Systemic Mastocytosis, Aggressive (ASM)Phase 2NCT00233454
Phase 2 Midostaurin in Aggressive Systemic Mastocytosis and Mast Cell Leukemia
A Phase 2 study testing Midostaurin in people with Systemic Mastocytosis, Aggressive (ASM) and Leukemia, Mast Cell, run by Jason Robert Gotlib at 3 sites in United States.
Trial summary
The safety and efficacy of midostaurin (PKC412), a novel investigational drug, will be evaluated on the basis of response rate, when administered to patients with aggressive systemic mastocytosis (ASM) or mast cell leukemia (MCL) Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Systemic Mastocytosis, Aggressive (ASM), Leukemia, Mast Cell, Hematological Non-mast Cell Lineage Disease (AHNMD)
- What is being tested?
- Midostaurin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 26 participants
- Where
- 3 sitesUnited States
- Study dates
- Mar 2005to 16 Apr 2011
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- At least 18 years of age.
- Karnofsky performance status (KPS) of > 30% (equivalent to ECOG 0 to 3)
- Mast cell disease, histologically confirmed and documented to be
- Aggressive systemic mastocytosis (ASM) OR
- Mast cell leukemia (MCL) meeting the following criteria
- Meets criteria for systemic mastocytosis
Show all 20Show fewer
- Biopsy indicates diffuse infiltration by atypical, immature mast cells
- Bone marrow aspirate smears show at least 20% mast cells
- Confirmed availability of tissue sample within 6 months prior to entry into study, for evaluation of KIT mutation status of the tumor cells. Subjects who have systemic mastocytosis PLUS eosinophilia AND known positivity for FIP1L1-PDGFR-alpha fusion are eligible only if they have demonstrated relapse or disease progression on prior imatinib therapy
- Blood levels of liver enzymes within normal limits (EXCEPTION: If the sole cause of elevated blood levels of liver enzymes is ASM/MCL, then AST and ALT ≤ 4X upper limit of normal (ULN), and/or bilirubin ≤ 4X ULN)
- Serum creatinine < 2.0 mg/dL
- If ANC < 1500/mm3; Hb < 10 g/dL; platelets < 75,000/mm3; AND/OR other blood values are > grade 2, then the relationship of these cytopenia(s) should be established as related to ASM or MCL on the basis of presence of mast cell infiltrate in the screening bone marrow exam and/or the presence of disease-related hypersplenism
- Prior use of glucocorticoids must be tapered off within 14 days of Day 1 of midostaurin treatment (EXCEPTION: If in the opinion of the investigator, the subject can be tapered off glucocorticoids, then dosage should be tapered to the minimal dose possible before first treatment with midostaurin)
- Negative serum pregnancy test for women of childbearing potential within 48 hours prior to administration of study drug
- Written informed consent.
- Anyone of reproductive potential must agree to use barrier contraceptives for the duration of the study
- Women of childbearing potential must have a negative serum pregnancy test 48 hours prior to administration of study drug, and must agree to:
- Use barrier contraception for the duration of the study
- Use barrier contraception for 3 months post-study
- Not breast-feed
Who cannot join
- Active pulmonary disease based on physical assessment or lateral chest X-ray, considered by the investigator to be unrelated to mastocytosis
- Any pulmonary infiltrate or abnormality on the baseline chest X-ray known to be new in the previous 4 weeks (EXCEPTION: pleural effusion related to systemic mastocytosis, eg, secondary to ascites, AND not causing symptomatic respiratory complaints, may be eligible)
- Cardiovascular disease, including congestive heart failure
- Myocardial infarction within 6 months
- Poorly-controlled hypertension with any Grade 3/4 cardiac problems (per New York Heart Association Criteria)
- Uncontrolled diabetes
Show all 17Show fewer
- Chronic renal disease
- Active uncontrolled infection
- Known malignant disease involving the central nervous system (CNS)
- Known confirmed diagnosis of HIV infection or active viral hepatitis.
- Any other known disease, or concurrent severe and/or uncontrolled medical condition which could compromise participation in the study, including but not limited to:
- Received any investigational agent, chemotherapy, or 2-chlorodeoxyadenosine (2-CdA) within 30 days prior to Day 1 of PKC412 treatment.
- Received interferon-alpha within 30 days prior to Day 1 of midostaurin treatment.
- Received hematopoietic growth factor support within 14 days of Day 1 of midostaurin treatment.
- Any surgical procedure, excluding central venous catheter placement or other minor procedures (eg, skin biopsy) within 14 days of Day 1 of midostaurin treatment
- Pregnant or breast-feeding
- Unwilling or unable to comply with the protocol
Trial locations and contacts
3 sites in 1 country.
