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) Mutatio
- Conditions
- Relapsed/Refractory Leukemias / Acute Leukemias10024324
- Registration Number
- NL-OMON56180
- Lead Sponsor
- Syndax Pharmaceuticals, Inc
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- Not specified
- Target Recruitment
- 6
Diagnosis
1. Patients in phase 1 Arm A and Arm B must have active acute leukemia
harboring KMT2A rearrangement or NPM1 mutation (bone marrow blasts >=5% or
reappearance of blasts in peripheral blood) as defined by the National
Comprehensive Cancer Network (NCCN) guidelines in the NCCN Clinical Practice
Guidelines in Oncology (NCCN Guidelines®) for Acute Lymphoblastic Leukemia
(Version 1.2020) and Acute Myeloid Leukemia (Version 3.2020) (National
Comprehensive Cancer Network 2020; National Comprehensive Cancer Network 2020).
Patients in phase 1 Arm C, Arm D, Arm E and Arm F 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 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) (National Comprehensive Cancer Network 2020; National
Comprehensive Cancer Network 2020).
• acute leukemia harboring an KMT2A rearrangement, NUP98 rearrangement, or NPM1
mutation that have detectable disease in the bone marrow not meeting criterion
for active leukemia as described above.
2. Phase 1: see more details in the protocol.
• Note that phase 1 is not applicable for the Netherlands.
3. 3. 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) (National Comprehensive Cancer Network 2020; National
Comprehensive Cancer Network 2020).
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.
Mutational status is to be reviewed locally to determine patient eligibility in
Phase 2 and confirmed centrally. Central confirmation of KMT2Ar status will be
obtained by fluorescence in situ hybridization (11q23 MLL-Break Apart FISH
testing Flagship Biosciences, Morrisville, NC). NPM1 mutational status
confirmation will be obtained by PCR based amplification and sequencing (Focus
Myeloid panel, Flagship Biosciences, Morrisville, NC). All assays will be
conducted in a CLIA certified laboratory. Patients whose mutational status
cannot be confirmed centrally, or whose final pathology or flow reports do not
confirm the presence of >=5% bone marrow blasts, will be replaced to ensure a
sufficient number of patients for the primary efficacy analyses.
Disease Status
4. Recurrent or refractory AML/ALL or MPAL, as defined by standardized criteria
(for example, European LeukemiaNet criteria [Döhner 2017]; International
Working Group criteria [Cheson 2003]) after standard of care therapy, including
but not limited to one or two 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 (including allogeneic [HSCT] are eligible. Refractory
or relapsed leukemia is defined by presence of >=5% blasts in the bone marrow
and/or persistence or reappearance of peripheral blasts. Patient
Diagnosis
1. Diagnosis of active acute promyelocytic leukemia.
2. Isolated extramedullary relapse (Phase 2 only).
3. Active CNS disease (cytologic, such as any blasts on cytospin, or
radiographic). Patients who have cleared CNS disease by at least one negative
tap prior to dosing may be enrolled, and prophylactic intrathecal chemotherapy
may be continued while on trial.
The following patients are required to have a lumbar puncture or Ommaya
reservoir tap during the screening period:
• Signs and symptoms of CNS disease
•
• AML with monocytic phenotype.
• WBC >=50,000 /µL at presentation.
• History of CNS or any extramedullary disease.
• ALL or MPAL.
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 or positive HBV deoxyribonucleic acid [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 (Section 8.2.7).
9. Gastrointestinal Disease:
• Any gastrointestinal issue of the upper GI tract likely to affect oral drug
absorption or ingestion (gastric bypass, gastroparesis, etc).
• 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 (eg, 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 patient is not receiving any systemic therapy or
radiation.
12. Concurrent malignancy must be in complete remission (CR) or no evidence of
disease (NED) during this timeframe.
13. History of or any concurrent condition, therapy, laboratory abnormality, or
allergy to excipients (see formulation details in Investigator Brochure) that
in the Investigator*s opinion might confound the results of th
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method