Clinical trial NCT03745716: APR-246 & Azacitidine for the Treatment of TP53 Mutant Myelodysplastic Syndromes (MDS)
Official title: A Phase III Multicenter, Randomized, Open Label Study of APR-246 in Combination With Azacitidine Versus Azacitidine Alone for the Treatment of (Tumor Protein) TP53 Mutant Myelodysplastic Syndromes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: MDS
Lead sponsor: Aprea Therapeutics
Sponsor class: INDUSTRY
First posted: 2018-11-19
Enrollment: 154
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This will be a Phase III, multicenter, randomized study to compare the rate of CR and duration of CR, in patients with TP53-mutated MDS who will receive APR-246 and azacitidine or azacitidine alone.

Treatment will be administered on an outpatient basis. No investigational or commercial agents or therapies other than those described below may be administered with the intent to treat the patient's disease.

Patients will be randomized (1:1) to one of two arms: stratified by age (\< 65 years versus ≥ 65):

* Experimental arm: APR-246 + azacitidine; or
* Control arm: Azacitidine
Primary purpose: TREATMENT

Brief summary: A Phase III, multicenter, randomized study to compare the rate of complete response (CR) and duration of CR, in patients with TP53-mutated MDS who will receive APR-246 and azacitidine or azacitidine alone.

Detailed description: A Phase III, multicenter, randomized study to compare the rate of CR and duration of CR, in patients with TP53-mutated MDS who will receive APR-246 and azacitidine or azacitidine alone.

Treatment will be administered on an outpatient basis. No investigational or commercial agents or therapies other than those described below may be administered with the intent to treat the patient's disease.

Patients will be randomized (1:1) to one of two arms:

1. Experimental arm: APR-246 + azacitidine; or
2. Control arm: Azacitidine

Eligibility criteria: Inclusion Criteria:

* Signed Informed Consent (ICF) and is able to comply with protocol requirements
* Documented diagnosis of MDS, according to World Health Organization (WHO) classification
* Patient has adequate organ function as defined by the following laboratory values:

  1. Creatinine clearance \> 30 mL/min (by Cockcroft-Gault method)
  2. Total serum bilirubin \< 1.5 x Upper Limit of Normal (ULN) or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert's Syndrome or hemolysis or who required regular blood transfusions
  3. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 2.5 x ULN
* Age ≥18 years at the time of signing the informed consent form (ICF)
* Having at least one TP53 mutation which is not benign or likely benign
* Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
* If of childbearing potential, negative pre-treatment urine or serum pregnancy test
* If of childbearing potential (males and females), willing to use an effective form of contraception such as latex condom, hormonal birth control, intrauterine device or double barrier method during chemotherapy treatment and for at least six months thereafter

Exclusion Criteria:

* Patient has a known history of human immunodeficiency virus (HIV) or active hepatitis B or active hepatitis C infection (testing not mandatory)
* Patient has any of the following cardiac abnormalities (as determined by treating MD):

  1. Myocardial infarct within six months prior to registration,
  2. New York Heart Association Class II or worse heart failure (Appendix II) or known left ventricular ejection fraction (LVEF) \< the institution lower limit of normal as assessed by echocardiogram
  3. A history of familial long QT syndrome,
  4. Clinically significant pericardial disease
  5. Electrocardiographic evidence of acute ischemia
  6. Symptomatic atrial or ventricular arrhythmias not controlled by medications
  7. QTc ≥ 470 msec (QT cardiac interval)
  8. Bradycardia (\<40 bpm)
* Concomitant malignancies or previous malignancies with less than a 1-year disease free interval at the time of signing consent. Patients with adequately resected basal or squamous cell carcinoma of the skin, or adequately resected carcinoma in situ (e.g. cervix) may enroll irrespective of the time of diagnosis
* Prior exposure to azacitidine, decitabine or investigational hypomethylating agent
* Prior exposure to intensive chemotherapy
* Use of cytotoxic chemotherapeutic agents, or experimental agents (agents that are not commercially available) for the treatment of MDS within 14 days of the first day of study drug treatment
* No concurrent use of erythroid stimulating agents
* Patients with history of allogeneic stem cell transplantation
* Pregnant women are excluded from this study because APR-246 has not been studied in pregnant patients. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with APR 246, breastfeeding should be discontinued if the mother is treated with APR-246.
* Patients with active uncontrolled infections

Primary outcomes:
measure: Complete Response Rate (CR)
timeFrame: 12 months
Secondary outcomes:
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Palo Alto
country: United States
facility: Stanford University Cancer Research Center
state: California
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Hollywood
country: United States
facility: Memorial Health Care System South Florida
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Chicago
country: United States
facility: Robert H Lurie Comprehensive Cancer Center, Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University Of Chicago Medicine
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics, Holden Cancer Center
state: Iowa
city: New Orleans
country: United States
facility: Ochsner Cancer Institute
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins Medical Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University St. Louis
state: Missouri
city: New York
country: United States
facility: Cornell Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania, Abramson Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center, Hillman Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Nantes
country: France
facility: CHU Nantes
city: Nice
country: France
facility: CHU Nice
city: Paris
country: France
facility: Hôpital Saint-Louis
city: Toulouse
country: France
facility: IUCT Oncopole
Study officials:
affiliation: Moffitt Cancer Center, Tampa, US
name: David Sallman, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: