A Study of APG-115 Alone or Combined With Azacitidine in Patients With AML, CMML, or MDS

Sponsor

Ascentage Pharma Group Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04358393

Collaborator

(none)

Enrollment

Locations

Arms

48.9

Anticipated Duration (Months)

8.6

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
AML Acute Myeloid Leukemia Chronic Myelomonocytic Leukemia CMML Myelodysplastic Syndromes High-risk Myelodysplastic Syndrome MDS	Drug: APG-115 Drug: 5-azacitidine	Phase 1/Phase 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

69 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Dec 4, 2020

Anticipated Primary Completion Date :

Dec 30, 2023

Anticipated Study Completion Date :

Dec 30, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: APG-115 monotherapy Monotherapy given in part 1	Drug: APG-115 APG-115 given once daily on day 1-5 of every 28 day cycle
Experimental: APG-115 + 5-azacitidine combination Combination therapy given in part 2	Drug: APG-115 APG-115 given once daily on day 1-5 of every 28 day cycle Drug: 5-azacitidine 5-AZA is given at 75 mg/m˄2/d subcutaneously daily on Day 1-7 every 28 days Other Names: Vidaza Azadine

Arm

Intervention/Treatment

Experimental: APG-115 monotherapy

Monotherapy given in part 1

Drug: APG-115

APG-115 given once daily on day 1-5 of every 28 day cycle

Experimental: APG-115 + 5-azacitidine combination

Combination therapy given in part 2

Drug: APG-115

APG-115 given once daily on day 1-5 of every 28 day cycle

Drug: 5-azacitidine

5-AZA is given at 75 mg/m˄2/d subcutaneously daily on Day 1-7 every 28 days

Other Names:

Vidaza

Azadine

Outcome Measures

Primary Outcome Measures

Maximum Tolerated Dose [28 days]
Part I is to assess the safety and tolerability of APG-115 by assessing the dose-limiting toxicity (DLT) of APG-115. End points include: Incidence of DLTs during the first 3 weeks of treatment of each dose cohort; Severity and frequency of any adverse event(s) (AE) and serious adverse event(s) (SAE) based on NCI CTCAE 5.0

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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.
Adequate organ function as defined below:
Liver function (total bilirubin < or = 1.5 x upper limit of normal (ULN), aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) <3 x ULN
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)
Known cardiac ejection fraction of > or = 45% within the past 3 months
Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
A negative serum pregnancy test is required within 1 week for all women of childbearing potential prior to enrolling on this trial.
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.
Subject must have a projected life expectancy of at least 12 weeks.
Subject has a white blood cell count < 25 × 10˄9/L. Note: Hydroxyurea is permitted to meet this criteria.

Exclusion:

Pregnant women are excluded.
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.
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.
Have acute promyelocytic leukemia.
Active infection requiring systemic antibiotic/antifungal medication, known clinically active hepatitis B or C, or HIV infection.
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.
Documented hypersensitivity to any of the components of the therapy program
Active, uncontrolled central nervous system (CNS) leukemia will not be eligible.
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.
Any prior systemic MDM2-p53 inhibitor treatment
Any other condition or circumstance that would, in the opinion of the investigator, make the patient unsuitable for participation in the study.
History of other malignancies within 2 years prior to study entry, with the exception of:
Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast
Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin
Previous malignancy confined and surgically resected (or treated with other modalities) with curative intention: requires discussion with sponsor
Failure to have recovered (Grade > 1) from prior treatment (including chemotherapy, targeted therapy, immunotherapy, experimental agents, radiation, or surgery)
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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Banner MD Anderson Cancer Center	Gilbert	Arizona	United States	85234
2	Rocky Mountain Cancer Centers	Denver	Colorado	United States	80218
3	Duke University	Durham	North Carolina	United States	27710
4	Texas Oncology - Baylor Charles A. Sammons Cancer Center	Dallas	Texas	United States	75246
5	MD Anderson	Houston	Texas	United States	77030
6	Texas Oncology - Tyler	Tyler	Texas	United States	75702
7	Virginia Cancer Specialists	Fairfax	Virginia	United States	22031
8	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109