EL625 in Persistent Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

• Sponsor: David Rizzieri (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00636155
• Collaborator: Eleos, Inc. (Industry)
• Enrollment: 20
• Location: 1
• Arm: 1
• Duration (Months): 51
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this research study is to see if the investigational drug EL625, when combined with traditional chemotherapy (rituximab, fludarabine, and cyclophosphamide), is effective in Persistent Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL)

Condition or Disease	Intervention/Treatment	Phase
Lymphoma, Small Lymphocytic; Leukemia, Lymphocytic, Chronic	Drug: cenersen sodium; Drug: Rituximab; Drug: Cyclophosphamide; Drug: Fludarabine	Phase 2

Detailed Description

Chronic lymphocytic leukemia (CLL) and small B-cell lymphocytic lymphoma (SLL) are thought to be different manifestations of the same disease. Treatment options for CLL/SLL range from a watch and wait approach to bone marrow transplant. Currently there is no consensus on the best treatment regimen and new approaches to treatment are needed.

EL625 is a 20-mer antisense molecule which binds to a coding region of exon 10 in p53 RNA transcripts. It can bind to both mutant and wild type p53. p53 is involved in regulating apoptosis and DNA repair in cells. When genetic damage occurs p53 is upregulated. As the expression of p53 increases in normal cells they are more likely to undergo apoptosis rather than cell cycle arrest and DNA repair. However in malignant cells, for a given level of DNA damage they are more likely to undergo cell cycle arrest and repair rather than apoptosis. Because EL625 is theorized to increase response to chemotherapy, we propose adding EL625 to a combination of fludarabine, cyclophosphamide and rituximab.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of EL625 in Patients in Persistent Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
• Study Start Date: Feb 1, 2008
• Actual Primary Completion Date: Aug 1, 2011
• Actual Study Completion Date: May 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: all patients EL625 combined with traditional chemotherapy (rituximab, fludarabine, and cyclophosphamide)	Drug: cenersen sodium; 2.4 mg/kg/day as a continuous infusion over 24 hours starting on day one and ending on day 4; Other Names: EL625 ; Drug: Rituximab; 375 mg/m2 on day 2; Other Names: Rituxan ; Drug: Cyclophosphamide; 250 mg/m2 on days 2, 3, and 4; Other Names: Cytoxan ; Drug: Fludarabine; 25 mg/m2 on days 2, 3, and 4; Other Names: Fludara

Outcome Measures

Primary Outcome Measures

1. Number of Patients With an Overall Response (Complete Response + Partial Response) [every 3 cycles]

   Overall Response is the total number of participants with a Complete (CR) or Partial (PR) response. CR requires the absence of lymphadenopathy, hepatomegaly or splenomegaly and constitutional symptoms and a normal CBC; bone marrow must be at least normocellular for age, with less than 30% nucleated cells being lymphocytes with no lymphoid nodules. Partial Response: requires ≥ 50% decrease in one of the following: peripheral blood lymphocyte count, lymphadenopathy, enlargement of liver and/or spleen, or bone marrow involvement by CLL AND at least one hematologic parameter met for 2 months.

Secondary Outcome Measures

1. Progression Free Survival [5 years]

   Progression is defined as at least one of the following: 1) ≥ 50% increase in the sum of the products of at least two lymph nodes one two consecutive determinations (at least one node must be ≥ 2 cm); appearance of new palpable lymph nodes, 2) ≥ 50% increase in the size of the liver and/or spleen; appearance of palpable hepatomegaly or splenomegaly, which was not previously present, 3) ≥ 50% increase in the absolute number of circulating lymphocytes to at least 5,000/µl or 4)Transformation to a more aggressive histology.

2. Overall Survival [5 years]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with a diagnosis of CLL/SLL who have received at least one prior treatment regimen and have persistent disease (i.e. any evidence of active disease). Patients with a chromosome 17 abnormality or a p53 mutation of any type may be enrolled without having received prior treatment.

• Patients must be 18 years of age or older.

• Patient has an estimated or measured creatinine clearance ≥30 ml/min at study enrollment.

• AST, ALT, total bilirubin < than 2.5 times the upper limit of normal.

• WBC > 1.5; ANC >500; Plt >50,000 unless documented as due to disease

• ECOG performance status of 0-2.

• Voluntary written informed consent before performance of any study-related procedure not part of normal medical care.

• Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for 2 weeks after administration of the study drug.

• Male subject agrees to use an acceptable method for contraception for the duration of the study therapy and for 2 weeks after administration of study drug.

Exclusion Criteria:

• Female who is pregnant or lactating.

• Serious medical or psychiatric illness likely to interfere with participation in this clinical study.

• Patients with another malignancy within the last three years (from documentation of remission) other than basal or squamous cell skin cancer, resected early stage prostate cancer not requiring systemic treatment or CIS of the cervix or fully treated early stage prostate cancer.

• Significant cardiac or vascular events within 6 months: acute MI, unstable angina, severe peripheral vascular disease (ischemic pain at rest class 3 or worse, non-healing ulcers/wounds, congestive heart failure (NYHA class ≥ 2), uncontrolled cardiac arrhythmias, and disseminated intravascular coagulation.

• Patients who are unable to refrain from taking acetaminophen

• Investigational agent within 14 days of enrolling on the study.

• Patients unable or unwilling to refrain from antioxidants including vitamin A, vitamin C, vitamin E, lycopene, lutein, grape seed extract, pycnogenol, green tea extract, and the like.

• Patients who have received a prior allogenic stem cell transplant and have at least 2.5% donor cells still evident on engraftment studies.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke University Medical Center	Durham	North Carolina	United States	27710

Sponsors and Collaborators

• David Rizzieri
• Eleos, Inc.

Investigators

• Principal Investigator: David Rizzieri, MD, Duke University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: David Rizzieri, Associate Professor of Medicine, Duke University
• ClinicalTrials.gov Identifier: NCT00636155
• Other Study ID Numbers: Pro00001363
• First Posted: Mar 14, 2008
• Last Update Posted: Nov 28, 2012
• Last Verified: Nov 1, 2012

• Keywords provided by David Rizzieri, Associate Professor of Medicine, Duke University: Small Lymphocytic Lymphoma; Chronic Lymphocytic Leukemia; EL625; cenersen
• Additional relevant MeSH terms: Lymphoma; Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Cyclophosphamide; Rituximab; Fludarabine

Study Results

Participant Flow

Recruitment Details	All patients were enrolled from Duke University Medical Center.

Arm/Group Title	All Patients
Arm/Group Description	EL625 2.4mg/kg/day as a continuous infusion daily for 4 days combined rituximab 375mg/m2 IV on day 2, fludarabine IV 25mg/m2 over 30 minutes on days 2- 4 and cyclophosphamide IV 250mg/m2 over 1 hour on days 2-4.
Period Title: Overall Study
STARTED	20
COMPLETED	2
NOT COMPLETED	18

Baseline Characteristics

Arm/Group Title	All Patients
Arm/Group Description	EL625 2.4mg/kg/day as a continuous infusion daily for 4 days combined rituximab 375mg/m2 IV on day 2, fludarabine IV 25mg/m2 over 30 minutes on days 2- 4 and cyclophosphamide IV 250mg/m2 over 1 hour on days 2-4.
Overall Participants	20
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	12 60%
>=65 years	8 40%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	62
Sex: Female, Male (Count of Participants)
Female	3 15%
Male	17 85%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 5%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 5%
White	18 90%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Number of Patients With an Overall Response (Complete Response + Partial Response)
Description	Overall Response is the total number of participants with a Complete (CR) or Partial (PR) response. CR requires the absence of lymphadenopathy, hepatomegaly or splenomegaly and constitutional symptoms and a normal CBC; bone marrow must be at least normocellular for age, with less than 30% nucleated cells being lymphocytes with no lymphoid nodules. Partial Response: requires ≥ 50% decrease in one of the following: peripheral blood lymphocyte count, lymphadenopathy, enlargement of liver and/or spleen, or bone marrow involvement by CLL AND at least one hematologic parameter met for 2 months.
Time Frame	every 3 cycles

Outcome Measure Data

Analysis Population Description

Patients completing at least 2 cycles of treatment

Arm/Group Title	All Patients
Arm/Group Description	Patients treated with cenersen, fludarabine, cyclphosphamide and rituximab
Measure Participants	17
Number [participants]	9 45%

2. Secondary Outcome

Title	Progression Free Survival
Description	Progression is defined as at least one of the following: 1) ≥ 50% increase in the sum of the products of at least two lymph nodes one two consecutive determinations (at least one node must be ≥ 2 cm); appearance of new palpable lymph nodes, 2) ≥ 50% increase in the size of the liver and/or spleen; appearance of palpable hepatomegaly or splenomegaly, which was not previously present, 3) ≥ 50% increase in the absolute number of circulating lymphocytes to at least 5,000/µl or 4)Transformation to a more aggressive histology.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

