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

NCT01312818 | Terminated Phase 2 Results DMC

• 4 other identifiers: 2008LS113MT2008-33R1010M91973X05323
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

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.

Conditions

Acute Lymphoblastic Leukemia

Outcome Measures

Primary Outcomes (1)

• Number of Subjects Who Achieved Complete Remission of Their Disease

  Complete Remission (CR): A CR requires that the following be recorded concurrently: an absolute neutrophil count (segs and bands) \> 1000/μL, no circulating blasts, platelets \> 100,000/μL; adequate bone marrow cellularity with trilineage hematopoiesis, and \< 5% marrow leukemia blast cells. All previous extramedullary manifestations of disease must be absent. If patients continue on with treatment, there can be no evidence of recurrence of ALL for at least 4 weeks.

  Day 30

Secondary Outcomes (2)

• Number of Subjects Experiencing Drug Related Adverse Events

  Day 1 of Treatment to 30 Days Post Treatment

• Number of Subjects With Activated Caspases and Other Regulators of Apoptosis

  From Day 1 to 30 Days After Last Dose

Study Arms (1)

Chemotherapy

EXPERIMENTAL

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

Drug: Bortezomib; Drug: Vorinostat; Drug: Dexamethasone; Drug: Methotrexate; Drug: Imatinib mesylate

Interventions

Bortezomib DRUG

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

Also known as: Velcade(R)

Chemotherapy

Vorinostat DRUG

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

Also known as: suberoylanilide hydroxamic acid (SAHA), Zolinza

Chemotherapy

Dexamethasone DRUG

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

Also known as: Decadron

Chemotherapy

Methotrexate DRUG

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

Also known as: Trexall, amethopterin

Chemotherapy

Imatinib mesylate 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.

Also known as: Gleevec(R)

Chemotherapy

Eligibility Criteria

• Age: 2 Years - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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:

You may not qualify if:

• 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.

Sponsors & Collaborators

• Masonic Cancer Center, University of Minnesota: lead
• Millennium Pharmaceuticals, Inc.: collaborator

Study Sites (1)

Masonic Cancer Center, University if Minnesota

Minneapolis, Minnesota, 55455, United States

Location

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Interventions

Bortezomib; Vorinostat; Dexamethasone; Calcium Dobesilate; Methotrexate; Imatinib Mesylate

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Anilides; Amides; Aniline Compounds; Amines; Hydroxamic Acids; Hydroxylamines; Hydroxy Acids; Carboxylic Acids; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Benzamides; Benzoates; Acids, Carbocyclic; Piperazines; Pyrimidines

Results Point of Contact

• Title: Dr. Michael Burke, MD
• Organization: University of Minnesota, Pediatric Hematology Dept.

612-672-7422

Study Officials

• Michael Burke, MD

  Masonic Cancer Center, University of Minnesota

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 9, 2011
• First Posted: March 11, 2011
• Study Start: June 1, 2011
• Primary Completion: January 1, 2013
• Study Completion: January 1, 2013
• Last Updated: December 28, 2017
• Results First Posted: May 15, 2015

Record last verified: 2017-12

Locations

US (1)