Trial Title:
Testing the Combination of an Anti-Cancer Drug, Iadademstat, With Other Anti-Cancer Drugs (Venetoclax and Azacitidine) for Treating AML
NCT ID:
NCT06514261
Condition:
Acute Myeloid Leukemia
Conditions: Official terms:
Azacitidine
Venetoclax
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Azacitidine
Description:
Given IV or SC
Arm group label:
Treatment (iadademstat, venetoclax, azacitidine)
Other name:
5 AZC
Other name:
5-AC
Other name:
5-Azacitidine
Other name:
5-Azacytidine
Other name:
5-AZC
Other name:
Azacytidine
Other name:
Azacytidine, 5-
Other name:
Ladakamycin
Other name:
Mylosar
Other name:
U-18496
Other name:
Vidaza
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo blood sample collection
Arm group label:
Treatment (iadademstat, venetoclax, azacitidine)
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
Arm group label:
Treatment (iadademstat, venetoclax, azacitidine)
Intervention type:
Procedure
Intervention name:
Buccal Swab
Description:
Undergo buccal swab
Arm group label:
Treatment (iadademstat, venetoclax, azacitidine)
Other name:
Buccal Scraping
Other name:
Buccal Smear
Other name:
Buccal swab/scraping
Other name:
Buccal Swabbing
Intervention type:
Drug
Intervention name:
Iadademstat
Description:
Given PO
Arm group label:
Treatment (iadademstat, venetoclax, azacitidine)
Other name:
ORY 1001
Other name:
ORY-1001
Other name:
RG 6016
Other name:
RG6016
Other name:
RO 7051790
Other name:
RO7051790
Other name:
trans-N1-((1R,2S)-2-Phenylcyclopropyl)-1,4-cyclohexanediamine
Intervention type:
Drug
Intervention name:
Venetoclax
Description:
Given PO
Arm group label:
Treatment (iadademstat, venetoclax, azacitidine)
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 safety, side effects and best dose of iadademstat with
azacitidine and venetoclax for the treatment of patients with acute myeloid leukemia
(AML) who have not receive treatment (treatment naive). Chemotherapy drugs, such as
iadademstat and azacitidine work in different ways to stop the growth of cancer cells,
either by killing the cells, by stopping them from dividing, or by stopping them from
spreading. 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 iadademstat with azacitidine and venetoclax may be safe
and tolerable in treating patients with treatment naive AML.
Detailed description:
PRIMARY OBJECTIVE:
I. To determine the recommended phase 2 dose (RP2D) and safety profile of iadademstat in
combination with venetoclax and azacitidine.
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity, including evaluating the overall response
rate (ORR), defined as complete remission (CR), CR with incomplete hematologic recovery
(Cri), or CR with partial hematologic recovery (CRh).
II. To evaluate the measurable residual disease (MRD)-negative composite CR (cCR) rate
after 1, 2, and 3 cycles using multiparameter flow cytometry (MFC) and evaluate
event-free survival (EFS), overall survival (OS), and duration of response (DoR).
III. To determine if treatment will be associated with expansion of high risk molecular
(PTPN11, NRAS, KRAS, NF1, and TP53) and cytogenetic (complex karyotype) markers over
time.
EXPLORATORY OBJECTIVES:
I. To determine the rate of MRD-negative cCR across molecular (PTPN11, NRAS, KRAS, NF1,
and TP53) and cytogenetic (complex karyotype) subgroups.
II. To document the effect of therapy on LSD1-target engagement.
III. To determine if secondary resistance (remission with therapy then relapse) in both
arms is associated with:
IIIa. Acquisition of resistance mutations including BCL-2 and BAX; IIIb. Development or
expansion of mutations that activate RAS/MAPK/FLT3 including NRAS, KRAS, PTPN11, NF1, and
FLT3-ITD; IIIc. Over-expression of resistance proteins such as MCL-1 or BCL-XL. IV. To
determine pharmacokinetics (PK) in the triplet therapy of iadademstat, azacitidine, and
venetoclax.
V. To explore PK/pharmacodynamic (PD) relationship of iadademstat and venetoclax in
patients who received the triplet therapy of iadademstat, azacitidine, and venetoclax.
VI. To evaluate the association between time to achieve an MRD-negative cCR and EFS, OS,
and DoR.
OUTLINE: This is a dose-escalation study of iadademstat and venetoclax in combination
with azacitidine.
INDUCTION: Patients receive iadademstat orally (PO) once per day (QD) on days 1-5, 8-12,
and may also receive it on days 15-19, venetoclax PO QD on days 1-14 or 1-21 and
azacitidine intravenously (IV) over 10-40 minutes or subcutaneously (SC) on days 1-7 or
1-5 and 8-9 of each cycle. Cycles repeat every 28 days for 3 cycles in the absence of
disease progression or unacceptable toxicity. Patients may also undergo buccal swab
collection on study.
CONSOLIDATION: Patients receive iadademstat PO QD on days 1-5, 8-12 and may also receive
it on days 15-19, venetoclax PO QD on days 1-7 or 1-14 and azacitidine IV over 10-40
minutes or SC on days 1-7 or 1-5 and 8-9 of each cycle. Cycles repeat every 28 days for
up to 2 years in the absence of disease progression or unacceptable toxicity. Patients
undergo blood sample collection and may undergo bone marrow aspiration throughout the
study.
