There are 17 clinical trials
The objective is to compare efficacy and safety of AB1010 at 3 or 6 mg/kg/day in treatment of patients with mastocytosis with handicap and bearing activating point mutations in the phosphotransferase domain of c-Kit such as the main mutation Asp-816-Val (D816V).
A 12-week With Possible Extension, Prospective, Multicenter, Randomized, Open-label, 2-parallel Group, Phase IIa Study to Compare Efficacy and Safety of AB1010 at 3 or 6 mg/kg/Day in Treatment of Patients With Mastocytosis With Handicap and Bearing Activating Point Mutations in the Phosphotransferase Domain of c-Kit Such as the Main Mutation Asp-816-Val (D816V). --- Asp-816-Val ---
A 12-week With Possible Extension, Prospective, Multicenter, Randomized, Open-label, 2-parallel Group, Phase IIa Study to Compare Efficacy and Safety of AB1010 at 3 or 6 mg/kg/Day in Treatment of Patients With Mastocytosis With Handicap and Bearing Activating Point Mutations in the Phosphotransferase Domain of c-Kit Such as the Main Mutation Asp-816-Val (D816V). --- Asp-816-Val --- --- D816V ---
Masitinib in Patients With Mastocytosis With Handicap and Bearing the D816V Mutation The objective is to compare efficacy and safety of AB1010 at 3 or 6 mg/kg/day in treatment of patients with mastocytosis with handicap and bearing activating point mutations in the phosphotransferase domain of c-Kit such as the main mutation Asp-816-Val (D816V). --- D816V ---
Masitinib in Patients With Mastocytosis With Handicap and Bearing the D816V Mutation The objective is to compare efficacy and safety of AB1010 at 3 or 6 mg/kg/day in treatment of patients with mastocytosis with handicap and bearing activating point mutations in the phosphotransferase domain of c-Kit such as the main mutation Asp-816-Val (D816V). --- D816V --- --- Asp-816-Val ---
Masitinib in Patients With Mastocytosis With Handicap and Bearing the D816V Mutation The objective is to compare efficacy and safety of AB1010 at 3 or 6 mg/kg/day in treatment of patients with mastocytosis with handicap and bearing activating point mutations in the phosphotransferase domain of c-Kit such as the main mutation Asp-816-Val (D816V). --- D816V --- --- Asp-816-Val --- --- D816V ---
Pruritus score at week 12 Number of flushes per week at week 12 Hamilton score at week 12 Fatigue Impact scale at week 12. Inclusion Criteria: 1. Patients with one of the following documented mastocytosis: - Smouldering systemic mastocytosis - Indolent systemic mastocytosis with organomegaly - Indolent Systemic Mastocytosis having 2 infiltrated organs (skin and bone-marrow) - Any mastocytosis with in the last 6 months at least 3 anaphylactic shocks or syncops requiring either use of adrenaline or medical assistance - Cutaneous Mastocytosis (CM) 2. Skin biopsy-documented mastocytosis and evaluable disease based upon: - Histological criteria: typical infiltrates of mast cells in a multifocal or diffuse pattern in skin biopsy - Clinical criteria: typical skin lesions (maculopapular, urticaria pigmentosa, mastocytoma) 3. Missing data (c-kit molecular analysis not done) or documented presence of an activating point mutation in the phosphotransferase domain of c-kit such as D816V c-kit mutation in at least one infiltrated organ (bone marrow or skin) 4. Refractory to at least one of the symptomatic treatments such as: - Anti H1 - Anti H2 - Proton pump inhibitor - Osteoclast inhibitor - Cromoglycate Sodium - Antileukotriene - Other therapies used for the symptomatic care 5. Handicap defined as at least one of the following handicaps: - pruritus score ≥ 6 - number of flushes per week ≥ 7 - number of stools per day ≥ 4 , - number of mictions per day ≥ 8 , - QLQ-C30 score ≥ 60, - Hamilton score ≥ 10 Exclusion Criteria: 1. Patients with one of the following mastocytosis: - Systemic Mastocytosis with an Associated clonal Hematologic Non Mast cell lineage Disease (SM-AHNMD) - Mast cell leukemia (MCL) - Aggressive systemic mastocytosis (ASM) 2. Patient with a major surgery within 2 weeks prior to study entry 3. --- D816V ---
- Patient has a known diagnosis of human immunodeficiency virus (HIV) infection Inclusion Criteria: 1. Patients with one of the following documented mastocytosis: - Smouldering systemic mastocytosis - Indolent systemic mastocytosis with organomegaly - Indolent Systemic Mastocytosis having 2 infiltrated organs (skin and bone-marrow) - Any mastocytosis with in the last 6 months at least 3 anaphylactic shocks or syncops requiring either use of adrenaline or medical assistance - Cutaneous Mastocytosis (CM) 2. Skin biopsy-documented mastocytosis and evaluable disease based upon: - Histological criteria: typical infiltrates of mast cells in a multifocal or diffuse pattern in skin biopsy - Clinical criteria: typical skin lesions (maculopapular, urticaria pigmentosa, mastocytoma) 3. Missing data (c-kit molecular analysis not done) or documented presence of an activating point mutation in the phosphotransferase domain of c-kit such as D816V c-kit mutation in at least one infiltrated organ (bone marrow or skin) 4. Refractory to at least one of the symptomatic treatments such as: - Anti H1 - Anti H2 - Proton pump inhibitor - Osteoclast inhibitor - Cromoglycate Sodium - Antileukotriene - Other therapies used for the symptomatic care 5. Handicap defined as at least one of the following handicaps: - pruritus score ≥ 6 - number of flushes per week ≥ 7 - number of stools per day ≥ 4 , - number of mictions per day ≥ 8 , - QLQ-C30 score ≥ 60, - Hamilton score ≥ 10 Exclusion Criteria: 1. Patients with one of the following mastocytosis: - Systemic Mastocytosis with an Associated clonal Hematologic Non Mast cell lineage Disease (SM-AHNMD) - Mast cell leukemia (MCL) - Aggressive systemic mastocytosis (ASM) 2. Patient with a major surgery within 2 weeks prior to study entry 3. --- D816V ---
Description: Pruritus score at week 12 Number of flushes per week at week 12 Hamilton score at week 12 Fatigue Impact scale at week 12
Measure: efficacy on handicaps Time: week 12Anaphylaxis is a serious allergic reaction that develops rapidly and can cause death. Some patients experience anaphylaxis is association with exercise, a disorder called exercise-induced anaphylaxis. A subset of patients with unexplained anaphylaxis, especially those with hypotension during the anaphylactic episodes, have been shown to have abnormal, clonal populations of a certain cell type, mast cells, in the bone marrow. This has been described in at least one patient with exercise-induced anaphylaxis. The investigators would like review the findings in a group of patients with exercise-induced anaphylaxis who have undergone evaluation for the presence of abnormal, clonal mast cells.
Presence of clonal mast cells in bone marrow as assessed by D816V c-kit mutation or CD25 will be recorded for each participant.. Number of participants with presence of clonal abnormalities in the bone marrow specimen. --- D816V ---
Presence of clonal mast cells in bone marrow as assessed by D816V c-kit mutation or CD25 will be recorded for each participant. --- D816V ---
Description: Presence of clonal mast cells in bone marrow as assessed by D816V c-kit mutation or CD25 will be recorded for each participant.
Measure: Number of participants with presence of clonal abnormalities in the bone marrow specimen Time: BaselineDescription: Presence of clonal mast cells in bone marrow as assessed by D816V c-kit mutation or CD25 will be recorded for each participant. The data will be reported as the number of participant with exercise induced anaphylaxis carrying these clonal mast cells in this observational study. Presence of mast cells will be correlated with clinical parameters such as symptoms experienced during anapylaxis.
Measure: Number of participants with presence of clonal abnormalities in the bone marrow specimen Time: BaselineThe objective of this study is to compare the safety and efficacy of masitinib (AB1010) to placebo in patients with mastocytosis with handicap.
The objective of this phase 3 study was therefore to evaluate masitinib efficacy and safety in severe systemic mastocytosis patients, with or without D816V mutation of c-Kit. --- D816V ---
Description: The prospectively declared primary endpoint (4R75%) was cumulative response in at least one of four severe baseline symptoms of mast cell mediator release (pruritus, flushes, depression, or asthenia). Response was defined as a 75% improvement from baseline for any of these four symptoms. Cumulative response was defined as the number of actual responses between weeks 8 and 24, divided by the total number of possible responses over the same treatment period (ie, with five scheduled visits, each patient had a maximum of five to 20 possible responses depending on the number of severe baseline symptoms).
Measure: Cumulative response (4R75%) Time: 24 weeksDescription: Cumulative response in at least one of three severe baseline symptoms (pruritus, flushes, or depression)
Measure: Cumulative response (3R75%) Time: 24 weeksDescription: Cumulative response in at least one of three severe baseline symptoms (pruritus or flushes)
Measure: Cumulative response (2R75%) Time: 24 weeksThis is a Phase 1, open-label, first-in-human (FIH) dose-escalation study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of DCC-2618, administered orally (PO), in adult patients with advanced malignancies. The study consists of 2 parts, a dose-escalation phase and an expansion phase.
Patients with de novo imatinib resistant mutations, such as but not limited to KIT D816V or PDGFRA D842V, are eligible without prior imatinib therapy. --- D816V ---
Description: Dose limiting toxicities, AEs, SAEs, discontinuation of drug due to toxicity, physical exams and ECOG PS, ophthalmologic examinations, changes from baseline in laboratory parameters, electrocardiograms, LVEF, and vital signs.
Measure: Safety/tolerability of oral DCC-2618: incidence of adverse events Time: Approximately 24 monthsDescription: Objective response rate (ORR); Disease control rate (DCR)
Measure: Expansion Phase: Assess Antitumor Activity of DCC-2618 in all diseases Time: Approximately 24 monthsDescription: Objective response rate (ORR); Disease control rate (DCR)
Measure: Escalation Phase: Assess Antitumor Activity of DCC-2618 in patients with advanced malignancies Time: Approximately 24 monthsThis is a Phase 1, open-label, dose-escalation study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antineoplastic activity of avapritinib (also known as BLU-285), administered orally (PO), in adult patients with advanced systemic mastocytosis and other relapsed or refractory myeloid malignancies. The study consists of 2 parts, a dose-escalation part (Part 1) and an expansion part (Part 2).
Changes in levels of serum tryptase and levels of V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) D816V allele burden in blood. --- D816V ---
Description: Blood samples may be taken at pre-dose, and 0.5, 1, 2, 4, 8 and 24 hrs post dose (plus 10 and 48 hrs post dose in Part 2) on Cycle 1 Day 1 and Cycle 1 Day 15, Pre-dose of Cycle 2 to 4, Day 1
Measure: Maximum plasma concentration of avapritinib Time: Every cycle (28 days) up to cycle 4Description: Blood samples may be taken at pre-dose, and 0.5, 1, 2, 4, 8 and 24 hrs post dose (plus 10 and 48 hrs post dose in Part 2) on Cycle 1 Day 1 and Cycle 1 Day 15, Pre-dose of Cycle 2 to 4, Day 1
Measure: Time to maximum plasma concentration of avapritinib Time: Every cycle (28 days) up to cycle 4Description: Including complete remission (CR), CR with partial recovery of peripheral blood (CRh), partial remission (PR) and clinical improvement (CI) using modified International Working Group Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European competence network on mastocytosis (ECNM) criteria; and duration of response (DOR)
Measure: Overall Response Rate Time: 8, 24, 40, 68 and every 24 weeks until patient terminates from the study (approximately 24 months)Description: Defined as change from Baseline
Measure: Changes in patient reported symptoms and quality of life using the Patient Global Impression of Symptom Severity (PGIS) scale Time: Part 2 only - Day 1 of Cycles 1-12Description: Defined as change from Baseline
Measure: Changes in patient reported quality of life using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C-30) Time: Part 2 only - Day 1 of Cycles 1-12Description: Defined as change from Baseline
Measure: Changes in patient reported outcomes using the advanced SM symptom assessment form (AdvSM-SAF) Time: Part 2 only - daily from Day -7 through Cycle 12Description: mL
Measure: Change in liver volume by imaging Time: Day 1 of Cycles 5-18, and every 6 cycles thereafter (each cycle is 28 days)Description: mL
Measure: Change in spleen volume by imaging Time: Day 1 of Cycles 5-18, and every 6 cycles thereafter (each cycle is 28 days)This is a 12 weeks study aimed at assessing the safety and efficacy of 2 doses of AB1010 in patients suffering from indolent systemic mastocytosis with handicap.
Phase IIa, Open-label, Randomized Study of Oral AB1010 in Patients With Systemic Indolent Mastocytosis With Handicap and Not Bearing Activating Point Mutations in the Phosphotransferase Domain of c-Kit Such as the Main Mutation Asp-816-Val (D816V). --- Asp-816-Val ---
Phase IIa, Open-label, Randomized Study of Oral AB1010 in Patients With Systemic Indolent Mastocytosis With Handicap and Not Bearing Activating Point Mutations in the Phosphotransferase Domain of c-Kit Such as the Main Mutation Asp-816-Val (D816V). --- Asp-816-Val --- --- D816V ---
3. The absence of an activating point mutation in the phosphotransferase domain of c-Kit such as D816V c-Kit mutation in at least one of the two infiltrated organs: bone marrow and/or skin and/or other tissue. --- D816V ---
Mastocytosis is a disorder characterized by presence of excessive numbers of mast cells in skin, bone marrow and internal organs. It can affect both children and adults, males and females and individuals from all ethnic backgrounds, although precise demographic information about the affected populations is not available as it is a rare disorder. Mastocytosis in children is generally limited to the skin and follows a self limited course, while it is a disorder of the hematopoietic stem cell associated with somatic mutations of the c-kit gene in most patients with adult-onset of disease. There is no known curative therapy for most patients with systemic mastocytosis. Recent research studies identified several subtypes of disease with distinct clinical and pathologic features, however, a precise understanding of the incidence as well as molecular pathology of different disease subtypes is lacking. This study aims to examine molecular and cellular pathological aspects of disease in patients with mastocytosis and correlate findings with clinical presentation and prognosis. Patients will undergo a routine history and physical examination, and diagnostic tests will be ordered as dictated by each patient's clinical presentation. Blood and bone marrow will be obtained for diagnostic and research purposes. Genetic analysis of the c-kit gene regulating mast cell growth and differentiation will be performed. It is hoped that findings obtained from this study will help to design novel therapies for mastocytosis and other disorders in which mast cells play a critical role.
Proportion of KIT D816V mutation in blood, bone marrow and sorted mast cells. --- D816V ---
KIT D816V mutation was assessed in patient samples containing various proportions of neoplastic mast cells.. Inclusion Criteria: - Confirmed or suspected diagnosis of mastocytosis. --- D816V ---
Description: Patients were categorized into one of the clonal and non-clonal mast cell disorder categories after availability of diagnostic data
Measure: Proportion of the patients with clonal and non-clonal mast cell disorders Time: 1 weekDescription: KIT D816V mutation was assessed in patient samples containing various proportions of neoplastic mast cells.
