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JOURNAL ONKOLOGIE – STUDIE

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

Rekrutierend

NCT-Nummer:
NCT04041050

Studienbeginn:
November 2019

Letztes Update:
06.07.2021

Wirkstoff:
Navitoclax, Ruxolitinib, Celecoxib

Indikation (Clinical Trials):
Neoplasms, Myeloproliferative Disorders

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 1

Sponsor:
AbbVie

Collaborator:
-

Studienleiter

ABBVIE INC.
Study Director
AbbVie

Kontakt

Studienlocations
(3 von 24)

Universitaetsklinikum Freiburg /ID# 222791
79106 Freiburg
(Baden-Württemberg)
GermanyNoch nicht rekrutierend» Google-Maps
Charite Universitaetsklinikum Berlin - Campus Virchow /ID# 224835
13353 Berlin
(Berlin)
GermanyNoch nicht rekrutierend» Google-Maps
Klinikum Kassel /ID# 225440
34125 Kassel
(Hessen)
GermanyNoch nicht rekrutierend» Google-Maps
Universitaetsmedizin Rostock /ID# 225436
18057 Rostock
(Mecklenburg-Vorpommern)
GermanyNoch nicht rekrutierend» Google-Maps
UCLA /Id# 222784
90095-1678 Los Angeles
United StatesNoch nicht rekrutierend» Google-Maps
Northwestern University Feinberg School of Medicine /ID# 224203
60611-2927 Chicago
United StatesNoch nicht rekrutierend» Google-Maps
Gabrail Cancer Center Research /ID# 228924
44718 Canton
United StatesNoch nicht rekrutierend» Google-Maps
Virginia Commonwealth University Medical Center Main Hospital /ID# 228169
23219 Richmond
United StatesNoch nicht rekrutierend» Google-Maps
UCL Saint-Luc /ID# 225314
1200 Woluwe-Saint-Lambert
BelgiumNoch nicht rekrutierend» Google-Maps
ASST Spedali civili di Brescia /ID# 224962
25123 Brescia
ItalyRekrutierend» Google-Maps
Istituto Romagnolo per lo Studio dei Tumori Dino Amadori IRCCS /ID# 224071
47014 Meldola
ItalyNoch nicht rekrutierend» Google-Maps
Azienda ULSS 8 Berica/Ospedale San Bortolo di Vicenza /ID# 224963
36100 Vicenza
ItalyNoch nicht rekrutierend» Google-Maps
Shonan Kamakura General Hospital /ID# 224315
247-8533 Kamakura-shi
JapanRekrutierend» Google-Maps
Kindai University Hospital /ID# 213241
589-8511 Osakasayama-shi
JapanRekrutierend» Google-Maps
Osaka University Hospital /ID# 213235
565-0871 Suita-shi
JapanRekrutierend» Google-Maps
Juntendo University Hospital /ID# 213255
113-8431 Bunkyo-ku
JapanRekrutierend» Google-Maps
University of Yamanashi Hospital /ID# 229279
409-3821 Chuo-shi
JapanRekrutierend» Google-Maps
Hospital Duran i Reynals /ID# 224007
08907 Hospitalet de Llobregat
SpainRekrutierend» Google-Maps
CLINICA UNIVERSIDAD DE NAVARRA-Pamplona /ID# 224839
31008 Pamplona
SpainRekrutierend» Google-Maps
CLINICA UNIVERSIDAD DE NAVARRA-Madrid /ID# 226041
28027 Madrid
SpainRekrutierend» Google-Maps
China Medical University Hosp /ID# 215634
40447 Taichung City
TaiwanRekrutierend» Google-Maps
Kaohsiung Medical University Chung-Ho Memorial Hospital /ID# 215631
80708 Kaohsiung
TaiwanRekrutierend» Google-Maps
Guy's and St Thomas' NHS Found /ID# 223963
SE1 9RT London
United KingdomNoch nicht rekrutierend» Google-Maps
Oxford Univ Hosp NHS Trust /ID# 225377
OX3 7LE Oxford
United KingdomNoch nicht rekrutierend» Google-Maps
Alle anzeigen

