Dasatinib in Treating Patients With Chronic Lymphocytic Leukemia

• Sponsor: OHSU Knight Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT01441882
• Collaborator: Oregon Health and Science University (Other)
• Enrollment: 19
• Location: 1
• Arm: 1
• Duration (Months): 75
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This phase II trial studies how well dasatinib works in treating patients with chronic lymphocytic leukemia (CLL). Dasatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Condition or Disease	Intervention/Treatment	Phase
Refractory Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage II Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage IV Chronic Lymphocytic Leukemia	Drug: Dasatinib; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To estimate the biologic target activity of dasatinib in CLL patients found to have pre-treatment in vitro dasatinib cytotoxicity (as defined by a >= 50% decrease in absolute lymphocyte count and/or bone marrow CLL count and/or lymph node or spleen size).

SECONDARY OBJECTIVES:

1. To evaluate overall objective response rates per CLL National Cancer Institute (NCI) working group.

2. To determine drug safety and tolerability of dasatinib in patients with CLL.

3. To determine overall (OS) and progression-free survival (PFS).

TERTIARY OBJECTIVES:

1. To determine if v-src avian sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (SRC), Bruton agammaglobulinemia tyrosine kinase (BTK), or tec protein tyrosine kinase (TEC) family kinase inhibition correlates with clinical response.

2. To determine which prognostic subgroups (presence of >= 1 of the following: 11q or 17p deletion; cluster of differentiation [CD]38 or zeta-chain-associated protein kinase 70 [Zap 70] expression; unmutated immunoglobulin heavy chain [IgVH]) respond to dasatinib therapy.

3. To evaluate differences in baseline CLL gene expression between CLL samples that are sensitive or in-sensitive to dasatinib.

4. To analyze changes in CLL gene expression after dasatinib treatment. V. To evaluate dasatinib pharmacokinetics. VI. To evaluate changes in type I receptor tyrosine kinase-like orphan receptor (ROR-1) expression with dasatinib treatment.

5. To correlate response to pre-clinical IC50 in the presence/absence of HS-5 conditioned media.

6. To explore role of possible kinase mutations related to dasatinib response.

7. To measure chemokines before and during treatment.

OUTLINE:

Patients receive dasatinib orally (PO) once daily (QD) during course 1 and if tolerated, twice daily (BID) in subsequent courses. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Dasatinib in Chronic Lymphocytic Leukemia in Patients Who Exhibit in Vitro Dasatinib Sensitivity
• Study Start Date: Oct 1, 2011
• Actual Primary Completion Date: Jul 12, 2016
• Actual Study Completion Date: Jan 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (dasatinib) Patients receive dasatinib PO QD during course 1 and if tolerated, BID in subsequent courses. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.	Drug: Dasatinib; Given PO; Other Names: BMS-354825 Sprycel ; Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies

Outcome Measures

Primary Outcome Measures

1. The Number of Participants With In Vitro Dasatinib Sensitivity in Predicting Clinical Activity [8 weeks]

   Defined by a decrease in absolute lymphocyte count, as determined by peripheral blood complete blood count (CBC) with differential or by bone marrow examination of 50 % and/or a decrease of detectable total lymph node size or spleen size by 50% (either by clinical examination contrast enhanced computed tomography [CT]).

Secondary Outcome Measures

1. Objective Response [Up to 2 years]

   Proportion of patients achieving the endpoint along with its 95% exact binomial confidence interval will be presented. Complete Response (CR): present >=2 mos: no symptoms of CLL, normal findings on exam, ALC < 4.000/mm3, ANC >1.500/ mm3, platelet (PLT) count (ct) >100.000/ mm3, hemoglobin (Hgb) concentration >11 g/dL (untransfused), bone marrow (BM) lymphocytosis <30%, and no nodules (lymphoid aggregates) on BM biopsy. Partial Response (PR): present >=2 months: a reduction in prev. enlarged nodes, spleen, & liver by at least 50%. ANC >= 1.500/ mm3 or PLT ct >= 100.000/ mm3 or Hgb concentration >=11 g/dL or 50% improvement over pre-therapy reductions in Hgb concentration and/or PLT ct. Nodular PR: persistent BM nodules or infiltrates seen on BM biopsy those achieving a CR or PR. Stable Disease (SD): Does not meet CR or PR, but also not progressive disease (PD). PD: 50% size increase of lymph node, spleen, liver; or histologic (e.g. Richter's) transformation (per NCI and iwCLL).

2. Overall Survival [Up to 2 years]

   Kaplan-Meier method will be used to estimate the survival curve.

3. Progression-free Survival [Up to 2 years]

   Kaplan-Meier method will be used to estimate the survival curve.

4. Incidence of Adverse Events (Number of Participants Affected) [Up to 4 years]

   Assessed According to the NCI Common Terminology Criteria for Adverse Events Version 4.0. Adverse events will be tabulated and summarized according to key reporting criteria (i.e., grade or seriousness, unanticipated, treatment attribution). Refer to the Adverse Event tables below for specific details.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal information

• Eastern Cooperative Oncology Group (ECOG) =< 2

• In vitro dasatinib sensitivity (IC 50 =< 50 nm per MTS assay)

• Diagnosis of CLL and must meet one of the following:

• Relapsed CLL in all patients who have failed at least one prior treatment, regardless of risk group

• OR De novo (treatment-naïve) patients age >= 65 who are not candidates for or do not want to pursue aggressive chemotherapy treatment

• Have indications for treatment or evidence of progressive disease defined as follows (1996 NCI working group):

• Massive or progressive splenomegaly

• Massive lymph nodes (>= 10 cm), nodal clusters (>= 10 cm), or progressive lymphadenopathy

• Symptomatic anemia and/or thrombocytopenia (Rai stages III or IV disease)

• Autoimmune hemolytic anemia and/or thrombocytopenia that are poorly responsive to corticosteroid therapy

• Progressive lymphocytosis with increase in lymphocyte count of >= 50% over a 2-month period or an anticipated doubling time of < 6 months

• Repeated episodes of infection

• Have not received CLL treatment within the past 2 weeks

• Total bilirubin < 2.0 x upper limit of normal (ULN)

• Aspartate aminotransferase (AST) =< 2.5 x ULN

• Alanine aminotransferase (ALT) =< 2.5 x ULN

• Serum creatinine < 2.0 x ULN

• International normalized ratio (INR) =< 1.2

• Platelet (Plt) count > 30,000

• Ability to take oral medication (dasatinib must be swallowed whole)

• No clinically significant infections as determined by the investigator

• Normal corrected QT (QTc) interval (< 450 msec)

• Serum potassium and magnesium are within normal limits

• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (sensitivity =< 25 IU HCG/L) within 72 hours prior to the start of study drug administration

• Persons of reproductive potential must agree to use an adequate method of contraception throughout treatment and for at least 4 weeks after study drug is stopped prior to study enrollment; women of childbearing potential must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy

• After consent, discontinuation ("washout period") of any medications known to contribute significantly to the risk of QT prolongation or interfere with cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) mediated drug metabolism

• Patient agrees to discontinue St. John's Wort while receiving dasatinib therapy (discontinue St. John's Wort at least 5 days before starting dasatinib)

• Patient agrees that IV bisphosphonates will be withheld for the first eight weeks of dasatinib therapy due to risk of hypocalcemia

• Patient agrees to discontinue anti-coagulants and anti-platelet drugs; note: a low dose aspirin regimen (81mg QD) is permitted with close monitoring of the subject's platelets for a level >= 50,000/mm^3

Exclusion Criteria:

• Patients may not receive concurrent chemotherapy, radiotherapy, or immunotherapy

• Pleural or pericardial effusion of any grade

• Uncontrolled angina, > New York Heart Association (NYHA) class III congestive heart failure or myocardial infarction (MI) within 6 months prior to study enrollment

• Diagnosed congenital long QT syndrome

• Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes)

• Prolonged QTc interval on pre-entry electrocardiogram (> 450 msec)

• Subjects who are detained or imprisoned are not eligible

• History of significant bleeding disorder unrelated to cancer, including:

• Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease)

• Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies)

• May not take concomitant medications that are generally accepted to have a risk of causing Torsades de Pointes including: (patients must discontinue drug 7 days prior to starting dasatinib)

• Quinidine, procainamide, disopyramide

• Amiodarone, sotalol, ibutilide, dofetilide

• Erythromycin, clarithromycin

• Chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide

• Cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, sparfloxacin, lidoflazine

• Patients already taking other CYP inducers or inhibitors other than those listed above are eligible for the study only after principal investigator (PI) review; dose adjustments and/or monitoring of drug levels where applicable will be made as needed by the PI after consultation with pharmacy

• Women who:

• Are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 4 weeks after cessation of study drug, or

• Have a positive pregnancy test at baseline, or

• Are pregnant or breastfeeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	OHSU Knight Cancer Institute	Portland	Oregon	United States	97239

