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JOURNAL ONKOLOGIE – STUDIE

Dose Escalation/ Expansion Study of CA-4948 as Monotherapy in Patients With AML or MDS

Rekrutierend

NCT-Nummer:
NCT04278768

Studienbeginn:
Juli 2020

Letztes Update:
12.03.2024

Wirkstoff:
Emavusertib, Venetoclax

Indikation (Clinical Trials):
Leukemia, Preleukemia, Leukemia, Myeloid, Leukemia, Myeloid, Acute, Myelodysplastic Syndromes, Syndrome

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
-

Sponsor:
Curis, Inc.

Collaborator:
-

Kontakt

Studienlocations
(3 von 30)

Marien Hospital Dusseldorf; Klinik fur Onkologie und Hamatologie, Palliativmedizin
40479 Düsseldorf
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
Universitatsklinikum Leipzig; Medizinische Klinik und Poliklinik I
04103 Leipzig
(Sachsen)
GermanyRekrutierend» Google-Maps
Klinikum rechts der Isar der Technischen Universitat Munchen
81675 München
(Bayern)
GermanyRekrutierend» Google-Maps
Universitatsklinikum Munster
48149 Münster
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
Winship Cancer Institute
30322 Atlanta
United StatesRekrutierend» Google-Maps
Northwestern Memorial Hospital
60611 Chicago
United StatesRekrutierend» Google-Maps
University of Chicago Medical Center
60637 Chicago
United StatesNoch nicht rekrutierend» Google-Maps
Dana Farber Cancer Institute
02215 Boston
United StatesRekrutierend» Google-Maps
Oncology Hematology West, PC dba Nebraska Cancer Specialists
68130 Omaha
United StatesRekrutierend» Google-Maps
Albert Einstein Medical College
10461 Bronx
United StatesRekrutierend» Google-Maps
University of Rochester Medical Center
14642 Rochester
United StatesRekrutierend» Google-Maps
Novant Health Hematology - Forsyth
27103 Winston-Salem
United StatesRekrutierend» Google-Maps
The Ohio State University Wexner Medical Center - James Cancer Hospital
43210 Columbus
United StatesRekrutierend» Google-Maps
The University of Texas MD Anderson Cancer Center
77030 Houston
United StatesRekrutierend» Google-Maps
Vseobecna Fakultni nemocnice v Praze
12 808 Praha 2
CzechiaNoch nicht rekrutierend» Google-Maps
Service d'hématologie clinique CHU de Nice
6200 Nice
FranceRekrutierend» Google-Maps
Edith Wolfson Medical Center
5822012 H̱olon
IsraelRekrutierend» Google-Maps
Azienda Ospedaliera Santa Croce e Carle
Cuneo
ItalyRekrutierend» Google-Maps
Instituto Romagnolo per lo Studio dei Tumori "Dino Amadori"
Meldola
ItalyRekrutierend» Google-Maps
Uniwersyteckie Centrum Kliniczne Osrodek Badan Klinicznych Wczesnych Faz
80-214 Gdańsk
PolandRekrutierend» Google-Maps
University Hospital in Krakow
31 501 Kraków
PolandRekrutierend» Google-Maps
Hospital de la Santa Creu I Sant Pau (Neuvo Hospital)
Barcelona
SpainRekrutierend» Google-Maps
Hospital Universitaro del a Princesa
28006 Madrid
SpainRekrutierend» Google-Maps
Hospital Universitario Virgen del Rocio
Sevilla
SpainRekrutierend» Google-Maps
Alle anzeigen

Studien-Informationen

Detailed Description:

The primary objective of the Phase 1 portion of the study is to determine the maximum

tolerated dose (MTD) and Recommended Phase 2 Dose (RP2D) for emavusertib in monotherapy in

patients with AML, intermediate high risk, high risk MDS based on the safety and

tolerability, dose-limiting toxicities (DLTs), and Pharmacokinetic (PK)/Pharmacodynamic (PD)

findings.

The primary objective of the Phase 1b portion of the study is to determine MTD and RP2D for

emavusertib in combination with azacitidine (AZA) in treatment naïve patients with hrMDS or

in combination with venetoclax (VEN) in relapsed/ refractory (R/R) patients with AML or high

risk myelodysplastic syndrome (hrMDS) after first line treatment based on the safety and

tolerability, DLTs and PK and pharmacodynamic findings. Note, this portion of the study is no

longer enrolling patients.

