Mittwoch, 27. Januar 2021
Navigation öffnen
Anzeige:
Imfinzi NSCLC
Imfinzi NSCLC

JOURNAL ONKOLOGIE – STUDIE

A Study of Gilteritinib (ASP2215) Combined With Chemotherapy in Children, Adolescents and Young Adults With FMS-like Tyrosine Kinase 3 (FLT3)/Internal Tandem Duplication (ITD) Positive Relapsed or Refractory Acute Myeloid Leukemia (AML)

Rekrutierend

NCT-Nummer:
NCT04240002

Studienbeginn:
Februar 2020

Letztes Update:
08.01.2021

Wirkstoff:
Gilteritinib, Fludarabine, Cytarabine, Granulocyte colony-stimulating factor (G-CSF)

Indikation (Clinical Trials):
Leukemia, Leukemia, Myeloid, Leukemia, Myeloid, Acute

Geschlecht:
Alle

Altersgruppe:
Kinder (0-17)

Phase:
-

Sponsor:
Astellas Pharma Global Development, Inc.

Collaborator:
-

Studienleiter

Medical Director
Study Director
Astellas Pharma Global Development

Kontakt

Astellas Pharma Global Development
Kontakt:
Phone: 800-888-7704
E-Mail: Astellas.registration@astellas.com
» Kontaktdaten anzeigen

Studienlocations (3 von 15)

Site DE49002
79106 Freiburg
(Baden-Württemberg)
GermanyRekrutierend» Google-Maps
Site DE49004
45147 Essen
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
Site DE49001
06120 Halle (Saale)
(Sachsen-Anhalt)
GermanyRekrutierend» Google-Maps
Alle anzeigen

Studien-Informationen

Brief Summary:

The purpose of the phase 1 portion (dose escalation) of the study will be to establish an

optimally safe and biologically active recommended phase 2 dose (RP2D) and/or to determine

maximum tolerated dose (MTD) for gilteritinib in sequential combination with fludarabine,

cytarabine and granulocyte colony-stimulating factor (FLAG). The purpose of the phase 2

portion (dose expansion) is to determine complete remission (CR) rates and composite complete

remission (CRc) rates after two cycles of therapy. The study will also assess safety,

tolerability and toxicities of gilteritinib in combination with FLAG, evaluate FLT3

inhibition, assess pharmacokinetics (PK), perform serial measurements of minimal residual

disease, obtain preliminary estimates of 1-year event free survival (EFS) and overall

survival (OS) rate and assess the acceptability as well as palatability of the formulation.

One cycle is defined as 28 days of treatment. A participant completing 2 cycles in phase 1 or

2 will have the option to participate in long term treatment (LTT) with gilteritinib (for up

to 2 years).

Ein-/Ausschlusskriterien

Inclusion Criteria:

- Subject is aged ≥ 6 months and < 21 years of age at the time of signing informed

consent and/or assent, as applicable.

- For phase 2: Enrollment of subjects from 6 months to less than 1 year and 1 year

to less than 2 years will be dependent on the establishment of recommended phase

2 dose (RP2D) in the respective for age groups during phase 1.

- Subject has a diagnosis of acute myeloid leukemia (AML) according to The

French-American-British (FAB) classification with ≥ 5% blasts in the bone marrow, with

or without extramedullary disease (except subjects with active central nervous system

[CNS] leukemia).

- In the phase 1 portion of the study, subject must be in first or greater relapse

or refractory to induction therapy with no more than 1 attempt at remission

induction.

- For the phase 2 portion of the study, subject must be in first relapse.

- Subject has fully recovered from the acute toxic effects of all prior chemotherapy,

immunotherapy, or radiotherapy prior to entering this study.

- Myelosuppressive chemotherapy:

- For subject who relapses while receiving cytotoxic therapy, at least 21 days

must have elapsed since the completion of cytotoxic therapy and prior to

screening.

- Cytoreduction with hydroxyurea can be initiated and continued for up to 24

hours prior to the start of systemic protocol therapy (cycle 1 day -1).

Subject may also receive low dose cytarabine (100 mg/m^2 per dose once daily

for 5 days) for cytoreduction until 24 hours prior to cycle 1 day -1.

- Subject who has received other FLT3 inhibitors (e.g., lestaurtinib,

sorafenib, etc) is eligible for this study.

- Hematopoietic growth factors: at least 7 days must have elapsed since the

completion of therapy with a growth factor and prior to screening.

- Biologic (anti-neoplastic agent): at least 7 days must have elapsed since the

completion of therapy with a biologic agent and prior to screening. For agents

that have known adverse events (AEs) occurring beyond 7 days after

administration, this period must be extended beyond the time during which AEs are

known to occur.

- X-ray treatment (XRT):

- 14 days must have elapsed for local palliative XRT for CNS chloromas and

prior to screening; no washout period is necessary for other chloromas;

- Prior to screening, 90 days must have elapsed if the subject had a prior

traumatic brain injury or has received craniospinal XRT.

- For subject undergoing hematopoietic stem cell transplant (HSCT), at least 90 days

must have elapsed since HSCT and subject must not have active graft-versus-host

disease (GVHD).

- Subject has Karnofsky score ≥ 50 (if the subject is of ≥ 16 years of age) or Lansky

score of ≥ 50 (if the subject is < 16 years of age). A score < 50 is acceptable if

related to the subject's leukemia.

- Subject must meet the following criteria as indicated on the clinical laboratory

tests.

- Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x

upper limit normal (ULN) for age

- Total serum bilirubin ≤ 1.5 x ULN for age

- Serum creatinine ≤ 1.5 x ULN for age or an estimated glomerular filtration rate

of > 60 mL/min/1.73 m^2.

- A female subject is eligible to participate if she is not pregnant and at least 1 of

the following conditions applies:

- Not a woman of childbearing potential (WOCBP) OR

- WOCBP who agrees to follow the contraceptive guidance throughout the treatment

period and for at least 180 days after the final study drug administration.

- Female subject must agree not to breastfeed starting at Screening, and throughout the

study period and for 60 days after the final study drug administration.

- Female subject must not donate ova starting at Screening and throughout the study, and

for 180 days after the final study drug administration.

- A male subject with female partner(s) of childbearing potential must agree to use

contraception during the treatment period and for at least 120 days after the final

study drug administration. (all countries except United Kingdom, Germany and Canada)

- A male subject with female partner(s) of childbearing potential must agree to use

contraception during the treatment period and for at least 180 days after the final

study drug administration. (in United Kingdom, Germany and Canada)

- A male subject must not donate sperm during the treatment period and for at least 120

days after the final study drug administration.

- Male subject with a pregnant or breastfeeding partner(s) must agree to remain

abstinent or use a condom for the duration of the pregnancy or time partner is

breastfeeding throughout the study period and for 120 days after the final study drug

administration. (all countries except United Kingdom, Germany and Canada)

- Male subject with a pregnant or breastfeeding partner(s) must agree to remain

abstinent or use a condom for the duration of the pregnancy or time partner is

breastfeeding throughout the study period and for 180 days after the final study drug

administration. (United Kingdom, Germany and Canada)

- Subject and subject's parent(s) or legal guardian agrees not to participate in another

interventional study while on treatment.

- In United Kingdom, Germany and Canada: Live Vaccines - At least 6 weeks must have

elapsed since the administration of the last dose of a live vaccine and prior to the

initiation of study treatment (cycle 1, day -1)

Exclusion Criteria:

- Subject has active CNS leukemia.

