MyelofibrosisPhase 1NCT02370706
Study of the Safety of PIM447 in Combination With Ruxolitinib (INC424) and LEE011 in Patients With Myelofibrosis
A Phase 1 study testing PIM447, Ruxolitinib and LEE011 in people with Myelofibrosis, run by Novartis Pharmaceuticals at 9 sites in 8 countries.
Trial summary
This is a phase Ib study with the primary purpose is to estimate the MTD and/or RDE for the triple combination of PIM447, formerly LGH447, plus ruxolitinib and LEE011 as well as for the doublets, PIM447 plus ruxolitinib, and LEE011 plus ruxolitinib, in patients with myelofibrosis (MF). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Myelofibrosis
- What is being tested?
- PIM447, Ruxolitinib and LEE011
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 15 participants
- Where
- 9 sitesin 8 countries
- Study dates
- 21 May 2015to 9 Nov 2020
- 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
- Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
- Patient must be diagnosed with JAK2V617F-positive primary or secondary MF.
- Dose-escalation and Expansion parts: Patients with a < 35% reduction in spleen volume by MRI/CT or < 50% reduction in spleen size by physical exam, with or without corresponding symptomatic improvement, after at least 6 months of treatment with single agent ruxolitinib at an optimal dose level in line with the label recommendations. Expansion parts only: Ruxolitinib-naive patients and patients who have been previously treated with single agent ruxolitinib and are relapsed and/or refractory.
- Patients must have splenomegaly measuring at least 5 cm by MRI at baseline.
- Have adequate bone marrow function:
- Platelets ≥ 100,000 mm3 without the assistance of growth factors or platelet transfusions
- Absolute Neutrophil Count (ANC) ≥ 1500/mm3 without growth factor support within 7 days prior to testing
- Hemoglobin ≥ 9 g/dL.
Who cannot join
- Systemic antineoplastic therapy (including unconjugated therapeutic antibodies, toxin immunoconjugates, and alpha-interferon) or any experimental therapy within 14 days or 5 half-lives, whichever is shorter, before the first dose of study treatment
- Major surgery within 2 weeks before the first dose of either study drug.
- Patients who have had splenic irradiation within 2 weeks prior to Screening or prior splenectomy.
- Patients with AML, MDS, or peripheral blasts ≥ 10 %
- Prior autologous or allogeneic stem cell transplant at any time.
- Patients who are currently receiving treatment with a prohibited medication that cannot be discontinued at least one week prior to the start of treatment:
Show all 12Show fewer
- substrates of CYP3A4/5, CYP2B6 or CYP2D6 that have a narrow therapeutic window
- strong inhibitors of CYP3A4/5 or CYP2D6
- potent inducers of CYP3A4/5 or CYP2D6
- Serum total bilirubin > 1.5 x upper limit of normal (ULN) except in patients with Gilbert's syndrome who are excluded if the total bilirubin is > 3.0 x ULN or direct bilirubin > 1.5 x ULN, or aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) or ALT (SGPT) > 3 x ULN, except in patients with MF involvement of the liver who are excluded if AST or ALT > 5 x ULN.
- Serum creatinine > 1.5 x ULN or calculated creatinine clearance < 60 ml/min according to Cockcroft-Gault equation
- Electrolyte abnormalities CTCAE grade ≥ 2 (e.g. serum potassium, magnesium and calcium) unless they can be repleted during screening and are deemed not clinically significant by the Investigator.
Trial locations and contacts
9 sites in 8 countries.
9 sites in 8 countries
Germany2 sites
Novartis Investigative Site
Mainz, 55131
Novartis Investigative Site
Ulm, 89081
About this study
Official title: A Phase Ib, Multi-center, Open-label, Dose-escalation Study of PIM447 in Combination With Ruxolitinib (INC424) and LEE011 Administered Orally in Patients With Myelofibrosis
This is a phase Ib study with the primary purpose is to estimate the MTD and/or RDE for the triple combination of PIM447, formerly LGH447, plus ruxolitinib and LEE011 as well as for the doublets, PIM447 plus ruxolitinib, and LEE011 plus ruxolitinib, in patients with myelofibrosis (MF). Each regimen will be assessed for safety, tolerability, pharmacokinetics (PK) and pharmacodynamic effects, and preliminary anti-myelofibrosis activity, including changes in spleen volume, JAK2V617F allele burden, and hematologic response.
- Conditions
- Myelofibrosis
- Being tested
- PIM447, Ruxolitinib, LEE011
- Keywords
- PIM447, LGH447, PIM inhibitor, LEE011, CDK 4/6 inhibitor, ruxolitinib, INC424, Jakavi®, Jakafi®, INCB18424, JAK inhibitor, myelofibrosis, PMF, PPV-MF, PET-MF
- Medical subject headings
- Primary Myelofibrosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PIM447Drug
pan-pim inhibitor
RuxolitinibDrug
JAK1/JAK2 inhibitor
LEE011Drug
CDK4/6 inhibitor
| Study group | Role | What they receive |
|---|---|---|
| Dose Escalation Arm 1 | Experimental | Not described Receives: Drug: PIM447; Drug: Ruxolitinib |
| Dose Escalation Arm 2 | Experimental | Not described Receives: Drug: Ruxolitinib; Drug: LEE011 |
| Dose Escalation Arm 3 | Experimental | Not described Receives: Drug: PIM447; Drug: Ruxolitinib; Drug: LEE011 |
| Dose Expansion Arm 1 | Experimental | Not described Receives: Drug: PIM447; Drug: Ruxolitinib |
| Dose Expansion Arm 2 | Experimental | Not described Receives: Drug: Ruxolitinib; Drug: LEE011 |
| Dose Expansion Arm 3 | Experimental | Not described Receives: Drug: PIM447; Drug: Ruxolitinib; Drug: LEE011 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence of dose limiting toxicities during the first cycle of study treatment
To estimate the maximum tolerated dose and/or recommended dose for expansion for each of the following three treatment arms in patients with myelofibrosis (MF): PIM447 plus ruxolitinib (doublet), LEE011 plus ruxolitinib (doublet), PIM447 plus ruxolitinib and LEE 011 (triple combination).
Measured: Cycle 1 (28 days)
Secondary outcomes (7)
Number of participants with adverse events/serious adverse events
Frequency and severity of adverse events (AEs), serious AEs (SAEs), changes in laboratory values, and electrocardiograms (ECGs), as a measure of safety and tolerability. Assessments consisted of recording all adverse events (AEs) and serious adverse events (SAEs), the regular monitoring of hematology, blood chemistry, urinalysis, and coagulation parameters, as well as electrocardiograms.
Measured: Approximately 27 months (end of study)
Proportion of patients achieving ≥ 35% reduction in spleen volume by magnetic resonance imaging (MRI) at Week 24
To assess preliminary anti-myelofibrosis activity of PIM447 plus ruxolitinib, LEE011 plus ruxolitinib, and the triple combination PIM447 plus ruxolitinib and LEE011.
Measured: 24 weeks
Changes in ratio of mutant to wild type JAK2 alleles (i.e. allele burden)
To assess preliminary anti-myelofibrosis activity of PIM447 plus ruxolitinib, LEE011 plus ruxolitinib, and the triple combination PIM447 plus ruxolitinib and LEE011.
Measured: Approximately 27 months (end of study)
Change in platelets, neutrophils, and hemoglobin
To assess preliminary anti-myelofibrosis activity of PIM447 plus ruxolitinib, LEE011 plus ruxolitinib, and the triple combination PIM447 plus ruxolitinib and LEE011.
Measured: Approximately 27 months (end of study)
Change in bone marrow fibrosis and histomorphology
To assess preliminary anti-myelofibrosis activity of PIM447 plus ruxolitinib, LEE011 plus ruxolitinib, and the triple combination PIM447 plus ruxolitinib and LEE011.
Measured: Approximately 27 months (end of study)
Determine single and multiple dose pharmacokinetics (PK) profiles
Plasma concentration-time profiles of PIM447, ruxolitinib, and LEE011. PK parameters, including but not limited to Cmax, AUCinf, AUClast, AUCtau, T½, Tmax, accumulation ratio (Racc), CL/F, and Vz/F
Measured: Approximately 12 months
Change in spleen volume as measured by MRI from baseline
To assess preliminary anti-myelofibrosis activity of PIM447 plus ruxolitinib, LEE011 plus ruxolitinib, and the triple combination PIM447 plus ruxolitinib and LEE011.
Measured: Approximately 27 months (end of study)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Feb 2015 (estimated)
- Study start21 May 2015
- Primary completion9 Nov 2020
- Study completion9 Nov 2020
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
- Health services research
- Allocation
- Not applicable
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 15 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02370706
- Sponsor's protocol ID
- CPIM447X2104C
- Other IDs
- 2014-003801-14, 2014
- Status last verified
- Feb 2022
- First submitted
- 6 Feb 2015
- Last updated
- 9 Feb 2022
- 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 9 Feb 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase Ib, Multi-center, Open-label, Dose-escalation Study of PIM447 in Combination With Ruxolitinib (INC424) and LEE011 Administered Orally in Patients With Myelofibrosis
- ClinicalTrials.gov ID
- NCT02370706
- Acronym / sponsor ID
- CPIM447X2104C
- Conditions
- Myelofibrosis
- Keywords
- PIM447, LGH447, PIM inhibitor, LEE011, CDK 4/6 inhibitor, ruxolitinib, INC424, Jakavi®
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 15 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- 21 May 2015 (actual)
- Primary completion
- 9 Nov 2020 (actual)
- Study completion
- 9 Nov 2020 (actual)
- First posted
- 25 Feb 2015 (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.
