A study to investigate the short- and long-term safety and tolerability of the drug SNDX-5613 in Patients with Relapsed/Refractory Leukemias. Various doses of SNDX-5613 will be investigated.
- Conditions
- Relapsed or Refractory Acute LeukemiasMedDRA version: 20.1Level: LLTClassification code 10024330Term: Leukemia acuteSystem Organ Class: 100000004864Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2020-004104-34-FR
- Lead Sponsor
- Syndax Pharmaceuticals, Inc
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 333
Diagnosis:
1. Patients in Arms A and B must have active acute leukemia harboring mixed lineage leukemia (MLL) rearrangement or NPM1c mutation as defined by the National Comprehensive Cancer Network (NCCN) in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Acute Lymphoblastic Leukemia (Ver 1.2020) and Acute Myeloid Leukemia (Ver 3.2020).
Patients in Arm C and Arm D must meet one of the following 2 criteria:
•active acute leukemia (bone marrow blasts =5% or reappearance of blasts in
peripheral blood) as defined by the guidelines above.
•acute leukemia harboring an MLL rearrangement or Nucleophosmin 1 mutation (NPM1c) mutation that have detectable disease in the bone marrow not meeting criterion for active leukemia as described above.
2. Phase 1: Documented R/R acute leukemia:
• Arm A: Patients must not be receiving any strong CYP3A4 inhibitor/inducers or fluconazole. Patients who were receiving a strong CYP3A4 inhibitor/inducer or fluconazole must have discontinued the medication at least 7days prior to enrollment.
• Arm B: Patients must be receiving itraconazole, ketoconazole, posaconazole, or voriconazole for antifungal prophylaxis for at least 7days prior to enrollment and while on SNDX-5613 treatment. Patients must not be receiving any other strong CYP3A4 inhibitors/inducers.
• Arm C: Patients must weigh =35 kg and be willing to receive daily cobicistat from C1D2 for at least 28 days. Patients must not be receiving any other strong or moderate CYP3A4 inhibitors/inducers. Patients who were receiving a moderate/strong CYP3A4 inhibitor/inducer must have discontinued the medication at least 7days prior to enrollment.
Arm D: Patients must be receiving fluconazole (moderate CYP3A4 inhibitor) for at least 7 days prior to enrollment and while on SNDX-5613 treatment. Patients must not be receiving any other strong or moderate CYP3A4 inhibitors/inducers.
3. Phase 2: Documented R/R acute leukemia:
Cohort 2A: Documented R/R acute lymphoblastic leukemia (ALL)/mixed phenotype acute leukemia (MPAL) with a mixed lineage leukemia-rearranged (MLLr) translocation.
Cohort 2B: Documented R/R AML with an MLLr translocation.
Cohort 2C: Documented R/R AML with NPM1c.
Mutational status is to be reviewed locally to determine patient eligibility in Phase 2 and confirmed centrally.
Disease Status:
4. Recurrent or refractory AML/ALL or MPAL, as defined by standardized criteria after standard of care therapy. Patients with persistent leukemia after initial therapy or with recurrence of leukemia at any time after achieving a response during or after the course of treatment are eligible.
• White blood cell (WBC) count must be below 25,000/µL at time of enrollment.
Patients may receive cytoreduction prior to enrollment.
Age/Weight:
5. Male or female patient aged =30 days. Patients intend to receive SNDX-5613 in combination with cobicistat must weigh =35 kg.
Performance Level:
6. Eastern Cooperative Oncology Group performance status score 0-2 (if aged =18yrs); Karnofsky Performance Scale of =50 (if aged =16yrs and <18yrs); Lansky Performance Score of =50 (if aged <16yrs).
Prior Therapy:
7. Any prior treatment-related toxicities resolved to =Grade 1 prior to enrollment, with the exception of =Grade 2 neuropathy or alopecia.
8. 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).
9. Stem
Diagnosis:
1. Active diagnosis of acute promyelocytic leukemia.
2. Isolated extramedullary relapse.
3. Active CNS disease (cytologic or radiographic). Refer to the protocol for details of patients that are required to have a lumbar puncture or Ommaya reservoir tap during the screening period.
Infection:
4. Detectable human immunodeficiency virus (HIV) viral load within the previous 6 months. Patients with a known history of HIV 1/2 antibodies must have viral load testing prior to study enrollment.
5. Hepatitis B (defined as hepatitis B virus [HBV] surface antigen positive and HBV core antibody positive, with positive HBV deoxyribonucleic acid [DNA], or HBV positive core antibody alone with positive HBV DNA.
6. Hepatitis C (defined as positive hepatitis C [HCV] antibody with reflex to positive HCV ribonucleic acid [RNA]).
Pregnancy and Breast-Feeding:
7. Pregnant or nursing women. Negative serum pregnancy tests are required during Screening and a negative serum or urine pregnancy test is required within 72 hours prior to receiving the first study drug administration, in females of childbearing potential. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
Concurrent Conditions:
8. 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.
• QTc using Fridericia’s correction (QTcF) >450 msec.
9. Gastrointestinal Disease:
• Any gastrointestinal issue of the upper GI tract likely to affect oral drug absorption or ingestion.
• Cirrhosis with a Child-Pugh score of B or C.
10. Graft-Versus-Host Disease (GVHD): Signs or symptoms of acute or chronic GVHD >Grade 0 within 4 weeks of enrollment. All transplant patients must have been off all systemic immunosuppressive therapy and calcineurin inhibitors for at least 4 weeks prior to enrollment. Patients may be on physiological doses of steroids.
11. 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 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 patient is not receiving any systemic therapy or radiation. Concurrent malignancy must be in complete remission (CR) or no evidence of disease (NED) during this timeframe.
12. History of or any concurrent condition, therapy, laboratory abnormality, or allergy to excipients that in the Investigator’s opinion might confound the results of the study, interfere with the patient’s participation for the full duration of the study, or is not in the best interest of the patient to participate.
Concomitant Medications and Interventions:
13. Any commercially available or investigational antileukemic therapy other than SNDX-5613, with the following exceptions:
• Short-term administration of corticosteroid and/or hydroxyurea for cytoreduction.
• Intrathecal chemotherapy for CNS prophylaxis is permitted after Cycle 1 (C1) is complete, at the treating physician’s discretion.
14. In Phase 1 the following Exclusions apply:
• Arm A: Concurrent use of strong inhibitors or inducers of CYP3A4 and fluconazole, which should be di
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method