- Subject has uncontrolled or significant cardiovascular disease, including:

- Diagnosed or suspected congenital long QT syndrome or any history of clinically

significant ventricular arrhythmias (such as ventricular tachycardia, ventricular

fibrillation, or Torsades de Pointes (TdP)); any history of arrhythmia will be

discussed with the sponsor prior to subject's entry into the study

- Prolonged Fridericia's Correction Formula (QTcF) interval on pre-entry

electrocardiogram (ECG) (≥ 450 ms)

- Any history of second or third degree heart block (may be eligible if the subject

currently has a pacemaker)

- Heart rate < 50 beats/minute on pre-entry ECG

- Uncontrolled hypertension

- Complete left bundle branch block

- Subject has systemic fungal, bacterial, viral or other infection that is exhibiting

ongoing signs/symptoms related to the infection without improvement despite

appropriate antibiotics or other treatment. The subject needs to be off pressors and

have negative blood cultures for 48 hours.

- Subject is receiving or plans to receive concomitant chemotherapy, radiation therapy,

or immunotherapy other than as specified in the protocol.

- Subject has active clinically significant graft-versus-host disease (GVHD) or is on

treatment with systemic corticosteroids and is receiving > 0.5 mg/kg of prednisone (or

equivalent) daily dose for GVHD.

- Subject has active malignant tumors other than AML.

- Subject has any significant concurrent disease, illness, psychiatric disorder or

social issue that would compromise subject safety or compliance; interfere with

consent, study participation, follow-up or interpretation of study results.

- Subject has hypokalemia and/or hypomagnesemia at Screening (defined as values below

institutional lower limit of normal [LLN]). Repletion of potassium and magnesium

levels during the screening period is allowed.

- Subject requires treatment with concomitant drugs that are strong inducers of

cytochrome P450 (CYP)3A/P-glycoprotein (P-gp).

- Subject is known to have human immunodeficiency virus infection.

- Subject has active hepatitis B or C, or other active hepatic disorder.

- Subject must wait for at least 5 half-lives after stopping therapy with any

investigational agent and before starting gilteritinib.

- In United Kingdom, Germany and Canada: Subject has a known or suspected

hypersensitivity to gilteritinib, cytarabine, fludarabine, granulocyte

colony-stimulating factor (G-CSF) or any components of the formulation used.

Studien-Rationale

Primary outcome:

1. Number of participants with dose limiting toxicity (DLT) (phase 1/dose escalation) (Time Frame - Up to 28 days):
A DLT is defined as any of the events meeting the DLT criteria that occur during the observation period and that is considered to be possibly or probably related to gilteritinib. Nonhematologic Dose-limiting Toxicity will be defined as grade 3 or 4 nonhematologic toxicity attributable to gilteritinib that persists for > 48 hours without resolution to grade ≤ 2, will have gilteritinib dosing interrupted. Exceptions include the toxicities commonly seen with intensive AML reinduction regimens. Hematologic Dose-limiting Toxicity will be defined as failure to recover a peripheral absolute neutrophil count (ANC) > 500/μL and non-transfusion dependent platelet count > 20000/μL due to documented bone marrow aplasia/hypoplasia for greater than or equal to 50 days from the start of cycle 1 day 1. Failure to recover peripheral counts due to disease involvement of the bone marrow will not be considered dose-limiting toxicity.

2. Complete Remission (CR) rate after 2 cycles of therapy (phase 2) (Time Frame - Up to 56 days):
CR rate is defined as the number of participants who achieve the best response of CR divided by the number of participants in the analysis population. Complete remission is defined as having bone marrow regenerating normal hematopoietic cells and achieving a morphologic leukemia-free state and must have an absolute neutrophil count (ANC) ≥ 1 x 10^9/L and platelet count ≥ 100 x 10^9/L and normal marrow differential with < 5% blasts, and they will be red blood cell (RBC) and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). There should be no evidence of extramedullary leukemia.

3. Composite complete remission (CRc) rate after 2 cycles of therapy (phase 2) (Time Frame - Up to 56 days):
CRc rate is defined as the number of participants who achieve the best response of CRc (CR, CRp,or CRi) divided by the number of participants in the analysis population. Complete remission with incomplete platelet recovery (CRp) is defined as achieving CR except for incomplete platelet recovery (< 100 x 10^9/L) at a post baseline visit. Complete remission with incomplete hematologic recovery (CRi) is defined as achieving CR except for incomplete hematological recovery with residual neutropenia < 1 x 10^9/L with or without complete platelet recovery at a post baseline visit. Red blood cell (RBC) and platelet transfusion independence is not required.

