MyelofibrosisPhase 1NCT01730248
A Study to Find the Maximum Tolerated Dose of the Experimental Combination of the Drugs INC424 and BKM120 in Patients With Primary or Secondary Myelofibrosis
A Phase 1 study testing INC424 and BKM120 in people with Myelofibrosis, run by Novartis Pharmaceuticals at 15 sites in 9 countries.
Trial summary
The purpose of this phase Ib clinical trial is to evaluate the safety of the combination of INC424 and BKM120 in the myelofibrosis population and to establish the maximum tolerated dose and or the Recommended Phase II dose of the combination guided by the Bayesian dose escalation model. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Myelofibrosis
- What is being tested?
- INC424 and BKM120
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 63 participants
- Where
- 15 sitesin 9 countries
- Study dates
- 18 Dec 2012to 28 Sep 2017
- Phase
- Phase 1
- Are there results?
- None posted in the registry
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
- Diagnosed with PMF, PPV-MF or PET-MF irrespective of JAK2 mutation status
- Myelofibrosis patients requiring therapy must be classified as intermediate risk level 1 )1 or more prognostic factors defined by IWG) with at least one criteria other than age
- Must have palpable spleen of at least 5 cm from the costal margin to the point of greatest splenic profusion at Screening
- Must have active symptoms of MF (one symptom score of at least 5 or two symptom scores of at least 3 at Screening) (per MFSSF 0-10)
- PLT counts > or = 75X 10^9/L at Screening or Cycle 1 Day 1 (not with aid of transfusions
Who cannot join
- Pregnant or nursing women
- WOCBP not using highly effective methods of contraception
- Sexually active males who refuse condom use
- Previous Treatment with one of the following: PI3 K inhibitors and AKT inhibitors; JAK inhibitors that resulted in clinically significant toxicities per the Investigator;
- Patients who have had splenic irradiation within 12 months prior to Screening
- Patients with specific mood disorders
Show all 10Show fewer
- Any history of bleeding diathesis
- Patients receiving the following treatments / medications:
- EIAED within 2 wks. prior to study treatment; medication known to prolong QT interval or induce Torsades de Pointes; treatment with potent systemic systemic inhibitor or systemic inducer of CYP3A4; any use of drug that interferes with coagulation or inhibits PLT function
- -current and willing candidates for a stem cell transplantation
Trial locations and contacts
15 sites in 9 countries.
15 sites in 9 countries
United Kingdom3 sites
Novartis Investigative Site
Edgbaston, Birmingham, B15 2WB
Novartis Investigative Site
London, NW1 2BU
Novartis Investigative Site
London, SE1 9RT
Australia2 sites
Novartis Investigative Site
Herston, Queensland, 4029
Novartis Investigative Site
Melbourne, Victoria, 3000
Germany2 sites
Novartis Investigative Site
Berlin, 13353
Novartis Investigative Site
Rostock, 18057
Israel2 sites
Novartis Investigative Site
Jerusalem, 91120
Novartis Investigative Site
Ramat Gan, 5265601
Italy2 sites
Novartis Investigative Site
Florence, FI, 50134
Novartis Investigative Site
Varese, VA, 21100
About this study
Official title: A Phase Ib, Open-label, Multi-center, Two-arm, Dose-finding Study to Assess Safety and Efficacy of the Oral Combination or INC424 (INC424) and BKM120 in Patients With Primary Myelofibrosis (PMF), Postpolycythemia Vera-myelofibrosis (PPV-MF), or Post-essential Thrombocythemia-myelofibrosis (PET-MF)
The purpose of this phase Ib clinical trial is to evaluate the safety of the combination of INC424 and BKM120 in the myelofibrosis population and to establish the maximum tolerated dose and or the Recommended Phase II dose of the combination guided by the Bayesian dose escalation model. INC424 has shown efficacy in myelofibrosis (MF) and is approved in the US and EU for the treatment of MF. BKM120 is a PI3K inhibitor. Preclinical and early clinical experience support inhibition of the PI3K/mTOR pathway in MF as aberrant activation of the pathway has been observed in MF models and may contribute to the pathogenesis of the disease.
- Conditions
- Myelofibrosis
- Being tested
- INC424, BKM120
- Keywords
- Myelofibrosis,, PMF,, PPV-MF,, PET-MF,, Primary Myelofibrosis,, Post-polycythemia vera myelofibrosis,, Post-essential thrombocythemia myelofibrosis
- Medical subject headings
- Primary Myelofibrosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
INC424Drug
5 mg tablets administered orally twice daily
BKM120Drug
10 mg and 50 mg hard gelatin capsules administered orally once daily
| Study group | Role | What they receive |
|---|---|---|
| JAK Inhibitor Naive | Experimental | Two treatment periods applicable to all patients; Treatment Period (6 cycles / 28 days per cycle) and Extension Period ( 6 or more cycles of 28 days, with visits every 28days for 6 cycles and then visits every 12 weeks) following the treatment period dependent on patient continued eligibility. Two Study Phases: Dose Escalation Phase to determine maximum tolerated dose (MTD) / Recommended Phase II dose (RPIID) \& an Expansion Phase Receives: Drug: INC424; Drug: BKM120 |
| Prior JAK Inhibitor | Experimental | Two treatment periods applicable to all patients; Treatment Period (6 cycles / 28 days per cycle) and Extension Period (6 or more cycles of 28 days, with visits every 28 days for 6 cycles then visits every 12 weeks) following the treatment period dependent on patient continued eligibility. Two Study Phases: Dose Escalation Phase to determine MTD / RPIID \& an Expansion Phase Receives: Drug: INC424; Drug: BKM120 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence of dose limiting toxicities
The incidence of dose limiting toxicities will be analyzed to establish the maximum tolerated dose. To assess the maximum tolerated dose, labs and adverse events are monitored.
Measured: baseline, when the maximum tolerated dose is established.
Secondary outcomes (14)
Frequency of adverse events
Adverse Events are monitored at each study visit and 30 days post last dose of study drug
Measured: after each cohort is enrolled at baseline until the maximum tolerated dose is established
Frequency of serious adverse events
Serious Adverse events monitored at each study visit and 30 days post last dose of study drug
Measured: after each cohort is enrolled at baseline until the maximum tolerated dose is established
Abnormalities in vital signs
cycle = 28 days
Measured: baseline, days 2, 8, 15, 22 of cycle 1, day 1 and 15 at Cycle 2, Day 1 from cycle 3 to 12, day 28 on Cycle 12 and every 12 weeks from Week 60 to 96 and at End of treatment
Laboratory test values including Imaging (electrocardiograms (ECGs), abdominal MRI/CT, ECHO/MUGA
ECGs are performed baseline, days 2, 8, 15, 22 of cycle 1 then day 1 from Cycle 2 to cycle 12, and at cycle 12 day 28 and every 12 weeks and end of treatment. Magnetic resonance imaging (MRI) or Cat Scan (CT) performed at baseline, cycle 4 day 1, cycle 7 day 1, cycle 12 day 28, then every 24 weeks , and end of treatment if not done in past 12 weeks. Echocardiography (ECHO) or Multiple Gated Acquisition (MUGA) is performed at baseline and then every 4 cycles until cycle 12, then every 24 weeks therafter or as clinically indicated until Week 96. Hematology is performed at baseline and days 2, 5, 8, 11, 15, 18, 22, 25 of cycle 1, weekly in cycle 2, then on every scheduled visit (D1 of Cycle 3 to 12, at Cycle 12 Day 28 ,then every 12 weeks) and end of treatment.