After completion of study treatment, patients are followed every 3-4 months for up to 2
years.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Patients must have established and confirmed diagnosis of intermediate or
adverse-risk AML according to the European LeukemiaNet 2022 classification criteria
- Previously untreated AML excluding hydroxyurea and all-trans retinoic acid (ATRA).
ATRA would only be used for suspected AML
- Age ≥ 18 years. Because no dosing or adverse event data are currently available on
the use of iadademstat in combination with venetoclax and azacitidine in patients <
18 years of age, children are excluded from this study
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
- Patient is able to swallow oral medications
- Patient must have a body weight of at least 50 kg due to the use of flat doses
- Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) OR direct
bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 x ULN or ≤ 3 x ULN if
patient has Gilbert's disease
- Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/
alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3 ×
institutional ULN or < 5 ULN if due to AML
- Chronic kidney disease (CKD)-epidemiology collaboration (EPI) glomerular filtration
rate (GFR) ≥ 40 mL/min/1.73 m^2
- Peripheral white blood cell (WBC) count < 25 x 10^9/L on day 1 prior to treatment
initiation. Hydroxyurea for up to 2 weeks is allowed for cytoreduction until 24
hours prior to study treatment
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV
viral load must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load
- 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
- Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional Classification. To be
eligible for this trial, patients should be class II or better. Patients with a
troponin leak (i.e. elevated troponin levels at presentation without evidence of an
active myocardial infarction (MI) are eligible
- The effects of iadademstat on the developing human fetus are unknown. For this
reason and because LSD1 inhibitors as well as other therapeutic agents used in this
trial are known to be teratogenic, females of child-bearing potential must agree to
use adequate contraception (hormonal or barrier method of birth control; abstinence)
prior to study entry, for the duration of study participation, and for 180 days
after the last dose of study medication. 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. Males with female partners of
child-bearing potential treated or enrolled on this protocol must also agree to use
adequate contraception prior to the study, for the duration of study participation,
and 180 days after the last dose of study medication. Women of child-bearing
potential agree not to donate or freeze egg(s) during the course of this study or
within 180 days after receiving their last dose of study drug. Male patients agree
not to donate sperm during the course of this study or within 180 days after
receiving their last dose of study drug
- 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 are willing and able to receive intensive induction chemotherapy
- Patients have isolated myeloid sarcoma or acute promyelocytic leukemia (APL)
French-American-British (FAB) M3
- Patients who have not recovered from adverse events of grade 3 or more due to prior
anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of
alopecia
- Patients who are receiving any other investigational agents
- Patients who have active central nervous system (CNS) involvement by AML
- Patients who have disseminated intravascular coagulopathy with active systemic
bleeding or venous or atrial signs of thrombosis
- Patients who require treatment while on study with concomitant drugs that target the
5HT2B receptor or the sigma nonspecific receptor (e.g., escitalopram, fluoxetine,
sertraline) except for drugs that are considered absolutely essential for the care
of the patient and with appropriate treatment monitoring
- Patients with manifestations of malabsorption due to prior gastrointestinal (GI)
surgery, GI disease, or for an unknown reason that may alter the absorption of oral
drugs. In addition, patients with enteric stomata are also excluded
- History of allergic reactions attributed to compounds of similar chemical or
biologic composition to iadademstat, azacitidine, mannitol, or venetoclax
- Iadademstat Concomitant Medication Considerations: Patients are not allowed to
receive prophylactic hematopoietic colony stimulating factors, any complementary or
alternative medicine (any of various systems of healing or treating disease [as
non-prescription drugs, herbal medicine and homeopathy])
- Patients should not use strong CYP3A inhibitors with the exception of antifungals
for which standard of care (SOC) dose modifications of venetoclax exist
- Patients with uncontrolled intercurrent illness or any other significant
condition(s) that would make participation in this protocol unreasonably hazardous.
This includes, but is not limited to:
- Myocardial infarction with evidence of residual abnormalities within 3 months
prior to enrollment (Troponin leak alone not included if no residual
dysfunction);
- New York Heart Association (NYHA) Class III or IV heart failure;
- Severe uncontrolled ventricular arrhythmias;
- Electrocardiographic evidence of acute ischemia or active life-threatening
conduction system abnormalities:
- Since patients with AML frequently require supportive care with agents
that affect the QTc, if clinically indicated, obtain an electrocardiogram
(ECG) prior to enrollment
- As infection is a common feature of AML, patients with active infection are
permitted to enroll provided that the infection is under control (i.e., no signs of
severe systemic inflammatory response that makes patient clinically unstable in the
opinion of the investigator, and the patient is hemodynamically stable). Patients
with uncontrolled infection shall not be enrolled until the infection is treated and
brought under control
- Pregnant women are excluded from this study because iadademstat is LSD1 inhibitor
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 iadademstat, breastfeeding should be discontinued if
the mother is treated with iadademstat. These potential risks may also apply to
other agents used in this study
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
UPMC Hillman Cancer Center LAO
Address:
City:
Pittsburgh
Zip:
15232
Country:
United States
Status:
Recruiting
Contact:
Last name:
Natalie Galanina
Phone:
412-692-4724
Email:
galaninan@upmc.edu
Investigator:
Last name:
Natalie Galanina
Email:
Principal Investigator
Start date:
July 15, 2025
Completion date:
September 16, 2026
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/NCT06514261
