Vorinostat, Fludarabine Phosphate, Cyclophosphamide, and Rituximab in Treating Patients With Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

NCT00918723 | Completed Phase 1 Results

• 3 other identifiers: PSOC 2401NCI-2010-00324P30CA015704
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 2

Brief Summary

This phase I/II trial studies the side effects and best dose of vorinostat when given together with fludarabine phosphate, cyclophosphamide, and rituximab and to see how well they work in treating patients with previously untreated B-cell chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fludarabine phosphate and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Giving vorinostat together with fludarabine phosphate, cyclophosphamide, and rituximab may be a better treatment for CLL or SLL.

Conditions

Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Small Lymphocytic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma

Outcome Measures

Primary Outcomes (3)

• Maximum Tolerated Dose (MTD) of Vorinostat That Can be Combined With Fludarabine Phosphate, Cyclophosphamide and Rituximab (FCR) (Phase I)

  The MTD of vorinostat in combination with FCR will be defined as the dose level immediately below the dose level at which greater than or equal to 2 patients out of 6 of a cohort experience dose-limiting toxicity. Toxicities will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Doses of vorinostat analyzed to reach the MTD were 200 mg, 300 mg and 400 mg.

  28 days

• Percentage of Patients With Progression-free Survival at 2 Years

  Progression-free survival (PFS): The length of time during and after the treatment that a patient lives with the disease but it does not get worse. Progressive disease is specified by the NCI (National Cancer Institute) working group guidelines and additional CT (computerized tomography) scan requirements: Lymphadenopathy, \> 50% increase in the sum of the products of at least two lymph nodes on two consecutive determinations; one lymph node must be at least 2 cm. An increase in the liver or spleen size by 50% or more by CT scan or the de novo appearance of hepatomegaly or splenomegaly. An increase in the number of blood lymphocytes by 50% or more with at least 5000 B lymphocytes per microliter. Transformation to a more aggressive histology or occurrence of cytopenia (neutropenia, anemia, or thrombocytopenia) attributable to CLL.

  2 years

• Overall Survival

  Overall survival (OS): The percentage of people in a study who are still alive at for a certain period of time after they started treatment.

  2 years

Secondary Outcomes (2)

• To Eliminate Residual Disease (Documented by Flow Cytometry and/or Polymerase Chain Reaction [PCR]) in Patients Who Have Achieved Complete Response (CR) After Fludarabine, Cyclophosphamide, and Rituximab (FCR) Plus Vorinostat

  Within 21 days prior to starting maintenance therapy

• To Estimate the Rate of Conversion of Partial Response (PR) to Complete Response (CR) After Fludarabine, Cyclophosphamide and Rituximab (FCR) Plus Vorinostat

  After completion of maintenance therapy (24 months after start of maintenance)

Study Arms (1)

Treatment (induction and maintenance chemotherapy)

EXPERIMENTAL

INDUCTION THERAPY: Patients receive vorinostat PO once daily on days 1-5 and 8-12; cyclophosphamide IV over 30-60 minutes and fludarabine phosphate IV over 30-60 minutes on days 1-3; and rituximab IV on day 1, 2, 3, 4, or 5. Treatment repeats every 28 days for 4-6 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Beginning 3 months after the completion of induction therapy, patients receive vorinostat PO on days 1-14 and rituximab IV on day 1. Treatment repeats every 3 months for 2 years in the absence of disease progression or unacceptable toxicity.

Drug: Fludarabine Phosphate; Drug: Cyclophosphamide; Biological: Rituximab; Drug: Vorinostat

Interventions

Fludarabine Phosphate DRUG

Given IV

Also known as: 2-F-ara-AMP, Beneflur, SH T 586

Treatment (induction and maintenance chemotherapy)

Cyclophosphamide DRUG

Given IV

Treatment (induction and maintenance chemotherapy)

Rituximab BIOLOGICAL

Given IV

Also known as: MOAB IDEC-C2B8

Treatment (induction and maintenance chemotherapy)

Vorinostat DRUG

Given PO

Also known as: L-001079038, SAHA, Suberanilohydroxamic Acid, Suberoylanilide Hydroxamic Acid

Treatment (induction and maintenance chemotherapy)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have a confirmed diagnosis of CLL/SLL
• Patients with previously untreated cluster of differentiation (CD)20+ CLL/SLL must have either Rai stage III/IV disease or be Rai stage I/II with evidence of disease activity as defined by the National Cancer Institute (NCI) 1996 guidelines; patients with SLL must be Stage III or IV per Ann Arbor staging system
• Patient must have consented to participate in the study and signed and dated an appropriate institutional review board (IRB)-approved consent form that conforms to federal and institutional guidelines
• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
• Patient must have an anticipated (untreated) survival of at least 3 months
• Female patient of childbearing potential has a negative serum pregnancy test beta-human chorionic gonadotropin (hCG) within 2 weeks prior to receiving the first dose of vorinostat
• Female patient is either post menopausal, free from menses for \>= 2 years, surgically sterilized or willing to use 2 adequate barrier methods of contraception to prevent pregnancy or agrees to abstain from heterosexual activity throughout the study, starting with Visit 1
• Male patients not sterilized must be willing to use adequate barrier methods of contraception to prevent pregnancy or agrees to abstain from heterosexual activity throughout the study, starting with Visit 1
• Absolute Neutrophil Count (ANC) \>= 1,500/mcL
• Platelets \>= 100,000/mcL
• Hemoglobin \>= 9 g/dL
• Prothrombin time or international normalized ratio (INR) =\< 1.5 upper limit of normal (ULN) unless receiving therapeutic anticoagulation
• Partial thromboplastin time (PTT) =\< 1.2 times the ULN unless the patient is receiving therapeutic anticoagulation
• Potassium level within normal limits
• Magnesium level within normal limits

You may not qualify if:

• Patients who have received cytotoxic chemotherapy, radiation therapy, immunotherapy, or cytokine treatment prior to study entry for CLL/SLL; patients who have received systemic steroids within 1 week of study entry are excluded, except patients on maintenance steroid therapy for a noncancerous disease
• Patients with active hemolysis
• Patients must not require sustained transfusion support of blood products
• Patients who have undergone treatment with either stem cell or bone marrow transplant
• Patients with active obstructive hydronephrosis
• Patients with evidence of any significant systemic illness, active hepatitis B infection, active viral hepatitis infection or other active infection at the time of study entry
• Patients with New York Heart Association class III or IV heart disease symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or other serious illness, such as acute or chronic graft versus host disease, that would preclude evaluation
• Patients with congenital long QT syndrome and patients taking antiarrhythmic medicines or other medicinal products that lead to QT prolongation will only be eligible if their baseline corrected QT (QTc) prolongation is =\< 500 msec
• Patients with known human immunodeficiency virus (HIV) infection
• Patients who are pregnant or nursing
• Patients with known brain or leptomeningeal involvement by malignancy
• Patients who have, in the opinion of the investigator, other medical, social, or psychosocial factors that may negatively impact compliance or their safety by participation in this study
• Patient is currently participating or has participated in a study with an investigational compound or device within 30 days of initial dosing with study drugs(s)
• Patient had prior treatment with an histone deacetylases (HDAC) inhibitor (e.g., romidepsin \[Depsipeptide\], NSC-630176, MS 275, LAQ-824, belinostat \[PXD-101\], LBH589, MGCD0103, CRA024781, etc); patients who have received compounds with HDAC inhibitor-like activity, such as valproic acid, as anti-tumor therapy should not enroll in this study; patients who have received such compounds for other indications, e.g. valproic acid for epilepsy, may enroll after a 30-day washout period
• Patient with a history of a prior malignancy with the exception of cervical intraepithelial neoplasia; non-melanoma skin cancer; adequately treated localized prostate carcinoma with prostate-specific antigen (PSA) =\< 1.0; or who has undergone potentially curative therapy with no evidence of that disease for five years, and/or who is deemed at low risk for recurrence by his/her treating physician

Sponsors & Collaborators

• Fred Hutchinson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (2)

Swedish Cancer Institute-Breast Center at First Hill Campus

Seattle, Washington, 98104, United States

Location

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Seattle, Washington, 98109, United States

Location

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

fludarabine phosphate; Cyclophosphamide; Rituximab; Vorinostat

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Anilides; Amides; Aniline Compounds; Amines; Hydroxamic Acids; Hydroxylamines; Hydroxy Acids; Carboxylic Acids

Results Point of Contact

• Title: Dr. Mazyar Shadman
• Organization: Fred Hutchinson Cancer Research Center

mshadman@fredhutch.org

2066675467

Study Officials

• Mazyar Shadman

  Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 9, 2009
• First Posted: June 11, 2009
• Study Start: June 1, 2009
• Primary Completion: October 1, 2016
• Study Completion: October 1, 2016
• Last Updated: February 25, 2020
• Results First Posted: February 8, 2018

Record last verified: 2020-02

Locations

US (2)