United States3 sites
Dana Farber Cancer Institute
Boston, Massachusetts, 02115
Washington University-St. Louis
St Louis, Missouri, 63110
Stanford University School of Medicine
Stanford, California, 94305
About this study
Official title: A Single Arm, Phase 2, Open-Label Study to Determine the Efficacy of Twice Daily Oral Dosing of PKC412 <Midostaurin> Administered to Patients With Aggressive Systemic Mastocytosis (ASM) and Mast Cell Leukemia (MCL)
The safety and efficacy of midostaurin (PKC412), a novel investigational drug, will be evaluated on the basis of response rate, when administered to patients with aggressive systemic mastocytosis (ASM) or mast cell leukemia (MCL)
Read the detailed description
This study assesses the activity and safety profile of twice-daily oral doses of midostaurin in patients with aggressive systemic mastocytosis (ASM) or mast cell leukemia (MCL) with or without associated clonal hematological non-mast cell lineage disease (AHNMD).
Aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) are characterized by excessive bone marrow production of mast cells which can can infiltrate tissues and release harmful substances, resulting in organ damage. These diseases have very limited treatment options and poor prognosis. Existing treatments for in advanced mast cell disease, eg, interferon-alpha; corticosteroids; and/or cladribine, exhibit low response rates that are usually partial in nature.
- Conditions
- Systemic Mastocytosis, Aggressive (ASM), Leukemia, Mast Cell, Hematological Non-mast Cell Lineage Disease (AHNMD)
- Being tested
- Midostaurin
- Medical subject headings
- Mastocytosis, Systemic, Aggression, Leukemia, Mast-Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MidostaurinDrug
Also called PKC412, CGP41251, CGP41231
Midostaurin is a broad-spectrum protein kinase inhibitor, acting on conventional PKC isoforms (α, β, γ); PDFRβ; VEGFR2; Syk; PKCη; Flk-1; Flt3; Cdk1/B; PKA; c-Kit; c-Fgr; c-Src; VEGFR1; and EGFR
| Study group | Role | What they receive |
|---|---|---|
| Midostaurin | Experimental | 100 mg midostaurin twice daily as oral capsules Receives: Drug: Midostaurin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Subjects With Clinical Response [Partial Response (PR) + Complete Response (CR)]
Clinical Response [PR + CR] will be assessed after 2 cycles of treatment, with each cycle being 28 days (4 weeks) in length.
Except as otherwise noted, the minimum criteria for PR is improvement by at least 50% from the baseline value towards the indicated value for one or more of the criteria below:
BONE MARROW \& BLOOD
- ANC <1000/uL
- Hb <10 g/dL
- Platelets >100,000/uL LIVER
- If hepatomegaly with ascites, decrease in frequency of paracenteses by 50%
- Elevated enzyme levels > upper limit of normal (ULN)
- Hypoalbuminemia < ULN
- Portal hypertension > ULN SPLEEN
- If palpable splenomegaly with hypersplenism/thrombocytopenia, hypersplenism markers improved GI TRACT
- If malabsorption with hypoalbuminemia and/or weight loss, albumin improved BONES
- If huge osteolyses or/and severe osteoporosis with pathologic fractures, partial resolution of osteolyses
Subjects with PR or greater continue, those without response discontinue.
Measured: 2 months
Secondary outcomes (2)
Overall Survival (OS)
Overall survival will be assessed after 12 cycles of treatment, with each cycle being 28 days (4 weeks) in length. 12 cycles of treatment is considered to be about 11 months.
Measured: 11 months
Overall Survival (OS)
Overall survival was assessed as the median duration of survival at the time of data cut-off, and reported with 95% confidence interval.
Measured: 40 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Oct 2005 (estimated)
- Study startMar 2005
- Primary completion18 Jun 2010
- Study completion16 Apr 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Systemic Mastocytosis, Aggressive (ASM)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 26 participants (actual)
Sponsor and investigators
- Lead sponsor
- Jason Robert Gotlib
- Sponsor type
- University, hospital or other
- Collaborators
- Novartis, Novartis Pharmaceuticals
- Responsible party
- Sponsor-investigator, Jason Robert Gotlib, Stanford University
- Investigators
- Jason Robert Gotlib, Principal investigator, Stanford University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00233454
- Sponsor's protocol ID
- IRB-13704
- Other IDs
- 95242, HEMMPD0003, CPKC412D2201, 2213
- Status last verified
- Sep 2018
- First submitted
- 3 Oct 2005
- Last updated
- 20 Sep 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No
Publications
Paschka P, Marcucci G, Ruppert AS, Mrozek K, Chen H, Kittles RA, Vukosavljevic T, Perrotti D, Vardiman JW, Carroll AJ, Kolitz JE, Larson RA, Bloomfield CD; Cancer and Leukemia Group B. Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study. J Clin Oncol. 2006 Aug 20;24(24):3904-11. doi: 10.1200/JCO.2006.06.9500.