Measure: Proportion of KIT D816V mutation in blood, bone marrow and sorted mast cells Time: 1 weekThis phase II trial studies how well ponatinib hydrochloride works in treating patients with cancer that has spread to other parts of the body (metastatic), has failed previous treatment (refractory), and has one of several alterations, or mutations, in its deoxyribonucleic acid (DNA) sequence. Ponatinib hydrochloride may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether a patient's genetic alterations may affect how well ponatinib hydrochloride works.
- Patients with known ponatinib-resistant gene alterations - PDGFRA D842V mutation - cKIT D816V mutation - FLT3 D835V/Y/H/F or Y842C mutations - FGFR3 K652E mutation - Major surgery (e.g. --- D842V --- --- D816V ---
Description: The proportion of responses for the purposes of the decision rule will be calculated out of all eligible patients who receive any treatment. Assuming the number of responses is binomially distributed, 95% binomial confidence intervals will also be calculated for the estimate of the proportion of responses.
Measure: Overall response, defined as the number of patients who achieve any response according to disease type in the first 6 courses of treatment Time: Up to 6 monthsDescription: Frequency and severity of adverse events will be collected and summarized by descriptive statistics. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns for each of the cohorts as well as across cohorts. In addition, all adverse event data that is graded as 3, 4, or 5 will be reviewed and classified as either "unrelated" or "unlikely to be related" to study treatment in the event of an actual relationship developing.
Measure: Incidence of toxicity, defined as adverse events that are classified as either possibly, probably, or definitely related to study treatment per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 Time: Up to 30 days after last dose of study drugDescription: Collected and summarized by descriptive statistics. In addition, the proportion of patients who go off treatment due to adverse reactions or even those who refuse further treatment for lesser toxicities that inhibit their willingness to continue participation on the trial will be captured.
Measure: Tolerability of the regimen, assessed by the number of patients who required dose modifications and/or dose delays Time: Up to 30 days after last dose of study drugDescription: Kaplan-Meier curves will be used to estimate the survival distribution.
Measure: Overall survival Time: The time from treatment initiation to death, assessed up to 52 weeksDescription: Kaplan-Meier curves will be used to estimate the survival distribution.
Measure: Progression free survival Time: The time from treatment initiation to progression or death, assessed up to 52 weeksDescription: Calculated by the number of patients who have achieve a response and/or are progression-free and alive at 6 months divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for CBR will be calculated.
Measure: Clinical benefit rate (CBR) Time: 6 monthsDescription: Correlative gene and protein markers will be summarized univariately in a quantitative manner and also summarized by clinical outcome group (e.g. response vs. no response). Graphical analyses will be largely used to assess potential patterns and relationships; e.g. side-by-side boxplots to assess differences in continuous marker levels between those with vs. without the clinical improvement (e.g. response vs. no response). Overall, hypothesis testing will largely be avoided given the sample size limitations.
Measure: Correlative gene and protein markers Time: Up to 3 years (time of progression)Rationale: Patients with indolent or smoldering systemic mastocytosis can have severe disabling symptoms. Almost all patients have fatigue, a compromised quality of life, hampering normal functioning. Because this form of mastocytosis is not considered life-threatening, mast cell eradication has never been applied and patients receive only symptomatic therapy with histamine blockers. Midostaurin, a c-KIT inhibitor has shown activity regarding symptom control and decrease of malignant mast cells in patients with aggressive systemic mastocytosis (ASM) or mast cell leukemia
Number and grading of Common Terminology Criteria adverse events during the 6 months of therapy.. Inclusion Criteria: - Patients with Indolent Systemic Mastocytosis (ISM) or Smouldering Systemic Mastocytosis (SSM) according to the WHO criteria - Presence of the D816V c-KIT mutation - Serum tryptase > 20 mg/l - Serious mediator-related symptoms that cannot be controlled by H1 and H2 blocking drugs. --- D816V ---
- Any known other present malignancy, non-melanoma skin cancers excluded - History of malignancy within the last 5 years, non-melanoma skin cancers excluded - Any serious comorbidity interfering with therapy compliance and follow-up compliance - Pregnancy - Patients not willing or who are not able to comply with contraceptive measures Inclusion Criteria: - Patients with Indolent Systemic Mastocytosis (ISM) or Smouldering Systemic Mastocytosis (SSM) according to the WHO criteria - Presence of the D816V c-KIT mutation - Serum tryptase > 20 mg/l - Serious mediator-related symptoms that cannot be controlled by H1 and H2 blocking drugs. --- D816V ---
Description: Percent change in the total score ("Sumscore") of all symptoms assessed by the Mastocytosis Symptom Assessment Form (MSAF) after 12 weeks.
Measure: Symptom Scoring Time: 12 weeksDescription: persistence of improvement symptom score at 6 months.
Measure: Persistence of improvements Time: 6 monthsDescription: Percent change in the mast cell burden (bone marrow infiltrate, skin infiltrate, serum tryptase levels) after 6 months.
Measure: Mast cell burden Time: 6 monthsDescription: Number and grading of Common Terminology Criteria adverse events during the 6 months of therapy.
Measure: Adverse events Time: 6 monthsThis is an open-label, single arm, Phase 2 study evaluating the efficacy and safety of avapritinib (BLU-285) in patients with advanced systemic mastocytosis (AdvSM), including patients with aggressive SM (ASM), SM with associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL)
Change in V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog aspartate 816 valine (KIT D816V) mutation burden. --- D816V ---
Description: 0 - 80 points (higher value represents worse symptom outcomes)
Measure: Mean Change from Baseline in Advanced Systemic Mastocytosis-Symptom Assessment Form (AdvSM-SAF) Total Symptom Score Time: 10 MonthsDescription: Months
Measure: Time-to-response (TTR) Time: 10 MonthsDescription: Months
Measure: Duration of Response (DOR) Time: 10 MonthsDescription: Months
Measure: Progression-free Survival (PFS) Time: 10 MonthsDescription: Months
Measure: Overall Survival (OS) Time: 10 MonthsDescription: percentage
Measure: Changes in bone marrow mast cells Time: 10 MonthsDescription: ng/mL
Measure: Change in serum tryptase Time: 10 MonthsDescription: percentage
Measure: Change in V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog aspartate 816 valine (KIT D816V) mutation burden Time: 10 MonthsDescription: mL
Measure: Change in liver volume by imaging Time: 10 MonthsDescription: mL
Measure: Change in spleen volume by imaging Time: 10 MonthsDescription: 0 - 10 points (higher value represents worse symptom outcomes)
Measure: Change in PGIS Time: 10 MonthsDescription: 0 - 100 points (lower value represents worse quality of life)
Measure: Change in EORTC QLQ-C30 Time: 10 MonthsDescription: CTCAE version 4.0
Measure: Safety of Avapritinib as assessed by incidence of adverse events Time: 10 MonthsDescription: h•ng/mL
Measure: Area Under Curve (0 to Tau) for Avapritinib Time: 4 MonthsThis is a Phase 2, randomized, double-blind, placebo-controlled study comparing the efficacy and safety of avapritinib + best supportive care (BSC) with placebo + BSC in patients with indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM) whose symptoms are not adequately controlled by BSC. The study will be conducted in 3 parts. All patients will receive treatment with avapritinib during Part 3 including those rolling over from the placebo group.
Change in V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog aspartate 816 valine (KIT D816V) allele burden in blood. --- D816V ---
Description: 0 - 120 points (higher value represents worse symptom outcomes)
Measure: Mean change in ISM Symptom Assessment Form (ISM-SAF) total symptom score (TSS) in patients with ISM and SSM (Part 2) Time: 12 weeksDescription: 0 - 120 points (higher value represents worse symptom outcomes)
Measure: Mean change in ISM Symptom Assessment Form (ISM-SAF) total symptom score (TSS) in patients with ISM and SSM (long term, Part 3) Time: Up to 5 yearsDescription: CTCAE version 5.0
Measure: Safety of avapritinib as assessed by number of adverse events (long term, Part 3) Time: Up to 5 yearsDescription: 0 - 100 points (higher value represents worse symptom outcomes)
Measure: Change in Mastocytosis Quality of Life Questionnaire (MC-QoL) Time: Each study visit through Part 3 Week 52Description: 0 - 10 points (higher value represents worse symptom outcomes)
Measure: Change in Patient's Global Impression of Symptom Severity (PGIS) Time: Each study visit through Part 3 Week 52Description: 0 - 100 points (higher value represents better symptom outcomes)
Measure: Change in 12-item Short Form Health Survey (SF-12) Time: Each study visit through Part 3 Week 52Description: 1 - 7 (higher value represents worse symptom outcomes)
Measure: Change in Patients' Global Impression of Change (PGIC) Time: Each study visit through Part 3 Week 52Description: 0 - 100 (higher value represents better symptom outcomes)
Measure: Change in EuroQuol 5 Dimensions 5 Levels (EQ 5D-5L) Time: Each study visit through Part 3 Week 52Description: CTCAE version 5.0
Measure: Safety of avapritinib as assessed by number of adverse events Time: Up to 5 yearsDescription: h•ng/mL
Measure: Area Under Curve (0 to Tau) for avapritinib (Parts 1 and 2 only) Time: Every cycle (28 days) up to cycle 4The purpose of this study is to evaluate the safety and efficacy of the tyrosine kinase inhibitor, imatinib mesylate (Gleevec ) in reducing peripheral blood eosinophilia in patients with the myeloid form of hypereosinophilic syndrome (HES). Patients with the hypereosinophilic syndrome who meet a set of criteria designed to select patients with the myeloid form of the disease, as well as patients without myeloid disease who are refractory to standard therapy for HES, will be admitted on this protocol. A thorough clinical evaluation will be performed with emphasis on potential sequelae of eosinophil-mediated tissue damage. A baseline bone marrow will be obtained to exclude leukemia or lymphoma and to assess the degree and nature of eosinophilopoiesis. Bone marrow, blood cells and/or serum will also be collected to test for the presence of a recently described mutation that is associated with imatinib-responsiveness in HES, and to provide reagents (such as DNA, RNA, and specific antibodies) and for use in the laboratory to address issues related to the mechanism of action of imatinib mesylate in HES. Imatinib mesylate will be initiated at a dose of 400 mg daily, the FDA-approved dose for the treatment of chronic myelogenous leukemia. In patients who demonstrate a complete clinical and hematologic response to imatinib therapy and who do not have life-threatening disease, the dose will be decreased gradually to 100mg daily and then discontinued. In order to minimize bone marrow suppression, other myelosuppressive agents will be tapered and discontinued during the first week of therapy with imatinib mesylate. Complete blood counts will be performed weekly for the first month and biweekly thereafter. Clinical assessments will be performed every three months to assess progression of end organ damage. In patients who demonstrate a complete clinical and hematologic response to imatinib therapy and who do not have life-threatening disease, the dose will be decreased gradually to 100 mg daily and then discontinued. In the event of clinical, hematologic or molecular relapse during the taper, the imatinib dose will be increased to a maximum of 600 mg daily to achieve a second remission. Laboratory monitoring will be performed as above except for molecular monitoring which will be monitored monthly if drug is discontinued or molecular relapse occurs. Once a stable dosing regimen is achieved for greater than or equal to 6 months in subjects who have undergone dose descalation or greater than or equal to 2 years in subjects receiving 300-400 mg of imatinib daily who did not qualify for dose de-escalation, the frequency of NIH visits and end organ assessments will be decreased to 6 months, with molecular monitoring every 3 months and monthly routine laboratory assessments.