The primary objective of the Phase 2a portion of the study (emavusertib monotherapy

expansion) is to assess anti-cancer activity of CA-4948 at the RP2D in patients with R/R AML

with FMS-like tyrosine kinase-3 (FLT-3) mutations, or patients with R/R hrMDS or R/R AML with

spliceosome mutations of SF3B1 or U2AF1.

Emavusertib is formulated as tablets for twice daily oral administration. Each treatment

cycle will be 28 days in length and repeated in the absence of toxicity. Patients who

tolerate emavusertib may continue to receive emavusertib until progression of disease,

intolerable toxicity, lack of clinical benefit, withdrawal from the trial, or study

termination.

The emavusertib starting dose level will be 200 mg twice daily (BID) which was determined to

be safe, capable of achieving relevant levels of drug exposure as well as demonstrating signs

of biologic activity and clinical efficacy in an ongoing study (Study CA-4948-101). For phase

1, emavusertib is taken daily for 28 days of a 28 day cycle. For Phase 1b, emavusertib is

taken daily for 21 days of a 28 day cycle in combination with venetoclax.

Venetoclax will be administered at 100 mg orally (Day 1) per the product label at the same

time each day with a ramp up over 3 days to 400 mg for 21 days of the 28-day Cycle. Second

and subsequent cycles start with the target dose level.

In each of the Phase 1/1b cohorts, three patients with AML or MDS were enrolled at the

designated dose. If none of the first 3 patients experience a DLT during the first cycle,

patients may be enrolled into the next higher dose level. If 1 patient out of the first 3

experiences a DLT, the dose level may be expanded with an additional 3 patients. If 2 or 3

patients out of the first six experienced a DLT, this will be considered a DLT rate above the

MTD (> 33%), and additional enrollment will proceed at a lower dose level. Any adverse

reaction that lead to dose reduction or discontinuation is considered a DLT unless the

adverse reaction is clearly and solely related to disease.

The RP2D will be determined by the Clinical Safety Committee (CSC) in consultation with the

Sponsor, considering all aspects of safety, tolerability, biologic activity, pharmacokinetics

and preliminary efficacy in the trial population. The intent of the RP2D is to provide a dose

and schedule that will maximize the opportunity for clinical benefit, while minimizing the

risk of toxicity. The RP2D may be below the MTD. The CSC may request enrollment of additional

patients at any previously-explored dose level in order to make an appropriate RP2D or MTD

determination.

The expansion phase will begin once the RP2D from Phase 1 Dose Escalation phase has been

identified. There will be 3 Cohorts and patients will be assigned to each Cohort based on

baseline disease:

1. R/R AML with FLT3 mutations who have been previously treated with a FLT3 inhibitor;

2. R/R AML with spliceosome mutations of SF3B1 or U2AF1; and

3. R/R hrMDS (IPSS-R score > 3.5) with spliceosome mutations of SF3B1 or U2AF1

All patients have had ≤ 2 lines of prior systemic anticancer treatment.

Ein-/Ausschlusskriterien

Inclusion Criteria:

1. Males and females ≥18 years of age

2. Life expectancy of at least 3 months

3. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤1

4. Cytomorphology based confirmed diagnosis of MDS or AML (as per WHO 2016

classification) with the following characteristics.

Phase 1 Dose Escalation (Monotherapy)

• AML (primary or secondary, including treatment-related) after failing at least 1

standard treatment (may include chemotherapy, re induction therapy or stem cell

transplantation).

OR

• Higher-risk R/R MDS that are considered resistant/refractory following at least 2 to

3 cycles of hypermethylating agent (HMA) or evidence of early progression

Phase 2a Dose Expansion (Monotherapy)

Patients with:

- R/R AMLwith FLT3 mutations who have been previously treated with a FLT3 inhibitor

- R/R AML with spliceosome mutations of SF3B1 or U2AF1

- R/R hrMDS (IPSS-R score > 3.5) with spliceosome mutations of SF3B1 or U2AF1

- Number of pretreatments: 1 or 2

5. Acceptable organ function at screening

6. Ability to swallow and retain oral medications

7. Negative serum pregnancy test in women of childbearing potential

8. Women of childbearing potential and men who partner with a woman of childbearing

potential must agree to use highly effective contraceptive methods for the duration of

the study and for 90 days after the last dose of emavusertib

9. Willing and able to provide written informed consent and comply with the requirements

of the trial

10. Able to undergo serial bone marrow sampling and peripheral blood sampling

Exclusion Criteria:

