Trial Title:
Testing the Anti-cancer Drug, Cirtuvivint, and Its Combination With ASTX727 and ASTX727 With Venetoclax to Improve Outcomes in Patients With Acute Myeloid Leukemia and Myelodysplastic Syndromes
NCT ID:
NCT06484062
Condition:
Acute Myeloid Leukemia
Myelodysplastic Syndrome
Recurrent Acute Myeloid Leukemia
Recurrent Myelodysplastic Syndrome
Refractory Acute Myeloid Leukemia
Refractory Myelodysplastic Syndrome
Conditions: Official terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Preleukemia
Myelodysplastic Syndromes
Syndrome
Recurrence
Venetoclax
Decitabine
Decitabine and cedazuridine drug combination
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Not yet recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Sequential Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo blood sample collection
Arm group label:
Cohort I (cirtuvivint)
Arm group label:
Cohort II (cirtuvivint)
Arm group label:
Cohort III (cirtuvivint, ASTX727)
Arm group label:
Cohort IV (cirtuvivint, ASTX727, venetoclax)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Procedure
Intervention name:
Bone Marrow Aspiration
Description:
Undergo bone marrow aspiration and biopsy
Arm group label:
Cohort I (cirtuvivint)
Arm group label:
Cohort II (cirtuvivint)
Arm group label:
Cohort III (cirtuvivint, ASTX727)
Arm group label:
Cohort IV (cirtuvivint, ASTX727, venetoclax)
Intervention type:
Procedure
Intervention name:
Bone Marrow Biopsy
Description:
Undergo bone marrow aspiration and biopsy
Arm group label:
Cohort I (cirtuvivint)
Arm group label:
Cohort II (cirtuvivint)
Arm group label:
Cohort III (cirtuvivint, ASTX727)
Arm group label:
Cohort IV (cirtuvivint, ASTX727, venetoclax)
Other name:
Biopsy of Bone Marrow
Other name:
Biopsy, Bone Marrow
Intervention type:
Drug
Intervention name:
Cirtuvivint
Description:
Given PO
Arm group label:
Cohort I (cirtuvivint)
Arm group label:
Cohort II (cirtuvivint)
Arm group label:
Cohort III (cirtuvivint, ASTX727)
Arm group label:
Cohort IV (cirtuvivint, ASTX727, venetoclax)
Intervention type:
Drug
Intervention name:
Decitabine and Cedazuridine
Description:
Given PO
Arm group label:
Cohort III (cirtuvivint, ASTX727)
Arm group label:
Cohort IV (cirtuvivint, ASTX727, venetoclax)
Other name:
ASTX 727
Other name:
ASTX-727
Other name:
ASTX727
Other name:
C-DEC
Other name:
CDA Inhibitor E7727/Decitabine Combination Agent ASTX727
Other name:
Cedazuridine/Decitabine Combination Agent ASTX727
Other name:
Cedazuridine/Decitabine Tablet
Other name:
DEC-C
Other name:
Inaqovi
Other name:
Inqovi
Intervention type:
Procedure
Intervention name:
Echocardiography
Description:
Undergo ECHO
Arm group label:
Cohort I (cirtuvivint)
Arm group label:
Cohort II (cirtuvivint)
Arm group label:
Cohort III (cirtuvivint, ASTX727)
Arm group label:
Cohort IV (cirtuvivint, ASTX727, venetoclax)
Other name:
EC
Intervention type:
Procedure
Intervention name:
Multigated Acquisition Scan
Description:
Undergo MUGA
Arm group label:
Cohort I (cirtuvivint)
Arm group label:
Cohort II (cirtuvivint)
Arm group label:
Cohort III (cirtuvivint, ASTX727)
Arm group label:
Cohort IV (cirtuvivint, ASTX727, venetoclax)
Other name:
Blood Pool Scan
Other name:
Equilibrium Radionuclide Angiography
Other name:
Gated Blood Pool Imaging
Other name:
Gated Heart Pool Scan
Other name:
MUGA
Other name:
MUGA Scan
Other name:
Multi-Gated Acquisition Scan
Other name:
Radionuclide Ventriculogram Scan
Other name:
Radionuclide Ventriculography
Other name:
RNV Scan
Other name:
RNVG
Other name:
SYMA Scanning
Other name:
Synchronized Multigated Acquisition Scanning
Intervention type:
Drug
Intervention name:
Venetoclax
Description:
Given PO
Arm group label:
Cohort IV (cirtuvivint, ASTX727, venetoclax)
Other name:
ABT 199
Other name:
ABT-0199
Other name:
ABT-199
Other name:
ABT199
Other name:
GDC 0199
Other name:
GDC-0199
Other name:
GDC0199
Other name:
RG7601
Other name:
Venclexta
Other name:
Venclyxto
Summary:
This phase I trial tests the safety, side effects, and best dose of SM08502 (cirtuvivint)
alone and in combination with ASTX727, as well as ASTX727 and venetoclax in treating
patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
Cirtuvivint may stop the growth of cancer cells by blocking some of the enzymes needed
for cell growth. ASTX727 is a combination of two drugs, decitabine and cedazuridine.
Decitabine is in a class of medications called hypomethylation agents. It works by
helping the bone marrow produce normal blood cells and by killing abnormal cells in the
bone marrow. Cedazuridine is in a class of medications called cytidine deaminase
inhibitors. It prevents the breakdown of decitabine, making it more available in the body
so that decitabine will have a greater effect. Venetoclax is in a class of medications
called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by
blocking BCL-2, a protein needed for cancer cell survival. Giving cirtuvivint alone or in
combination with ASTX727 or ASTX727 and venetoclax may be safe, tolerable, and/or
effective in treating patients with AML and MDS.
Detailed description:
PRIMARY OBJECTIVE:
I. To determine the recommended phase 2 dose (RP2D) of SM08502 (cirtuvivint) as
monotherapy in Relapsed/Refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic
syndromes (MDS) (Cohort I and II) and in combination with decitabine and cedazuridine
(ASTX727) in frontline MDS (Cohort III) and in combination with ASTX727 + venetoclax in
frontline AML (Cohort IV).
SECONDARY OBJECTIVES:
I. To assess the safety/tolerability of SM08502 (cirtuvivint) as monotherapy in R/R AML
and MDS (Cohort I and II) and in combination with ASTX727 in frontline MDS (Cohort III)
and in combination with ASTX727 + venetoclax in frontline AML (Cohort IV).
II. To assess the pharmacokinetics (PK), and pharmacodynamics (PD) of SM08502
(cirtuvivint) as monotherapy in R/R AML and MDS (Cohort I and II) and in combination with
ASTX727 in frontline MDS (Cohort III) and in combination with ASTX727 + venetoclax in
frontline AML (Cohort IV).
III. To determine the preliminary efficacy of the combination of SM08502 (cirtuvivint) as
monotherapy in R/R AML and MDS (Cohort I and II) and in combination with ASTX727 in
frontline MDS (Cohort III) and in combination with ASTX727 + venetoclax in frontline AML
(Cohort IV) by assessing the response rate as defined by the 2022 European LeukemiaNet
(ELN) response criteria for AML (Döhner et al., 2022) and International Working Group
(IWG) 2023 response criteria for MDS (Zeidan et al., 2023).
IV. To explore survival outcomes achieved with SM08502 (cirtuvivint) as monotherapy in
R/R AML and MDS (Cohort I and II) and in combination with ASTX727 in frontline MDS
(Cohort III) and in combination with ASTX727 + venetoclax in frontline AML (Cohort IV) by
assessing 1 year event free survival (EFS) and overall survival (OS) rate.
V. To observe and record anti-tumor activity. VI. To evaluate the best schedule to move
forward with in Phase 2.
OUTLINE: This is a dose-escalation study of cirtuvivint as monotherapy, followed by an
expansion study in combination with ASTX727 and ASTX727 plus venetoclax. Patients are
assigned to 1 of 4 cohorts.
COHORT I: Patients receive cirtuvivint orally (PO) once daily (QD) Monday-Friday on days
1-5, 8-12, 15-19, and 22-26 of each cycle. Cycles repeat every 28 days in the absence of
disease progression or unacceptable toxicity. Patients undergo echocardiography (ECHO) or
multigated acquisition scan (MUGA) at screening. In addition, patients undergo blood
sample collection and bone marrow aspiration and biopsy at screening and on study.
COHORT II: Patients receive cirtuvivint PO once QD on days 1, 4, 8, 11, 15, 18, 22, and
25 of each cycle. Cycles repeat every 28 days in the absence of disease progression or
unacceptable toxicity. Patients undergo ECHO or MUGA at screening. In addition, patients
undergo blood sample collection and bone marrow aspiration and biopsy at screening and on
study.
COHORT III: Patients receive cirtuvivint PO QD on days 1, 4, 8, 11, 15, 18, 22, and 25
and ASTX727 PO QD on days 1-5 of each cycle. Cycles repeat every 28 days in the absence
of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA at
screening. In addition, patients undergo blood sample collection and bone marrow
aspiration and biopsy at screening and on study.
COHORT IV: Patients receive cirtuvivint PO QD on days 1, 4, 8, 11, 15, 18, 22, and 25,
ASTX727 PO QD on days 1-5 and venetoclax PO QD on days 1-28 of each cycle. Cycles repeat
every 28 days in the absence of disease progression or unacceptable toxicity. Patients
undergo ECHO or MUGA at screening. In addition, patients undergo blood sample collection
and bone marrow aspiration and biopsy at screening and on study.
After completion of study treatment, patients are followed up for 30 days, every 3 months
for 2 years then every 6 months for up to 3 years.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- In Cohorts I and II, patients must have R/R AML and MDS (venetoclax naïve or
venetoclax exposed)
- Relapsed AML is defined as the appearance of 5% or greater myeloblasts in the
bone marrow or peripheral blood after achieving a complete remission (CR), CR
with partial hematologic recovery (CRh), or CR with incomplete hematologic
recovery (CRi). Patients with mutations in FLT3, IDH1 or IDH2 must have failed
or been intolerant of a Food and Drug Administration (FDA) approved FLT3, IDH1
or IDH2 inhibitor before enrolling on study
- Refractory AML is defined as failure to achieve a CR, CRh, or CRi after one of
the following regimens: (i) Two cycles of intensive induction chemotherapy with
a cytarabine containing regimen (e.g., 7+3, mitoxantrone, etoposide, cytarabine
[MEC], high-dose cytarabine [HIDAC], etc.) or, (ii) Two cycles of
hypomethylating agent (HMA)/venetoclax or low-dose cytarabine (LDAC)/glasdegib
or, (iii) Four cycles of HMA monotherapy
- Relapsed MDS is defined as: (i) Intermediate, high, or very high-risk disease
by International Prognostic Scoring System-Revised (IPSS-R) and, (ii) Any
relapse after achieving any 2023 IWG MDS defined response
- Refractory MDS is defined as: (i) Intermediate, high, or very high-risk disease
by IPSS-R and > 5% blasts in the bone marrow or peripheral blood, (ii) Failure
to achieve a response (as per IWG 2006 criteria) after four cycles of HMA
monotherapy, or (iii) Two cycles of HMA + venetoclax
- In Cohort III, patients must have frontline MDS with intermediate, high, or very
high-risk disease by IPSS-R and > 5% blasts in the bone marrow or peripheral blood.