EXCLUSION CRITERIA: 1. Pregnancy or nursing women 2. HIV positivity or other known immunodeficiency 3. D816V KIT-positive systemic mastocytosis 4. Absolute neutrophil count less than 1000/mm(3) or platelet count less than 10,000/mm(3) or less than 50,000/m(3) with clinical evidence of bleeding. --- D816V ---
Description: The percentage of subjects who reach and eosinophil count in the normal range
Measure: peripheral blood absolute eosinophil count. Time: one month (for imatinib) and 3 months (for ruxolitinib).Description: The % of subjects who reach an eosinophil count in the normal range
Measure: peripheral blood eosinophil count Time: 3,6,9 and 12 monthsDescription: The % of subjects who reach an eosinophil count below 1500/mm3
Measure: peripheral blood eosinophil count Time: 1, 3, 6, 9, and 12 monthsDescription: The % of subjects who achieve molecular remission on therapy
Measure: abnormal tyrosine kinase (i.e., FIP1L1-PDGFRA, JAK2 V617F) Time: every 3 months for 5 yearsDescription: The duration of remission following cessation of therapy
Measure: clinical, hematologic and molecular remission Time: every 3 months for 5 yearsThe aim of this study is to evaluate the efficacy in terms of clinical and biological response rates of Cladribine plus Pegylated Interpheron alpha-2a therapy in patients with advanced systemic mastocytosis carrying D816V or other exon 17 KIT mutations.
Subcutaneous Cladribine Plus Pegylated Interpheron Alfa-2a in Advanced Systemic Mastocytosis With D816V and Other Exon 17 KIT Mutations.. Cladribine Plus Pegylated Interpheron Alfa-2a in Systemic Mastocytosis The aim of this study is to evaluate the efficacy in terms of clinical and biological response rates of Cladribine plus Pegylated Interpheron alpha-2a therapy in patients with advanced systemic mastocytosis carrying D816V or other exon 17 KIT mutations. --- D816V ---
Subcutaneous Cladribine Plus Pegylated Interpheron Alfa-2a in Advanced Systemic Mastocytosis With D816V and Other Exon 17 KIT Mutations.. Cladribine Plus Pegylated Interpheron Alfa-2a in Systemic Mastocytosis The aim of this study is to evaluate the efficacy in terms of clinical and biological response rates of Cladribine plus Pegylated Interpheron alpha-2a therapy in patients with advanced systemic mastocytosis carrying D816V or other exon 17 KIT mutations. --- D816V --- --- D816V ---
- Diagnosis of advanced systemic mastocytosis (aggressive systemic mastocytosis or proggressing systemic mastocytosis) with D816V or other exon 17 KIT mutations. --- D816V ---
Description: Evaluation of bone marrow response will be assessed by immunohistochemestry, citology, flow cytometry and molecular analyses of bone marrow samples.
Measure: To evaluate the effect of therapy on bone marrow mast cell infiltration. Time: 6 monthsDescription: Serum tryptase and any other mastocytosis-related altered biochemical parameter at diagnosis will be measured monthly until the end of therapy.
Measure: To determine the effect of therapy on serum tryptase levels and other altered peripheral blood parameters due to mastocytosis. Time: 6 monthsDescription: Specific questionnaires regarding mast cell-mediator release symptoms will be filled monthly by each patient until the end of therapy.
Measure: To evaluate the effect of therapy on mast cell-mediator release symptoms: pruritus, flushing, gastrointestinal symptoms or anaphylaxis). Time: 6 monthsDescription: Potentially drugs-related adverse events will be recorded in each case following accepted criteria (NIH CTCAE).
Measure: To determine de safety of combined therapy with low doses of cladribine plus pegylated interpheron alpha-2a. Time: 6 monthsDescription: Evaluation of cutaneous response will be assessed by macroscopic inspection including photographs and by skin immunohistochemestry.
Measure: To evaluate the effect of therapy on mastocytosis skin lesions. Time: 6 mothsDescription: Evaluation of organomegalies response will be assessed by abdominal ultrasound and/or computerized tomography.
Measure: To evaluate the effect of therapy on mastocytosis-related organomegalies. Time: 6 monthsDescription: Evaluation of bone response will be assessed by X-ray survey and/or computerized tomography.