1. Diagnosed with acute promyelocytic leukemia (APL, M3)

2. Has known active central nervous system (CNS) leukemia

3. Allogeneic hematopoietic stem cell transplant (Allo-HSCT) within 60 days of the first

dose of emavusertib, or clinically significant graft-versus-host disease (GVHD)

requiring ongoing up titration of immunosuppressive medications prior to start of

emavusertib

4. Chronic myeloid leukemia (CML)

5. Any prior systemic anti-cancer treatment such as chemotherapy, immunomodulatory drug

therapy, etc., received within 3 weeks (or 5 half-lives) prior to start of

emavusertib.

Localized radiation or surgical resection of skin cancers allowed.

6. Use of any investigational agent within 3 weeks or 5 half-lives, whichever is shorter,

prior to start of emavusertib

7. Presence of an acute or chronic toxicity resulting from prior anti-cancer therapy,

with the exception of alopecia that has not resolved to Grade ≤ 1within 7 days prior

to start of emavusertib; presence of any acute or chronic non-hematological toxicity ≥

Grade 3 at Screening, or prior to start of emavusertib must resolve to ≤ Grade 2.

8. Known allergy or hypersensitivity to any component of the formulation of emavusertib

9. Major surgery, other than diagnostic surgery, <28 days from the start of emavusertib;

minor surgery <14 days from the start of emavusertib

10. Patients with active advanced malignant solid tumors

11. Known to be human immunodeficiency virus (HIV) positive or have an acquired

immunodeficiency syndrome-related illness

12. Hepatitis B virus (HBV) DNA positive or Hepatitis C virus (HCV) infection <6 months

prior to start of emavusertib unless viral load is undetectable, or HCV with cirrhosis

13. Uncontrolled or severe cardiovascular diseaseincluding myocardial infarction or

unstable angina within 6 months prior to CA-4948, New York Heart Association Class II

or greater congestive heart failure, or left ventricular ejection fraction < 40% by

echocardiogram or multi-gated acquisition scan, serious arrhythmias uncontrolled on

treatment, clinically significant pericardial disease, cardiac amyloidosis, congenital

long QT syndrome, or QTc with Fridericia's correction (QTcF) that is unmeasurable or >

450 msec on Screening electrocardiogram (ECG)

14. Gastrointestinal disease or disorder that could interfere with the swallowing, oral

absorption, or tolerance of emavusertib

15. Pregnant or lactating

16. Systemic fungal, bacterial, viral, or other infection that is not controlled

17. Any other severe, acute, or chronic medical, psychiatric or social condition, or

laboratory abnormality that may increase the risk of trial participation or

emavusertib administration

Studien-Rationale

Primary outcome:

1. Determine Maximum Tolerated Dose (MTD) of emavusertib (CA-4948) monotherapy (Phase 1) (Time Frame - 28 days):
The highest dose at which there is <33% Dose Limiting Toxicity rate in the first cycle of treatment in a minimum of 6 patients.

2. Determine the Recommended Phase 2 Dose (RP2D) of emavusertib monotherapy (Phase 1) (Time Frame - 24 months):
The RP2D will be determined by the Clinical Safety Committee (CSC) in consultation with the Sponsor, considering all aspects of safety, tolerability, biologic activity, pharmacokinetics and preliminary efficacy in the trial population. The intent of an RP2D is to provide a dose and schedule that will maximize the opportunity for clinical benefit, while minimizing the risk of toxicity.

3. Determine Maximum Tolerated Dose (MTD) of emavusertib in combination with venetoclax (Phase 1b) (Time Frame - 28 days):
The highest dose at which there is <33% Dose Limiting Toxicity rate in the first cycle of treatment in a minimum of 6 patients.

4. Determine the Recommended Phase 2 Dose (RP2D) of emavusertib in combination with venetoclax (Phase 1b) (Time Frame - 24 months):
The RP2D will be determined by the Clinical Safety Committee (CSC) in consultation with the Sponsor, considering all aspects of safety, tolerability, biologic activity, pharmacokinetics and preliminary efficacy in the trial population. The intent of an RP2D is to provide a dose and schedule that will maximize the opportunity for clinical benefit, while minimizing the risk of toxicity.

5. To assess anti-cancer activity (Phase 2a - AML patients) (Time Frame - 24 months):
Proportion of patients who achieve CR + CRh

6. To assess anti-cancer activity (Phase 2a - hrMDS patients) (Time Frame - 24 months):
Overall response rate: proportion of patients who achieve CR+PR

7. To assess safety (Phase 1b) (Time Frame - 24 months):
Clinical safety assessments including frequency of adverse events (AEs)

Secondary outcome:

1. To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Cmax (Phase 1 and 1b) (Time Frame - 24 months):
maximum plasma concentration (Cmax)

2. To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Cmin (Phase 1 and Phase 1b) (Time Frame - 24 months):
trough plasma concentration (Cmin)

3. To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Tmax (Phase 1 and 1b) (Time Frame - 24 months):
Time to maximum plasma concentration

4. To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Area under the plasma concentration versus time curve(AUC) [0-24] (Phase 1 and 1b) (Time Frame - 24 months):
Area under the plasma concentration-time curve from 0 to 24 hours

5. To characterize the pharmacokinetic (PK) parameters of emavusertib measured by AUC[INF] (Phase 1 and 1b) (Time Frame - 24 months):
Area under the plasma concentration-time curve from 0 to infinity

6. To characterize the pharmacokinetic (PK) parameters of emavusertib measured by T 1/2 (Phase 1 and 1b) (Time Frame - 24 months):
Plasma terminal elimination half-life (T 1/2)

7. To assess clinical response (Phase 1 and 1b) (Time Frame - 24 months):
For AML: assessed by proportion of patients who reach complete response (CR) + complete response with partial hematological recovery (CRh) assessed by proportion of patients who reach complete response with incomplete hematologic recovery (CRi) or CR or Crh For hrMDS: overall response rate of CR+partial response (PR)

8. To assess clinical response (Phase 1 and 1b) (Time Frame - 24 months):
Assessed by transfusion independence

9. To assess tolerability and long term safety (Phase 2a) (Time Frame - 24 months):
Clinical safety assessments including frequency of adverse events (AEs)

10. To assess clinical response (Phase 2a) (Time Frame - 24 months):
For AML - assessed by proportion of patients who achieve CR or CRh or CRi; For hrMDS - assessed by proportion of patients who achieve CR or PR or mCR

11. To assess clinical response (Phase 2a) (Time Frame - 24 months):
Assessed by duration of response (DOR)

12. To assess clinical response (Phase 2a) (Time Frame - 24 months):
Assessed by time to response

13. To assess clinical response (Phase 2a) (Time Frame - 24 months):
Assessed by transfusion independence

14. To assess clinical response (Phase 2a) (Time Frame - 24 months):
Assessed by overall survival (OS)

Studien-Arme

  • Experimental: Emavusertib (CA-4948) dose escalation
    Patients receive emavusertib monotherapy BID daily. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Experimental: Emavusertib dose escalation + Venetoclax
    The starting dose for emavusertib will be 200 mg BID for 21 days of a 28-day Cycle. Anticipated emavusertib doses will be 200 and 300 mg BID. Venetoclax will be administered at 100 mg orally (Day 1) per the product label at the same time each day with a ramp up over 3 days to 400 mg for 21days of a 28-day Cycle. Second and subsequent cycles start with target dose level. This arm of the study has been closed to enrollment.
  • Experimental: Emavusertib monotherapy dose expansion
    The Expansion phase will begin once the RP2D from Phase 1 Dose Escalation phase has been identified. There will be 3 Cohorts and patients will be assigned to each Cohort based on baseline disease.

Geprüfte Regime

  • Emavusertib (CA-4948):
    Emavusertib is formulated as a tablet for oral administration for BID dosing in consecutive 28-day cycles. Emavusertib is a novel small molecule inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4). IRAK4 kinase plays an essential role in toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways and these pathways are frequently dysregulated in non-Hodgkin's lymphoma and AML/MDS malignancies.
  • Venetoclax:
    Ventoclax is B-cell lymphoma-2 (BCL-2) inhibitor. Venetoclax will be administered at 100 mg orally (Day 1) per the product label at the same time each day with a ramp up over 3 days to 400 mg for 21days of a 28-day Cycle. Second and subsequent cycles start with target dose level.
  • Emavusertib (CA-4948):
    Emavusertib is formulated as a tablet for oral administration for BID dosing for 21 days (Days 1-21) of a 28-day Cycle.

Quelle: ClinicalTrials.gov


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