All patients who received treatment

Arm/Group Title	All Patients
Arm/Group Description	Patients treated with cenersen, fludarabine, cyclphosphamide and rituximab
Measure Participants	20
Median (95% Confidence Interval) [months]	5.3

3. Secondary Outcome

Title	Overall Survival
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

All patients who received treatment

Arm/Group Title	All Patients
Arm/Group Description	Patients treated with cenersen, fludarabine, cyclphosphamide and rituximab
Measure Participants	20
Median (95% Confidence Interval) [months]	10.6

Adverse Events

Time Frame	Adverse events were collected from the start of study treatment until 30 days after the last dose.
Adverse Event Reporting Description	Other AE section contains all AEs, including SAEs, regardless of attribution to study drug
Arm/Group Title	All Patients
Arm/Group Description	EL625 2.4mg/kg/day as a continuous infusion daily for 4 days combined rituximab 375mg/m2 IV on day 2, fludarabine IV 25mg/m2 over 30 minutes on days 2- 4 and cyclophosphamide IV 250mg/m2 over 1 hour on days 2-4.
All Cause Mortality
	All Patients
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	All Patients
	Affected / at Risk (%)	# Events
Total	8/20 (40%)
Blood and lymphatic system disorders
Febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infe	3/20 (15%)	3
Hemolysis (e.g., immune hemolytic anemia, drug-related hemolysis)	1/20 (5%)	1
Investigations
Neutrophils / granulocytes (ANC / AGC)	1/20 (5%)	1
Nervous system disorders
Cognitive disturbance	1/20 (5%)	1
Syncope (fainting)	1/20 (5%)	1
Renal and urinary disorders
Cystitis	1/20 (5%)	1
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/20 (5%)	1
Skin and subcutaneous tissue disorders
Ulceration	1/20 (5%)	1
Other (Not Including Serious) Adverse Events
	All Patients
	Affected / at Risk (%)	# Events
Total	20/20 (100%)
Blood and lymphatic system disorders
Hemoglobin	10/20 (50%)	16
Hemolysis (e.g., immune hemolytic anemia, drug-related hemolysis)	1/20 (5%)	2
Febrile neutropenia (fever of unknown origin w/oclinically or microbiologically documented infe	7/20 (35%)	9
Pain - Lymph node	1/20 (5%)	1
Cardiac disorders
Palpitations	2/20 (10%)	2
Supraventricular and nodal arrhythmia - Atrial fibrillation	1/20 (5%)	3
Supraventricular and nodal arrhythmia - Sinus bradycardia	2/20 (10%)	2
Supraventricular and nodal arrhythmia - Sinus tachycardia	1/20 (5%)	1
Cardiac General - Other	1/20 (5%)	1
Supraventricular and nodal arrhythmia - Atrial flutter	1/20 (5%)	1
Eye disorders
Dry Eye Syndrome	1/20 (5%)	1
Vision - blurred vision	3/20 (15%)	3
Gastrointestinal disorders
Constipation	7/20 (35%)	9
Diarrhea	5/20 (25%)	5
Dysphagia (difficulty swallowing	1/20 (5%)	1
Hemorrhoids	1/20 (5%)	1
Mucositis / stomatitis (clinical exam) - Oral cavity	3/20 (15%)	3
Nausea	8/20 (40%)	10
Obstruction, GI - Ileum	1/20 (5%)	1
Vomiting	1/20 (5%)	1
Pain - Abdomen NOS	1/20 (5%)	1
Pain - Dental / teeth / peridontal	1/20 (5%)	1
General disorders
Fatigue (asthenia, lethargy, malaise)	11/20 (55%)	15
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10^9/L)	3/20 (15%)	3
Rigors / chills	5/20 (25%)	6
Edema: limb	4/20 (20%)	5
Pain - Other	1/20 (5%)	1
Hepatobiliary disorders
Liver dysfunction / failure (clinical)	1/20 (5%)	1
Immune system disorders
Allergic reaction / hypersensitivity (including drug fever)	2/20 (10%)	3
Allergy / Immunology - Other	2/20 (10%)	2
Infections and infestations
Infection - Other	3/20 (15%)	4
Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils - Bladder (urin	1/20 (5%)	1
Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils-Lip / perioral	1/20 (5%)	2
Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils - Rectum	2/20 (10%)	2
Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils - Urinary tract	1/20 (5%)	1
Investigations
Leukocytes (total WBC)	8/20 (40%)	13
Neutrophils / granulocytes (ANC / AGC)	6/20 (30%)	7
Platelets	14/20 (70%)	16
INR (International Normalized Ratio of prothrombin time	1/20 (5%)	1
Weight gain	2/20 (10%)	2
Weight loss	3/20 (15%)	3
Alkaline phosphatase	1/20 (5%)	1
AST, SGOT (serum glutamic oxaloacetic transaminase)	2/20 (10%)	2
Bilirubin (hyperbilirubinemia)	2/20 (10%)	2
Creatinine	2/20 (10%)	2
Metabolic / Laboratory - Other	2/20 (10%)	2
Metabolism and nutrition disorders
Anorexia	5/20 (25%)	5
Albumin, serum-low (hypoalbuminemia)	3/20 (15%)	4
Calcium, serum-high (hypercalcemia)	1/20 (5%)	1
Calcium, serum-low (hypocalcemia)	4/20 (20%)	6
Glucose, serum-high (hyperglycemia)	5/20 (25%)	10
Magnesium, serum-low (hypomagnesemia)	3/20 (15%)	3
Potassium, serum-low (hypokalemia)	4/20 (20%)	4
Sodium, serum-low (hyponatremia)	3/20 (15%)	4
Uric Acid, serum-high (hyperuricemia)	1/20 (5%)	2
Musculoskeletal and connective tissue disorders
Arthritis (non-septic)	2/20 (10%)	2
Joint-function	1/20 (5%)	1
Muscle weakness, generalized or specific area (not due to neuropathy) - Whole body / generalized	2/20 (10%)	2
Musculoskeletal - Flank pain	1/20 (5%)	1
Pain - Back	1/20 (5%)	1
Pain - Bone	1/20 (5%)	1
Pain - Chest wall	1/20 (5%)	1
Pain - Extremity-limb	1/20 (5%)	1
Pain - Joint	1/20 (5%)	1
Pain - Neck	1/20 (5%)	3
Nervous system disorders
Taste Alteration (dysgeusia)	2/20 (10%)	3
Cognitive disturbance	1/20 (5%)	1
Dizziness	4/20 (20%)	7
Memory Impairment	2/20 (10%)	2
Neuropathy: motor	1/20 (5%)	1
Neuropathy: sensory	2/20 (10%)	2
Somnolence / depressed level of consciousness	1/20 (5%)	2
Syncope (fainting)	2/20 (10%)	2
Pain - Head / headache	6/20 (30%)	6
Psychiatric disorders
Insomnia	5/20 (25%)	7
Confusion	2/20 (10%)	2
Mood Alteration - Agitation	1/20 (5%)	2
Mood Alteration - Anxiety	3/20 (15%)	3
Mood Alteration - Depression	1/20 (5%)	1
Psychosis (hallucinations / delusions)	2/20 (10%)	2
Renal and urinary disorders
Hemorrhage, GU - Kidney	2/20 (10%)	2
Cystitis	2/20 (10%)	2
Renal Failure	1/20 (5%)	1
Urinary frequency / urgency	5/20 (25%)	6
Urinary retention (including neurogenic bladder)	1/20 (5%)	1
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	1/20 (5%)	1
Edema: pulmonary	2/20 (10%)	2
Pulmonary / Upper Respiratory - Sore throat	1/20 (5%)	1
Bronchospasm, wheezing	1/20 (5%)	1
Cough	6/20 (30%)	6
Dyspnea (shortness of breath)	7/20 (35%)	11
Hypoxia	3/20 (15%)	3
Pulmonary / Upper Respiratory - Other	1/20 (5%)	1
Skin and subcutaneous tissue disorders
Sweating (diaphoresis)	4/20 (20%)	4
Dermatology / Skin - Other	5/20 (25%)	5
Dry Skin	2/20 (10%)	2
Hair Loss / Alopecia (scalp or body)	1/20 (5%)	1
Pruritus / itching	1/20 (5%)	1
Rash / desquamation	5/20 (25%)	5
Ulceration	3/20 (15%)	3
Petechiae / purpura (hemorrhage / bleeding into skin or mucosa)	1/20 (5%)	1
Vascular disorders
Hypotension	3/20 (15%)	5
Hot flashes / flushes	1/20 (5%)	1
Hemorrhage / Bleeding - Other	1/20 (5%)	1
Dermal change lymphedema, phlebolymphedema	3/20 (15%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.