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.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Syndax Pharmaceuticals Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

31 May 2022 → ongoing

Decision date (initial)

2024-08-23

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Syndax Pharmaceuticals, Inc

External identifiers

EU CT number

2024-513759-34-00

EudraCT number

2020-004104-34

ClinicalTrials.gov

NCT04065399

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Therapy, Others, Pharmacokinetic, Efficacy, Safety

Phase 1
The objectives for Phase 1 of this study apply to all arms unless otherwise stated in the objective.
• To determine the safety, tolerability, maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D) of SNDX-5613 in patients with relapsed/refractory (R/R) acute leukemia in each of the arms studied.
• To characterize the pharmacokinetics (PK) parameters of SNDX-5613 and relevant metabolites in each of the arms studied.
Phase 2
• Cohorts 2A-2C: To assess the complete remission (CR)+ complete remission with partial hematologic recovery (CRh) rate.
• Cohorts 2A-2C: To evaluate short- and long-term safety and tolerability of SNDX-5613.
• Cohort 2D: To compare the bioavailability of the SNDX-5613 formulations being investigated when they are given without any CYP3A4i under fasting conditions in patients with acute leukemia.

Secondary objectives 1

1. Phase I The secondary objective of Phase 1 is to compare the PK parameters of SNDX-5613 and relevant metabolites when administered in a tablet formulation compared with a capsule formulation. Phase 2 Cohorts 2A-2C: • To assess postbaseline transfusion independence. • To assess the composite definition of complete remission (CRc) rate [CR + CRh + complete remission with incomplete hematologic recovery (CRi) + complete remission with incomplete platelet recovery (CRp)]. • To assess the overall response rate (ORR) (CRc + morphological leukemia-free state [MLFS] + partial remission [PR]). • To assess the time to response (TTR), duration of response (DOR), and event free survival (EFS). • To assess overall survival (OS). • To characterize PK parameters of SNDX-5613 and relevant metabolites. Cohort 2D: •To supplement the bioavailability comparison by evaluating an additional PK parameter. • To monitor the safety and tolerability of SNDX-5613.

