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JOURNAL ONKOLOGIE – STUDIE

ASSURE Acalabrutinib Safety Study in Untreated and Relapsed or Refractory Chronic Lymphocytic Leukemia Patients

Rekrutierend

NCT-Nummer:
NCT04008706

Studienbeginn:
September 2019

Letztes Update:
15.01.2021

Wirkstoff:
Acalabrutinib

Indikation (Clinical Trials):
Leukemia, Leukemia, Lymphoid, Leukemia, Lymphocytic, Chronic, B-Cell

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 3

Sponsor:
AstraZeneca

Collaborator:
Parexel

Studienleiter

Adel Habib, MD
Study Director
AstraZeneca
Dr. Carsten Niemann, MD
Principal Investigator
Rigshospitalet, Denmark

Kontakt

AstraZeneca Clinical Study Information Center
Kontakt:
Phone: 1-877-240-9479
E-Mail: information.center@astrazeneca.com
» Kontaktdaten anzeigen

Studienlocations (3 von 148)

Research Site
53127 Bonn
(Nordrhein-Westfalen)
GermanyNoch nicht rekrutierend» Google-Maps
Research Site
99084 Erfurt
(Thüringen)
GermanyNoch nicht rekrutierend» Google-Maps
Research Site
15236 Frankfurt
(Brandenburg)
GermanyRekrutierend» Google-Maps
Research Site
50226 Frechen
(Nordrhein-Westfalen)
GermanyZurückgezogen» Google-Maps
Research Site
74072 Heilbronn
(Baden-Württemberg)
GermanyRekrutierend» Google-Maps
Research Site
67655 Kaiserslautern
(Rheinland-Pfalz)
GermanyZurückgezogen» Google-Maps
Research Site
50674 Köln
(Nordrhein-Westfalen)
GermanyZurückgezogen» Google-Maps
Research Site
32457 Porta Westfalica
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
Research Site
74523 Schwäbisch Hall
(Baden-Württemberg)
GermanyRekrutierend» Google-Maps
Research Site
89081 Ulm
(Baden-Württemberg)
GermanyNoch nicht rekrutierend» Google-Maps
Research Site
33705 Saint Petersburg
United StatesRekrutierend» Google-Maps
Research Site
11040 New Hyde Park
United StatesNoch nicht rekrutierend» Google-Maps
Research Site
10003 New York
United StatesNoch nicht rekrutierend» Google-Maps
Research Site
75390 Dallas
United StatesNoch nicht rekrutierend» Google-Maps
Research Site
22060 Fort Belvoir
United StatesNoch nicht rekrutierend» Google-Maps
Research Site
30130-100 Belo Horizonte
BrazilNoch nicht rekrutierend» Google-Maps
Research Site
01308-050 Sao Paulo
BrazilNoch nicht rekrutierend» Google-Maps
Research Site
J4V 2H1 Greenfield Park
CanadaNoch nicht rekrutierend» Google-Maps
Research Site
93009 Bobigny Cedex
FranceNoch nicht rekrutierend» Google-Maps
Research Site
69373 LYON cedex 08
FranceNoch nicht rekrutierend» Google-Maps
Research Site
3318 AT Dordrecht
NetherlandsNoch nicht rekrutierend» Google-Maps
Research Site
603126 Nizhny Novgorod
Russian FederationRekrutierend» Google-Maps
Research Site
185019 Petrozavodsk
Russian FederationRekrutierend» Google-Maps
Research Site
191024 Saint Petersburg
Russian FederationRekrutierend» Google-Maps
Research Site
194291 Saint Petersburg
Russian FederationRekrutierend» Google-Maps
Research Site
197341 Saint Petersburg
Russian FederationRekrutierend» Google-Maps
Research Site
197110 Saint-Petersburg
Russian FederationRekrutierend» Google-Maps
Research Site
197022 St. Petersburg
Russian FederationRekrutierend» Google-Maps
Research Site
197341 St. Petersburg
Russian FederationRekrutierend» Google-Maps
Research Site
FY3 8NR Blackpool
United KingdomNoch nicht rekrutierend» Google-Maps
Research Site
BH7 7DW Bournemouth
United KingdomNoch nicht rekrutierend» Google-Maps
Research Site
CF14 4XW Cardiff
United KingdomNoch nicht rekrutierend» Google-Maps
Research Site
EH4 2XU Edinburgh
United KingdomNoch nicht rekrutierend» Google-Maps
Research Site
L7 8XP Liverpool
United KingdomNoch nicht rekrutierend» Google-Maps
Research Site
EC1M 6BQ London
United KingdomNoch nicht rekrutierend» Google-Maps
Research Site
M20 4BX Manchester
United KingdomNoch nicht rekrutierend» Google-Maps
Research Site
OX4 6LB Oxford
United KingdomNoch nicht rekrutierend» Google-Maps
Research Site
EH54 6PP West Lothian
United KingdomNoch nicht rekrutierend» Google-Maps
Alle anzeigen

Studien-Informationen

Detailed Description:

This is a Phase 3b, multicenter, open-label, single-arm study to evaluate the safety and

efficacy of acalabrutinib 100 mg bid in approximately 600 participants with chronic

lymphocytic leukemia (CLL). Participants will be enrolled into 3 cohorts: treatment-naive

(TN) (minimum of 300 participants), relapsed/refractory (R/R) (approximately 200

participants), and prior bruton tyrosine kinase inhibitor (BTKi) therapy (up to 70 to 100

participants). Assessment of response and progression will be conducted by the investigator

in accordance with the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018

criteria. Overall response assessments will be based on evaluation of physical examinations,

recording of symptoms, radiologic evaluations, and hematologic evaluations. Study treatment

(acalabrutinib 100 mg bid) will be administered until disease progression, unacceptable

toxicity, 48 cycles of study treatment, withdrawal of consent, loss to follow-up, death, or

study termination by the sponsor, whichever comes first (each cycle is 28 days). In-clinic

visits will occur every cycle for the first 6 cycles, and then every 3 cycles for the next 6

cycles. After 12 cycles "in-clinic visits" will occur every 6 cycles. Safety follow up visits

will occur approximately 30 days from the last dose of study treatment. If a participant

continues to derive benefit from treatment at the end of 48 cycles, they will continue to be

provided with study treatment. This may include, but not be limited to, transition to a

long-term extension trial, continuous supply in this trial (for eg in countries where

regulatory approval is not obtained, or drug is not reimbursed) or switching to commercial

drug as permitted by local regulations. Participants who remain in the trial after the

completion of 48 cycles will be followed for disease progression, description of all

subsequently administered anticancer therapies, and IWCLL indication for initiation of

subsequent anticancer therapies q24w via standard practice until transition to regulatory

approved off-study acalabrutinib, withdrawal of consent, lost to follow-up, death, or study

termination by the sponsor. Participants who switch to off-study acalabrutinib will be

considered as having completed the study and therefore will not have any additional study

assessments, including the disease follow-up period. The duration of the study will be

approximately 72 months from the first participant enrolled. This duration includes an

estimated 24-month recruitment time and an assumed 48 cycles of study treatment (28 days per

cycle).

Ein-/Ausschlusskriterien

Inclusion Criteria:

1. Men and women ≥18 years of age (or the legal age of consent in the jurisdiction in

which the study is taking place)

2. Diagnosis of CLL that meets published diagnostic criteria (Hallek et al. 2018):

1. Monoclonal B-cells (either kappa or lambda light chain restricted) that are

clonally co-expressing ≥1 B-cell marker (CD19, CD20, and CD23) and CD5

2. Prolymphocytes may comprise <55% of blood lymphocytes

3. Presence of ≥5 × 109 B lymphocytes/L (5000/μL) in the peripheral blood (at any

point since the initial diagnosis)

3. Active disease as per at least 1 of the following IWCLL 2018 criteria

1. Evidence of progressive marrow failure as manifested by the development of, or

worsening of, anemia (hemoglobin <10 g/dL) and/or thrombocytopenia (platelets

<100,000/μL).

2. Massive (i.e., ≥6 cm below the left costal margin), progressive, or symptomatic

splenomegaly.

3. Massive nodes (i.e., ≥10 cm in the longest diameter), progressive, or symptomatic

lymphadenopathy

4. Progressive lymphocytosis with an increase of >50% over a 2-month period or a

lymphocyte doubling time (LDT) of <6 months. LDT may be obtained by linear

regression extrapolation of absolute lymphocyte count obtained at intervals of 2

weeks over an observation period of 2 to 3 months. In subjects with initial blood

lymphocyte counts of <30x109/L (30,000/μL), LDT should not be used as a single

parameter to define indication for treatment. In addition, factors contributing

to lymphocytosis or lymphadenopathy other than CLL (e.g., infections) should be

excluded.

5. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard

therapy

6. B-symptoms documented in the subject's chart with supportive objective measures,

as appropriate, defined as ≥1 of the following disease-related symptoms or signs:

o- Unintentional weight loss ≥10% within the previous 6 months before screening

o- Significant fatigue (Eastern Cooperative Oncology Group [ECOG] performance

status ≥2; inability to work or perform usual activities) o- Fevers higher than

100.5°F or 38.0°C for ≥2 weeks before screening without evidence of infection o-

Night sweats for ≥1 month before screening without evidence of infection

4. Must meet 1 of the following criteria:

a. Have received no prior therapy for treatment of CLL and meets 1 of the following

criteria: i. A score of >6 on the Cumulative Illness Rating Scale (CIRS) ii.

Creatinine clearance of 30 to 69 mL/min using the Cockcroft-Gault equation b. Have

previously received therapy for CLL and have either refractory or relapsed CLL c. Have

received prior BTKi therapy (i.e., defined as a subject who discontinued a BTKi for

any reason except disease progression) for CLL d. Criterion deleted.

5. ECOG performance status of ≤2

6. Female subjects of childbearing potential (i.e., not surgically sterile or

postmenopausal) who are sexually active with a non-sterilized male partner must use ≥1

highly effective method of contraception from the time of screening and must agree to

continue using such precautions for 2 days after the last dose of study treatment.

Contraception measures and restrictions on sperm donation are not required for male

subjects.

7. Fluorescence in situ hybridization (FISH) within 60 days before or during screening

reflecting the presence or absence of del(17p), 13q del, 11q del, and trisomy of

chromosome 12 along with the percentage of cells with the deletion, along with TP53

sequencing. Subjects must also have molecular analysis to detect IGHV mutation status

at any time point since diagnosis.

8. Each subject (or legally authorized representative if allowed per local regulations)

must be willing and able to adhere to the study visit schedule, understand and comply

with other protocol requirements, and provide written informed consent and

authorization to use protected health information.

Exclusion Criteria:

1. Subjects who have had disease progression while on a BTKi for any malignant or

nonmalignant condition

2. Prior malignancy (other than CLL), except for adequately treated basal cell or

squamous cell skin cancer, in situ cancer, early stage prostate cancer, or other

cancer from which the subject has been disease-free for ≥2 years

3. History of confirmed progressive multifocal leukoencephalopathy

4. Significant cardiovascular disease such as symptomatic arrhythmias, congestive heart

failure, or myocardial infarction within 6 months before screening, or any Class 3 or

4 cardiac disease as defined by the New York Heart Association Functional

Classification, or corrected QT interval using Fridericia's formula (QTcF) >480 msec

at screening. Note: Subjects with rate-controlled, asymptomatic atrial fibrillation

are allowed to enroll in the study.

5. Malabsorption syndrome, disease significantly affecting gastrointestinal function,

resection of the stomach, extensive small bowel resection that is likely to affect

absorption, symptomatic inflammatory bowel disease, partial or complete bowel

obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.

6. Evidence of active Richter's transformation. If Richter's transformation is suspected

(i.e., lactate dehydrogenase [LDH] increased, asymmetric fast lymph node growth or

clinical suspicion), it should be ruled out with positron emission tomographycomputed

tomography (PET-CT) and/or biopsy according to guidelines.

7. Central nervous system (CNS) involvement by CLL.

8. Known history of human immunodeficiency virus, serologic status reflecting active

hepatitis B virus or hepatitis C virus infection, any uncontrolled active systemic

infection along with subjects who are on ongoing anti-infective treatment and subjects

who have received vaccination with a live attenuated vaccine within 4 weeks before the

first dose of study treatment.

1. Subjects who are hepatitis B core antibody (anti-HBc) positive and who are

hepatitis B surface antibody (anti-HBs) negative will need to have a negative

hepatitis B virus PCR result before enrollment. Those who are hepatitis B surface

antigen (HBsAg) positive or hepatitis B virus PCR positive will be excluded.

2. Subjects who are hepatitis C virus antibody positive will need to have a negative

hepatitis C virus PCR result before enroll.lment. Those who are hepatitis C virus

PCR positive will be excluded

9. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura

defined as declining hemoglobin or platelet count secondary to autoimmune destruction

within the screening period or requirement for high doses of steroids (>20 mg daily of

prednisone or equivalent for longer than 2 weeks).

10. History of stroke or intracranial hemorrhage within 6 months before the first dose of

study treatment.

11. History of bleeding diathesis (e.g., hemophilia or von Willebrand disease)

12. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before

screening.

13. Major surgical procedure within 4 weeks before first dose of study treatment. Note:

Subjects who have had major surgery must have recovered adequately from any toxicity

and/or complications from the intervention before the first dose of study treatment.

14. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole,

lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving

proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible

for enrollment in this study.

15. All subjects requiring or receiving anticoagulation with warfarin or equivalent

vitamin K antagonists (e.g., phenprocoumon) within 7 days before first dose of study

treatment.

16. Absolute neutrophil count (ANC) <0.50 x 109/L or platelet count <30 x 109/L, unless

proven due to CLL and raised above the limits by granulocyte colony-stimulating factor

(G-CSF) therapy and/or pooled platelet transfusion

17. Total bilirubin >3.0x upper limit of normal (ULN); or aspartate aminotransferase or

alanine aminotransferase >3.0x ULN. Exception will be for Gilbert syndrome; if an

investigator feels that a subject's total bilirubin is elevated secondary to

Gilbert's, the subject must have a documented unconjugated bilirubin being >80% of the

total bilirubin number. The investigator must also document that hemolysis has been

ruled out along with (near)-normal lactate dehydrogenase and haptoglobin

18. Estimated creatinine clearance of <30 mL/min, calculated using the formula of

Cockcroft and Gault or by direct assessment (i.e., creatinine clearance or ethylene

diamine tetra-acetic acid (EDTA) clearance measurement)

19. Breastfeeding or pregnant

20. Received any chemotherapy, external beam radiation, investigational drug, or any other

anti-CLL therapy within 30 days before first dose of study treatment

21. Concurrent participation in another therapeutic clinical study

22. History of interstitial lung disease

23. Requiring long-term (> 1 week) treatment with a strong cytochrome CYP3A

inhibitor/inducer. In addition, the use of strong or moderate CYP3A inhibitors or

inducers within 7 days of the first dose of study drug is prohibited.

Studien-Rationale

Primary outcome:

1. Number of participants with adverse events (Time Frame - From screening to safety follow-up period (approximately 30 days from last dose)):
To evaluate the safety and tolerability of acalabrutinib monotherapy in participants with TN or R/R CLL.



Secondary outcome:

1. Objective response rate (ORR) (Time Frame - 1 year after initial dose of study drug):
To evaluate the investigator-assessed ORR in participants receiving acalabrutinib monotherapy.

2. Duration of response (DOR) (Time Frame - The time from the first objective response to the time of documented disease progression or death due to any cause, whichever occurs first within the time period to complete up to 48 cycles of treatment (each cycle is 28 days)):
To evaluate the investigator-assessed DOR in participants receiving acalabrutinib monotherapy.

3. Progression-free survival (PFS) (Time Frame - The interval from the start of study treatment to completion of 48 cycles (each cycle is 28 days) or the earlier of the first documentation of disease progression or death from any cause):
To evaluate the investigator-assessed PFS in participants receiving acalabrutinib monotherapy.

Geprüfte Regime

  • Acalabrutinib (ACP-196):
    Acalabrutinib will be administered as one 100 mg capsule taken orally, twice daily with 8 ounces (approximately 240 mL) of water.

Quelle: ClinicalTrials.gov


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