Acute Myeloid Leukemia Clinical Trial
— AUGMENT-101Official 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
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.
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 GuidelinesĀ®) 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 GuidelinesĀ® 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. |
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 |
Lead Sponsor | Collaborator |
---|---|
Syndax Pharmaceuticals |
United States, Australia, Canada, France, Germany, Israel, Italy, Lithuania, Netherlands, Spain,
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 revumenib and relevant metabolites (Phase 1) | Approximately 1 year | |
Primary | Tmax (Phase 1) | Time to observed maximum plasma concentration of revumenib 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 revumenib 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 revumenib (Phase 2) | Approximately 3 years | |
Secondary | TTR (Phase 2) | To assess the time to response (TTR) of revumenib (Phase 2) | Approximately 34 months | |
Secondary | DOR (Phase 2) | To assess the duration of response (DOR) of revumenib (Phase 2) | Approximately 3 years | |
Secondary | EFS (Phase 2) | To assess the event free survival (EFS) of revumenib (Phase 2) | Approximately 3 years | |
Secondary | OS (Phase 2) | To assess overall survival (OS) of revumenib (Phase 2) | Approximately 5 years | |
Secondary | Cmax (Phase 2) | Cmax of revumenib and relevant metabolites (Phase 2) | Approximately 3 years | |
Secondary | Tmax (Phase 2) | Tmax of revumenib and relevant metabolites (Phase 2) | Approximately 3 years | |
Secondary | AUC0-t (Phase 2) | AUC0-t of revumenib and relevant metabolites (Phase 2) | Approximately 3 years |
Status | Clinical Trial | Phase | |
---|---|---|---|
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