Conditions and MedDRA coding

Relapsed or Refractory Acute Leukemias

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Diagnosis: Patients in Phase 1 Arm A and Arm B must have active acute leukemia harboring Lysine (K) methyltransferase 2A (KMT2A) rearrangement or Nucleophosmin 1 mutation (NPM1) mutation as defined by the National Comprehensive Cancer Network (NCCN) Guidelines stated in the protocol. Patients in Phase 1 Arm C, Arm D, Arm E and Arm F must meet 1 of the following 2 criteria: •active acute leukemia (bone marrow blasts ≥5% or reappearance of blasts inperipheral blood) as defined by the NCCN Guidelines stated in the protocol. •acute leukemia harboring an KMT2A rearrangement, Nucleoporin 98 (NUP98) rearrangement, or NPM1 mutation that have detectable disease in the bone marrow not meeting criterion for active leukemia as described above.
2. Prior Therapy: Any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment, with the exception of ≤Grade 2 neuropathy or alopecia.
3. Phase 1 and Phase 2 Cohorts 2A-2C only: Prior Therapy: Radiation Therapy: At least 60 days from prior total body irradiation (TBI), craniospinal radiation and/or ≥50% radiation of the pelvis, or at least 14days from local palliative radiation therapy.
4. Phase 1 and Phase 2 Cohorts 2A-2C only: Prior Therapy: Stem Cell Infusion: At least 60 days must have elapsed from hematopoietic stem cell transplant (HSCT) and at least 4 weeks must have elapsed from donor lymphocyte infusion (DLI).
5. Phase 2 Cohort 2D only: At least 14 days since any other investigational or commercially available antileukemic therapy, with the following exceptions: a) Cytoreductive therapy with hydroxyurea, low-dose cytarabine (20 mg/m2 /day SC for 10 days) or low-dose etoposide (up to 200 mg/day PO for 10 days) may be administered concurrently with SNDX-5613. b) Intrathecal chemotherapy for CNS prophylaxis is permitted at the treating physician’s discretion. c) Steroids at physiologic dosing (equivalent to ≤10 mg prednisone daily for patients ≥18 years or ≤10 mg/m2 /day for patients.
6. Phase 1 and Phase 2 Cohorts 2A-2C only: Prior Therapy: Immunotherapy: At least 42 days since prior immunotherapy, including tumor vaccines, and at least 21days since receipt of chimeric antigen receptor therapy or other modified T or Natural KIller (NK) cell therapy.
7. Phase 1 and Phase 2 Cohorts 2A-2C only: Prior Therapy: Antileukemia Therapy: At least 14 days, or 5 half-lives, whichever is shorter, since the completion of antileukemic therapy with the exceptions as defined in the protocol.
8. Phase 1 and Phase 2 Cohorts 2A-2C only: Prior Therapy: 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. See protocol for additional inclusion criteria.
9. Phase 1: • 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 weak, moderate, or strong 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 for at least 7 days prior to enrollment and while on SNDX-5613 treatment. Patients must not be receiving any other weak, moderate or strong CYP3A4 inhibitors/inducers. •Arms E: Patients must not be receiving any weak, moderate, or strong CYP3A4 inhibitors/inducers for at least 7 days prior to enrollment and while on SNDX5613 treatment. • Arm F: Patients must be receiving isavuconazole for at least 7 days prior to enrollment and while on SNDX-5613 treatment. Patients must not be receiving any other weak, moderate, or strong CYP3A4 inhibitors/inducers.
10. Phase 2: Documented R/R active acute leukemia. • Cohort 2A: Documented R/R ALL/MPAL with a KMT2A rearrangement. • Cohort 2B: Documented R/R AML with a KMT2A rearrangement. • Cohort 2C: Documented R/R AML with NPM1m. • Cohort 2D: Documented R/R acute leukemia with a genetic mutation expected to lead to HOX/MEIS upregulation (eg, KMT2Ar, NPM1m, NUP98r, etc), including patients who are MRD-positive by multiparametric flow cytometry or molecular methods only, and including patients with isolated extramedullary disease.
11. Disease Status: 4. Recurrent or refractory AML/ALL or MPAL, as defined by standardized criteria after standard of care therapy, including but not limited to one 1 or 2 cycles of intensive chemotherapy, or venetoclax combinations. 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. Applies only for Phase 2 Cohorts 2A-2C: Refractory or relapsed leukemia is defined by presence of ≥5% blasts in the bone marrow and/or persistence or reappearance of peripheral blasts. Patients who have <5% blasts in the bone marrow at baseline may be replaced to ensure a sufficient number of patients for the efficacy analyses.
12. Age/Weight: Male or female patient aged ≥6 months. Patients intended to receive SNDX-5613 in combination with cobicistat must weigh ≥35 kg. See Protocol Section 10.11.3.1 for age of inclusion criteria in Germany. Patients in Cohort 2D must be ≥18 years of age and have a body weight ≥40 kg.
13. Performance Level: Eastern Cooperative Oncology Group (ECOG) performance status score 0–2 Karnofsky Performance Scale of ≥50 ; Lansky Performance Score of ≥50 (if aged ≥12 years and <16 years). See Protocol Section 10.11.3.1 for ECOG performance status criteria in Germany.
14. See protocol for additional inclusion criteria.

Exclusion criteria 16

1. Diagnosis: Diagnosis of active acute promyelocytic leukemia.
2. Diagnosis: Isolated extramedullary relapse (Phase 2 Cohorts 2A-2C only).
3. Diagnosis: Active CNS disease. Refer to the protocol for further details.
4. Infection: 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. Infection: Hepatitis B (defined as hepatitis B virus [HBV] surface antigen positive and HBV core antibody positive, or positive HBV deoxyribonucleic acid [DNA].
6. Infection: Hepatitis C (defined as positive hepatitis C [HCV] antibody with reflex to positive HCV ribonucleic acid [RNA]).
7. Pregnancy and Breast-Feeding: Pregnant or nursing women. Negative serum pregnancy tests are required during Screening and a negative serum pregnancy test is required within 72 hours prior to receiving the first study drug administration, in females of childbearing potential.
8. Concurrent Conditions: Cardiac Disease: • Any of the following within the 6 months prior to study entry: myocardial infarction, uncontrolled/unstable angina, congestive heart failure, life-threatening, uncontrolled arrhythmia, cerebrovascular accident, or transient ischemic attack. • Corrected QT interval by Fridericia >450 msec.
9. Concurrent Conditions: Gastrointestinal (GI) Disease: • Any GI 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. Concurrent Conditions: 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 Conditions: 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.
12. Concurrent Conditions: Concurrent malignancy must be in complete remission or no evidence of disease during this timeframe.
13. Concurrent Conditions: 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.
14. Concomitant Medications and Interventions: 14. Any commercially available or investigational antileukemic therapy other than SNDX-5613, with exceptions as defined in the protocol.
15. Concomitant Medications and Interventions: Please refer to the protocol for the list of exclusion that apply to related to concomitant use of CYP3A4 inhibitors or inducers (Phase 1 and Phase 2).
16. Concomitant Medications and Interventions: Phase 1 and Phase 2: Patients 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 and the azoles permitted in the relevant arms of Phase 1 and in Phase 2. Please see Appendix 10.7 of the protocol for examples of medications that may be appropriate substitutes for such medications. Please refer to the protocol for additional exclusion criteria.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 8

1. Phase 1: Occurrence of dose-limiting toxicities (DLTs).
2. Phase 1: Frequency, duration, and severity of treatment-emergent adverse events (TEAEs), treatment-related TEAEs (TRAEs), and serious adverse events (SAEs).
3. Phase 1: Incidence and shifts of clinically significant clinical laboratory abnormalities.
4. Phase 1: Change from baseline in other observations related to safety, including electrocardiograms (ECGs), vital signs, ophthalmologic examination findings, and performance status.
5. Phase 1: Pharmacokinetic (PK) parameters: maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), area under the plasma concentration versus time curve (AUC) from time 0 to t (AUC0–t), AUC from time 0 to 24 hours (AUC0–24), apparent oral clearance (CL/F), apparent volume of distribution (Vz/F), and half-life (t1/2).
6. Phase 2: Cohorts 2A-2C: • CR+CRh rate. • Frequency, duration, and severity of TEAEs, TRAEs, and SAEs. • Incidence and shifts of clinically significant clinical laboratory abnormalities.
7. Phase 2: Cohorts 2A-2C: Change from baseline in other observations related to safety, including ECGs, vital signs, and performance status.
8. Phase 2: Cohort 2D: • Endpoints defined in protocol.

Secondary endpoints 3

1. Phase 1: • PK parameters.
2. Phase 2: Cohorts 2A-2C: • Transfusion independence, defined as any transfusion-free period lasting for at least 56 consecutive days, during which the patient is either on SNDX-5613 therapy or after cessation of SNDX-5613 therapy but prior to the start of new therapy.
3. Phase 2: Cohorts 2A-2C: • CRc rate (ie, CR+CRh+CRi+CRp). • ORR (CRc+MLFS+PR). • Time to response. • Duration of response. • Event free survival. • Overall survival. • PK parameters.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Syndax Pharmaceuticals Inc.

Sponsor organisation

Syndax Pharmaceuticals Inc.

Address

730 3rd Avenue Floor 9

City

New York

Postcode

10017-3206

Country

United States

Scientific contact point

Organisation

Syndax Pharmaceuticals Inc.

Contact name

Angie Smith

Public contact point

Organisation

Syndax Pharmaceuticals Inc.

Contact name

Syndax Clinical Trials

Third parties 9

Locations

6 EU/EEA countries · 18 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 123 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications