Dasatinib With Fludarabine and Rituximab in Relapsed and Refractory CLL and SLL

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01173679
• Collaborator: Dana-Farber Cancer Institute (Other), Beth Israel Deaconess Medical Center (Other), Bristol-Myers Squibb (Industry)
• Enrollment: 10
• Locations: 3
• Arm: 1
• Duration (Months): 54
• Patients Per Site: 3.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) are similar diseases of the white blood cells and are typically treated the same way. Recent research shows that a key enzyme in CLL cells is responsible for cell survival. This enzyme is called LYN kinase. Laboratory studies show that inhibition of LYN kinase in CLL cells results in the death of CLL cells. Dasatinib has the ability to inhibit LYN kinase and, therefore, should have some effect on CLL cells. The purpose of this study is to see of the study drug dasatinib, in combination with fludarabine and rituximab, is safe and effective to use for people with relapsed or refractory CLL/SLL.

Condition or Disease	Intervention/Treatment	Phase
Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma	Drug: dasatinib; Drug: Rituximab; Drug: fludarabine	Phase 2

Detailed Description

• Since the purpose of the study is to determine the response rate of the 3 drug regimen, everyone who participates will receive the same dose of the study drug, dasatinib and the 2 standard drugs, fludarabine and rituximab.

• Participants will receive the drugs dasatinib, fludarabine, and rituximab at the following time points through each cycle of treatment. A cycle of study treatment is 28 days. Dasatinib pills will be taken orally each day for the first 2 weeks of each cycle. Fludarabine will be give intravenously on three days of each cycle (Days 3-5 in the first cycle, days 1-3 after that). Rituximab will be given intravenously with a total dose of 375 mg/m2 each cycle (split on Days 3+4 in the first cycle and at the discretion of the treating physician after that on Days 1-3).

• The following procedures will be repeated throughout the study: medical history review; physical exam; performance status test; blood tests and EKG. They will occur daily during the first week of treatment, then weekly for the rest of cycle 1. After cycle 1 these procedures will be done once a week for 4 weeks then once a month for 6 months.

• Tumor assessments will be repeated once every 2 months for the first six months of the study, and then once every 6 months after that.

• Blood samples will be obtained in the first 5 days of treatment for pharmacokinetic studies and pharmacodynamic studies.

• Participants that are benefiting from the study treatment after the first cycle can continue to receive an additional 6 cycles of study treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Dasatinib With Fludarabine and Rituximab in Relapsed and Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma
• Study Start Date: Jul 1, 2010
• Actual Primary Completion Date: Jan 1, 2015
• Actual Study Completion Date: Jan 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Other: dasatinib, rituximab, fludarabine Single-arm, open-label	Drug: dasatinib; Taken orally once a day on days 1-14 of each 28-day cycle; Drug: Rituximab; Given intravenously, 375 mg/m2 each cycle (dose split, given on Days 3+4 of cycle 1, variable after that).; Drug: fludarabine; Given intravenously, 25 mg/m2/day, for 3 doses per cycle (Days 3-5 in cycle 1, Days 1-3 after that)

Outcome Measures

Primary Outcome Measures

1. Response Rate [2 years]

   To describe the response rate of complete response (CR) and partial response (PR) to treatment with this drug combination (SD=stable disease, PD=progressive disease)

Secondary Outcome Measures

1. Progression-Free and Overall Survival [2 years]

   To describe the progression-free and overall surivial

2. Toxicities [2 years]

   Dasatinib may enhance the myelosuppression expected from fludarabine. This toxicity will be monitored with frequent CBC's. If after Day 21 of a cycle there is a grade 4 cytopenia, a dose reduction will occur in the next cycle of treatment, and that cycle cannot start until the ANC > 1,000 and the platelets > 25,000. There is also a risk for pleural effusions with dasatinib, but the risk will be low, since there is a break from dasatinib dosing on days 15-28 of each cycle. Nevertheless, if a grade 2 pleural effusion occurs, there will be a dose reduction in the next cycle of treatment.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• CLL/SLL with cells positive by flow cytometry (or immunostaining) for CD19, CD23, and CD5. Patients may be CD23 negative as long as they are also cyclin D1 negative or t(11;14) negative.

