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JOURNAL ONKOLOGIE – STUDIE
AUGMENT-101

A Study of SNDX-5613 in R/R Leukemias Including Those With an MLL/KMT2A Gene Rearrangement or NPM1 Mutation

Rekrutierend

NCT-Nummer:
NCT04065399

Studienbeginn:
November 2019

Letztes Update:
25.03.2024

Wirkstoff:
SNDX-5613, cobicistat

Indikation (Clinical Trials):
Leukemia, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Leukemia, Biphenotypic, Acute, Acute Disease

Geschlecht:
Alle

Altersgruppe:
Alle

Phase:
-

Sponsor:
Syndax Pharmaceuticals

Collaborator:
-

Studienleiter

Angela R Smith, M.D.
Study Director
Syndax Pharmaceuticals

Kontakt

Studienlocations
(3 von 48)

Universitaetsklinikum Essen (AoR)
45147 Essen
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Benjamin Bietsch
E-Mail: Benjamin.Bietsch@uk-essen.de

Melanie Koch
E-Mail: koch@uk-essen.de» Ansprechpartner anzeigen
University Of California Care Medical Group - Norris Comprehensive Cancer Center And Hospital
90033 Los Angeles
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Shirley Sian
E-Mail: sian_s@med.usc.edu» Ansprechpartner anzeigen
Emory Winship Cancer Institute
30322 Atlanta
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Shannon Gleason, MLS, CCRC
Phone: 404-778-4334
Phone (ext.): 10808
E-Mail: shannon.gleason@emory.edu» Ansprechpartner anzeigen
University of Iowa hospital
52246 Iowa City
United StatesRekrutierend» Google-Maps
Dana Farber Cancer Institute
02215 Boston
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Morgan Johnson
Phone: 857-215-0238
E-Mail: Morgan_Johnson@DFCI.HARVARD.EDU

Lindsay Rae
Phone: 617-582-9169
E-Mail: Lindsey_Rae@DFCI.HARVARD.EDU» Ansprechpartner anzeigen
Washington University in St. Louis School of Medicine
63110 Saint Louis
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Hannah Hartman
Phone: 314-273-8628
E-Mail: hannahlhartman@wustl.edu

Madeline Stowe
E-Mail: mstowe@wustl.edu» Ansprechpartner anzeigen
Hackensack University Medical Center
07601 Hackensack
United StatesAbgeschlossen» Google-Maps
Huntsman Cancer Institute at the University of Utah
84112 Salt Lake City
United StatesAbgeschlossen» Google-Maps
Sir Charles Gairdner Hospital
6009 Nedlands
AustraliaRekrutierend» Google-Maps
Royal North Shore Hospital
2065 Saint Leonards
AustraliaRekrutierend» Google-Maps
Princess Maxima Center for Pediatric Oncology
3584 CS Utrecht
NetherlandsRekrutierend» Google-Maps
Ansprechpartner:
Secretary Trial and Data Centrum
E-Mail: tdcsecretary@prinsesmaximacentrum.nl» Ansprechpartner anzeigen
Alle anzeigen

Studien-Informationen

Detailed Description:

Phase 1: Oral SNDX-5613; sequential cohorts of escalating dose levels of SNDX-5613 to

identify the MTD and RP2D. Participants will be enrolled in one of six dose-escalation arms:

Arm A: Participants not receiving any strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducers

or fluconazole.

Arm B: Participants receiving itraconazole, ketoconazole, posaconazole, or voriconazole

(strong CYP3A4 inhibitors) for antifungal prophylaxis.

Arm C: Participants receiving SNDX-5613 and cobicistat.

Arm D: Participants receiving fluconazole (moderate CYP3A4 inhibitor) for antifungal

prophylaxis.

Arm E: Participants not receiving any weak, moderate, or strong CYP3A4 inhibitors/inducers.

Arm F: Participants receiving isavuconazole (moderate CYP3A4 inhibitor) for antifungal

prophylaxis.

In Phase 2, participants will be enrolled in 3 indication-specific expansion cohorts to

determine the efficacy, short- and long-term safety, and tolerability of SNDX-5613:

- Cohort 2A: Participants with KMT2Ar acute lymphoblastic leukemia (ALL)/mixed phenotype

acute leukemia (MPAL)

- Cohort 2B: Participants with KMT2A AML

- Cohort 2C: Participants with NPM1m AML

Ein-/Ausschlusskriterien

Inclusion Criteria:

Participants must have active acute leukemia (bone marrow blasts ≥5% or reappearance of

blasts in peripheral blood) as defined by the National Comprehensive Cancer Network (NCCN)

in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute

Lymphoblastic Leukemia (Version 1.2020) and Acute Myeloid Leukemia (Version 3.2020), or

acute leukemia harboring KMT2A rearrangement, NUP98 rearrangement, or NPM1 mutation that

have detectable disease in the bone marrow.

1. Phase 1:

- Arm A: Participants not receiving any strong CYP3A4 inhibitor/inducers or

fluconazole.

- Arm B: Participants receiving itraconazole, ketoconazole, posaconazole, or

voriconazole (strong CYP3A4 inhibitors) for antifungal prophylaxis.

- Arm C: Participants receiving SNDX-5613 in combination with cobicistat.

- Arm D: Participants receiving fluconazole (moderate CYP3A4 inhibitor).

- Arm E: Participants not receiving any weak, moderate, or strong CYP3A4

inhibitors/inducers.

- Arm F: Participants receiving isavuconazole (moderate CYP3A4 inhibitor) for

antifungal prophylaxis.

2. Phase 2:

Documented R/R active acute leukemia (bone marrow blasts ≥5% or reappearance of blasts

in peripheral blood) as defined by the NCCN Guidelines® for Acute Lymphoblastic

Leukemia (Version 1.2020) and Acute Myeloid Leukemia (Version 3.2020).

- Cohort 2A: Documented R/R ALL/MPAL with KMT2A rearrangement.

- Cohort 2B: Documented R/R AML with KMT2A rearrangement.

- Cohort 2C: Documented R/R AML with NPM1m.

3. White blood cell count below 25,000/ microliter at time of enrollment. Participants

may receive cytoreduction prior to enrollment per protocol-specified criteria.

4. Male or female participants aged ≥30 days old.

5. Eastern Cooperative Oncology Group (ECOG) performance status score 0-2 or

Karnofsky/Lansky score ≥50.

6. Any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment, with

the exception of ≤Grade 2 neuropathy or alopecia.

7. Radiation Therapy: At least 60 days from prior total body irradiation (TBI),

craniospinal radiation and/or ≥50% radiation of the pelvis, or at least 14 days from

local palliative radiation therapy (small port).

8. Stem Cell Infusion: At least 60 days must have elapsed from hematopoietic stem cell

transplant and at least 4 weeks must have elapsed from donor lymphocyte infusion.

9. Immunotherapy: At least 42 days since prior immunotherapy, including tumor vaccines,

and at least 21 days since receipt of chimeric antigen receptor therapy or other

modified T or NK cell therapy.

10. Antileukemia Therapy: At least 14 days, or 5 half-lives, whichever is shorter, since

the completion of antileukemic therapy.

11. Hematopoietic Growth Factors: At least 7 days since the completion of therapy with

short-acting hematopoietic growth factors and 14 days with long-acting growth factors.

12. Biologics: At least 90 days, or 5 half-lives, whichever is shorter, since the

completion of therapy with an antineoplastic biologic agent.

13. Steroids: At least 7 days since systemic glucocorticoid therapy, unless receiving

physiologic dosing or cytoreductive therapy.

14. Adequate organ function.

15. If of childbearing potential, willing to use a highly effective method of

contraception or double barrier method from the time of enrollment through 120 days

following the last study drug dose.

Exclusion Criteria:

Participants meeting any of the following criteria are not eligible for study

participation:

1. Diagnosis of active acute promyelocytic leukemia.

2. Isolated extramedullary relapse (Phase 2 only).

3. Active central nervous system disease (cytologic, such as any blasts on cytospin, or

radiographic).

4. Detectable human immunodeficiency virus (HIV) viral load within the previous 6 months.

Participants with a known history of HIV 1/2 antibodies must have viral load testing

prior to study enrollment.

5. Hepatitis B or C.

6. Pregnant or nursing women.

7. Cardiac Disease:

- Any of the following within the 6 months prior to study entry: myocardial

infarction, uncontrolled/unstable angina, congestive heart failure (New York

Heart Association Classification Class ≥II), life-threatening, uncontrolled

arrhythmia, cerebrovascular accident, or transient ischemic attack.

- Corrected QT interval (QTc) >450 milliseconds.

8. Gastrointestinal Disease:

- any gastrointestinal issue of the upper GI tract that might affect oral drug

absorption or ingestion (that is, gastric bypass, gastroparesis, etc).

- Cirrhosis with a Child-Pugh score of B or C.

9. Graft-Versus-Host Disease (GVHD): Signs or symptoms of acute or chronic GVHD >Grade 0

within 4 weeks of enrollment. All transplant participants must have been off all

systemic immunosuppressive therapy and calcineurin inhibitors for at least 4 weeks

prior to enrollment. Participants may be on physiological doses of steroids.

10. Concurrent malignancy in the previous 2 years with the exception of basal cell

carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (for

example, breast carcinoma, cervical cancer in situ, melanoma in situ) treated with

potentially curative therapy, or concurrent low-grade lymphoma, that is asymptomatic

and lacks bulky disease and shows no evidence of progression, and for which the

participant is not receiving any systemic therapy or radiation.

11. In Phase 1 and Phase 2: Participants requiring the concurrent use of medications known

or suspected to prolong the QT/QTc interval, with the exception of drugs with low risk

of QT/QTc prolongation that are used as standard supportive therapies (for example,

diphenhydramine, famotidine, ondansetron, Bactrim) and the azoles permitted in the

relevant arms of Phase 1 and in Phase 2.

Studien-Rationale

Primary outcome:

1. Occurrence of dose-limiting toxicities (DLTs) (Phase 1) (Time Frame - Approximately 1 year):
Assessed by the NCI CTCAE version 5.0 (Phase 1)

2. Number of participants with treatment-emergent adverse events (TEAEs) (Phase 1) (Time Frame - Approximately 1 year):
Assessed by the NCI CTCAE version 5.0 (Phase 1)

3. Cmax (Phase 1) (Time Frame - Approximately 1 year):
Maximum plasma concentration (Cmax) of SNDX-5613 and relevant metabolites (Phase 1)

4. Tmax (Phase 1) (Time Frame - Approximately 1 year):
Time to observed maximum plasma concentration of SNDX-5613 and relevant metabolites (Phase 1)

5. AUC0-t (Phase 1) (Time Frame - Approximately 1 year):
Area under the plasma concentration-time curve from time 0 to time of last measurable concentration (AUC0-t) of SNDX-5613 and relevant metabolites (Phase 1)

6. CR+CRh rate (Phase 2) (Time Frame - Approximately 3 years):
To assess the complete remission (CR) and complete remission with partial hematologic recovery (CRh) rate (Phase 2)

7. Number of participants with TEAEs (Phase 2) (Time Frame - Approximately 3 years):
Assessed by the NCI CTCAE version 5.0 (Phase 2)

Secondary outcome:

1. Transfusion independence (Phase 2) (Time Frame - Approximately 3 years):
Transfusion independence is defined as any transfusion-free period lasting for at least 56 consecutive days

2. CRc rate (Phase 2) (Time Frame - Approximately 3 years):
To assess the composite definition of complete remission (CRc) rate (Phase 2)

3. ORR (CRc+ morphological leukemia-free state [MLFS] + partial remission [PR]) (Phase 2) (Time Frame - Approximately 3 years):
To assess the overall response rate (ORR) of SNDX-5613 (Phase 2)

4. TTR (Phase 2) (Time Frame - Approximately 34 months):
To assess the time to response (TTR) of SNDX-5613 (Phase 2)

5. DOR (Phase 2) (Time Frame - Approximately 3 years):
To assess the duration of response (DOR) of SNDX-5613 (Phase 2)

6. EFS (Phase 2) (Time Frame - Approximately 3 years):
To assess the event free survival (EFS) of SNDX-5613 (Phase 2)

7. OS (Phase 2) (Time Frame - Approximately 5 years):
To assess overall survival (OS) of SNDX-5613 (Phase 2)

8. Cmax (Phase 2) (Time Frame - Approximately 3 years):
Cmax of SNDX-5613 and relevant metabolites (Phase 2)

9. Tmax (Phase 2) (Time Frame - Approximately 3 years):
Tmax of SNDX-5613 and relevant metabolites (Phase 2)

10. AUC0-t (Phase 2) (Time Frame - Approximately 3 years):
AUC0-t of SNDX-5613 and relevant metabolites (Phase 2)

Geprüfte Regime

  • SNDX-5613:
    SNDX-5613 orally
  • cobicistat:
    Phase 1 Arm C participants will receive 150 mg cobicistat daily.

Quelle: ClinicalTrials.gov


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