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

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. 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.
In addition, all patients must have:
• White blood cell (WBC) count below 25,000/µL at time of enrollment. Patients
may receive cytoreduction prior to enrollment per Inclusion Criterion 11 and 14.

Age/Weight
5. Male or female patient aged >=6 months. Patients intend to receive SNDX-5613
in combination with cobicistat must weigh >=35 kg.

Performance Level
6. Eastern Cooperative Oncology Group (ECOG) performance status score 0-2 (if
aged >=18 years); Karnofsky Performance Scale of >=50 (if aged >=16 years and <18
years); Lansky Performance Score of >=50 (if aged >=12 years and <16 years).

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 Cell Infusion: At least 60 days must have elapsed from HSCT and at
least 4 weeks must have elapsed from donor lymphocyte infusion (DLI).
10. 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.

11. Antileukemia Therapy: At least 14 days, or 5 half-lives, whichever is
shorter, since the completion of antileukemic therapy (for example, but not
limited to, small molecule or cytotoxic/myelosuppressive therapy), with the
following exceptions:
• Hydroxyurea for cytoreduction can be initiated and continued concomitantly
with SNDX-5613.
• Phase 1 patients may receive intrathecal chemotherapy at the time of
diagnostic lumbar puncture at least 24 hours prior to the start of SNDX-5613
and may continue prophylactic intrathecal chemotherapy beginning in Cycle 2, at
the treating physician*s discretion.
• Phase 2 and Phase 1 backfill patients may continue to receive prophylactic
intrathecal chemotherapy at any time at the treating physician*s discretion.

12. 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.
13. Biologics (eg, monoclonal antibody therapy): At least 90 days or 5
half-lives, whichever is shorter, since the completion of therapy with an
antineoplastic biologic agent.
14. Steroids: At least 7 days since systemic glucocorticoid therapy, unless
receiving physiologic dosing (equivalent to <=10 mg prednisone daily for
patients >=18 years or <=10 mg/m2/day for patients <18 years) or cytoreductive
therapy.

Adequate Organ Function Requirements within 10 Days of Treatment Initiation
15. Estimated glomerular filtration (GFR) based on local institutional practice
for age-appropriate determination (eg, Schwartz formula for pediatric patients
or Cockcroft Gault formula for adults): GFR >=60 mL/min/1.73m2.
16. Adequate liver function defined as:
• Total bilirubin <1.5 × the upper limit of normal (ULN) for age or normal
conjugated bilirubin.
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <3 × ULN
(unless attributed to leukemic involvement).

Reference tables for normal liver function criteria by age and sex are provided
in Section 10.9.
Other Adequate Organ Function Requirements.
17. Adequate cardiac function defined as ejection fraction (EF) of >50% by
echocardiogram or multigated acquisition (MUGA) scan.

Contraception
18. If a female 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. (See Section 10.4 for
details regarding contraception.)
19. If male who can father a child, agrees to use barrier contraception from
the time of enrollment through 120 days following the last study drug dose. See
Section 10.4 for details regarding contraception.)

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 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
14. 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.
• In the Phase 2 portion and Phase 1 backfill, intrathecal chemotherapy for CNS
prophylaxis is permitted, at the treating physician*s discretion. In the Phase
1 DLT evaluable cohort, CNS prophylaxis may continue starting in C2D1.

15. In Phase 1 some Exclusions apply. see more details in the protocol.
• Note that phase I is not applicable for the Netherlands.

In Phase 2: Patients who will not receive SNDX 5613 with co administration of a
strong CYP3A4 inhibitor must discontinue all strong CYP3A4 inhibitors at least
7 days prior to first dose of SNDX 5613. They will receive the SNDX 5613 RP2D
for patients who are not on a strong CYP3A4 inhibitor, and they may continue to
receive moderate or weak CYP3A4 inhibitors, including fluconazole and
isavuconazole.
Patients who will receive SNDX 5613 with co administration of a strong CYP3A4
inhibitor azole antifungal (itraconazole, ketoconazole, posaconazole, or
voriconazole) must have started the azole antifungal treatment at least 24
hours prior to enrollment. They will receive the SNDX 5613 RP2D for patients
who are on a strong CYP3A4 inhibitor.
Note that the RP2D for SNDX 5613 for patients on a strong CYP3A4 inhibitor
versus patients who are not on a strong CYP3A4 inhibitor is outlined in Table
9. Refer to Appendix 10.6 for examples of strong CYP3A4 inhibitors/inducers.

16. Participation in 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 (eg, diphenhydramine, famotidine, ondansetron,
Bactrim) and the azoles permitted whichthe relevant arms of Phase 1 and in
phase 2. Please see Appendix 10.7 for examples of medications that may be
appropriate substitutes for such medications.
17. Receipt of an investigational agent within 30 days of starting SNDX-5613
unless Inclusion Criteria 8, 9, 10, and 13 apply, then the longer period must
be applied. Patients may continue with noninterventional follow-up from
previous clinical studies.
18. Patients who have had prior exposure to a menin inhibitor.
19. Any concurrent systemic treatment to prevent GVHD.