A Phase Ib Study of Rezatapopt in Combination with Azacitidine or Azacitidine and Venetoclax in Patients with TP53Y220C Mutant Myeloid Malignancies (Acute Myeloid Leukemia or Myelodysplastic Syndrome)

Trial Title: A Phase Ib Study of Rezatapopt in Combination with Azacitidine or Azacitidine and Venetoclax in Patients with TP53Y220C Mutant Myeloid Malignancies (Acute Myeloid Leukemia or Myelodysplastic Syndrome)

NCT ID: NCT06616636

Condition: Myelodysplastic Syndrome
Acute Myeloid Leukemia

Conditions: Official terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Preleukemia
Myelodysplastic Syndromes
Syndrome
Azacitidine
Venetoclax

Study type: Interventional

Study phase: Phase 1

Overall status: Not yet recruiting

Study design:

Allocation: Non-Randomized

Intervention model: Single Group Assignment

Primary purpose: Treatment

Masking: None (Open Label)

Intervention:

Intervention type: Drug
Intervention name: Azacitidine
Description: Given by IV
Arm group label: Rezatapopt + Azacitidine
Arm group label: Rezatapopt + Azacitidine + Venetoclax

Intervention type: Drug
Intervention name: Rezatapopt
Description: Given orally with food
Arm group label: Rezatapopt + Azacitidine
Arm group label: Rezatapopt + Azacitidine + Venetoclax

Intervention type: Drug
Intervention name: Venetoclax
Description: Given by mouth
Arm group label: Rezatapopt + Azacitidine + Venetoclax

Summary: A non-randomized phase Ib study of PC14586 (PMV therapeutics) in patients diagnosed with TP53Y220C-mutant myeloid malignancies, including AML and MDS.

Detailed description: Primary Objective: To assess the safety and tolerability of rezatapopt in combination with AZA +/- VEN in patients with TP53Y220C -mutant myeloid malignancies (AML, MDS) Secondary Objectives: 1. To determine the clinical efficacy of rezatapopt in combination with AZA +/- VEN in R/R and newly diagnosed patients with TP53Y220C -mutant myeloid malignancies 2. To assess event free survival (EFS) and overall survival (OS) in patients receiving rezatapopt in combination with AZA +/- VEN 3. To assess duration of response in patients receiving rezatapopt in combination with AZA +/- VEN 4. Characterize the pharmacokinetics of rezatapopt in combination with AZA +/- VEN Exploratory Objectives: 1. To assess changes in the variant allele frequencies of TP53Y220C mutations via next-generation sequencing. 2. To describe mutational profiles of patients on study at screening, response and at relapse and correlate to clinical parameters. 3. To assess changes in clonal architecture based on bone marrow aspirate samples using single cell sequencing. 4. To evaluate for p53 activation and changes in the immunologic profile of patients of TP53Y220C mutations.

Criteria for eligibility:
Criteria:
Inclusion Criteria: 1. Patient is ≥ 18 years of age at the time of signing the informed consent form (ICF). 2. Patient is willing and able to adhere to the study visit schedule and other protocol requirements. 3. Patient has relapsed or primary refractory AML or MDS (cohort 1) 4. Patient has newly diagnosed AML or MDS (cohort 2) who is considered not eligible for intensive chemotherapy which must be defined as: Age 75 years or older, or Age 18 to 74 years with at least one of the following comorbidities: i. Severe cardiac disorder (eg, congestive heart failure requiring treatment, ejection fraction - 50%, or chronic stable angina). ii. Severe pulmonary disorder (eg, DLCO ≤65% or forced expiratory volume in 1 second [FEV1] - 65%). iii) Creatinine clearance ≥30 mL/min to <45 mL/min. iii. Moderate hepatic impairment with total bilirubin >1.5 to ≤3.0 × upper limit of normal (ULN) iv. ECOG performance status of >2 5. Any other comorbidity that per the investigator renders a patient inappropriate for intensive chemotherapy. 6. Patients with MDS must be classified as MDS-IB1 or IB2 as per WHO 2022 criteria32 7. TP53Y220C mutation confirmed by CLIA-approved local testing with a variant allele frequency >2%. 8. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 9. Patient has adequate organ function defined as: 1. Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 3 x ULN, unless considered due to leukemic organ involvement. 2. Serum total bilirubin ≤ 1.5 x ULN. Higher levels are acceptable if these can be attributed to ineffective erythropoiesis, leukemia organ involvement or Gilbert's syndrome. 3. Serum creatinine < 2 x ULN or creatinine clearance > 40 mL/min based on validated glomerular filtration rate (GFR) estimation (Cockcroft-Gault, CKD-epi, or MDRD equations). 10. Females of childbearing potential may participate provided they have a negative serum or urine pregnancy test at screening and a negative serum OR urine pregnancy test within 72 hours of starting on treatment. They also must agree to either abstain from sexual intercourse or use two forms of a highly effective method of contraception while on study and up to 3 months after the last dose of the study drug. 11. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) 14 days prior to study entry and for the duration of study participation. This includes all female patients between the onset of menses and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following: Postmenopausal (no menses in greater than or equal to 12 consecutive months). History of hysterectomy or bilateral salpingo-oophorectomy. Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy). History of bilateral tubal ligation or another surgical sterilization procedure. • Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device (IUD), Tubal Ligation or hysterectomy, Subject/Partner post vasectomy, Implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after completion of investigational agent administration. 12. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: 1. Patient has received prior chemotherapy, targeted therapy, immunotherapy, or treatment with an investigational anticancer agent within 14 days or 5 half-lives (if half-life is known), whichever is shorter, before receiving their first dose of study drug. 2. Patient has received radiotherapy within 14 days. 3. Patients with acute promyelocytic leukemia 4. Subject has immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation. 5. Patients with active, uncontrolled leukemia involvement of the CNS 6. Subject has known active viral infection with human immunodeficiency virus (HIV), or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) 7. Subject is known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally. 8. Subject has active uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment). 9. Patient has any unresolved toxicities from prior anti-cancer therapy greater than Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2 prior chemotherapy induced neuropathy. 10. Patient has had major surgery within 2 weeks prior to the planned start of study treatment. 11. Female subject who is pregnant or lactating. 12. History of allergic reactions attributed to compounds of similar chemical or biologic composition to azacitidine, venetoclax, rezetapopt or other agents used in study.

Gender: All

Minimum age: 18 Years

Maximum age: N/A

Healthy volunteers: No

Locations:

Facility:
Name: The University of Texas MD Anderson Cancer Center

Address:
City: Houston
Zip: 77030
Country: United States

Contact:
Last name: Courtney DiNardo, MD

Phone: (713) 794-1141
Email: cdinardo@mdanderson.org

Contact backup:
Last name: Courtney DiNardo, MD

Start date: February 1, 2025

Completion date: August 27, 2029

Lead sponsor:
Agency: M.D. Anderson Cancer Center
Agency class: Other

Collaborator:
Agency: Memorial Sloan Kettering Cancer Center (MSK)
Agency class: Other

Collaborator:
Agency: PMV Pharmaceuticals, Inc
Agency class: Industry

Source: M.D. Anderson Cancer Center

Record processing date: ClinicalTrials.gov processed this data on November 12, 2024

Source: ClinicalTrials.gov page: https://clinicaltrials.gov/ct2/show/NCT06616636
http://www.mdanderson.org