• Participants must have received at least 1 prior regimen containing a purine analogue or have received at least 2 chemotherapy regimens not containing a purine analogue. Patients may be refractory to single-agent purine analogue treatment, but patients may not be refractory to a combination of purine analogue with rituximab. Patients may have received rituximab.

• 18 years of age or older

• Able to take oral medications

• ECOG Performance Status of 2 or better

• Adequate organ function to tolerate chemotherapy

• Women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to the start of study drug administration and agree to use and utilize an adequate method of contraception throughout treatment and for at least 4 weeks after study is stopped.

• Require treatment based on 1996 NCI-WG criteria updated in 2008 by the IWCLL

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

• Patient agrees that IV bisphosphonates will be withheld for the first 8 weeks of dasatinib

Exclusion Criteria:

• Pregnant or breastfeeding women

• Uncontrolled angina, congestive heart failure, or MI within 6 months

• Diagnosed or suspected congenital long QT syndrome

• Any history of clinically significant ventricular arrhythmias

• Prolonged QTc interval on pre-entry ECG

• Uncontrolled hypertension

• Hypokalemia or hypomagnesemia that is not corrected prior to dasatinib administration

• Patients should not be taking drugs that are generally accepted to have a risk of causing Torsades de Pointes

• Known HIV positive

• Known significant bleeding disorder unrelated to CLL

• Any significant pleural or pericardial effusion

• Patients may not have another malignancy that is uncontrolled or requires treatment within a year of starting this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
2	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02115
3	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Massachusetts General Hospital
• Dana-Farber Cancer Institute
• Beth Israel Deaconess Medical Center
• Bristol-Myers Squibb

Investigators

• Principal Investigator: Philip Amrein, MD, Massachusetts General Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Philip C. Amrein, M.D., Assistant Professor of Medicine, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT01173679
• Other Study ID Numbers: 09-325
• First Posted: Aug 2, 2010
• Last Update Posted: Apr 14, 2017
• Last Verified: Mar 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Philip C. Amrein, M.D., Assistant Professor of Medicine, Massachusetts General Hospital: CLL; fludarabine; rituximab; dasatinib; refractory; relapsed
• Additional relevant MeSH terms: Lymphoma; Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; Fludarabine; Dasatinib

Study Results

Participant Flow

Arm/Group Title	Dasatinib, Rituximab, Fludarabine
Arm/Group Description	Single-arm dasatinib: Taken orally once a day on days 1-14 of each 28-day cycle Rituximab: Given intravenously, 375 mg/m2 each cycle (dose split, given on Days 3+4 of cycle 1, variable after that). fludarabine: Given intravenously, 25 mg/m2/day, for 3 doses per cycle (Days 3-5 in cycle 1, Days 1-3 after that)
Period Title: Overall Study
STARTED	10
COMPLETED	9
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Dasatinib, Rituximab, Fludarabine
Arm/Group Description	Single-arm dasatinib: Taken orally once a day on days 1-14 of each 28-day cycle Rituximab: Given intravenously, 375 mg/m2 each cycle (dose split, given on Days 3+4 of cycle 1, variable after that). fludarabine: Given intravenously, 25 mg/m2/day, for 3 doses per cycle (Days 3-5 in cycle 1, Days 1-3 after that)
Overall Participants	10
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	68
Sex: Female, Male (Count of Participants)
Female	3 30%
Male	7 70%
Region of Enrollment (Count of Participants)
United States	10 100%

Outcome Measures

1. Primary Outcome

Title	Response Rate
Description	To describe the response rate of complete response (CR) and partial response (PR) to treatment with this drug combination (SD=stable disease, PD=progressive disease)
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dasatinib, Rituximab, Fludarabine
Arm/Group Description	Single-arm, open-label dasatinib: Taken orally once a day on days 1-14 of each 28-day cycle Rituximab: Given intravenously, 375 mg/m2 each cycle (dose split, given on Days 3+4 of cycle 1, variable after that). fludarabine: Given intravenously, 25 mg/m2/day, for 3 doses per cycle (Days 3-5 in cycle 1, Days 1-3 after that)
Measure Participants	10
CR	2 20%
PR	2 20%
SD	5 50%
PD	1 10%