Sponsors and Collaborators

• OHSU Knight Cancer Institute
• Oregon Health and Science University

Investigators

• Principal Investigator: Stephen Spurgeon, OHSU Knight Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Stephen Spurgeon, Associate Professor, OHSU Knight Cancer Institute
• ClinicalTrials.gov Identifier: NCT01441882
• Other Study ID Numbers: IRB00006146; NCI-2011-03136; HEM 10010-L; OHSU-6146; BMS CA180-280; IRB00006146
• First Posted: Sep 28, 2011
• Last Update Posted: Apr 8, 2021
• Last Verified: Mar 1, 2021

• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Dasatinib

Study Results

Participant Flow

Arm/Group Title	Treatment (Dasatinib)
Arm/Group Description	Patients receive dasatinib PO QD during course 1 and if tolerated, BID in subsequent courses. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Dasatinib: Given PO Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies
Period Title: Overall Study
STARTED	19
COMPLETED	13
NOT COMPLETED	6

Baseline Characteristics

Arm/Group Title	Treatment (Dasatinib)
Arm/Group Description	Patients receive dasatinib PO QD during course 1 and if tolerated, BID in subsequent courses. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Dasatinib: Given PO Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies
Overall Participants	13
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	8 61.5%
>=65 years	5 38.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.6 (9.8)
Sex: Female, Male (Count of Participants)
Female	5 38.5%
Male	8 61.5%
Region of Enrollment (Count of Participants)
United States	13 100%

Outcome Measures

1. Primary Outcome

Title	The Number of Participants With In Vitro Dasatinib Sensitivity in Predicting Clinical Activity
Description	Defined by a decrease in absolute lymphocyte count, as determined by peripheral blood complete blood count (CBC) with differential or by bone marrow examination of 50 % and/or a decrease of detectable total lymph node size or spleen size by 50% (either by clinical examination contrast enhanced computed tomography [CT]).
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Dasatinib)
Arm/Group Description	Patients receive dasatinib PO QD during course 1 and if tolerated, BID in subsequent courses. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Dasatinib: Given PO Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies
Measure Participants	13
In vitro dasatinib sensitivity in predicting clini	5 38.5%
ABS lymph ct decrease > 50%	4 30.8%
Total lymph size decrease > 50%	4 30.8%
Spleen decrease by > 50%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment (Dasatinib)
	Comments	Percent change from baseline in responders compared to non-responders (lymph node size).
	Type of Statistical Test	Non-Inferiority
	Comments	A non-parametric two-sided Mann-Whitney test was run assuming non-Gaussian distributions. Two-tailed with 95% confidence intervals.
Statistical Test of Hypothesis	p-Value	0.0106
	Comments
	Method	t-test, 2 sided
	Comments	Threshold for statistical significance is 0.05.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment (Dasatinib)
	Comments	Percent change from baseline in responders compared to non-responders (Absolute Lymphocyte Count (ALC)).
	Type of Statistical Test	Non-Inferiority
	Comments	A non-parametric two-sided Mann-Whitney test was run assuming non-Gaussian distributions. Two-tailed with 95% confidence intervals.
Statistical Test of Hypothesis	p-Value	0.19860
	Comments
	Method	t-test, 2 sided
	Comments	Threshold for statistical significance is 0.05.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment (Dasatinib)
	Comments	Percent change from baseline in responders compared to non-responders (spleen size).
	Type of Statistical Test	Non-Inferiority
	Comments	A non-parametric two-sided Mann-Whitney test was run assuming non-Gaussian distributions. Two-tailed with 95% confidence intervals.
Statistical Test of Hypothesis	p-Value	0.5167
	Comments
	Method	t-test, 2 sided
	Comments	Threshold for statistical significance is 0.05.

