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

Acute Myeloid Leukemia Clinical Trial

— AUGMENT-101  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04065399
• Other study ID #: SNDX-5613-0700
• Secondary ID: 2020-004104-34
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: November 5, 2019
• Est. completion date: December 2024

Study information

• Verified date: March 2024
• Source: Syndax Pharmaceuticals
• Contact: Syndax Pharmaceuticals
• Phone: 781-419-1400
• Email: clinicaltrials[@]syndax.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Phase 1 dose escalation will determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of SNDX-5613 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 SNDX-5613.

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 413
• Est. completion date: December 2024
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 30 Days and older

Eligibility

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.

Related Conditions & MeSH terms

• Acute Disease
• Acute Leukemia of Ambiguous Lineage
• Acute Lymphoblastic Leukemia
• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Biphenotypic, Acute
• Mixed Lineage Acute Leukemia
• Mixed Phenotype Acute Leukemia
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

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

Locations

Country	Name	City	State
Australia	Alfred Hospital	Melbourne
Australia	Peter MacCallum Cancer Centre (PMCC)	Melbourne	Victoria
Australia	Sir Charles Gairdner Hospital	Nedlands
Australia	Royal Melbourne Hospital (RMH)	Parkville	Victoria
Australia	Royal North Shore Hospital	Saint Leonards
Canada	The Hospital for Sick Children	Toronto
Canada	University Health Network	Toronto
France	Centre Hospitalier Lyon Sud	Pierre-Benite
France	Institut Gustave Roussy-Gustave Roussy Cancer Center -DITEP	Villejuif
Germany	Universitaetsklinikum Essen (AoR)	Essen
Germany	Universitaetsmedizin Greifswald	Greifswald
Germany	Universitaetsmedizin Der Johannes	Gutenberg
Israel	Rambam Health Care Campus (RHCC	Haifa
Israel	Hadassah Medical Center- Ein Kerem	Jerusalem
Israel	Shaare Zedek Medical Center	Jerusalem
Israel	Galilee Medical Center	Nahariya
Israel	Rabin Medical Center	Petach Tikva
Israel	Sheba Medical Center	Ramat Gan
Italy	IRCCS Azienda Ospedaliero Universitaria di Bologna	Bologna
Italy	Istituto Romagnolo Per Lo Studio dei tumori Dino Amadori	Meldola
Italy	S Bortolo Hospital AULSS 8 Berica	Vicenza
Lithuania	Vilnius University Hospital Santaros Klinikos	Vilnius
Netherlands	Princess Maxima Center for Pediatric Oncology	Utrecht
Spain	Institut Catala d'Oncologia (ICO) - Hospital Duran i Reynals	Hospitalet De Llobregat
Spain	Hospital Universitario Virgen del Rocio	Seville
Spain	Hospital Universitari i Politecnic La Fe de Valencia	Valencia
United States	Children's Healthcare of Atlanta	Atlanta	Georgia
United States	Emory Winship Cancer Institute	Atlanta	Georgia
United States	University of Colorado	Aurora	Colorado
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	The University of Chicago Medical Center	Chicago	Illinois
United States	University of Cincinnati	Cincinnati	Ohio
United States	Ohio State University	Columbus	Ohio
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Duke University Medical Center	Durham	North Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	University of Iowa hospital	Iowa City	Iowa
United States	University Of California Care Medical Group - Norris Comprehensive Cancer Center And Hospital	Los Angeles	California
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Montefiore Medical Center	New York	New York
United States	Stanford Cancer Institute	Palo Alto	California
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon
United States	Washington University in St. Louis School of Medicine	Saint Louis	Missouri
United States	Huntsman Cancer Institute at the University of Utah	Salt Lake City	Utah
United States	Florida Cancer Specialists and Research Institute	Sarasota	Florida
United States	Moffitt Cancer Center	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Syndax Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Canada,  France,  Germany,  Israel,  Italy,  Lithuania,  Netherlands,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Occurrence of dose-limiting toxicities (DLTs) (Phase 1)	Assessed by the NCI CTCAE version 5.0 (Phase 1)	Approximately 1 year
Primary	Number of participants with treatment-emergent adverse events (TEAEs) (Phase 1)	Assessed by the NCI CTCAE version 5.0 (Phase 1)	Approximately 1 year
Primary	Cmax (Phase 1)	Maximum plasma concentration (Cmax) of SNDX-5613 and relevant metabolites (Phase 1)	Approximately 1 year
Primary	Tmax (Phase 1)	Time to observed maximum plasma concentration of SNDX-5613 and relevant metabolites (Phase 1)	Approximately 1 year
Primary	AUC0-t (Phase 1)	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)	Approximately 1 year
Primary	CR+CRh rate (Phase 2)	To assess the complete remission (CR) and complete remission with partial hematologic recovery (CRh) rate (Phase 2)	Approximately 3 years
Primary	Number of participants with TEAEs (Phase 2)	Assessed by the NCI CTCAE version 5.0 (Phase 2)	Approximately 3 years
Secondary	Transfusion independence (Phase 2)	Transfusion independence is defined as any transfusion-free period lasting for at least 56 consecutive days	Approximately 3 years
Secondary	CRc rate (Phase 2)	To assess the composite definition of complete remission (CRc) rate (Phase 2)	Approximately 3 years
Secondary	ORR (CRc+ morphological leukemia-free state [MLFS] + partial remission [PR]) (Phase 2)	To assess the overall response rate (ORR) of SNDX-5613 (Phase 2)	Approximately 3 years
Secondary	TTR (Phase 2)	To assess the time to response (TTR) of SNDX-5613 (Phase 2)	Approximately 34 months
Secondary	DOR (Phase 2)	To assess the duration of response (DOR) of SNDX-5613 (Phase 2)	Approximately 3 years
Secondary	EFS (Phase 2)	To assess the event free survival (EFS) of SNDX-5613 (Phase 2)	Approximately 3 years
Secondary	OS (Phase 2)	To assess overall survival (OS) of SNDX-5613 (Phase 2)	Approximately 5 years
Secondary	Cmax (Phase 2)	Cmax of SNDX-5613 and relevant metabolites (Phase 2)	Approximately 3 years
Secondary	Tmax (Phase 2)	Tmax of SNDX-5613 and relevant metabolites (Phase 2)	Approximately 3 years
Secondary	AUC0-t (Phase 2)	AUC0-t of SNDX-5613 and relevant metabolites (Phase 2)	Approximately 3 years

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