Secondary outcome:

1. Number of participants with Adverse Events (AEs) (Time Frame - Up to 2 years plus 28 day follow up):
An AE is any untoward medical occurrence in a participant administered a study drug, and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product whether or not considered related to the medicinal product.

2. Number of participants with vital sign abnormalities and /or adverse events (AEs) (Time Frame - Up to 2 years):
Number of participants with potentially clinically significant vital sign values.

3. Number of participants with laboratory value abnormalities and/or adverse events (AEs) (Time Frame - Up to 2 years):
Number of participants with potentially clinically significant laboratory values.

4. Number of participants with electrocardiogram (ECG) abnormalities and/or adverse events (AEs) (Time Frame - Up to 2 years):
Number of participants with potentially clinically significant ECG values.

5. Percentage of inhibition of phosphorylated FLT3 in participants. (Time Frame - Up to 49 days):
Inhibition of FLT3 phosphorylation after drug treatment will be determined relative to pre-treatment phosphorylated FLT3 levels in participants to assess the relationship with gilteritinib dose. Phosphorylated FLT3 will be measured by plasma inhibitory activity (PIA) assay.

6. Pharmacokinetics (PK) of gilteritinib: oral clearance (CL/F) (Time Frame - Up to 45 days):
CL/F will be reported from the PK plasma samples collected.

7. PK of gilteritinib: apparent volume of distribution (Vd/F) (Time Frame - Up to 45 days):
Vd/F will be reported from the PK plasma samples collected.

8. PK of gilteritinib: Maximum Concentration (Cmax) (Time Frame - Up to 45 days):
Cmax will be reported from the PK plasma samples collected.

9. PK of gilteritinib: Time of Maximum Concentration (tmax) (Time Frame - Up to 45 days):
tmax will be reported from the PK plasma samples collected.

10. PK of gilteritinib: Area Under the Concentration (AUC) (Time Frame - Up to 45 days):
AUC will be reported from the PK plasma samples collected.

11. Duration of Event Free Survival (EFS) (Time Frame - Up to 2 years):
EFS is defined as the time from the date of enrollment until the date of documented relapse (excluding relapse after PR), treatment failure or death, whichever occurs first. If a participant experiences relapse or death, the participant is defined as having EFS event related to either "relapse" or "death", and the event date is the date of relapse or death. If a participant fails to achieve any of the response of CR, CRp, CRi or PR during the treatment period, the participant is defined as having EFS event related to treatment failure, and the event date is the enrollment date. For a participant who is not known to have had a relapse or treatment failure or death event, EFS is censored at the date of last relapse-free disease assessment. Participant is not censored at hematopoietic stem cell transplant (HSCT).

12. Duration of Overall survival (OS) (Time Frame - Up to 4 years and 2 months):
OS is defined as the time from the date of enrollment until the date of death from any cause. For a participant who is not known to have died by the end-of-study follow-up, OS is censored at the date of last contact.

13. The number of participants with negative minimal residual disease (MRD) status (Time Frame - Up to 2 years):
MRD negative status will be defined as FLT3-internal tandem duplication (ITD) signal ratio ≤ 10^-4.

14. Number of participants with MRD negative status in relation to CR rate (Time Frame - Up to 2 years):
MRD negative status will be defined as FLT3-internal tandem duplication (ITD) signal ratio ≤ 10^-4.

15. Number of participants with MRD negative status in relation to CRc rate (Time Frame - Up to 2 years):
MRD negative status will be defined as FLT3-internal tandem duplication (ITD) signal ratio ≤ 10^-4.

16. Number of participants with MRD negative status in relation to Overall survival (OS) (Time Frame - Up to 2 years):
MRD negative status will be defined as FLT3-internal tandem duplication (ITD) signal ratio ≤ 10^-4.

17. Clinical Outcome Assessment of Taste (Time Frame - Up to 57 days):
The acceptability and palatability of gilteritinib oral formulation as assessed by the participant using a single scale. The 5 point facial hedonic scale has high to low as: Liked it Very Much, Liked it a Little, Not sure, Disliked it a Little, Disliked it Very Much.

Studien-Arme

  • Experimental: Dose Escalation - 2 years to less than 21 years of age
    Participants will be administered fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) chemotherapy on days -1 to 5 and gilteritinib will be administered once per day on days 8 to 21 at the assigned dose. Participants may receive prophylactic intrathecal cytarabine at the start of the cycle, as per institutional standards. A participant completing 2 cycles (cycle is defined as 28 days) will have the option to participate in long term treatment (LTT) with gilteritinib (for up to 2 years).
  • Experimental: Dose Escalation - 1 year to less than 2 years of age
    Participants will be administered fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) chemotherapy on days -1 to 5 and gilteritinib will be administered once per day on days 8 to 21 at the assigned dose. Participants may receive prophylactic intrathecal cytarabine at the start of the cycle, as per institutional standards. A participant completing 2 cycles (cycle is defined as 28 days) will have the option to participate in long term treatment (LTT) with gilteritinib (for up to 2 years).
  • Experimental: Dose Escalation - 6 months to less than 1 year of age
    Participants will be administered fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) chemotherapy on days -1 to 5 and gilteritinib will be administered once per day on days 8 to 21 at the assigned dose. Participants may receive prophylactic intrathecal cytarabine at the start of the cycle, as per institutional standards. A participant completing 2 cycles (cycle is defined as 28 days) will have the option to participate in long term treatment (LTT) with gilteritinib (for up to 2 years).
  • Experimental: Dose Expansion
    Participants will be administered fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) chemotherapy on days -1 to 5 and gilteritinib will be administered once per day on days 8 to 21 at the dose determined in dose escalation portion. Participants may receive prophylactic intrathecal cytarabine at the start of the cycle, as per institutional standards. A participant completing 2 cycles (cycle is defined as 28 days) will have the option to participate in long term treatment (LTT) with gilteritinib (for up to 2 years).

Geprüfte Regime

  • gilteritinib (ASP2215):
    Administered orally.
  • fludarabine:
    Administered by intravenous (IV) infusion
  • cytarabine:
    Administered by intravenous (IV) infusion
  • granulocyte colony-stimulating factor (G-CSF):
    Administered by subcutaneous injection

Quelle: ClinicalTrials.gov


ASH 2020
  • Phase-III-Studie ASCEMBL bei resistenten/intoleranten Patienten mit CML: STAMP-Inhibitor Asciminib deutlich effektiver als TKI Bosutinib
  • Ruxolitinib-resistente/-intolerante MF-Patienten profitieren im klinischen Alltag möglicherweise von einer Rechallenge
  • Real-world-Daten zu PV: Rechtzeitige Umstellung von HU auf Ruxolitinib wirkt möglicherweise Anstieg thromboembolischer Ereignisse entgegen
  • 5-Jahres-Daten der RESPONSE-2-Studie: Überlegenheit von Ruxolitinib gegenüber BAT im Langzeitverlauf bestätigt
  • Phase-I-Studie: Anhaltendes molekulares Ansprechen mit neuem BCR-ABL-Inhibitor Asciminib bei CML-Patienten mit T315I-Resistenzmutation
  • Patienten mit ITP sind emotional erheblich belastet
  • r/r DLBCL: Vielversprechende erste Daten zur CAR-T-Zell-Therapie mit Tisagenlecleucel in Kombination mit Ibrutinib
  • r/r FL: CAR-T-Zell-Therapie mit Tisagenlecleucel wirksam und sicher
  • Myelofibrose: Ruxolitinib-Startdosis von 10 mg 2x tägl. auch bei initial niedriger Thrombozytenzahl sicher anwendbar
  • Phase-III-Studie REACH3: Ruxolitinib bei chronischer steroidrefraktärer oder steroidabhängiger GvHD wirksamer als die beste verfügbare Therapie