2. Secondary Outcome

Title	Progression-Free and Overall Survival
Description	To describe the progression-free and overall surivial
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dasatinib, Rituximab, Fludarabine
Arm/Group Description	Single-arm dasatinib: Taken orally once a day on days 1-14 of each 28-day cycle Rituximab: Given intravenously, 375 mg/m2 each cycle (dose split, given on Days 3+4 of cycle 1, variable after that). fludarabine: Given intravenously, 25 mg/m2/day, for 3 doses per cycle (Days 3-5 in cycle 1, Days 1-3 after that)
Measure Participants	10
Progression-free survival	8.75
Overall survival	24

3. Secondary Outcome

Title	Toxicities
Description	Dasatinib may enhance the myelosuppression expected from fludarabine. This toxicity will be monitored with frequent CBC's. If after Day 21 of a cycle there is a grade 4 cytopenia, a dose reduction will occur in the next cycle of treatment, and that cycle cannot start until the ANC > 1,000 and the platelets > 25,000. There is also a risk for pleural effusions with dasatinib, but the risk will be low, since there is a break from dasatinib dosing on days 15-28 of each cycle. Nevertheless, if a grade 2 pleural effusion occurs, there will be a dose reduction in the next cycle of treatment.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dasatinib, Rituximab, Fludarabine
Arm/Group Description	Single-arm dasatinib: Taken orally once a day on days 1-14 of each 28-day cycle Rituximab: Given intravenously, 375 mg/m2 each cycle (dose split, given on Days 3+4 of cycle 1, variable after that). fludarabine: Given intravenously, 25 mg/m2/day, for 3 doses per cycle (Days 3-5 in cycle 1, Days 1-3 after that)
Measure Participants	10
3	4 40%
4	3 30%
5	0 0%
Did not have any	3 30%
3	3 30%
4	3 30%
5	0 0%
Did not have any	4 40%
3	1 10%
4	0 0%
5	0 0%
Did not have any	9 90%
3	1 10%
4	0 0%
5	0 0%
Did not have any	9 90%
3	1 10%
4	0 0%
5	0 0%
Did not have any	9 90%
3	1 10%
4	0 0%
5	0 0%
Did not have any	9 90%
3	1 10%
4	0 0%
5	0 0%
Did not have any	9 90%
3	0 0%
4	0 0%
5	1 10%
Did not have any	9 90%

Adverse Events

Arm/Group Title	Dasatinib, Rituximab, Fludarabine
Arm/Group Description	Single-arm dasatinib: Taken orally once a day on days 1-14 of each 28-day cycle Rituximab: Given intravenously, 375 mg/m2 each cycle (dose split, given on Days 3+4 of cycle 1, variable after that). fludarabine: Given intravenously, 25 mg/m2/day, for 3 doses per cycle (Days 3-5 in cycle 1, Days 1-3 after that)
All Cause Mortality
	Dasatinib, Rituximab, Fludarabine
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Dasatinib, Rituximab, Fludarabine
	Affected / at Risk (%)	# Events
Total	2/10 (20%)
Respiratory, thoracic and mediastinal disorders
Pneumonitis	1/10 (10%)	1
Pneumonia	1/10 (10%)	1
Other (Not Including Serious) Adverse Events
	Dasatinib, Rituximab, Fludarabine
	Affected / at Risk (%)	# Events
Total	10/10 (100%)
Blood and lymphatic system disorders
Anemia	5/10 (50%)	14
Febrile neutropenia	3/10 (30%)	4
Thrombotic thrombocytopenic purpura	2/10 (20%)	2
Leukocytosis	1/10 (10%)	2
Platelets	1/10 (10%)	1
Cardiac disorders
Heart failure	1/10 (10%)	1
Endocrine disorders
Hyperthyroidism	1/10 (10%)	1
Eye disorders
Conjunctivitis	1/10 (10%)	1
Gastrointestinal disorders
Nausea	5/10 (50%)	7
Diarrhea	4/10 (40%)	4
Abdominal pain	3/10 (30%)	4
Constipation	2/10 (20%)	2
Vomiting	2/10 (20%)	2
Ascites	1/10 (10%)	1
Dyspepsia	1/10 (10%)	1
Gastritis	1/10 (10%)	1
Gastrointestinal pain	1/10 (10%)	1
Ileal perforation	1/10 (10%)	1
Gastrointestinal disorders - Other, specify	1/10 (10%)	1
Taste disturbance	1/10 (10%)	1
General disorders
Fatigue	5/10 (50%)	18
Chills	4/10 (40%)	8
General disorders and administration site conditions - Other, specify	3/10 (30%)	4
Edema limbs	2/10 (20%)	3
Fever	2/10 (20%)	2
Infusion related reaction	1/10 (10%)	1
Pain	1/10 (10%)	1
Back- pain	1/10 (10%)	1
	8/10 (80%)	10
Immune system disorders
Allergic reaction	1/10 (10%)	1
Infections and infestations
Mucosal infection	2/10 (20%)	3
Upper respiratory infection	2/10 (20%)	2
Infections and infestations - Other, specify	2/10 (20%)	2
Gum infection	1/10 (10%)	1
Skin infection	1/10 (10%)	1
Injury, poisoning and procedural complications
Bruising	1/10 (10%)	1
Investigations
Platelet count decreased	5/10 (50%)	14
White blood cell decreased	4/10 (40%)	11
Blood bilirubin increased	4/10 (40%)	9
Neutrophil count decreased	4/10 (40%)	5
Alkaline phosphatase increased	2/10 (20%)	4
Aspartate aminotransferase increased	2/10 (20%)	4
Lymphocyte count increased	2/10 (20%)	3
Lymphocyte count decreased	2/10 (20%)	2
Alanine aminotransferase increased	1/10 (10%)	2
Creatinine increased	1/10 (10%)	1
Metabolism and nutrition disorders
Hyperglycemia	4/10 (40%)	8
Hypophosphatemia	3/10 (30%)	3
Hyperkalemia	2/10 (20%)	3
Dehydration	2/10 (20%)	2
Hyperuricemia	2/10 (20%)	2
Hypocalcemia	2/10 (20%)	2
Hyponatremia	2/10 (20%)	2
Anorexia	1/10 (10%)	1
Hypermagnesemia	1/10 (10%)	1
Hypernatremia	1/10 (10%)	1
Hypoalbuminemia	1/10 (10%)	1
Hypokalemia	1/10 (10%)	1
Musculoskeletal and connective tissue disorders
Pain in extremity	2/10 (20%)	5
Generalized muscle weakness	2/10 (20%)	2
Muscle weakness right-sided	2/10 (20%)	2
Back pain	1/10 (10%)	1
Chest wall pain	1/10 (10%)	1
Muscle weakness lower limb	1/10 (10%)	1
Nervous system disorders
Acoustic nerve disorder NOS	1/10 (10%)	1
Brachial plexopathy	1/10 (10%)	1
Headache	1/10 (10%)	1
Movements involuntary	1/10 (10%)	1
Renal and urinary disorders
Acute kidney injury	1/10 (10%)	1
Respiratory, thoracic and mediastinal disorders
Cough	4/10 (40%)	12
Dyspnea	4/10 (40%)	9
Bronchial stricture	1/10 (10%)	2
Allergic rhinitis	1/10 (10%)	1
Bronchial obstruction	1/10 (10%)	1
Laryngopharyngeal dysesthesia	1/10 (10%)	1
Pleural effusion	1/10 (10%)	1
Skin and subcutaneous tissue disorders
Erythema multiforme	1/10 (10%)	1
Pruritus	1/10 (10%)	1
Skin and subcutaneous tissue disorders - Other, specify	1/10 (10%)	1
Vascular disorders
Hypertension	1/10 (10%)	1

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.