Clinical trial NCT04065399: A Study of Revumenib in R/R Leukemias Including Those With an MLL/KMT2A Gene Rearrangement or NPM1 Mutation
Official title: A Phase 1/2, Open-label, Dose-Escalation and Dose-Expansion Cohort Study of SNDX-5613 in Patients With Relapsed/Refractory Leukemias, Including Those Harboring an MLL/KMT2A Gene Rearrangement or Nucleophosmin 1 (NPM1) Mutation
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Acute Myeloid Leukemia
Acute Lymphoblastic Leukemia
Mixed Lineage Acute Leukemia
Mixed Phenotype Acute Leukemia
Acute Leukemia of Ambiguous Lineage
Keywords: AML
ALL
MPAL
MLAL
ALAL
relapsed leukemia
refractory leukemia
acute leukemia
KMT2A
NPM1
Lead sponsor: Syndax Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2019-08-22
Enrollment: 413
Sex: ALL
Minimum age (years): 30
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: Phase 1 will employ an accelerated titration design. The dose escalation will follow a modified Fibonacci sequence.
Primary purpose: TREATMENT

Brief summary: Phase 1 dose escalation will determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of revumenib in participants with acute leukemia.

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 revumenib.

Detailed description: Phase 1: Oral revumenib; sequential cohorts of escalating dose levels of revumenib 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 revumenib 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 revumenib:

* 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

Eligibility criteria: 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 revumenib 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.

Primary outcomes:
measure: Occurrence of dose-limiting toxicities (DLTs) (Phase 1)
timeFrame: Approximately 1 year
measure: Number of participants with treatment-emergent adverse events (TEAEs) (Phase 1)
timeFrame: Approximately 1 year
measure: Cmax (Phase 1)
timeFrame: Approximately 1 year
measure: Tmax (Phase 1)
timeFrame: Approximately 1 year
measure: AUC0-t (Phase 1)
timeFrame: Approximately 1 year
measure: CR+CRh rate (Phase 2)
timeFrame: Approximately 3 years
measure: Number of participants with TEAEs (Phase 2)
timeFrame: Approximately 3 years
Secondary outcomes:
measure: Transfusion independence (Phase 2)
timeFrame: Approximately 3 years
measure: CRc rate (Phase 2)
timeFrame: Approximately 3 years
measure: ORR (CRc+ morphological leukemia-free state [MLFS] + partial remission [PR]) (Phase 2)
timeFrame: Approximately 3 years
measure: TTR (Phase 2)
timeFrame: Approximately 34 months
measure: DOR (Phase 2)
timeFrame: Approximately 3 years
measure: EFS (Phase 2)
timeFrame: Approximately 3 years
measure: OS (Phase 2)
timeFrame: Approximately 5 years
measure: Cmax (Phase 2)
timeFrame: Approximately 3 years
measure: Tmax (Phase 2)
timeFrame: Approximately 3 years
measure: AUC0-t (Phase 2)
timeFrame: Approximately 3 years
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: University Of California Care Medical Group - Norris Comprehensive Cancer Center And Hospital
state: California
city: Palo Alto
country: United States
facility: Stanford Cancer Institute
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Sarasota
country: United States
facility: Florida Cancer Specialists and Research Institute
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Emory Winship Cancer Institute
state: Georgia
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Chicago
country: United States
facility: The University of Chicago Medical Center
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa hospital
state: Iowa
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University in St. Louis School of Medicine
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Montefiore Medical Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute at the University of Utah
state: Utah
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre (PMCC)
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital (RMH)
state: Victoria
city: Melbourne
country: Australia
facility: Alfred Hospital
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
city: Saint Leonards
country: Australia
facility: Royal North Shore Hospital
city: Toronto
country: Canada
facility: University Health Network
city: Toronto
country: Canada
facility: The Hospital for Sick Children
city: Paris
country: France
facility: Hospital Saint-Louis - APHP
city: Pessac
country: France
facility: Centre Hospitalier Universitaire (CHU) de Bordeaux
city: Pierre-Benite
country: France
facility: Centre Hospitalier Lyon Sud
city: Villejuif
country: France
facility: Institut Gustave Roussy-Gustave Roussy Cancer Center -DITEP
city: Ulm
country: Germany
facility: University Hospital Of Ulm, Universitatsklinikum Ulm
state: Baden-Württemberg
city: Essen
country: Germany
facility: Universitaetsklinikum Essen (AoR)
city: Greifswald
country: Germany
facility: Universitaetsmedizin Greifswald
city: Gutenberg
country: Germany
facility: Universitaetsmedizin Der Johannes
city: Hamburg
country: Germany
facility: Universitaetsklinikum Hamburg-Eppendorf
city: Leipzig
country: Germany
facility: University of Leipzig
city: Nürnberg
country: Germany
facility: Klinikum Nuernberg Nord
city: Haifa
country: Israel
facility: Rambam Health Care Campus (RHCC
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
city: Jerusalem
country: Israel
facility: Hadassah Medical Center- Ein Kerem
city: Nahariya
country: Israel
facility: Galilee Medical Center
city: Petach Tikva
country: Israel
facility: Rabin Medical Center
city: Ramat Gan
country: Israel
facility: Sheba Medical Center
city: Bologna
country: Italy
facility: IRCCS Azienda Ospedaliero Universitaria di Bologna
city: Meldola
country: Italy
facility: Istituto Romagnolo Per Lo Studio dei tumori Dino Amadori
city: Milan
country: Italy
facility: IRCCS-Istituto Europeo di Oncologia
city: Roma
country: Italy
facility: Universita Cattolica Fondazione Policlinico Agostino Gemelli
city: Vicenza
country: Italy
facility: S Bortolo Hospital AULSS 8 Berica
city: Vilnius
country: Lithuania
facility: Vilnius University Hospital Santaros Klinikos
city: Utrecht
country: Netherlands
facility: Princess Maxima Center for Pediatric Oncology
city: San Juan
country: Puerto Rico
facility: Hospital Centro Comprensivo de Cancer UPR
city: Hospitalet De Llobregat
country: Spain
facility: Institut Catala d'Oncologia (ICO) - Hospital Duran i Reynals
city: Seville
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe de Valencia
Study officials:
affiliation: Syndax Pharmaceuticals
name: Angela R Smith, M.D.
role: STUDY_DIRECTOR
References:
citation: Sasca D, Guezguez B, Kuhn MWM. Next generation epigenetic modulators to target myeloid neoplasms. Curr Opin Hematol. 2021 Sep 1;28(5):356-363. doi: 10.1097/MOH.0000000000000673.
citation: Jimenez JA, Apfelbaum AA, Hawkins AG, Svoboda LK, Kumar A, Ruiz RO, Garcia AX, Haarer E, Nwosu ZC, Bradin J, Purohit T, Chen D, Cierpicki T, Grembecka J, Lyssiotis CA, Lawlor ER. EWS-FLI1 and Menin Converge to Regulate ATF4 Activity in Ewing Sarcoma. Mol Cancer Res. 2021 Jul;19(7):1182-1195. doi: 10.1158/1541-7786.MCR-20-0679. Epub 2021 Mar 19.