Clinical trial NCT04358393: A Study of APG-115 Alone or Combined With Azacitidine in Patients With AML, CMML, or MDS
Official title: A Phase Ib/II Study of APG-115 Alone or in Combination With Azacitidine in Patients With Relapse/Refractory AML, CMML or MDS
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: AML
Acute Myeloid Leukemia
Chronic Myelomonocytic Leukemia
CMML
Myelodysplastic Syndromes
High-risk Myelodysplastic Syndrome
MDS
Keywords: TP53
Lead sponsor: Ascentage Pharma Group Inc.
Sponsor class: INDUSTRY
First posted: 2020-04-24
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This is a two Part study in patients with relapsed/refractory acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), or high risk myelodysplastic syndrome (MDS) that will initially evaluate the safety and tolerability of APG-115 as a single agent in Part 1, followed by a combination of APG-115 + 5-azacitidine (5-AZA) in Part 2.

Detailed description: Part 1: Dose escalation of APG-115 will use standard 3+3 design. APG-115 is administered orally once daily (QD) on Day 1-5 every 28-day cycle. The starting target dose is 100 mg (dose level; DL1) and will be increased in subsequent cohorts to 150 mg (DL2), 200 mg (DL3), and 250 mg (DL4), accordingly.

Part 2: Dose escalation of APG-115 in combination with 5-AZA will use standard 3+3 design. 5-AZA is administered at 75 mg/m˄2/d subcutaneously daily on Day 1-7 every 28 days.

Eligibility criteria: Inclusion Criteria:

1. Patients with a diagnosis of histologically confirmed relapsed or refractory AML, CMML, or high-risk MDS (overall revised international prognostic scoring system (IPSS-R) score \> 3, including intermediate, high, or very high risk) by World Health Organization (WHO) classification for which no available standard therapies are indicated or anticipated to result in a durable response.
2. Adequate organ function as defined below:

   1. Liver function (total bilirubin \< or = 1.5 x upper limit of normal (ULN), aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) \<3 x ULN
   2. Kidney function (defined as a calculated creatinine clearance ≥ 60 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft Gault formula)
   3. Known cardiac ejection fraction of \> or = 45% within the past 3 months
3. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
4. A negative serum pregnancy test is required within 1 week for all women of childbearing potential prior to enrolling on this trial.
5. Patient must have the ability to understand the requirements of the study and signed informed consent. A signed informed consent by the patient or legally authorized representative is required prior to their enrollment on the protocol.
6. Subject must have a projected life expectancy of at least 12 weeks.
7. Subject has a white blood cell count \< 25 × 10˄9/L. Note: Hydroxyurea is permitted to meet this criteria.

Exclusion:

1. Pregnant women are excluded.
2. Uncontrolled intercurrent illness including, but not limited to active uncontrolled infection, symptomatic congestive heart failure (NYHA Class III or IV), unstable angina pectoris, clinically significant cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
3. Have had leukemia therapy for 14 days prior to starting investigational drug. However, patients with rapidly proliferative disease may receive hydroxyurea as needed until 24 hours prior to starting therapy on this protocol and during the first cycle of study.
4. Have acute promyelocytic leukemia.
5. Active infection requiring systemic antibiotic/antifungal medication, known clinically active hepatitis B or C, or HIV infection.
6. Have received allogeneic hematopoietic stem cell transplant (HSCT) within 12 months prior to the first dose, or who have active/ongoing graft-versus host disease (GVHD), or require continued treatment with systemic immunosuppressive agents (calcineurin inhibitors within 4 weeks prior to the first dose), or received autologous hematopoietic stem cell transplantation within 6 months prior to the first dose.
7. Documented hypersensitivity to any of the components of the therapy program
8. Active, uncontrolled central nervous system (CNS) leukemia will not be eligible.
9. Men and women of childbearing potential who do not practice contraception. Women of childbearing potential and men must agree to use at least 1 form of barrier birth control (such as condom) prior to study entry and for the duration of study participation.
10. Any prior systemic MDM2-p53 inhibitor treatment
11. Any other condition or circumstance that would, in the opinion of the investigator, make the patient unsuitable for participation in the study.
12. History of other malignancies within 2 years prior to study entry, with the exception of:

    1. Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast
    2. Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin
    3. Previous malignancy confined and surgically resected (or treated with other modalities) with curative intention: requires discussion with sponsor
13. Failure to have recovered (Grade \> 1) from prior treatment (including chemotherapy, targeted therapy, immunotherapy, experimental agents, radiation, or surgery)
14. Significant screening electrocardiogram (ECG) abnormalities including left bundle branch block, 2nd degree atrioventricular (AV) block type II, 3rd degree block, or corrected QT interval (QTc) ≥470 msec

Primary outcomes:
measure: Maximum Tolerated Dose
timeFrame: 28 days
Secondary outcomes:
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Denver
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Dallas
country: United States
facility: Texas Oncology - Baylor Charles A. Sammons Cancer Center
state: Texas
city: Houston
country: United States
facility: MD Anderson
state: Texas
city: Tyler
country: United States
facility: Texas Oncology - Tyler
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists
state: Virginia
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
Study officials:
affiliation: Ascentage Pharma Group Inc.
name: Yifan Zhai, MD, PhD
role: STUDY_CHAIR
References: