Primary: To estimate the MTD and/or RDE for each of the following three treatment arms in patients with myelofibrosis.* PIM447 plus ruxolitinib (doublet)* Ribociclib (LEE011) plus ruxolitinib (doublet)* PIM447 plus ruxolitinib and Ribociclib (LEE011…
ID
Source
Brief title
Condition
- Haematological disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Incidence of DLTs in Cycle 1
Secondary outcome
Frequency and severity of Adverse events
% of patients achieving *35% reduction in spleen volume
Changes in allele burden
Change in platelets, neutrophils and hemoglobin
Changes in bone marrow fibrosis and histomorphology
Plasma concentration of PIM447, Ribociclib (LEE011) and ruxolitinib. Pk
parameters
Background summary
The JAK2 inhibitor ruxolitinib is an effective therapy for patients with MF
that results in reduction of splenomegaly, and improvement symptoms associated
with the disease. However, a significant unmet medical needs remain for more
treatment options, for example while patients can see a gradual return of both
over time. Building upon the experience with ruxolitinib, strategies combining
JAK2 inhibitors with novel agents, such as PIM447 and Ribociclib (LEE011),
provide an opportunity to achieve additional disease altering activity in MF,
through impacting JAK2V617F allele burden (=ratio of mutant to wild type JAK2
alleles) and reducing bone marrow fibrosis.
The triple combination of PIM447 plus ruxolitinib and Ribociclib (LEE011),
shows marked reduction in JAK2V617F allele burden in a pre-clinical in vivo
model compared to that seen with ruxolitinib monotherapy. In the current study,
PIM447 and Ribociclib (LEE011) are combined with ruxolitinib to determine the
safety, tolerability, PK and pharmacodynamic effects, as well as preliminary
anti-myelofibrosis activity. Combining ruxolitinib with PIM447 and/or
Ribociclib (LEE011) in this study may lead to greater decreases in spleen
volume and promote marked reductions in JAK2V617F allele burden in patients
administered the triple combination, potentially defining a novel therapeutic
regimen that displays disease altering activity and having an impact on overall
survival.
Study objective
Primary:
To estimate the MTD and/or RDE for each of the following three treatment arms
in patients with myelofibrosis.
* PIM447 plus ruxolitinib (doublet)
* Ribociclib (LEE011) plus ruxolitinib (doublet)
* PIM447 plus ruxolitinib and Ribociclib (LEE011) (triple combination)
Secondary: Safety and tolerability, preliminary anti-myelofibrosis activity, PK
profiles.
Study design
Multicenter phase 1b open-label dose escalation and dose expansion study.
Three treatment arms:
* Arm 1 PIM447 plus ruxolitinib (INC424)
* Arm 2 Ribociclib (LEE011) plus ruxolitinib
* Arm 3 PIM447 plus ruxolitinib and Ribociclib (LEE011).
Arm 1 and 2 will start simultaneously. Arm 3 will start after review of the
available safety and efficacy data of arms 1 and 2.
The study treatment will be administered during 28-days cycles. All treatments
will be administered daily orally.
Treatment period until disease progression or unacceptable side effects.
Approx. 92 patients.
Intervention
Treatment with PIM447+ ruxolitinib, Ribociclib (LEE001)+ ruxolitinib or
PIM447+Ribociclib (LEE011)+ruxolitinib.
Oral intake.
Study burden and risks
Risk: Adverse effects of the combination of study drugs. Risks of assessments
e.g. bone marrow aspirate and biopsy, blood draw.
Burden: Cycles of 4 weeks. Cycle 1: 6 visits, cycle 2 4 visits, from cycle 3
onwards 2 visits. Duration mostly 2-3 hours. Two visits 8-10 hours.
Physical examination: cycle 1-2 twice, from cycle 3 onwards once/cycle.
Following any study drug dose increase or when adding a third study drug, vital
signs (heart rate, blood pressure, and temperature) will be done on Day 1 and
Day 15 of the first and second cycle of the new dose level.
Blood tests (approx. 3-6 ml/occasion): cycle 1-2 4 times, from cycle 3 onwards
twice/cycle. Following any study drug dose increase or when adding a third
study drug, blood tests on Day 1 and Day 15 of the first and second cycle of
the new dose level will be done. Extra blood draws for PK (4 (8 times)-24
(twice)ml) and biomarkers (6(4 times + every 6th cycle)-24 (once)ml). Following
any study drug dose increase or when adding a third study drug, blood draws for
PK on Day 1 and Day 15 of the first and second cycle of the new dose level will
be done and biomarkers on day 1 of the first cycle when a third study drug is
added.
Abdominal MRI-scan: every 3-6 cycles.
ECG: cycle 1; 3 times, from cycle 2 onwards once/cycle. Following any study
drug dose increase or when adding a third study drug, ECG pre and 4 hour post
dose will be done on Day 1 and Day 15 of the first and second cycle of the new
dose level.
Echocardiogram (MUGA-scan): screening.
Bone marrow aspirate and/or biopsy: screening and end of study.
Questionnaires: Myelofibrosis symptom score, patient global impression of
change,
Taking of mouth swab and 6 ml of blood twice for reseach on treatmetn
resistance (optional)
Optional storage of remaining blood, bone marrow, buccal swab for future
research.
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
* ECOG performance status 0, 1, 2.
* JAK2V617F-positive primary or secondary myelofibrosis.
* < 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 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.
* Splenomegaly measuring at least 5 cm by MRI at baseline.
* Adequate bone marrow function (Platelets * 100 x 10 9/L - Absolute Neutrophil Count * 1.5 x 109/L - Hb * 9 g/dL <= 5,58 mmol/L).
Exclusion criteria
* Systemic antineoplastic therapy or any experimental therapy within 14 days or 5 half-lives before the first dose of study treatment
* Major surgery within 2 weeks before the first dose of study drug.
* Splenic irradiation within 2 weeks prior to Screening or splenectomy.
* AML, MDS, or peripheral blasts > 5 %.
* Prior autologous or allogeneic stem cell transplant.
* Treatment with a prohibited medication that cannot be discontinued at least one week prior to the start of treatment (Appendix 1), including agents that are:
- 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
* Medication with a known risk of prolonging the QT interval or inducing Torsades de Pointes (protocol appendix 2).
* History of (or predisposition to) clinically significant bleeding, history of platelet dysfunction and/or bleeding diathesis, and/or regular use of drugs that interfere with coagulation or inhibit PLT function (Appendix 3). NOTE: low doses of aspirin * 125 mg/day are allowed.
* Total bilirubin > 1.5 x upper limit of normal (ULN), AST (SGOT) or ALT (SGPT) > 3 x ULN, except with liver involvement AST or ALT > 5 x ULN.
* Creatinine > 1.5 x ULN or calculated creatinine clearance < 60 ml/min according to Cockcroft-Gault equation.
* Electrolyte abnormalities CTCAE grade * 2
* Patients with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study treatments
* Unresolved nausea, vomiting, or diarrhea of CTCAE grade * 2.
* Active infection requiring systemic therapy or other severe infection within 2 weeks before the first dose of either study drug.
* Impaired cardiac function or clinically significant cardiac diseases (refer to exclusion criterion #19)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-003801-14-NL |
| ClinicalTrials.gov | NCT02370706 |
| CCMO | NL52606.078.15 |