APR-246 in Combination With Azacitidine for TP53 Mutated AML (Acute Myeloid Leukemia) or MDS (Myelodysplastic Syndromes) Following Allogeneic Stem Cell Transplant

Study Overview
=================
Brief Summary
-----------------
A multi-center, open label, Phase II clinical trial to assess the safety and efficacy of APR-246 in combination with azacitidine as maintenance therapy after allogeneic HSCT (hematopoietic stem cell transplant) for patients with TP53 mutant AML or MDS.

Detailed Description
-----------------
A multi-center, open label, Phase II clinical trial to assess the safety and efficacy of APR-246 in combination with azacitidine as maintenance therapy after allogeneic HSCT for patients with TP53 mutant AML or MDS. Patients will be prescreened for TP53 mutant AML or MDS before they have a HSCT. In order to proceed with APR-246 and azacitidine treatment, engraftment must be confirmed between Day 30 to Day 100 post-HSCT. APR-246 will be administered on Days 1-4, with azacitidine on Days 1-5, of every 28 day cycle. Patients may receive a maximum of 12 cycles.

Official Title
-----------------
Phase II Trial of APR-246 in Combination With Azacitidine as Maintenance Therapy for TP53 Mutated AML or MDS Following Allogeneic Stem Cell Transplant

Conditions
-----------------
Acute Myeloid Leukemia or Myelodysplastic Syndromes

Intervention / Treatment
-----------------
* Drug: APR-246


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient must have previously met pre-transplantation eligibility. Patient has received an allogeneic transplant for AML or MDS. Any standard (non-study) conditioning [MAC (myeloablative conditioning), RIC (reduced intensity conditioning), or NMA (non-myeloablative conditioning)] will be permitted. Patient is ≥ 30 days and ≤ 100 days from hematopoietic cell infusion. Patient is in complete remission after the transplant and has achieved engraftment. . Patients who have developed grades II-IV acute GVHD (graft versus host disease) will be allowed to initiate maintenance therapy based on the following criteria: Females must either: Be of non-childbearing potential postmenopausal (defined as at least 1 year without menses) prior to screening, or documented as surgically sterilized (e.g., hysterectomy or tubal ligation) at least 1 month prior to the screening visit Or, if of childbearing potential, Agree not to try to become pregnant during the study and for 6 months after the final study drug administration And have a negative serum pregnancy test at screening And, if heterosexually active, agree to consistently use highly effective contraception per locally accepted standards in addition to a barrier method starting at screening and throughout the study period and for 6 months after final study drug administration. Females must agree not to breastfeed or donate ova throughout the study drug treatment period and for 6 months after the final study drug administration. Males (even if surgically sterilized), and their partners who are women of childbearing potential must be using highly effective contraception in addition to a barrier method throughout the study drug treatment period. Males must not donate sperm throughout the study drug treatment period. Agrees not to participate in another interventional study while on treatment. Karnofsky Performance Status 70 or greater is required. Exclusion Criteria: Prior participation in an APR-246 study. Use of umbilical cord blood donor and stem cell source. Patient has uncontrolled infection. Use of investigational agent within 14 days of pre-HSCT screening or anytime thereafter. Use of hypomethylating agent, cytotoxic chemotherapeutic agents, or experimental agents (agents that are not commercially available) for the treatment of MDS or AML within 14 days of the first day of pre-HSCT screening or anytime thereafter. Patient has used experimental therapy for acute GVHD at any time post-transplant. Patient requires treatment with supplemental oxygen not including usage of non-invasive CPAP (continuous positive airways pressure) at night. Patient has any of the following cardiac abnormalities (as determined by treating physician): Myocardial infarct within six months prior to registration New York Heart Association Class II or worse heart failure or known LVEF (left ventricular ejection fraction) < the institution LLN (lower limit normal) A history of familial long QT syndrome Electrocardiographic evidence of acute ischemia at screening Symptomatic atrial or ventricular arrhythmias not controlled by medications QTc ≥ 470 ms calculated from a mean of 3 ECG (electrocardiogram) readings using Fridericia's correction (QTcF = QT/RR0.33) Bradycardia (<40 bpm) at screening

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: APR-246 will be administered on Days 1-4, with azacitidine on Days 1-5, of every 28 day cycle. Patients may receive a maximum of 12 cycles.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental arm: APR-246 + azacitidine<br>APR-246 and azacitidine maintenance therapy will continue for a maximum of 12 cycles | Drug: APR-246<br>* APR-246 will be administered on Days 1-4, with azacitidine on Days 1-5, of every 28 day cycle. Patients may receive a maximum of 12 cycles.<br>* Other names: Azacitidine;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess relapse-free survival (RFS) in patients with TP53 mutated AML or MDS after undergoing allogeneic hematopoietic stem cell transplant (HSCT). | Relapse-free survival (RFS) at 12 months 2. To evaluate the safety and tolerability of APR-246 in combination with azacitidine as maintenance treatment post-HSCT. | Through study completion, an average of 1 year |