This is a phase Ib study with the primary purpose is to estimate the MTD and/or RDE for the triple combination of PIM447, formerly LGH447, plus ruxolitinib and LEE011 as well as for the doublets, PIM447 plus ruxolitinib, and LEE011 plus ruxolitinib, in patients with myelofibrosis (MF). Each regimen will be assessed for safety, tolerability, pharmacokinetics (PK) and pharmacodynamic effects, and preliminary anti-myelofibrosis activity, including changes in spleen volume, JAK2V617F allele burden, and hematologic response.
Study design
- Primary purpose
- Health services research
- Allocation
- Not applicable
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| Dose Escalation Arm 1 | Experimental | Drug: PIM447, Drug: Ruxolitinib |
| Dose Escalation Arm 2 | Experimental | Drug: Ruxolitinib, Drug: LEE011 |
| Dose Escalation Arm 3 | Experimental | Drug: PIM447, Drug: Ruxolitinib, Drug: LEE011 |
| Dose Expansion Arm 1 | Experimental | Drug: PIM447, Drug: Ruxolitinib |
| Dose Expansion Arm 2 | Experimental | Drug: Ruxolitinib, Drug: LEE011 |
| Dose Expansion Arm 3 | Experimental | Drug: PIM447, Drug: Ruxolitinib, Drug: LEE011 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
- Patient must be diagnosed with JAK2V617F-positive primary or secondary MF.
- Dose-escalation and Expansion parts: Patients with a < 35% reduction in spleen volume by MRI/CT or < 50% reduction in spleen size by physical exam, with or without corresponding symptomatic improvement, after at least 6 months of treatment with single agent ruxolitinib at an optimal dose level in line with the label recommendations. Expansion parts only: Ruxolitinib-naive patients and patients who have been previously treated with single agent ruxolitinib and are relapsed and/or refractory.
- Patients must have splenomegaly measuring at least 5 cm by MRI at baseline.
- Have adequate bone marrow function:
Key exclusion criteria (12 listed)
- Systemic antineoplastic therapy (including unconjugated therapeutic antibodies, toxin immunoconjugates, and alpha-interferon) or any experimental therapy within 14 days or 5 half-lives, whichever is shorter, before the first dose of study treatment
- Major surgery within 2 weeks before the first dose of either study drug.
- Patients who have had splenic irradiation within 2 weeks prior to Screening or prior splenectomy.
- Patients with AML, MDS, or peripheral blasts ≥ 10 %
- Prior autologous or allogeneic stem cell transplant at any time.
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 |
|---|---|---|
| PIM447pan-pim inhibitor | Drug | Dose Escalation Arm 1, Dose Escalation Arm 3, Dose Expansion Arm 1, Dose Expansion Arm 3 |
| RuxolitinibJAK1/JAK2 inhibitor | Drug | Dose Escalation Arm 1, Dose Escalation Arm 2, Dose Escalation Arm 3, Dose Expansion Arm 1, Dose Expansion Arm 2, Dose Expansion Arm 3 |
| LEE011CDK4/6 inhibitor | Drug | Dose Escalation Arm 2, Dose Escalation Arm 3, Dose Expansion Arm 2, Dose Expansion Arm 3 |
Primary outcome
Incidence of dose limiting toxicities during the first cycle of study treatment
Time frame: Cycle 1 (28 days)
To estimate the maximum tolerated dose and/or recommended dose for expansion for each of the following three treatment arms in patients with myelofibrosis (MF): PIM447 plus ruxolitinib (doublet), LEE011 plus ruxolitinib (doublet), PIM447 plus ruxolitinib and LEE 011 (triple combination).
7 secondary outcomes
Number of participants with adverse events/serious adverse events
Time frame: Approximately 27 months (end of study)
Proportion of patients achieving ≥ 35% reduction in spleen volume by magnetic resonance imaging (MRI) at Week 24
Time frame: 24 weeks
Changes in ratio of mutant to wild type JAK2 alleles (i.e. allele burden)
Time frame: Approximately 27 months (end of study)
Change in platelets, neutrophils, and hemoglobin
Time frame: Approximately 27 months (end of study)
Change in bone marrow fibrosis and histomorphology
Time frame: Approximately 27 months (end of study)
Determine single and multiple dose pharmacokinetics (PK) profiles
Time frame: Approximately 12 months
Change in spleen volume as measured by MRI from baseline
Time frame: Approximately 27 months (end of study)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Feb 2022.
- Results for CPIM447X2104C can be found on the Novartis Clinical Trial Results Website.Link 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
9 sites in 8 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing PIM447, Ruxolitinib and LEE011 in people with Myelofibrosis, run by Novartis Pharmaceuticals at 9 sites in 8 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 8 inclusion and 12 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 9 Feb 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 9 sites in Germany, Australia, Canada, France, Italy and 3 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 is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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 during the first cycle of study treatment (time frame: Cycle 1 (28 days)). 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 9 Feb 2022.