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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AbbVie Deutschland GmbH & Co. KG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

22 Apr 2021 → ongoing

Decision date (initial)

2024-05-29

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

AbbVie Inc.

External identifiers

EU CT number

2023-507274-40-00

EudraCT number

2020-002597-27

ClinicalTrials.gov

NCT04041050

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Safety

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

Secondary objectives 1

1. The secondary objectives are to evaluate preliminary efficacy with MPN when administered as monotherapy and in combination with ruxolitinib. Safety evaluations will include adverse event (AE) monitoring, physical examinations, vital signs measurements, electrocardiogram (ECG) variables and clinical laboratory testing. Pharmacokinetic (PK) samples will be collected and analyzed for navitoclax (Parts 1, 2, 3, 4 and 5), ruxolitinib (Part 2 and 5 only), and celecoxib (Part 4 only). Plasma concentrations will be used to compute navitoclax, ruxolitinib, and celecoxib PK parameters as applicable.

Conditions and MedDRA coding

Myelofibrosis

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-000478-PIP02-18

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. Part 1 and Part 2 of the study are not being conducted within the EEA.
2. Part 4: Subject must have an ECOG performance status ≤ 2.
3. 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.
4. Part 5: Subjects with a documented diagnosis of primary MF as defined by the WHO classification, post-PV MF, or post-ET MF.
5. 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
6. Part 5: Subject must have an ECOG performance status ≤ 2.
7. Subjects ≥ 18 years old
8. Part 3: At screening or baseline (pre-dose on Day 1), subject has QTc interval by Fridericia's correction (QTcF) ≤ 450 msec.
9. 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.
10. 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
11. Part 3: Subject must have an ECOG performance status ≤ 2.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.

Exclusion criteria 18

1. Part 1 and Part 2 of the study are not being conducted within the EEA.
2. 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.
3. 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.
4. Part 4: Subject must not have received strong CYP3A or CYP2C9 inducers within 10 days prior to the first dose of study drugs.
5. 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.
6. 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.
7. 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.
8. 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.
9. Part 5: Subject must not have received strong CYP3A inducers within 10 days prior to the first dose of study drugs.
10. Part 5: Subject must not have received CYP2C9 inducers within 10 days prior to the first dose of study drugs.
11. Part 3: Subject must not show leukemic transformation (> 10% blasts in peripheral blood or bone marrow biopsy).
12. 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.
13. Part 3: Subject must not have had prior therapy with a BH3 mimetic compound.
14. 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.
15. Part 3: Subject must not have received strong CYP3A inducers within 10 days prior to the first dose of navitoclax.
16. Part 4: Subject must not show leukemic transformation (> 10% blasts in peripheral blood or bone marrow biopsy)."
17. 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.
18. Part 4: Subject must not have had prior therapy with a BH3 mimetic compound.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. 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.
2. 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.
3. 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 endpoints 4

1. 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
2. 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.
3. Pharmacokinetic Endpoint: Pharmacokinetic (PK) samples will be collected at specified time points and analyzed for navitoclax
4. Efficacy Endpoint: Preliminary efficacy will be evaluated.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 9

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AbbVie Deutschland GmbH & Co. KG

Sponsor organisation

AbbVie Deutschland GmbH & Co. KG

Address

Knollstrasse

City

Ludwigshafen Am Rhein

Postcode

67061

Country

Germany

Scientific contact point

Organisation

AbbVie Deutschland GmbH & Co. KG

Contact name

Global Clinical Trials Helpdesk

Public contact point

Organisation

AbbVie Deutschland GmbH & Co. KG

Contact name

Global Clinical Trials Helpdesk

Third parties 2

Locations

6 EU/EEA countries · 17 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

5 submissions — initial application plus substantial / non-substantial modifications