Studien-Informationen

Brief Summary:

There are 4 parts to this study for which the primary objectives are to evaluate safety and

tolerability, including dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of

navitoclax when administered alone (Part 1) or when administered in combination with

ruxolitinib (Part 2). In Part 2, participants must have been receiving a stable dose of

ruxolitinib therapy for at least 12 weeks prior to study enrollment. In Part 3, all eligible

participants will receive navitoclax, with the primary objective being to evaluate potential

navitoclax effect on QTc prolongation. In Part 4, effect of navitoclax is evaluated on the

PK, safety, and tolerability of a single dose of celecoxib in participants with

myeloproliferative neoplasm (MPN) or chronic myelomonocytic leukemia (CMML).

Ein-/Ausschlusskriterien

Inclusion Criteria:

Parts 1 and 2:

- Navitoclax Monotherapy (Part 1 Only - Japanese Participants):

- Documented diagnosis of myelofibrosis (MF), polycythemia vera (PV) or essential

thrombocythemia (ET) as defined by the World Health Organization (WHO)

classification.

- MF participants must have received and failed or are intolerant to ruxolitinib

therapy.

- ET or PV participants must be requiring cytoreduction who have failed or are

intolerant to at least one prior therapy, or who refuse standard therapy.

- Navitoclax + ruxolitinib Combination Therapy (Part 2 Only - Japanese and Taiwanese

Participants):

- Has documented diagnosis of primary MF, post-polycythemia vera MF (PPV-MF), or

post-essential thrombocythemia (PET-MF) as defined by the World Health

Organization (WHO) classification.

- Is ineligible or unwilling to undergo stem cell transplantation at time of study

entry.

- Has splenomegaly as defined by a spleen palpable >= 5 cm below costal margin or

spleen volume >= 50 cm^3 as assessed by magnetic resonance imaging (MRI) or

computed topography (CT) scan.

- Must have received ruxolitinib therapy for at least 12 weeks and be currently on

a stable dose of ruxolitinib (as described in the protocol).

- Must have adequate bone marrow, kidney, liver and hematology blood values as detailed

in the study protocol.

- Part 1 only: Cytoreduction for participants with ET and PV therapy within 14 days

prior to the first dose of navitoclax will be allowed pending additional discussion

with study doctor. Ruxolitinib for MF participants will not be allowed within 7 days

prior to the first dose of study drug and during navitoclax administration.

- Eastern Cooperative Oncology Group (ECOG) performance status <= 1.

Part 3 and Part 4:

- Part 3 Only: At screening or baseline (pre-dose on Day 1), participant has QT interval

corrected for heart rate (QTc) interval by Fridericia's correction (QTcF) <= 470 msec.

- Participants with a documented diagnosis of primary or secondary MF, ET, PV or chronic

myelomonocytic leukemia (CMML) as defined by the WHO classification.

- Participants must be requiring treatment and have failed or are intolerant to at least

one prior therapy or who refuse standard therapy.

- ECOG performance status <= 2.

- Must have adequate bone marrow, kidney, liver and hematology blood values as detailed

in the study protocol.

Exclusion Criteria:

Part 1 and 2:

- Shows leukemic transformation (> 10% blasts in peripheral blood or bone marrow

biopsy).

- Has a history of an active malignancy other than MPN within the past 2 years prior to

study entry (exceptions detailed in the protocol).

- Has a positive test result for HIV at screening.

- Has chronic active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection

requiring treatment.

- Has evidence of other clinically significant uncontrolled condition(s).

- Has previously taken a BH3 mimetic compound.

- Currently on medications that interfere with coagulation (including warfarin) or

platelet function with the exception of low dose aspirin (up to 100 mg) and

low-molecular-weight heparin (LMWH).

- Has received strong or moderate CYP3A inhibitors (e.g., ketoconazole, clarithromycin)

within 14 days prior to the administration of the first dose of navitoclax.

Part 3 and Part 4:

- Had prior therapy with a BH3 mimetic compound.

- 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.

- Have received strong CYP3A inducers within 10 days prior to the first dose of

navitoclax.

- Show leukemic transformation (> 10% blasts in peripheral blood or bone marrow biopsy).

- 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 Only:

- 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.

- Have received CYP2C9 inducers within 10 days prior to the first dose of study drugs.

Studien-Rationale

Primary outcome:

1. Number of Participants with Dose Limiting Toxicities (DLT) (Time Frame - Up to 28 days after the navitoclax initiation):
Dose limiting toxicities for dose escalation purposes will be determined on events that occur during the first 28-day cycle of navitoclax.

2. Maximum Observed Plasma Concentration (Cmax) of Navitoclax (Time Frame - Up to approximately 1 day):
Maximum Observed Plasma Concentration (Cmax) of Navitoclax.

3. Maximum Observed Plasma Concentration (Cmax) of Celecoxib (Part 4) (Time Frame - Up to approximately 1 day):
Maximum Observed Plasma Concentration (Cmax) of Celecoxib.

4. Time to Cmax (peak time, Tmax) of Navitoclax (Time Frame - Up to approximately 1 day):
Tmax defined as time to maximum observed plasma concentration of Navitoclax.

5. Time to Cmax (peak time, Tmax) of Celecoxib (Part 4) (Time Frame - Up to approximately 1 day):
Tmax defined as time to maximum observed plasma concentration of Celecoxib.

6. Area Under the Plasma Concentration-time Curve from time 0 to the time of the last measurable concentration (AUCt) of Navitoclax (Time Frame - Up to approximately 2 days):
Area under the plasma concentration-time curve from time zero to the last measurable concentration of Navitoclax.

7. Area Under the Plasma Concentration-time Curve from time 0 to the time of the last measurable concentration (AUCt) of Celecoxib (Part 4) (Time Frame - Up to approximately 2 days):
Area under the plasma concentration-time curve from time zero to the last measurable concentration of Celecoxib.

8. Number of Participants with Adverse Events (Time Frame - From first dose of study drug until 30 days following last dose of study drug (up to approximately 3 years).):
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.

9. Change in QT interval corrected for heart rate interval by Fridericia's correction formula (QTcF) (Part 3) (Time Frame - From first dose of study drug until 30 days following last dose of study drug.):
Change in QTCF (Part 3).

Secondary outcome:

1. Overall Response Rate (ORR) (Time Frame - Up to approximately 96 weeks):
ORR is defined as the sum of rates of complete remission (CR) + partial remission (PR) associated with the addition of navitoclax to ruxolitinib according to the International Working Group-Myeloproliferative Neoplasms Research and Treatment/European Leukemia Net (IWG-MRT/ELN) criteria.

Studien-Arme

  • Experimental: Part 1: Navitoclax Monotherapy
    Participants will receive various doses of navitoclax once daily (QD).
  • Experimental: Part 2: Navitoclax + Ruxolitinib Combination Therapy
    Participants will receive various doses of navitoclax once daily (QD) in combination with ruxolitinib twice daily (BID).
  • Experimental: Part 3: Navitoclax Monotherapy
    Participants will receive navitoclax Dose A once daily (QD).
  • Experimental: Part 4: Navitoclax + Celecoxib
    Participants will receive navitoclax dose A once daily (QD) from Day 3 through Day 16. Participants will also receive celecoxib singe dose on Day 1 and Day 7.

Geprüfte Regime

  • Navitoclax (ABT-263):
    Tablet; Oral
  • Ruxolitinib:
    Tablet; Oral
  • Celecoxib (Celebrex):
    Capsule; Oral

Quelle: ClinicalTrials.gov


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