A Study Evaluating Safety and Tolerability, and Pharmacokinetics of Navitoclax Alone and in Combination With Ruxolitinib in Participants With Myeloproliferative Neoplasm

Phase 1

Active, not recruiting

Conditions: Myelofibrosis
Myeloproliferative Neoplasms

Registration Number: 2023-507274-40-00

Lead Sponsor: AbbVie Deutschland GmbH & Co. KG

Brief Summary: The objectives of this study are to evaluate safety and tolerability, preliminary efficacy, and pharmacokinetics of navitoclax when administered as monotherapy and in combination with ruxolitinib in Japanese and/or Taiwanese subjects with MPN (Parts 1 and 2) and to evaluate the effect of navitoclax on corrected QTc interval by Fridericia's correction formula (QTcF) in subjects with MPN or CMML in the US and Europe (Part 3).

The primary objective in Part 4 is to evaluate the effect of navitoclax, a CYP2C9 inhibitor, on the pharmacokinetics, safety, and tolerability of a single dose of celecoxib, a sensitive CYP2C9 substrate, in subjects with MPN or CMML.

The primary objective in Part 5 is to evaluate the effect of navitoclax on the PK, safety, and tolerability of ruxolitinib in subjects with first-line and relapsed/refractory MF in the US and Europe

Detailed Description: Not available

Recruitment & Eligibility

Status: Ongoing, recruitment ended

Sex: Not specified

Target Recruitment: 60

Inclusion Criteria

Part 1 and Part 2 of the study are not being conducted within the EEA.

Part 3: Subject must be requiring treatment and have failed or are intolerant to at least one prior therapy and be ineligible for allogeneic stem cell transplantation. Subjects who refuse standard therapy may only be enrolled in regions where permitted by local regulations

Part 3: Subject must have an ECOG performance status ≤ 2.

Part 3: Subject must meet laboratory parameters for bone marrow reserves, platelet count, neutrophil count, renal function, hepatic function and enzymes, AST and ALT, Billirubin, coagulation, serum potassium and hypocalcemia.

Part 4: Subjects with a documented diagnosis of primary or secondary MF, ET, PV or chronic myelomonocytic leukemia (CMML) as defined by the WHO classification.

Part 4: Subject must be requiring treatment and have failed or are intolerant to at least one prior therapy and be ineligible for allogeneic stem cell transplantation. Subjects who refuse standard therapy may only be enrolled in regions where permitted by local regulations.

Part 6: Subject must currently be receiving navitoclax in France or Bulgaria in a navitoclax clinical trial (M16-191, M19-753, or M20-178) and, in the opinion of the treating investigator, deriving clinical benefit from ongoing navitoclax treatment.

Part 6: Subject must have completed assessments through the End of Treatment Visit / Treatment Completion Visit in their parent protocol prior to starting navitoclax under Extension Part 6.

Part 4: Subject must have an ECOG performance status ≤ 2.

Part 4: Subject must meet laboratory parameters for bone marrow reserves, platelet count, neutrophil count, renal function, hepatic function and enzymes, AST and ALT, Billirubin, coagulation and serum potassium.

Part 5: Subjects with a documented diagnosis of primary MF as defined by the WHO classification, post-PV MF, or post-ET MF.

Part 5: Subject must be requiring treatment for MF and must either have no prior treatment with a JAK2 inhibitor or have received treatment with ruxolitinib meeting at least one of the following criteria listed in protocol eligibility criteria

Part 5: Subject must have an ECOG performance status ≤ 2.

Subjects ≥ 18 years old

Part 3: At screening or baseline (pre-dose on Day 1), subject has QTc interval by Fridericia's correction (QTcF) ≤ 450 msec.

Part 3: Subjects with a documented diagnosis of primary or secondary MF, ET, PV or chronic myelomonocytic leukemia (CMML) as defined by the WHO classification.

Exclusion Criteria

Part 1 and Part 2 of the study are not being conducted within the EEA.

Part 5: Subject must not have received CYP2C9 inducers within 10 days prior to the first dose of study drugs.

Part 3: Subject must not show leukemic transformation (> 10% blasts in peripheral blood or bone marrow biopsy).

Part 3: Subject must not be currently on medications that interfere with coagulation (including warfarin) or platelet function except for low-dose aspirin (up to 100 mg) and LMWH.

Part 3: Subject must not have had prior therapy with a BH3 mimetic compound.

Part 3: Subject must not have received strong or moderate CYP3A inhibitors within 28 days or 5 half-lives of the drug (whichever is shorter) prior to the first dose of navitoclax.

Part 3: Subject must not have received strong CYP3A inducers within 10 days prior to the first dose of navitoclax.

Part 4: Subject must not show leukemic transformation (> 10% blasts in peripheral blood or bone marrow biopsy)."

Part 4: Subject must not be currently on medications that interfere with coagulation (including warfarin) or platelet function except for low-dose aspirin (up to 100 mg) and LMWH.