PubMed 16921041Gotlib JR, George TI, Linder A, et al. "Phase II Trial of the Tyrosine Kinase Inhibitor PKC412 in Advanced Systemic Mastocytosis: Preliminary Results." Blood. 16 November 2006;108(11)16:abs3609
Gotlib JR, George TI, Corless C, et al. "The KIT Tyrosine Kinase Inhibitor Midostaurin (PKC412) Exhibits a High Response Rate in Aggressive Systemic Mastocytosis(ASM): Interim Results of a Phase 2 Trial." Blood. 16 November 2007;110(11):abs 3536
Gotlib JR, DeAngelo DJ, George TI, et al. "KIT Inhibitor Midostaurin Exhibits a High Rate of Clinically Meaningful and Durable Responses in Advanced Systemic Mastocytosis: Report of a Fully Accrued Phase II Trial." Blood. 19 November 2010;116(21):abs316
Gotlib J, Kluin-Nelemans HC, George TI, Akin C, Sotlar K, Hermine O, Awan FT, Hexner E, Mauro MJ, Sternberg DW, Villeneuve M, Huntsman Labed A, Stanek EJ, Hartmann K, Horny HP, Valent P, Reiter A. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. N Engl J Med. 2016 Jun 30;374(26):2530-41. doi: 10.1056/NEJMoa1513098.
PubMed 27355533DeAngelo DJ, George TI, Linder A, Langford C, Perkins C, Ma J, Westervelt P, Merker JD, Berube C, Coutre S, Liedtke M, Medeiros B, Sternberg D, Dutreix C, Ruffie PA, Corless C, Graubert TJ, Gotlib J. Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial. Leukemia. 2018 Feb;32(2):470-478. doi: 10.1038/leu.2017.234. Epub 2017 Jul 24.
PubMed 28744009
Study at a glance
From the registry record, last updated by the sponsor on 20 Sep 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Single Arm, Phase 2, Open-Label Study to Determine the Efficacy of Twice Daily Oral Dosing of PKC412 <Midostaurin> Administered to Patients With Aggressive Systemic Mastocytosis (ASM) and Mast Cell Leukemia (MCL)
- ClinicalTrials.gov ID
- NCT00233454
- Acronym / sponsor ID
- IRB-13704
- Conditions
- Systemic Mastocytosis, Aggressive (ASM), Leukemia, Mast Cell, Hematological Non-mast Cell Lineage Disease (AHNMD)
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 26 participants (actual)
- Lead sponsor
- Jason Robert GotlibUniversity, hospital or other
- Collaborators
- Novartis, Novartis Pharmaceuticals
- Study start
- Mar 2005 (actual)
- Primary completion
- 18 Jun 2010 (actual)
- Study completion
- 16 Apr 2011 (actual)
- First posted
- 5 Oct 2005 (estimated)
- Results
- Posted 9 Jul 2015
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The safety and efficacy of midostaurin (PKC412), a novel investigational drug, will be evaluated on the basis of response rate, when administered to patients with aggressive systemic mastocytosis (ASM) or mast cell leukemia (MCL)
Detailed description
This study assesses the activity and safety profile of twice-daily oral doses of midostaurin in patients with aggressive systemic mastocytosis (ASM) or mast cell leukemia (MCL) with or without associated clonal hematological non-mast cell lineage disease (AHNMD).
Aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) are characterized by excessive bone marrow production of mast cells which can can infiltrate tissues and release harmful substances, resulting in organ damage. These diseases have very limited treatment options and poor prognosis. Existing treatments for in advanced mast cell disease, eg, interferon-alpha; corticosteroids; and/or cladribine, exhibit low response rates that are usually partial in nature.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Midostaurin | Experimental | Drug: Midostaurin100 mg midostaurin twice daily as oral capsules |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (20 listed)
- At least 18 years of age.
