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APR-246 & Azacitidine for the Treatment of TP53 Mutant Myelodysplastic Syndromes (MDS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03745716
Recruitment Status : Recruiting
First Posted : November 19, 2018
Last Update Posted : February 17, 2020
Sponsor:
Information provided by (Responsible Party):
Aprea Therapeutics AB

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.

Condition or disease Intervention/treatment Phase
MDS Drug: APR-246 + azacitidine Drug: Azacitidine Phase 3

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 156 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : January 11, 2019
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Azacitidine

Arm Intervention/treatment
Experimental: Experimental arm: APR-246 + azacitidine
Patients will be randomized (1:1) to one of two arms: stratified by age (< 65 years versus ≥ 65):
Drug: APR-246 + azacitidine

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


Experimental: Control arm: Azacitidine
Patients will be randomized (1:1) to one of two arms: stratified by age (< 65 years versus ≥ 65):
Drug: Azacitidine

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 Outcome Measures :
  1. To compare the complete response rate (CR) with APR 246 + azacitidine treatment vs. azacitidine only. [ Time Frame: Through study completion, an average of 1 year ]
    To compare the complete response rate, defined as the proportion of patients who achieve complete remission (CR), and duration of CR with APR 246 + azacitidine treatment vs. azacitidine only.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03745716


Contacts
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Contact: Eyal Attar, MD +1 617 804 6947 info@aprea.com

Locations
Show Show 28 study locations
Sponsors and Collaborators
Aprea Therapeutics AB
Investigators
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Principal Investigator: David Sallman, MD, PhD Moffitt Cancer Center, Tampa, US

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Responsible Party: Aprea Therapeutics AB
ClinicalTrials.gov Identifier: NCT03745716    
Other Study ID Numbers: A-18-15331
First Posted: November 19, 2018    Key Record Dates
Last Update Posted: February 17, 2020
Last Verified: February 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Preleukemia
Myelodysplastic Syndromes
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Azacitidine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors