of these 2 agents when used in combination along with the lack of over-riding toxicities and different mechanisms of action provide strong rationale for a clinical trial investigating bortezomib and vorinostat in combination. This trial will use the identified Phase II dose which is at or below the maximum tolerated dose for both agents which have very acceptable toxicity profiles and such should prove feasible and tolerable in this relapsed/refractory ALL population.

Detailed Description

This is a phase II study of bortezomib 1.3 mg/m^2 by intravenous pyelogram (IVP) on days 1, 4, 8, and 11, vorinostat 180 mg/m^2 by mouth (PO) per day (not to exceed 400 mg per day) days 1-14, and dexamethasone 6 mg/m^2 PO days 4-15 for the treatment of relapsed/refractory acute lymphoblastic leukemia (ALL). No more than 3 treatment courses may be given.

Conditions

Acute Lymphoblastic Leukemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Chemotherapy

Bortezomib IV Vorinostat PO Dexamethasone PO Intrathecal Methotrexate Imatinib Mesylate PO (for Ph+ ALL patients only)

Group Type: EXPERIMENTAL

Bortezomib

Intervention Type: DRUG

1.3 mg/m\^2 by intravenous pyelogram (IVP) over 3-5 seconds on days 1, 4, 8 and 11.

Vorinostat

Intervention Type: DRUG

180 mg/m\^2 (max dose 400mg) by mouth (PO) divided twice a day (BID) on days 1-14

Dexamethasone

Intervention Type: DRUG

6 mg/m\^2 by mouth (PO) divided twice a day (BID) on days 4-15.

Methotrexate

Intervention Type: DRUG

Intrathecal Methotrexate at age based dose on day 1 (repeat on day 15 or 16 for CNS positive patients only)

Imatinib mesylate

Intervention Type: DRUG

For Ph+ acute lymphoblastic leukemia (ALL) patients only:

Imatinib Mesylate is allowable at 340 mg/m2 PO once a day (rounded to the nearest 100 mg) for age ≤18 years and 400 mg for >18 years on Days 1-16.

Interventions

Bortezomib

1.3 mg/m\^2 by intravenous pyelogram (IVP) over 3-5 seconds on days 1, 4, 8 and 11.

Intervention Type: DRUG

Vorinostat

180 mg/m\^2 (max dose 400mg) by mouth (PO) divided twice a day (BID) on days 1-14

Intervention Type: DRUG

Dexamethasone

6 mg/m\^2 by mouth (PO) divided twice a day (BID) on days 4-15.

Intervention Type: DRUG

Methotrexate

Intrathecal Methotrexate at age based dose on day 1 (repeat on day 15 or 16 for CNS positive patients only)

Intervention Type: DRUG

Imatinib mesylate

For Ph+ acute lymphoblastic leukemia (ALL) patients only:

Imatinib Mesylate is allowable at 340 mg/m2 PO once a day (rounded to the nearest 100 mg) for age ≤18 years and 400 mg for >18 years on Days 1-16.

Intervention Type: DRUG

Other Intervention Names

Velcade(R); suberoylanilide hydroxamic acid (SAHA); Zolinza; Decadron; Trexall; amethopterin; Gleevec(R)

Eligibility Criteria

Inclusion Criteria

• Diagnosis of lymphoblastic lymphoma or acute lymphoblastic leukemia (ALL) with ≥ 5% blasts in the bone marrow (M2/M3) with or without extramedullary disease that meets one of the following criteria:

• Refractory Disease/Induction Failure: Failure to achieve initial remission after 2 attempts of standard induction therapy
• Relapsed Disease: Patients in relapse #1 or higher for whom standard curative therapies or therapies to prolong survival do not exist.

Patients who are Philadelphia chromosome-positive (Ph + ALL) are eligible provided they are not imatinib resistant or intolerant.

Patients with CNS positive disease will be eligible.

• Age 2 to 30 years
• Karnofsky ≥ 50% for patients 16 years and older and Lansky status ≥ 50 for patients under 16 years of age.
• Patients must have a life expectancy ≥ 8 weeks as determined by the enrolling investigator.
• Have acceptable organ function as defined within 7 days of starting treatment:

• Renal: creatinine clearance ≥ 70ml/min/1.73m^2 or serum creatinine based on age/gender as follows: Maximum serum creatinine (mg/dl) 0.8 for 2 years to <6 years; 1.0 for 6 years to <10 years; 1.2 for 10 years to <13 years; 1.5 male and 1.4 female for 13 years to <16 years; 1.7 male and 1.4 female for ≥ 16 years
• Hepatic: ALT < 5 x upper limit of normal (ULN) and total bilirubin ≤ 1.5x upper limit of normal (ULN) for age.
• Cardiac: left ventricular ejection fraction ≥ 40% by echocardiogram/multi gated acquisition scan (ECHO/MUGA). Normal QTc on electrocardiogram (EKG) (not to exceed upper limit of normal - men: 430 milliseconds (ms); women: 450 ms; children up to 15 years: 440 ms).
• Prior Therapy:

Exclusion Criteria

Cytotoxic therapy: Patients must have had their last dose of chemotherapy at least two weeks prior to study entry.

• Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor and at least 14 days since pegfilgrastim (Neulasta®) administration.
• Biologic (anti-neoplastic) therapy: At least 7 days since the completion of therapy with a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair.
• Monoclonal antibodies: At least 3 half-lives of the antibody after the last administration of a monoclonal antibody.
• Hematopoietic Stem Cell Transplant (HSCT): Patients who have experienced their relapse after a HSCT are eligible, provided they have no evidence of Graft-versus-Host Disease (GVHD).

• Women of child bearing potential must agree to use adequate contraception (diaphragm, birth control pills, injections, intrauterine device [IUD], surgical sterilization, subcutaneous implants, or abstinence, etc.) for the duration of treatment and for 2 months after the last dose of chemotherapy. Sexually active men must agree to use barrier contraceptive for the duration of treatment and for 2 months after the last dose of chemotherapy.
• Voluntary written 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/guardian at any time without prejudice to future medical care.

• Pregnant or lactating. The agents used in this study are known to be teratogenic to a fetus and there is no information on the excretion of agents into breast milk. Confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for surgically sterilized women.
• Known hypersensitivity to bortezomib, boron or mannitol or any of the agents or their ingredients used in this study.
• Inability to swallow capsules.
• Grade 2 or greater peripheral neuropathy within 14 days before study registration.
• Patients with untreated positive blood cultures or progressive infections as assessed by radiographic studies.
• Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure (appendix VI), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.
• Serious concomitant medical or psychiatric disorders (e.g., active infection, uncontrolled diabetes) that, in the opinion of the investigator, would compromise the safety of the patient or likely to interfere with participation in this clinical study.
• Diagnosed or treated for another malignancy within 3 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.
• Patient has received investigational drugs within the 14 days before study registration.
• Radiation therapy within 3 weeks before registration. Enrollment of patients 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.

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 30 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Millennium Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: collaborator

Masonic Cancer Center, University of Minnesota

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Michael Burke, MD

Role: PRINCIPAL_INVESTIGATOR

Masonic Cancer Center, University of Minnesota

Locations

Masonic Cancer Center, University if Minnesota

Minneapolis, Minnesota, United States

Countries

United States

Other Identifiers

MT2008-33R

Identifier Type: OTHER

Identifier Source: secondary_id

1010M91973

Identifier Type: OTHER

Identifier Source: secondary_id

X05323

Identifier Type: OTHER

Identifier Source: secondary_id

2008LS113

Identifier Type: -

Identifier Source: org_study_id