Measure: To evaluate the effect of therapy on mastocytosis-related bone alterations. Time: 6 monthsBackground: Mast cells help the body fight disease and heal wounds. People with indolent systemic mastocytosis (ISM) make too many mast cells. This causes pain, tiredness, digestive problems, and other symptoms. Researchers think the drug sarilumab could help. Objective: To see if sarilumab is a safe and effective treatment for people with ISM. Eligibility: Adults ages 18-75 with ISM who are enrolled in NIH study 02-I-0277 Design: Participants will be screened with: - Physical exam - Medical history - Blood and urine tests - Questionnaires - Bone marrow removed by a needle inserted into the hip bone - Ultrasound of the abdomen - Photographs of the skin Participants will repeat some screening tests at study visits. Participants will have a baseline visit in the hospital for 3 days. They will: - Be assigned to get either the study drug or a placebo. They will not know which one they get. - Have a skin punch biopsy: An instrument will remove a small piece of skin. - Get their first drug dose injected under their skin Participants will keep a side effect and medication diary during the study. Participants will visit the clinic to get a drug dose every 2 weeks, for a total of 8 doses. Participants will have a visit 2 weeks after their final dose. It will last up to 2 days. Participants will have another visit 12 weeks later. Participants may then continue this study for 1 more year. Those who continue will get sarilumab, even if they previously got the placebo, every 2 weeks. They will have visits every 6 weeks, and then every 3 months.
Decrease in the allelic frequency of D816V using PCR. --- D816V ---
This trial is for various types of malignancies which may depend on certain enzymes (tyrosine kinases) for growth. The objective of this study is to assess to what extent imatinib mesylate blocks these enzymes and to assess the effect on the malignancy.
Exclusion Criteria: 1. Certain leukaemias (abl-mutated), some gastrointestinal stromal tumours (c-KIT-positive) or certain systemic mastocytosis (if c- KIT D816V mutation). --- D816V ---
Not included: Patients with chronic myeloid leukemia, some other types of leukemias (abl-mutated) some types of gastrointestinal stromal tumours (c-KIT-positive), some systemic mastocytosis (if c-KIT D816V mutation), brain, prostate, breast or lung cancers. --- D816V ---
RATIONALE: Thalidomide may stop the growth of systemic mastocytosis by blocking blood flow to the disease. PURPOSE: This phase II trial is studying how well thalidomide works in treating patients with relapsed or progressive systemic mastocytosis.
DISEASE CHARACTERISTICS: - Diagnosis of systemic mastocytosis - Aggressive or borderline (smoldering) disease (in first line or more) - Relapsed or progressive disease - Measurable or evaluable disease - Presence of c-Kit D816V mutation in the skin, spine, or infiltrated organs - No nonsymptomatic mastocytosis PATIENT CHARACTERISTICS: - Life expectancy > 3 months - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception for 1 month prior to, during, and until first menstrual cycle after completion of study treatment - Bilirubin < 2 times normal (unrelated to disease) - Liver enzymes < 2 times normal (unrelated to disease) - Creatinine ≤ 300 mmol/L - No central or peripheral neuropathy leading to psychiatric concerns - No HIV positivity - No active infection or other serious underlying illness that would preclude treatment - No history of thromboembolism or deep vein thrombosis - No geographical, social, or psychological reasons preventing medical monitoring PRIOR CONCURRENT THERAPY: - More than 4 weeks since prior antitumor therapy (e.g., chemotherapy, radiotherapy) - No other concurrent treatment specific for this disease - No concurrent participation in another experimental drug trial DISEASE CHARACTERISTICS: - Diagnosis of systemic mastocytosis - Aggressive or borderline (smoldering) disease (in first line or more) - Relapsed or progressive disease - Measurable or evaluable disease - Presence of c-Kit D816V mutation in the skin, spine, or infiltrated organs - No nonsymptomatic mastocytosis PATIENT CHARACTERISTICS: - Life expectancy > 3 months - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception for 1 month prior to, during, and until first menstrual cycle after completion of study treatment - Bilirubin < 2 times normal (unrelated to disease) - Liver enzymes < 2 times normal (unrelated to disease) - Creatinine ≤ 300 mmol/L - No central or peripheral neuropathy leading to psychiatric concerns - No HIV positivity - No active infection or other serious underlying illness that would preclude treatment - No history of thromboembolism or deep vein thrombosis - No geographical, social, or psychological reasons preventing medical monitoring PRIOR CONCURRENT THERAPY: - More than 4 weeks since prior antitumor therapy (e.g., chemotherapy, radiotherapy) - No other concurrent treatment specific for this disease - No concurrent participation in another experimental drug trial Non Neoplastic Condition Precancerous Condition Disease Mastocytosis Precancerous Conditions Mastocytosis, Systemic OBJECTIVES: Primary - Determine the objective response rate at 6 months in patients with systemic mastocytosis treated with thalidomide. --- D816V ---
DISEASE CHARACTERISTICS: - Diagnosis of systemic mastocytosis - Aggressive or borderline (smoldering) disease (in first line or more) - Relapsed or progressive disease - Measurable or evaluable disease - Presence of c-Kit D816V mutation in the skin, spine, or infiltrated organs - No nonsymptomatic mastocytosis PATIENT CHARACTERISTICS: - Life expectancy > 3 months - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception for 1 month prior to, during, and until first menstrual cycle after completion of study treatment - Bilirubin < 2 times normal (unrelated to disease) - Liver enzymes < 2 times normal (unrelated to disease) - Creatinine ≤ 300 mmol/L - No central or peripheral neuropathy leading to psychiatric concerns - No HIV positivity - No active infection or other serious underlying illness that would preclude treatment - No history of thromboembolism or deep vein thrombosis - No geographical, social, or psychological reasons preventing medical monitoring PRIOR CONCURRENT THERAPY: - More than 4 weeks since prior antitumor therapy (e.g., chemotherapy, radiotherapy) - No other concurrent treatment specific for this disease - No concurrent participation in another experimental drug trial DISEASE CHARACTERISTICS: - Diagnosis of systemic mastocytosis - Aggressive or borderline (smoldering) disease (in first line or more) - Relapsed or progressive disease - Measurable or evaluable disease - Presence of c-Kit D816V mutation in the skin, spine, or infiltrated organs - No nonsymptomatic mastocytosis PATIENT CHARACTERISTICS: - Life expectancy > 3 months - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception for 1 month prior to, during, and until first menstrual cycle after completion of study treatment - Bilirubin < 2 times normal (unrelated to disease) - Liver enzymes < 2 times normal (unrelated to disease) - Creatinine ≤ 300 mmol/L - No central or peripheral neuropathy leading to psychiatric concerns - No HIV positivity - No active infection or other serious underlying illness that would preclude treatment - No history of thromboembolism or deep vein thrombosis - No geographical, social, or psychological reasons preventing medical monitoring PRIOR CONCURRENT THERAPY: - More than 4 weeks since prior antitumor therapy (e.g., chemotherapy, radiotherapy) - No other concurrent treatment specific for this disease - No concurrent participation in another experimental drug trial Non Neoplastic Condition Precancerous Condition Disease Mastocytosis Precancerous Conditions Mastocytosis, Systemic OBJECTIVES: Primary - Determine the objective response rate at 6 months in patients with systemic mastocytosis treated with thalidomide. --- D816V --- --- D816V ---
The aim of this study is to evaluate the efficacy in terms of clinical and biological response rates of Imatinib Mesylate therapy in patients with systemic mastocytosis lacking KIT mutations.
Systemic Mastocytosis Mastocytosis Mastocytosis, Systemic In vitro studies have proven that imatinib inhibits wild type Kit (wtKit) and suppresses proliferation of the HMC-1V560G cell line, while it is ineffective on inhibiting the growth of HMC-1V560G, D816V cells. --- D816V ---
In contrast, several experiments have provided compelling evidence regarding the resistance against the growth-inhibitory effects of imatinib on cells carrying the D816V KIT mutation. --- D816V ---
Description: The grade of bone marrow infiltration is evaluated before and after 6 months of therapy by bone marrow histology and cytology, and flow cytometry performed on highly-purified bone marrow mast cells from patients with B or C findings
Measure: To evaluate the effect of Imatinib Mesylate on the grade of bone marrow mast cells infiltration. Time: 6 monthsDescription: The grade of bone marrow infiltration is evaluated before and after 6 months of therapy by bone marrow histology and cytology, and flow cytometry performed on highly-purified bone marrow mast cells from patients without B or C findings, and from those with B or C findings who show response at the intermediate check-point (after 6 months of therapy)
Measure: To evaluate the effect of Imatinib Mesylate on the grade of bone marrow mast cells infiltration. Time: 12 monthsDescription: Skin lesions are evaluated before and after therapy by macroscopic examination and skin biopsy.
Measure: To evaluate the effect of Imatinib Mesylate on mastocytosis skin lesions. Time: 12 monthsDescription: Clinical symptoms such as pruritus, flushing, gastrointestinal symptoms and anaphylaxis are assessed before and after therapy using a clinical questionnaire that includes the type, frequency and severity of each symptom.
Measure: To evaluate the effect of Imatinib Mesylate on mastocytosis mast-cell related symptoms. Time: 12 monthsDescription: Organomegalies and adenomegalies are assessed before and after therapy by abdominal ultrasound.
Measure: To evaluate the effect of Imatinib Mesylate on mastocytosis-related megalies. Time: 12 monthsDescription: Bone alterations are assessed before and after therapy by X-ray survey.
Measure: To evaluate the effect of Imatinib Mesylate on mastocytosis-related bone alterations. Time: 12 monthsDescription: Genetic abnormalities are assessed before and after therapy by sequencyng analysis of the c-kit gene and the HUMARA assay.
Measure: To investigate changes after Imatinib Mesilate therapy in mast cell clonality. Time: 12 monthsDescription: Serum tryptase is measured before and after therapy.
Measure: To determine the effect of Imatinib Mesylate therapy on serum tryptase levels. Time: 12 monthsDescription: The psychological impact of the disease and the quality of life of patients are evaluated before and after therapy by the Dermatology Life Quality Index.
Measure: To determine the effect of Imatinib Mesylate therapy in the psychological impact of the disease and the quality of life. Time: 12 months