A Study of CTX-712 in Relapsed/Refractory Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndromes

Phase 1/2 Multicenter, Open-Label Study of CTX-712 in Patients With Relapsed/Refractory Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndromes

The goal of this phase 1/2 multicenter, open-label, single-arm dose escalation and expansion study is to assess the safety, tolerability, pharmacokinetic and pharmacodynamic profile of CTX-712 in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and higher risk myelodysplastic syndromes (HR-MDS), or MDS/MPN (including CMML).

The phase 1 part of the study consists of sequential standard 3 + 3 dose escalation, where patients will receive ascending doses of CTX-712 to determine the recommended phase 2 dose (RP2D) for further clinical development. This is followed by initial expansion cohorts in AML and/or HR-MDS where patients will be treated with CTX-712 at the RP2D to gain further confidence in the selected dose level. Additional expansion cohorts may be initiated if considered necessary. After RP2D is determined, Drug-Drug-Interaction cohorts will be started.

The phase 2 part of the study will commence after the RP2D has been identified and confirmed and will evaluate therapeutic activity in R/R AML or R/R HR-MDS, in addition to confirmation of the safety profile.

Inclusion criteria:

1. Age ≥18 years.

2. Diagnosis of AML, HR-MDS, or high marrow blast MDS/MPN (including CMML). Note: Only patients with AML and HR-MDS are eligible in the expansion cohorts.

3. Prior treatment history must include 1-4 prior lines of therapy. Note: 1-3 prior lines are allowed for patients in the expansion cohorts.

4. Adequate organ function evidenced by the following laboratory values:

   Creatinine clearance (CL) ≥60 mL/min

   • Total serum bilirubin < 1.5 × upper limit of normal (ULN)
   • Alanine aminotransferase (ALT)
   • Aspartate aminotransferase(AST) < 2.5 × ULN
   • White blood cell count at the time of the first dose <10 k/μL

5. Eastern Cooperative Oncology Group performance status ≤2.

6. Female patients of childbearing potential must have a negative pregnancy test within 7 days before study treatment initiation and if sexually active, agree to use a highly effective form of contraception throughout their participation during study treatment and up to 4 months after the last dose of study drug.

7. Male patients with female partners of childbearing potential must, even if surgically sterilized, agree to practice effective barrier contraception during the entire study treatment period and through four months after the last dose of study drug, or practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant.

Exclusion criteria:

1. Diagnosis of acute promyelocytic leukemia.

2. Isolated extramedullary relapse (phase 2 only).

3. Active central nervous system (CNS) leukemia.

4. History of other malignancy.

5. Any of the following cardiopulmonary abnormalities:

   1. Myocardial infarction within six months prior to registration.
   2. New York Heart Association Class III or IV heart failure or known left ventricular ejection fraction < 50%.
   3. A history of familial long QT syndrome.
   4. Symptomatic atrial or ventricular arrhythmias not controlled by medications.
   5. QTcF ≥ 470 msec calculated according to institutional guidelines, unless due to underlying bundle branch block and/or pacemaker and with approval of the medical monitor.
   6. Known moderate to severe and clinically significant chronic obstructive pulmonary disease, interstitial lung disease and/or pulmonary fibrosis (e.g., requiring home oxygen therapy).

6. Pregnancy and/or lactation.

7. Major surgery (excluding placement of vascular access) within 4 weeks prior to first dose of CTX-712.

8. History of allogeneic organ transplantation (excluding cornea).

9. History of allogenic hematopoietic stem cell transplantation within 6 months of planned study treatment initiation and/or graft-versus host disease grade ≥ 1 following allogenic hematopoietic stem cell transplantation.

10. History of or chimeric antigen receptor T-cell therapy or other modified T cell therapy.

11. Active, uncontrolled bacterial, fungal, or viral infection, including hepatitis B virus, hepatitis C virus, known human immunodeficiency virus, or acquired immunodeficiency syndrome related illness. Infections controlled with oral anti-infective agents, including prophylactic treatments, are allowed. Patient must be viral load negative.

12. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol.