Non-Hodgkin's Lymphoma
Conditions
Keywords
Non-Hodgkins Lymphoma, Relapsed Non Hodgkins Lymphoma, Refractory Non Hodgkins Lymphoma, Dasatinib
Brief summary
Primary Objective: * To determine the maximum tolerated dose (MTD) of Dasatinib in relapsed or refractory non-hodgkin's lymphoma (NHL) patients and to determine the safety of Dasatinib in NHL. Secondary Objectives: * To assess the complete and overall response rates for all Phase I and Phase II patients and to determine overall survival and event free survival for all Phase I and Phase II patients. * To assay the levels of kinase activity in NHL specimens and correlate this activity to patient outcomes.
Detailed description
Primary: * To determine the Maximum Tolerated Dose (MTD) of Dasatinib in relapsed or refractory Non-Hodgkin's lymphoma (NHL) patients and to determine the safety of Dasatinib in NHL Secondary Objective: * To assess the complete and overall response rates for all Phase I and Phase II patients and to assay the levels of kinase activity in NHL specimens and correlate this activity to patient outcomes. * To determine overall survival and event free survival for all Phase I and Phase II patients. Treatment Plan This study has two phases of treatment, Phase I and Phase II. The Phase I portion of the trial will consist of a dose escalation plan with 3-6 patients being enrolled into each dose cohort. The doses of Dasatinib used in Phase I are 100 mg, 150 mg, and 200 mg. The dose that is found to be tolerated the best and also has the best treatment results will be used for Phase II. An additional 29 patients will be enrolled into Phase II. All patients will receive Dasatinib in this study. Dasatinib will be administered orally (by mouth) once daily for 28 day cycles. A cycle will be considered 28 days. Dosing will be continuous with no interruptions, unless instructed to interrupt treatment by the treating physician. The patient will be restaged after every 2 cycles of therapy, every even cycle. Therapy may continue as long as there are no clinical signs of NHL progressing and the patient is tolerating the treatment with no side effects related to the therapy. If the patient is removed from study for any reason, he/she will be followed for survival until death.
Interventions
DRUGDasatinib
Dasatinib will be orally administered once daily for 28 day cycles. There will be three dose cohorts for the Dasatinib in the Phase I portion of this trial. A minimum of three patients will be enrolled into each of the following dose cohorts: Dose cohort # 1 will be 100 mg per day Dose cohort # 2 will be 150 mg per day Dose cohort # 3 will be 200 mg per day The MTD will be determined in the Phase I portion of this trial.
DRUGDasatinib Maximum Tolerated Dose
An additional 29 patients using the Two-Stage Simon design will be enrolled into Phase II using the MTD determined in Phase I.
Sponsors
Bristol-Myers Squibb
University of Nebraska
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed diagnosis of non-hodgkin's lymphoma that is recurrent or refractory after at least one prior therapy and for which no other potentially curative therapy is available. * Subject, age \> or = 19 years * Performance status (ECOG) 0-2 * Patients must have relapsed or refractory disease after at least one prior systemic therapy, with at least a 3 week interval from the completion of the most recent chemotherapy or radiotherapy regimen. Recover to ≤ grade 1 from all toxicities related to the prior treatments is required. * Patients must be ineligible or relapsed after an autologous or allogeneic stem cell transplant if clinically appropriate. * Adequate Laboratory Parameters: * ANC ≥ 1000/μL * Platelet count ≥ 50,000/μL * Total bilirubin \< 2.0 times the institutional upper limit of normal (ULN) * Hepatic enzymes (AST, ALT ) ≤ 2.5 times the institutional ULN * Serum creatinine \< 2.0 times the institutional ULN * PTT within institutional normal limits * Ability to take oral medication (dasatinib must be swallowed whole) * Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (sensitivity \< or = 25IU 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 6 months after study drug is stopped * Signed written informed consent including HIPAA according to institutional guidelines
Exclusion criteria
* No malignancy \[other than the one treated in this study\] which required systemic treatment within the past 3 years. * Concurrent medical condition which may increase the risk of toxicity, including: * Clinically significant pleural or pericardial effusion * Clinically-significant coagulation or platelet function disorder (e.g. known von Willebrand's disease) * Cardiac Symptoms, consider the following: * Uncontrolled angina, congestive heart failure or MI within (6 months) * 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 with hypokalemia or hypomagnesemia if it cannot be corrected * 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) * Ongoing or recent (\< or = 3 months) significant gastrointestinal bleeding * Concomitant Medications, consider the following prohibitions: * Drugs 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, pentamidine, sparfloxacin, lidoflazine. * The concomitant use of H2 blockers or proton pump inhibitors with dasatinib is not recommended. The use of antacids should be considered in place of H2 blockers or proton pump inhibitors in patients receiving dasatinib therapy. * Patient agrees to discontinue St. Johns Wort while receiving dasatinib therapy * Patient agrees that IV bisphosphonates will be withheld for the first 8 weeks of dasatinib therapy due to risk of hypocalcemia. * Patient may not be receiving any prohibited CYP3A4 inhibitors * Women: * Are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 4 weeks 6 months after cessation of study drug * Have a positive pregnancy test at baseline * Are pregnant or breastfeeding * Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Maximum Tolerated Dose | after 1-28 day cycle of therapy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Response Rates | after 2-28 day cycles of therapy | The Objective response rate (CR+PR) and the Clinical Benefit Rate (CR+PR+SD) were calculated according to revised response criteria for malignant lymphoma (Cheson) CR - Complete response is defined as: Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present prior to therapy. PR - Partial response is defined as: ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses. SD - Stable Disease is define as: Failing to attain the criteria needed for a PR, but not fulfilling those for progressive disease. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase I Participants Dasatinib will be orally administered once daily for 28 day cycles.
There will be three dose cohorts for the Dasatinib in the Phase I portion of this trial. A minimum of three patients will be enrolled into each of the following dose cohorts:
Dose cohort # 1 will be 100 mg per day Dose cohort # 2 will be 150 mg per day Dose cohort # 3 will be 200 mg per day | 16 |
| Phase II Participants Dasatinib:
The MTD will be determined in the Phase I portion of this trial. An additional 29 patients using the Two-Stage Simon design will be enrolled into Phase II using the MTD determined in Phase I. | 22 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Not evaluable | 0 | 0 | 2 | 7 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 2 | 3 |
Baseline characteristics
| Characteristic | Phase I Participants | Phase II Participants | Total |
|---|---|---|---|
| Age, Continuous | 59 years | 61 years | 59 years |
| Race/Ethnicity, Customized Ethnic Origin Black, Not Hispanic | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Ethnic Origin Caucasian | 16 Participants | 19 Participants | 35 Participants |
| Race/Ethnicity, Customized Ethnic Origin Hispanic | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Ethnic Origin Other | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United States | 16 Participants | 22 Participants | 38 Participants |
| Sex: Female, Male Female | 7 Participants | 8 Participants | 15 Participants |
| Sex: Female, Male Male | 9 Participants | 14 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 14 | 4 / 19 |
| other Total, other adverse events | 14 / 14 | 18 / 19 |
| serious Total, serious adverse events | 7 / 14 | 9 / 19 |
Outcome results
Primary
Maximum Tolerated Dose
Time frame: after 1-28 day cycle of therapy
Population: Two subjects enrolled in Phase 1 of the study were never treated and not included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Phase I Participants | Maximum Tolerated Dose | 200 milligrams PO daily |
Secondary
Number of Participants With Clinical Response Rates
The Objective response rate (CR+PR) and the Clinical Benefit Rate (CR+PR+SD) were calculated according to revised response criteria for malignant lymphoma (Cheson) CR - Complete response is defined as: Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present prior to therapy. PR - Partial response is defined as: ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses. SD - Stable Disease is define as: Failing to attain the criteria needed for a PR, but not fulfilling those for progressive disease.
Time frame: after 2-28 day cycles of therapy
Population: Of the 38 participants consented only 24 for were evaluable. See the participant flow section.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Phase I Participants | Number of Participants With Clinical Response Rates | Objective response rate | 7 Participants |
| All Phase I Participants | Number of Participants With Clinical Response Rates | Clinical Benefit Rate | 17 Participants |