No prior use of deoxyribonucleic acid methyltransferase inhibitor (DNMTi) therapy
(except one single cycle of DNMTi) is allowed. Prior use of erythropoiesis
stimulating agents (ESA), thrombopoietin agonists, lenalidomide, and luspatercept
are allowed
- In Cohort IV, patients must have frontline AML with age ≥ 75 years old or otherwise
considered unfit for intensive chemotherapy by treating physician, and had no prior
AML directed therapy. Patients cannot have acute promyelocytic leukemia or mixed
lineage leukemia. Prior therapy with DNMTi for a prior diagnosis of MDS/chronic
myelomonocytic leukemia (CMML) and use of hydroxyurea for cytoreduction as well as
up to 5 days of all-trans retinoic acid (ATRA) or up to 5 days of steroids or one
dose of cytarabine are allowed
- Age ≥ 18 years. Because no dosing or adverse event data are currently available on
the use of SM08502 (cirtuvivint) in combination with ASTX727 and venetoclax in
patients < 18 years of age, children are excluded from this study
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 3
- Total bilirubin ≤ 2 x institutional upper limit of normal (ULN) (unless bilirubin
rise is due to Gilbert's syndrome or of non-hepatic origin)
- Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) ≤
3 x institutional ULN (unless considered due to organ involvement by the patient's
myeloid malignancy) (in that case a cut off of ≤ 5 x institutional ULN will be used)
- Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73m^2
- If female, patient must be either:
- Postmenopausal (surgically sterile or age > 55 years with no menses for 12 or
more months without an alternative medical cause or age equal to 55 or less
with no menses for 12 or more months without an alternative medical cause and a
follicle stimulating hormone [FSH] level > 40 IU/L); or
- Of children bearing potential. These patients must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior
to study entry and for the duration of study participation. Should a woman
become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she should inform her treating physician
immediately. Patient must agree to have a negative urine or serum beta-human
chorionic gonadotropin (HCG) test result during screening and repeated within 7
days prior to study drug (local labs are allowed) to be eligible
- The effects of SM08502 (cirtuvivint), ASTX727, and venetoclax on the developing
human fetus are unknown. For this reason, and because these agents are known to be
teratogenic, women of child-bearing potential must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry and during the treatment therapy. Women of childbearing age should agree
to use adequate contraception for 7 months after completion of SM08502 (cirtuvivint)
administration. For ASTX727 and venetoclax, adequate contraception must continue for
at least 6 months after last dose of ASTX727 and 30 days after last dose of
venetoclax. Should a woman become pregnant or suspect she is pregnant while she or
her partner is participating in this study, she should inform her treating physician
immediately. Men treated or enrolled on this protocol must also agree to use
adequate contraception prior to the study and for the duration of the study and at
least 4 months after the last dose of SM08502 (cirtuvivint) and 3 months after last
dose of ASTX727. Women who are lactating must refrain from breastfeed during the
study and at least for two weeks after last dose of ASTX727 and 1 week after last
dose of venetoclax
- Patients with a prior or concurrent malignancy whose natural history or treatment
does not have the potential to interfere with the safety or efficacy assessment of
the investigational regimen are eligible for this trial
- HIV-infected patients on effective anti-retroviral therapy with undetectable viral
load within 6 months are eligible for this trial
- Ability to understand and the willingness to sign a written informed consent
document. Legally authorized representatives may sign and give informed consent on
behalf of study participants
Exclusion Criteria:
- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > grade 1) with the exception of alopecia or
abnormal blood counts
- Patients who are receiving any other investigational agents
- Systemic anti-leukemic therapy within 14 days of first day of study treatment. If on
venetoclax, then a wash-out period of at least five times the half-life of the
treatment. Exceptions: No wash-out required for intrathecal chemotherapy,
hydroxyurea, cytarabine (Ara-C), or palliative radiation therapy to painful sites of
leukemic disease
- Patient is receiving inhibitors or activators of flavin-containing monooxygenases
(FMO1 or FMO3), and these cannot be stopped at least 5 days prior to SM08502
(cirtuvivint) treatment start. These include chlorpromazine and imipramine
- Patient is receiving strong inhibitors or strong inducers of CYP3A4/5 and these
cannot be stopped at least 5 days prior to SM08502 (cirtuvivint) treatment start
- Strong inhibitors include grapefruit juice or grapefruit/grapefruit related
citrus fruits (e.g., Seville oranges, pomelos), ketoconazole, miconazole,
itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin,
indinavir, saquinavir, ritonavir, nelfinavir, amprenavir, fosamprenavir,
nefazodone, lopinavir, troleandomycin, mibefradil, and conivaptan. Examples may
be found at the FDA website. Refer to the prescribing information of
concomitant medications if in doubt or consult the sponsor for guidance
- Strong inducers include phenobarbital, rifampin, phenytoin, carbamazepine,
rifabutin, rifapentin, clevidipine, and St. John's Wort. Examples may be found
at the FDA website. Refer to the prescribing information of concomitant
medications if in doubt or consult the sponsor for guidance.
- While moderate inhibitors or moderate inducers of CYP3A4/5 are not an exclusion
criterium for the trial, it is preferred that moderate inhibitors or moderate
inducers of CYP3A4/5 be replaced prior to the first dose of SM08502
(cirtuvivint) and during study conduct where this is possible.
- Moderate inhibitors include erythromycin, ciprofloxacin, verapamil,
diltiazem, atazanavir, fluconazole, darunavir, delavirdine, amprenavir,
fosamprenavir, aprepitant, imatinib, tofisopam, and cimetidine. Examples
may be found at the FDA website. Refer to the prescribing information of
concomitant medications if in doubt or consult the sponsor for guidance
- Moderate inducers include bosentan, efavirenz, etravirine, modafinil, and
nafcillin. Examples may be found at the FDA website. Refer to the
prescribing information of concomitant medications if in doubt or consult
the sponsor for guidance
- History of allergic reactions attributed to compounds of similar chemical or
biologic composition to SM08502 (cirtuvivint), ASTX727 or venetoclax
- Chronic, active hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment.
Note: patients with serologic evidence of prior vaccination to HBV (i.e. hepatitis B
surface [HBs] antigen negative, anti-HBs antibody positive and anti-hepatitis B core
[HBc] antibody negative) or positive anti-HBc antibody from intravenous
immunoglobulins (IVIG) may participate. Patients who had prior HCV that has been
definitively treated with negative HCV viral load prior to study initiation and no
evidence of cirrhosis, are allowed to participate. If there is no known history of
HBV infection no HBV studies need to be obtained. If there is no known history of
HCV infection, no HCV studies need to be obtained
- Patients with uncontrolled intercurrent illness or any other significant
condition(s) that would make participation in this protocol unreasonably hazardous
- Pregnant and lactating women are excluded from this study because SM08502
(cirtuvivint) is a small molecule inhibitor of CLK DYRK with the potential for
teratogenic or abortifacient effects. Because there is an unknown but potential risk
for adverse events in nursing infants secondary to treatment of the mother with
SM08502 (cirtuvivint), breastfeeding should be discontinued if the mother is treated
with SM08502 (cirtuvivint). These potential risks may also apply to other agents
used in this study
- Patients with acute promyelocytic leukemia
- Subject has symptomatic central nervous system (CNS) involvement with AML
- Patient has immediate life-threatening, severe complications of their myeloid
malignancy such as uncontrolled bleeding and/or uncontrolled infection
- Patient has significant active cardiac disease within 6 months prior to the start of
study treatment, including uncontrolled New York Heart Association (NYHA) class III
or IV congestive heart failure; acute coronary syndrome (ACS); and/or stroke
- Left ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) or
multi-gated acquisition (MUGA) scan obtained within 30 days prior to the start of
study treatment
- Patient is known to have dysphagia, short-gut syndrome, gastroparesis, or other
conditions that limit the ingestion or gastrointestinal absorption of drugs
administered orally. Patient needs to be able to swallow pills
- Patient has active uncontrolled systemic fungal, bacterial, or viral infection
(defined as ongoing signs/symptoms related to the infection without improvement
despite appropriate antibiotics, antiviral therapy, and/or other treatment)
- Subject has QTc interval (i.e., Fridericia's correction formula [QTcF]) ≥ 480 ms or
other factors that increase the risk of QT prolongation or arrhythmic events (e.g.,
heart failure, hypokalemia, family history of long QT interval syndrome) at
screening
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Start date:
December 6, 2024
Completion date:
January 1, 2027
Lead sponsor:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
National Cancer Institute (NCI)
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06484062
