DASATINIB, Waldenstrom Macroglobulinemia
Conditions
Keywords
Waldenstrom Macroglobulinemia, DASATINIB
Brief summary
This is Phase I pilot, single center study designed to explore the safety of Dasatinib in symptomatic Waldenström Macroglobulinemia participants who are progressing on ibrutinib therapy with BTK Cys481 or PLCG2 mutations
Detailed description
This research study is a Pilot Study, which is the first time investigators are examining this drug in patients with Waldenström Macroglobulinemia who have progressed on ibrutinib. Patients who fulfill eligibility criteria will be entered into the trial to receive Dasatinib After the screening procedures confirm participation in the research study: The participant will be given a study drug-dosing calendar for each treatment cycle. In this research study, the investigators are planning to give Dasatinib, which is a targeted therapy intended to treat cancer by binding to the target protein called BTK. * BTK is believed to be an important target for treatment of patients with specific gene mutations. Some patients who have disease progression after taking ibrutinib have these gene mutations. * Making treatment decisions based on genetic testing is investigational, and the FDA has not approved this genetic testing. The U.S. Food and Drug Administration (FDA) has not approved Dasatinib for Waldenström Macroglobulinemia but it has been approved for other uses. Dasatinib is produced by Bristol-Myers Squibb.
Interventions
DRUGDasatinib
Oral, daily, dosing per protocol, once a day for cycle
Sponsors
Bristol-Myers Squibb
Jorge J. Castillo, MD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants must meet the following criteria on screening examination to be eligible to participate. Screening evaluations including consent, physical exam, and laboratory assessments will be done within 30 days prior to Cycle 1 Day 1. Bone marrow biopsy & aspirate, and CT C/A/P will be done within 90 days prior to Cycle 1 Day 1. * Clinicopathological diagnosis of Waldenstrom's Macroglobulinemia * Known tumor expression of mutated MYD88 performed by a CLIA certified laboratory. * Participants must have a BTKCys481 and/or PLCγ2 mutation. Genomic alterations must be confirmed via sequencing performed at NeoGenomics Laboratories * At least one previous therapy, with ibrutinib as the most recent treatment. Participants may remain on ibrutinib therapy during screening. A 1 day washout before starting dasatinib is required. * Documented disease progression on last regimen (ibrutinib) per the Sixth International Workshop on WM. One or more of the following: * 25% increase in serum IgM level with at least 500 mg/dL absolute increase from nadir with re-confirmation * Progression of clinically significant disease related symptoms * Symptomatic disease meeting criteria for treatment using consensus panel criteria from the Second International Workshop on WM \[26\]. One or more of the following: * Constitutional symptoms * Progressive or symptomatic lymphadenopathy or splenomegaly * Hemoglobin \<10 g/dL * Platelet count \<100 k/uL * Symptomatic peripheral neuropathy * Systemic amyloidosis * Renal insufficiency * Symptomatic cryoglobulinemia * Age 18 years or older * Measurable disease, defined as presence of immunoglobulin M (IgM) paraprotein with a minimum serum IgM level of \> 2 times the upper limit normal. * ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A) * Women of childbearing potential: Females of childbearing potential (FCBP) must agree to use two reliable forms of contraception simultaneously or have or will have complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) while participating in the study; and 2) for at least 28 days after discontinuation from the study. FCBP must be referred to a qualified provider of contraceptive methods if needed. * Men must agree to use a latex condom during sexual contact with a female of childbearing potential (FCBP) even if they have had a successful vasectomy. * Participants must have normal organ and marrow function as defined below: * Absolute neutrophil count ≥500/ uL (Growth factor not permitted) * Platelets ≥50,000/ uL (Platelet transfusion not permitted) * Hemoglobin ≥ 7 g/dL (RBC transfusion permitted) * Total bilirubin ≤ 2 mg/dL * Potassium ≥ LLN * Magnesium ≥ LLN * AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal * Estimated GFR ≥ 30 ml/min * Able to swallow pills. * Able to adhere to the study visit schedule and other protocol requirements. * Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
* Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study: * Lactating or pregnant women. * Participants who are receiving any other investigational agents. * Prior therapy with BCR-ABL inhibitors. * Known CNS lymphoma. * Symptomatic hyperviscosity requiring urgent therapy. * Human Immunodeficiency Virus (HIV), active infection with Hepatitis B Virus (HBV), and/or Hepatitis C Virus (HCV). * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, pleural or pericardial effusion, unstable angina pectoris, cardiac arrhythmia, QT Prolongation, or psychiatric illness/social situations that would limit compliance with study requirements. * Prolonged QTc interval on pre-entry electrocardiogram (\> 450 msec) * History clinically significant ventricular arrhythmias such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes * Known history of alcohol or drug abuse * On any active therapy for other malignancies with the exception of topical therapies for basal cell or squamous cell cancers of the skin. * History of non-compliance to medical regimens. * Treatment with strong CYP3A4/5 inhibitors or inducers * Participants who are taking St. Johns Wort. Must discontinue at least 5 days before starting dasatinib. * Treatment with H2 Antagonists and proton pump inhibitors
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With at Least One Treatment-Emergent Adverse Event | 2 years | Count of participants who experience a treatment-emergent adverse event |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate | 2 years | Percentage of patients with Complete Response (CR). Complete Response requires resolution of all symptoms, normalization of serum IgM with disappearance of IgM paraprotein, and resolution of any adenopathy or splenomegaly. |
| Very Good Partial Response Rate | 2 years | Percentage of patients with very good partial response (VGPR) to therapy. (VGPR is \>90% reduction in serum IgM from baseline) |
| Partial Response Rate | 2 years | Percentage of patients with partial response (PR) to therapy. (PR is 50-89% reduction in serum IgM from baseline) |
| Minimal Response Rate | 2 years | Percentage of patients with Minor Responses to therapy. (MR is 25-49% reduction in serum IgM from baseline) |
| Overall Response Rate | 2 years | Percentage of patients with an Overall Response. Overall Response Rate= Minor response (\>25%-50% reduction in serum IgM from baseline) + Partial Response (\>50-90% reduction in serum IgM from baseline) + Very Good Partial Response (\>90% reduction in serum IgM from baseline) + Complete Response (resolution of all symptoms, normalization of serum IgM with disappearance of IgM paraprotein, resolution of any adenopathy or splenomegaly). |
| Progressive Disease Rate | From first dose through disease progression, up to 2 years from baseline | Percentage of patients with who experienced disease progression on study. PD is \>25% increase in serum IgM from baseline with an absolute increase of at least 500 mg/dL, or progression of clinically significant disease related symptoms. Death from any cause or initiation of a new anti-neoplastic therapy will also be considered a progression event. An increase of 1 cm in any axis for adenopathy, or 2 cm in the craniocaudal axis of the spleen will be considered evidence of progression of extramedullary disease. Development of Bing Neel syndrome, or other extramedullary disease manifestations, as well as disease transformation will be considered as progressive events. |
| Progression Free Survival | From first dose through disease progression, up to 2 years from baseline | The amount of time between starting treatment and experiencing disease progression. PD is \>25% increase in serum IgM from baseline with an absolute increase of at least 500 mg/dL, or progression of clinically significant disease related symptoms. Death from any cause or initiation of a new anti-neoplastic therapy will also be considered a progression event. An increase of 1 cm in any axis for adenopathy, or 2 cm in the craniocaudal axis of the spleen will be considered evidence of progression of extramedullary disease. Development of Bing Neel syndrome, or other extramedullary disease manifestations, as well as disease transformation will be considered as progressive events. |
| Time to Next Therapy (TTNT) | From first dose through initiation of new therapy, up to 2 years from baseline | The amount of time between starting study treatment and initiating a new therapy |
| Overall Survival | From first dose through death, up to 2 years from baseline | The number of participants who are still alive at the end of follow-up. Participants were observed for up to 2 years after discontinuing study therapy for survival status. |
| Stable Disease Rate | 2 years | Percentage of patients with Stable disease to therapy. (SD is \<25% reduction in serum IgM from baseline). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dasatinib \-- After the screening procedures confirm participation in the research study: The participant will be given a study drug-dosing calendar for each treatment cycle.
Dasatinib: Oral Study Drug(s):
* Each study treatment cycle lasts 4 weeks during which time you will be taking the study drug one time per day.
* This will continue for up to 24 cycles.
Dasatinib: Oral, daily, dosing per protocol, once a day for cycle | 3 |
| Total | 3 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lack of Efficacy | 2 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Dasatinib |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Age, Continuous | 73 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Region of Enrollment United States | 3 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 3 |
| other Total, other adverse events | 3 / 3 |
| serious Total, serious adverse events | 2 / 3 |
Outcome results
Primary
Number of Participants With at Least One Treatment-Emergent Adverse Event
Count of participants who experience a treatment-emergent adverse event
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dasatinib | Number of Participants With at Least One Treatment-Emergent Adverse Event | 3 Participants |
Secondary
Complete Response Rate
Percentage of patients with Complete Response (CR). Complete Response requires resolution of all symptoms, normalization of serum IgM with disappearance of IgM paraprotein, and resolution of any adenopathy or splenomegaly.
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dasatinib | Complete Response Rate | 0 Participants |
Secondary
Minimal Response Rate
Percentage of patients with Minor Responses to therapy. (MR is 25-49% reduction in serum IgM from baseline)
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dasatinib | Minimal Response Rate | 0 Participants |
Secondary
Overall Response Rate
Percentage of patients with an Overall Response. Overall Response Rate= Minor response (\>25%-50% reduction in serum IgM from baseline) + Partial Response (\>50-90% reduction in serum IgM from baseline) + Very Good Partial Response (\>90% reduction in serum IgM from baseline) + Complete Response (resolution of all symptoms, normalization of serum IgM with disappearance of IgM paraprotein, resolution of any adenopathy or splenomegaly).
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dasatinib | Overall Response Rate | 0 Participants |
Secondary
Overall Survival
The number of participants who are still alive at the end of follow-up. Participants were observed for up to 2 years after discontinuing study therapy for survival status.
Time frame: From first dose through death, up to 2 years from baseline
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dasatinib | Overall Survival | 2 Participants |
Secondary
Partial Response Rate
Percentage of patients with partial response (PR) to therapy. (PR is 50-89% reduction in serum IgM from baseline)
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dasatinib | Partial Response Rate | 0 Participants |
Secondary
Progression Free Survival
The amount of time between starting treatment and experiencing disease progression. PD is \>25% increase in serum IgM from baseline with an absolute increase of at least 500 mg/dL, or progression of clinically significant disease related symptoms. Death from any cause or initiation of a new anti-neoplastic therapy will also be considered a progression event. An increase of 1 cm in any axis for adenopathy, or 2 cm in the craniocaudal axis of the spleen will be considered evidence of progression of extramedullary disease. Development of Bing Neel syndrome, or other extramedullary disease manifestations, as well as disease transformation will be considered as progressive events.
Time frame: From first dose through disease progression, up to 2 years from baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasatinib | Progression Free Survival | 5 months |
Secondary
Progressive Disease Rate
Percentage of patients with who experienced disease progression on study. PD is \>25% increase in serum IgM from baseline with an absolute increase of at least 500 mg/dL, or progression of clinically significant disease related symptoms. Death from any cause or initiation of a new anti-neoplastic therapy will also be considered a progression event. An increase of 1 cm in any axis for adenopathy, or 2 cm in the craniocaudal axis of the spleen will be considered evidence of progression of extramedullary disease. Development of Bing Neel syndrome, or other extramedullary disease manifestations, as well as disease transformation will be considered as progressive events.
Time frame: From first dose through disease progression, up to 2 years from baseline
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dasatinib | Progressive Disease Rate | 2 Participants |
Secondary
Stable Disease Rate
Percentage of patients with Stable disease to therapy. (SD is \<25% reduction in serum IgM from baseline).
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dasatinib | Stable Disease Rate | 3 Participants |
Secondary
Time to Next Therapy (TTNT)
The amount of time between starting study treatment and initiating a new therapy
Time frame: From first dose through initiation of new therapy, up to 2 years from baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasatinib | Time to Next Therapy (TTNT) | 6 months |
Secondary
Very Good Partial Response Rate
Percentage of patients with very good partial response (VGPR) to therapy. (VGPR is \>90% reduction in serum IgM from baseline)
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dasatinib | Very Good Partial Response Rate | 0 Participants |