Part 4: Subject must not have had prior therapy with a BH3 mimetic compound.

Part 4:Subject must not have received strong or moderate CYP3A inhibitors or CYP2C9 within 28 days or 5 half-lives of the drug (whichever is shorter) prior to the first dose of study drugs.

Part 4: Subject must not have received strong or moderate CYP2C9 inhibitors within 28 days or 5 half-lives of the drug (whichever is shorter) prior to the first dose of study drugs.

Part 4: Subject must not have received strong CYP3A or CYP2C9 inducers within 10 days prior to the first dose of study drugs.

Part 5: Subject must not have a history of an active malignancy other than MF within the past 2 years prior to study entry, except for: - Adequately treated in situ carcinoma of the cervix uteri - Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin - Asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy.

Part 5: Subject must not be currently on medications that interfere with coagulation (including warfarin) or platelet function except for low-dose aspirin (up to 100 mg) and LMWH.

Part 5: Subject must not have received strong CYP3A inhibitors within 28 days or 5 half-lives of the drug (whichever is shorter) prior to the first dose of study drugs.

Part 5: Subject must not have received CYP2C9 inhibitors within 28 days or 5 half-lives of the drug (whichever is shorter) prior to the first dose of study drugs.

Part 5: Subject must not have received strong CYP3A inducers within 10 days prior to the first dose of study drugs.

Study & Design

Study Type: Not specified

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Part 3: To evaluate the effect of navitoclax on corrected QTc interval by Fridericia's correction formula (QTcF) in subjects with MPN or CMML in the US and Europe.		Part 3: To evaluate the effect of navitoclax on corrected QTc interval by Fridericia's correction formula (QTcF) in subjects with MPN or CMML in the US and Europe.
Part 4: To evaluate the effect of navitoclax, a potential CYP2C9 inhibitor, on the pharmacokinetics, safety, and tolerability of a single dose of celecoxib, a sensitive CYP2C9 substrate, in subjects with MPN or CMML.		Part 4: To evaluate the effect of navitoclax, a potential CYP2C9 inhibitor, on the pharmacokinetics, safety, and tolerability of a single dose of celecoxib, a sensitive CYP2C9 substrate, in subjects with MPN or CMML.
Part 5: To evaluate the effect of navitoclax on the PK, safety, and tolerability of ruxolitinib in subjects with MF in the US and Europe.		Part 5: To evaluate the effect of navitoclax on the PK, safety, and tolerability of ruxolitinib in subjects with MF in the US and Europe.

Secondary Outcome Measures

Name	Time	Method
Safety Endpoint: Safety evaluations include adverse event (AE) monitoring, physical examinations, vital sign measurements, electrocardiogram (ECG) variables, and clinical laboratory testing (hematology, chemistry, coagulation, and urinalysis) as a measure of safety and tolerability		Safety Endpoint: Safety evaluations include adverse event (AE) monitoring, physical examinations, vital sign measurements, electrocardiogram (ECG) variables, and clinical laboratory testing (hematology, chemistry, coagulation, and urinalysis) as a measure of safety and tolerability
Pharmacodynamic Endpoint: Part 3 only- ECG variables will include QTcF, heart rate, PR interval (time from the onset of the P wave to the start of the QRS complex), QRS duration, and waveform composition.		Pharmacodynamic Endpoint: Part 3 only- ECG variables will include QTcF, heart rate, PR interval (time from the onset of the P wave to the start of the QRS complex), QRS duration, and waveform composition.
Pharmacokinetic Endpoint: Pharmacokinetic (PK) samples will be collected at specified time points and analyzed for navitoclax		Pharmacokinetic Endpoint: Pharmacokinetic (PK) samples will be collected at specified time points and analyzed for navitoclax
Efficacy Endpoint: Preliminary efficacy will be evaluated.		Efficacy Endpoint: Preliminary efficacy will be evaluated.

Trial Locations

Locations (16): KBC Zagreb
🇭🇷
Grad Zagreb, Croatia
Klinikum Kassel GmbH
🇩🇪
Kassel, Germany
Medical Center - University Of Freiburg
🇩🇪
Freiburg Im Breisgau, Germany
Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia
🇮🇹
Brescia, Italy
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
🇮🇹
Rome, Italy
Clinica Universidad De Navarra
🇪🇸
Pamplona, Spain
Institut Catala D'oncologia
🇪🇸
L'hospitalet De Llobregat, Spain
Centre Hospitalier Universitaire Amiens Picardie
🇫🇷
Amiens Cedex 1, France
Hospices Civils De Lyon
🇫🇷
Pierre Benite, France
Centre Hospitalier Universitaire D'Angers
🇫🇷
Angers, France
Scroll for more (6 remaining)
KBC Zagreb
🇭🇷Grad Zagreb, Croatia
Nadira Durakovic
Site contact
38512376445
kbc-zagreb@kbc-zagreb.hr