Measured: Day 1, 2, 5, 8, 11, 18, 22, 25 of cycle 1, weekly in cycle 2, then at every scheduled visit including End of treatment visit
Maximum plasma concentration (Cmax)
To characterize the pharmacokinetics (PK) of INC424 alone or in combination with BKM120
Measured: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8
Maximum plasma concentration time (Tmax)
To characterize the pharmacokinetics (PK) of INC424 alone or in combination with BKM120
Measured: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8
Area under the plasma concentration time curve (AUC)
To characterize the pharmacokinetics (PK) of INC424 alone or in combination with BKM120
Measured: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8
Maximum plasma concentration (Cmax)
To characterize the pharmacokinetics (PK) of BKM120 alone or in combination with INC424
Measured: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8
Maximum plasma concentration time (Tmax)
To characterize the pharmacokinetics (PK) of BKM120 alone or in combination with INC424
Measured: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8
Area under the plasma concentration time curve (AUC)
To characterize the pharmacokinetics (PK) of BKM120 alone or in combination with INC424
Measured: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8
Duration of adverse events
Adverse Events are monitored at each study visit and 30 days post last dose of study drug
Measured: after each cohort is enrolled at baseline until the maximum tolerated dose is established
Severity of adverse events
Adverse Events are monitored at each study visit and 30 days post last dose of study drug
Measured: after each cohort is enrolled at baseline until the maximum tolerated dose is established
Severity of serious adverse events
Serious Adverse events monitored at each study visit and 30 days post last dose of study drug
Measured: after each cohort is enrolled at baseline until the maximum tolerated dose is established
Duration of serious adverse events
Adverse Events are monitored at each study visit and 30 days post last dose of study drug
Measured: after each cohort is enrolled at baseline until the maximum tolerated dose is established
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Nov 2012 (estimated)
- Study start18 Dec 2012
- Primary completion28 Sep 2017
- Study completion28 Sep 2017
Why it stopped: Decision by Sponsor to to terminate the study early.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for MyelofibrosisStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- 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 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 63 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Incyte Corporation
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01730248
- Sponsor's protocol ID
- CINC424A2104
- Status last verified
- Mar 2019
- First submitted
- 12 Nov 2012
- Last updated
- 19 Dec 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 19 Dec 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase Ib, Open-label, Multi-center, Two-arm, Dose-finding Study to Assess Safety and Efficacy of the Oral Combination or INC424 (INC424) and BKM120 in Patients With Primary Myelofibrosis (PMF), Postpolycythemia Vera-myelofibrosis (PPV-MF), or Post-essential Thrombocythemia-myelofibrosis (PET-MF)
- ClinicalTrials.gov ID
- NCT01730248
- Acronym / sponsor ID
- CINC424A2104
- Conditions
- Myelofibrosis
- Keywords
- Myelofibrosis,, PMF,, PPV-MF,, PET-MF,, Primary Myelofibrosis,, Post-polycythemia vera myelofibrosis,, Post-essential thrombocythemia myelofibrosis
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Decision by Sponsor to to terminate the study early.
- Enrolment
- 63 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Collaborators
- Incyte Corporation
- Study start
- 18 Dec 2012 (actual)
- Primary completion
- 28 Sep 2017 (actual)
- Study completion
- 28 Sep 2017 (actual)
- First posted
- 21 Nov 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this phase Ib clinical trial is to evaluate the safety of the combination of INC424 and BKM120 in the myelofibrosis population and to establish the maximum tolerated dose and or the Recommended Phase II dose of the combination guided by the Bayesian dose escalation model. INC424 has shown efficacy in myelofibrosis (MF) and is approved in the US and EU for the treatment of MF. BKM120 is a PI3K inhibitor. Preclinical and early clinical experience support inhibition of the PI3K/mTOR pathway in MF as aberrant activation of the pathway has been observed in MF models and may contribute to the pathogenesis of the disease.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| JAK Inhibitor Naive | Experimental | Drug: INC424, Drug: BKM120Two treatment periods applicable to all patients; Treatment Period (6 cycles / 28 days per cycle) and Extension Period ( 6 or more cycles of 28 days, with visits every 28days for 6 cycles and then visits every 12 weeks) following the treatment period dependent on patient continued eligibility. Two Study Phases: Dose Escalation Phase to determine maximum tolerated dose (MTD) / Recommended Phase II dose (RPIID) \& an Expansion Phase |
| Prior JAK Inhibitor | Experimental | Drug: INC424, Drug: BKM120Two treatment periods applicable to all patients; Treatment Period (6 cycles / 28 days per cycle) and Extension Period (6 or more cycles of 28 days, with visits every 28 days for 6 cycles then visits every 12 weeks) following the treatment period dependent on patient continued eligibility. Two Study Phases: Dose Escalation Phase to determine MTD / RPIID \& an Expansion Phase |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Diagnosed with PMF, PPV-MF or PET-MF irrespective of JAK2 mutation status
- Myelofibrosis patients requiring therapy must be classified as intermediate risk level 1 )1 or more prognostic factors defined by IWG) with at least one criteria other than age
- Must have palpable spleen of at least 5 cm from the costal margin to the point of greatest splenic profusion at Screening
- Must have active symptoms of MF (one symptom score of at least 5 or two symptom scores of at least 3 at Screening) (per MFSSF 0-10)
- PLT counts > or = 75X 10^9/L at Screening or Cycle 1 Day 1 (not with aid of transfusions
Key exclusion criteria (10 listed)
- Pregnant or nursing women
- WOCBP not using highly effective methods of contraception
- Sexually active males who refuse condom use
- Previous Treatment with one of the following: PI3 K inhibitors and AKT inhibitors; JAK inhibitors that resulted in clinically significant toxicities per the Investigator;
- Patients who have had splenic irradiation within 12 months prior to Screening
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 |
|---|---|---|
| INC4245 mg tablets administered orally twice daily | Drug | JAK Inhibitor Naive, Prior JAK Inhibitor |
| BKM12010 mg and 50 mg hard gelatin capsules administered orally once daily | Drug | JAK Inhibitor Naive, Prior JAK Inhibitor |
Primary outcome
Incidence of dose limiting toxicities
Time frame: baseline, when the maximum tolerated dose is established.
The incidence of dose limiting toxicities will be analyzed to establish the maximum tolerated dose. To assess the maximum tolerated dose, labs and adverse events are monitored.
14 secondary outcomes
Frequency of adverse events
Time frame: after each cohort is enrolled at baseline until the maximum tolerated dose is established
Frequency of serious adverse events
Time frame: after each cohort is enrolled at baseline until the maximum tolerated dose is established
Abnormalities in vital signs
Time frame: baseline, days 2, 8, 15, 22 of cycle 1, day 1 and 15 at Cycle 2, Day 1 from cycle 3 to 12, day 28 on Cycle 12 and every 12 weeks from Week 60 to 96 and at End of treatment
Laboratory test values including Imaging (electrocardiograms (ECGs), abdominal MRI/CT, ECHO/MUGA
Time frame: Day 1, 2, 5, 8, 11, 18, 22, 25 of cycle 1, weekly in cycle 2, then at every scheduled visit including End of treatment visit
Maximum plasma concentration (Cmax)
Time frame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8
Maximum plasma concentration time (Tmax)
Time frame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8
Area under the plasma concentration time curve (AUC)
Time frame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8
Maximum plasma concentration (Cmax)
Time frame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8
Maximum plasma concentration time (Tmax)
Time frame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8
Area under the plasma concentration time curve (AUC)
Time frame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8
Duration of adverse events
Time frame: after each cohort is enrolled at baseline until the maximum tolerated dose is established
Severity of adverse events
Time frame: after each cohort is enrolled at baseline until the maximum tolerated dose is established
Severity of serious adverse events
Time frame: after each cohort is enrolled at baseline until the maximum tolerated dose is established
Duration of serious adverse events
Time frame: after each cohort is enrolled at baseline until the maximum tolerated dose is established
Results and safety
The study was stopped early (reason given: Decision by Sponsor to to terminate the study early.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Dec 2020.
- Results for INC424A2104 can be found on the Novartis Clinical Trial Results WebsiteLink provided by the sponsor.
- 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.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
15 sites in 9 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing INC424 and BKM120 in people with Myelofibrosis, run by Novartis Pharmaceuticals at 15 sites in 9 countries.
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 5 inclusion and 10 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: stopped early, as of the sponsor's last update on 19 Dec 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 15 sites in United Kingdom, Australia, Germany, Israel, Italy and 4 more countries. 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Decision by Sponsor to to terminate the study early.). Results are not available in the source record.
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?
Incidence of dose limiting toxicities (time frame: baseline, when the maximum tolerated dose is established.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 19 Dec 2020.