- Karnofsky performance status (KPS) of > 30% (equivalent to ECOG 0 to 3)
- Mast cell disease, histologically confirmed and documented to be
- Confirmed availability of tissue sample within 6 months prior to entry into study, for evaluation of KIT mutation status of the tumor cells. Subjects who have systemic mastocytosis PLUS eosinophilia AND known positivity for FIP1L1-PDGFR-alpha fusion are eligible only if they have demonstrated relapse or disease progression on prior imatinib therapy
- Blood levels of liver enzymes within normal limits (EXCEPTION: If the sole cause of elevated blood levels of liver enzymes is ASM/MCL, then AST and ALT ≤ 4X upper limit of normal (ULN), and/or bilirubin ≤ 4X ULN)
Key exclusion criteria (17 listed)
- Active pulmonary disease based on physical assessment or lateral chest X-ray, considered by the investigator to be unrelated to mastocytosis
- Any pulmonary infiltrate or abnormality on the baseline chest X-ray known to be new in the previous 4 weeks (EXCEPTION: pleural effusion related to systemic mastocytosis, eg, secondary to ascites, AND not causing symptomatic respiratory complaints, may be eligible)
- Cardiovascular disease, including congestive heart failure
- Myocardial infarction within 6 months
- Poorly-controlled hypertension with any Grade 3/4 cardiac problems (per New York Heart Association Criteria)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MidostaurinAlso: PKC412, CGP41251, CGP41231Midostaurin is a broad-spectrum protein kinase inhibitor, acting on conventional PKC isoforms (α, β, γ); PDFRβ; VEGFR2; Syk; PKCη; Flk-1; Flt3; Cdk1/B; PKA; c-Kit; c-Fgr; c-Src; VEGFR1; and EGFR | Drug | Midostaurin |
Primary outcome
Subjects With Clinical Response [Partial Response (PR) + Complete Response (CR)]
Time frame: 2 months
Clinical Response [PR + CR] will be assessed after 2 cycles of treatment, with each cycle being 28 days (4 weeks) in length. Except as otherwise noted, the minimum criteria for PR is improvement by at least 50% from the baseline value towards the indicated value for one or more of the criteria below: BONE MARROW \& BLOOD * ANC <1000/uL * Hb <10 g/dL * Platelets >100,000/uL LIVER * If hepatomegaly with ascites, decrease in frequency of paracenteses by 50% * Elevated enzyme levels > upper limit of normal (ULN) * Hypoalbuminemia < ULN * Portal hypertension > ULN SPLEEN * If palpable splenomegaly with hypersplenism/thrombocytopenia, hypersplenism markers improved GI TRACT * If malabsorption with hypoalbuminemia and/or weight loss, albumin improved BONES * If huge osteolyses or/and severe osteoporosis with pathologic fractures, partial resolution of osteolyses Subjects with PR or greater continue, those without response discontinue.
2 secondary outcomes
Overall Survival (OS)
Time frame: 11 months
Overall Survival (OS)
Time frame: 40 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Sep 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 16921041Paschka P, Marcucci G, Ruppert AS, Mrozek K, Chen H, Kittles RA, Vukosavljevic T, Perrotti D, Vardiman JW, Carroll AJ, Kolitz JE, Larson RA, Bloomfield CD; Cancer and Leukemia Group B. Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study. J Clin Oncol. 2006 Aug 20;24(24):3904-11. doi: 10.1200/JCO.2006.06.9500.
- Results publicationGotlib JR, George TI, Linder A, et al. "Phase II Trial of the Tyrosine Kinase Inhibitor PKC412 in Advanced Systemic Mastocytosis: Preliminary Results." Blood. 16 November 2006;108(11)16:abs3609
- Results publicationGotlib JR, George TI, Corless C, et al. "The KIT Tyrosine Kinase Inhibitor Midostaurin (PKC412) Exhibits a High Response Rate in Aggressive Systemic Mastocytosis(ASM): Interim Results of a Phase 2 Trial." Blood. 16 November 2007;110(11):abs 3536
- Results publicationGotlib JR, DeAngelo DJ, George TI, et al. "KIT Inhibitor Midostaurin Exhibits a High Rate of Clinically Meaningful and Durable Responses in Advanced Systemic Mastocytosis: Report of a Fully Accrued Phase II Trial." Blood. 19 November 2010;116(21):abs316
- Results publication: PubMed 27355533Gotlib J, Kluin-Nelemans HC, George TI, Akin C, Sotlar K, Hermine O, Awan FT, Hexner E, Mauro MJ, Sternberg DW, Villeneuve M, Huntsman Labed A, Stanek EJ, Hartmann K, Horny HP, Valent P, Reiter A. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. N Engl J Med. 2016 Jun 30;374(26):2530-41. doi: 10.1056/NEJMoa1513098.
- Results publication: PubMed 28744009DeAngelo DJ, George TI, Linder A, Langford C, Perkins C, Ma J, Westervelt P, Merker JD, Berube C, Coutre S, Liedtke M, Medeiros B, Sternberg D, Dutreix C, Ruffie PA, Corless C, Graubert TJ, Gotlib J. Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial. Leukemia. 2018 Feb;32(2):470-478. doi: 10.1038/leu.2017.234. Epub 2017 Jul 24.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jason Robert Gotlib principal investigator
Stanford University
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Midostaurin in people with Systemic Mastocytosis, Aggressive (ASM) and Leukemia, Mast Cell, run by Jason Robert Gotlib at 3 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 20 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 20 Sep 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 9 Jul 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Subjects With Clinical Response [Partial Response (PR) + Complete Response (CR)] (time frame: 2 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00233454, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Sep 2018.