2. Secondary Outcome

Title	Objective Response
Description	Proportion of patients achieving the endpoint along with its 95% exact binomial confidence interval will be presented. Complete Response (CR): present >=2 mos: no symptoms of CLL, normal findings on exam, ALC < 4.000/mm3, ANC >1.500/ mm3, platelet (PLT) count (ct) >100.000/ mm3, hemoglobin (Hgb) concentration >11 g/dL (untransfused), bone marrow (BM) lymphocytosis <30%, and no nodules (lymphoid aggregates) on BM biopsy. Partial Response (PR): present >=2 months: a reduction in prev. enlarged nodes, spleen, & liver by at least 50%. ANC >= 1.500/ mm3 or PLT ct >= 100.000/ mm3 or Hgb concentration >=11 g/dL or 50% improvement over pre-therapy reductions in Hgb concentration and/or PLT ct. Nodular PR: persistent BM nodules or infiltrates seen on BM biopsy those achieving a CR or PR. Stable Disease (SD): Does not meet CR or PR, but also not progressive disease (PD). PD: 50% size increase of lymph node, spleen, liver; or histologic (e.g. Richter's) transformation (per NCI and iwCLL).
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Dasatinib)
Arm/Group Description	Patients receive dasatinib PO QD during course 1 and if tolerated, BID in subsequent courses. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Dasatinib: Given PO Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies
Measure Participants	13
Complete Response (CR)	0 0%
Partial Response (PR)	2 15.4%
Partial Response with Lymphocytosis (PR-L)	2 15.4%
Stable Disease (SD)	8 61.5%
Progression	1 7.7%

3. Secondary Outcome

Title	Overall Survival
Description	Kaplan-Meier method will be used to estimate the survival curve.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Given the significant evolution of the treatment landscape, overall survival was no longer deemed to be a worthwhile/meaningful endpoint. Patients were lost to follow up and data was not collected.

Arm/Group Title	Treatment (Dasatinib)
Arm/Group Description	Patients receive dasatinib PO QD during course 1 and if tolerated, BID in subsequent courses. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Dasatinib: Given PO Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies
Measure Participants	0

4. Secondary Outcome

Title	Progression-free Survival
Description	Kaplan-Meier method will be used to estimate the survival curve.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Given the significant evolution of the treatment landscape, overall survival was no longer deemed to be a worthwhile/meaningful endpoint. Patients were lost to follow up and data was not collected.

Arm/Group Title	Treatment (Dasatinib)
Arm/Group Description	Patients receive dasatinib PO QD during course 1 and if tolerated, BID in subsequent courses. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Dasatinib: Given PO Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies
Measure Participants	0

5. Secondary Outcome

Title	Incidence of Adverse Events (Number of Participants Affected)
Description	Assessed According to the NCI Common Terminology Criteria for Adverse Events Version 4.0. Adverse events will be tabulated and summarized according to key reporting criteria (i.e., grade or seriousness, unanticipated, treatment attribution). Refer to the Adverse Event tables below for specific details.
Time Frame	Up to 4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Dasatinib)
Arm/Group Description	Patients receive dasatinib PO QD during course 1 and if tolerated, BID in subsequent courses. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Dasatinib: Given PO Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies
Measure Participants	13
Count of Participants [Participants]	8 61.5%

Adverse Events

Time Frame	Adverse events were collected within 30 days of discontinuation of study drug, up to 4 years.
Adverse Event Reporting Description	Adverse events were tabulated and summarized according to key reporting criteria (i.e., grade or seriousness, unanticipated, treatment attribution).
Arm/Group Title	Treatment (Dasatinib)
Arm/Group Description	Patients receive dasatinib PO QD during course 1 and if tolerated, BID in subsequent courses. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Dasatinib: Given PO Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies
All Cause Mortality
	Treatment (Dasatinib)
	Affected / at Risk (%)	# Events
Total	0/13 (0%)
Serious Adverse Events
	Treatment (Dasatinib)
	Affected / at Risk (%)	# Events
Total	8/13 (61.5%)
Blood and lymphatic system disorders
Edema	1/13 (7.7%)	1
Bilateral leg edema	1/13 (7.7%)	1
Leukocytosis	1/13 (7.7%)	1
Thrombocytopenia	2/13 (15.4%)	2
Neutropenia	1/13 (7.7%)	1
Anemia	2/13 (15.4%)	2
Hyperkalemia	1/13 (7.7%)	1
Eye disorders
Conjunctivitis	1/13 (7.7%)	1
Gastrointestinal disorders
Colitis	1/13 (7.7%)	1
General disorders
Fatigue	2/13 (15.4%)	2
vasovagal reaction	1/13 (7.7%)	1
Infections and infestations
Pneumonia	1/13 (7.7%)	1
Metabolism and nutrition disorders
Hypocalcemia	1/13 (7.7%)	1
Skin and subcutaneous tissue disorders
Facial Swelling	1/13 (7.7%)	1
basal cell carcinoma	1/13 (7.7%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Dasatinib)
	Affected / at Risk (%)	# Events
Total	0/13 (0%)

Limitations/Caveats

No limitations or caveats are noted at this time.

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.