This is an open-label, dose-escalation Phase 1/2 study to assess the safety of ASTX660,
determine the maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and recommended
dosing regimen, and to obtain preliminary efficacy, pharmacokinetic (PK), and target
engagement data, in subjects with advanced solid tumors or lymphoma for whom standard
life-prolonging measures are not available.
ASTX660 is a synthetic small molecule dual antagonist of cellular inhibitor of apoptosis
protein (cIAP) 1 and X-linked inhibitor of apoptosis protein (XIAP) that has been shown to
have potent proapoptotic and tumor growth inhibitory activity in nonclinical models. ASTX660
has not been previously evaluated in human subjects. The Phase 1 portion of the study will
determine the MTD, RP2D, and recommended dosing regimen. The Phase 2 portion will evaluate
activity in selected tumor types.
Subjects will continue to receive their assigned treatment throughout the study until the
occurrence of disease progression, death, or unacceptable treatment-related toxicity, or
until the study is closed by the sponsor.
Tolerability and safety of study treatment will be evaluated throughout the study by
collection of clinical and laboratory data. In Phase 2, antitumor response will be assessed
using computed tomography (CT) or magnetic resonance imaging (MRI) scans or other appropriate
disease evaluation methods. In subjects with solid tumors, response will be evaluated
according to standard Response Evaluation Criteria in Solid Tumors (RECIST v1.1; Appendix 3).
In subjects with DLBCL and PTCL, antitumor response will be evaluated according to the 2014
Lugano classification (Appendix 5). In subjects with CTCL, global overall response criteria
will be used, based on skin, blood, node, and viscera assessments (Appendix 4).
1. Able to understand and comply with the protocol and study procedures, understand the
risks involved in the study, and provide written informed consent before any
study-specific procedure is performed.
2. Men and women 18 years of age or older.
3. Subjects with histologically or cytologically confirmed advanced solid tumors or
lymphoma that is metastatic or unresectable, and for whom standard life-prolonging
measures are not available. Specific tumor types that will be selected for study in
Phase 2 are detailed in the protocol.
a) For Phase 2 Cohort 3, subjects must have histologically confirmed PTCL (local
pathology report) as defined by 2016 World Health Organization (WHO) classification.
The following subtypes are eligible for the study: adult T-cell lymphoma/leukemia,
extranodal natural killer (NK)/T-cell lymphoma nasal type, enteropathy-associated
T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, hepatosplenic
T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, peripheral T-cell
lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, follicular
T-cell lymphoma, nodal peripheral T-cell with T-follicular helper (THF) phenotype, and
anaplastic large-cell lymphoma.
4. For Phase 2 Cohorts 3 and 4, patients must have evidence of documented progressive
disease and must have received at least two prior systemic therapies.
1. Subjects with CD30-positive lymphoma must have received, be ineligible for, or
intolerant to brentuximab vedotin.
2. Subjects with mycosis fungoides or Sezary syndrome must have received, be
ineligible or intolerant to mogamulizumab.
5) In the Phase 2 portion of the protocol only, subjects must have measurable
disease according to response criteria appropriate for their type of cancer.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
7. Acceptable organ function, as evidenced by the following laboratory data:
1. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=2.0 * upper
limit of normal (ULN).
2. Total serum bilirubin <=1.5 * ULN
3. Absolute neutrophil count (ANC):
- Phase 1 and 2 (except Phase 2 subjects with known lymphoma) >=1500 cells/mm3
- Phase 2 subjects with known lymphoma: >=1000 cells/mm3 (>750 cell/mm3 for
subjects with lymphoma in bone marrow)
4. Platelet count:
- Phase 1 and 2 (except Phase 2 subject with known lymphoma) >=100,000 cells/mm3
- Phase 2 subjects with known lymphoma: >= 50,000 cells/mm3; >=25,000 cells/mm3 for
subjects with lymphoma in bone marrow
5. Serum creatinine levels <= 1.5 * ULN, or calculated (by Cockcroft-Gault formula or
other accepted formula) or measure creatinine clearance >=50 mL/min.
6. Amylase and lipase <=ULN [Applies to Phase 2].
8. Women of child-bearing potential (according to recommendations of the Clinical
Trial Facilitation Group [CTFG]; see protocol for details) must not be pregnant or
breastfeeding and must have a negative pregnancy test at screening. Women of
child-bearing potential and men with female partners of child-bearing potential must
agree to practice 2 highly effective contraceptive measures of birth control (as
described in the protocol) and must agree not to become pregnant or father a child
while receiving treatment with study drug and for at least 3 months after completing
treatment. Contraceptive measures which may be considered highly effective comprise
combined hormonal contraception (oral, vaginal, or transdermal) or progestogen-only
hormonal contraception (oral, injectable, implantable) associated with inhibition of
ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal
occlusion, sexual abstinence, and surgically successful vasectomy. Abstinence is
acceptable only if it is consistent with the preferred and usual lifestyle of the
subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, or postovulation
methods) and withdrawal are not acceptable methods of birth control.
1. Hypersensitivity to ASTX660, excipients of the drug product, or other components of
the study treatment regimen.
2. Poor medical risk because of systemic diseases (e.g. active uncontrolled infections)
in addition to the qualifying disease under study.
3. Life-threatening illness, significant organ system dysfunction, or other condition
that, in the investigator's opinion, could compromise subject safety or the integrity
of the study outcomes, or interfere with the absorption or metabolism of ASTX660.
4. History of, or at risk for, cardiac disease, as evidenced by 1 or more of the
1. Abnormal left ventricular ejection fraction (LVEF; <50%) or echocardiogram ECHO
or multiple gated acquisition scan (MUGA). [Applies to both Phase 1 and Phase 2.]
2. Congestive cardiac failure of >= Grade 3 severity according to New York Heart
Association (NYHA) functional classification defined as subjects with marked
limitation of activity and who are comfortable only at rest.
3. Unstable cardiac disease including angina or hypertension as defined by the need
for overnight hospital admission within the last 3 months (90 days).
4. History or presence of complete left bundle branch block, heart block, cardiac
pacemaker or significant arrhythmia.
5. Concurrent treatment with any medical that prolongs QT interval and may induce
torsades de pointes, and which cannot be discontinued at least 2 weeks before
treatment with ASTX660. [Applies to Phase 1 only].
6. Personal history of long QTc syndrome or ventricular arrhythmias including
7. Screening 12-lead ECG with measurable QTc interval (according to either
Fridericia's or Bazett's correction) of >=470 msec).
h) Any other condition that, in the opinion of the investigator, could put the subject
at increased cardiac risk.
5. Known history of human immunodeficiency virus (HIV) infection, or seropositive results
consistent with active hepatitis B virus (HBV) or active hepatitis C virus (HCV)
6. Grade 2 or greater neuropathy [Applies to Phase 1]. Grade 3 or greater neuropathy
[Applies to Phase 2].
7. Known brain metastases, unless stable or previously treated.
8. Known significant mental illness or other conditions such as active alcohol or other
substance abuse that, in the opinion of the investigator, predisposes the subject to
high risk of noncompliance with the protocol treatment or assessments.
9. Prior anticancer treatments or therapies within the indicated time window prior to
first dose of study treatment (ASTX660), as follows:
- Cytotoxic chemotherapy or radiotherapy within 3 weeks prior and any encountered
treatment-related toxicities (excepting alopecia) not resolved to Grade 1 or less
[Phase 1] or Grade 2 or less [Phase 2].
- Skin directed treatments, including topicals and radiation within 2 weeks prior.
- Monoclonal antibodies within 4 weeks prior and any encountered treatment-related
toxicities not resolved to Grade 1 or less [Phase 1] or Grade 2 or less [Phase
- Investigational drugs (small molecules or biologics) within the longer of 2 weeks
or 5 half-lives prior to study treatment and any encountered treatment-related
toxicities not resolved to Grade 1 or less [Phase 1] or Grade 2 or less [Phase