Palbociclib, All-Trans Retinoic Acid, and Venetoclax in Relapsed or Refractory Acute Myeloid Leukemia

A Phase Ib/II, Multicenter, Open-Label, Single-Arm Study of Palbociclib, All-Trans Retinoic Acid, and Venetoclax in Patients With Relapsed or Refractory Acute Myeloid Leukemia

This is a prospective, multicenter, single-arm, open-label Phase Ib/II clinical trial evaluating the safety, tolerability, and preliminary efficacy of palbociclib, all-trans retinoic acid (ATRA), and venetoclax (PAV regimen) in adult patients with relapsed or refractory acute myeloid leukemia (AML).

The Phase Ib portion will use a standard 3+3 dose-escalation design to evaluate dose-limiting toxicities (DLTs), determine the maximum tolerated dose (MTD), and establish the recommended Phase II dose (RP2D). The Phase II portion will use Simon's two-stage design to further evaluate the antileukemic activity and safety of the combination regimen, with overall response rate (ORR) as the primary efficacy endpoint.

Additional assessments will include complete remission (CR), complete remission with incomplete hematologic recovery (CRi), measurable residual disease (MRD) negativity, event-free survival (EFS), overall survival (OS), and duration of response (DOR). Exploratory analyses will investigate treatment-associated changes in leukemic cell differentiation and apoptosis and identify potential biomarkers associated with treatment response.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Myeloblastic Leukemia
• Intervention / Treatment: Drug: Palbociclib; Drug: All-trans retinoic acid; Drug: Venetoclax

• Study Type: Interventional
• Enrollment (Estimated): 55
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• China
  • Jiangxi
    • Nanchang, Jiangxi, China, 330000
      • Second Affiliated Hospital of Nanchang University
      • Contact: linhu hu; Phone Number: +86 13907984324; Email: hulinhui1992@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

**Inclusion Criteria:**

1. The participant or their legally authorized representative must provide written informed consent and be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

2. Adults aged 18 years or older.

3. Histologically, immunophenotypically, cytogenetically, or molecularly confirmed relapsed or refractory acute myeloid leukemia (R/R AML) according to WHO classification criteria. Relapsed or refractory AML is defined as failure to achieve remission after at least one cycle of standard induction therapy or recurrence of disease after achieving remission.

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

5. Life expectancy greater than 3 months.

6. Adequate organ function, defined as:

   • Total bilirubin ≤1.5 × upper limit of normal (ULN).
   • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN, or ≤5 × ULN if the elevation is attributable to leukemic involvement.
   • Creatinine clearance ≥30 mL/min.
   • Left ventricular ejection fraction (LVEF) ≥50%.
   • Corrected QT interval using Fridericia's formula (QTcF) ≤450 ms for males or ≤470 ms for females.

7. White blood cell (WBC) count <25 × 10⁹/L before the first dose of study treatment. Cytoreduction with hydroxyurea or leukapheresis is permitted before treatment initiation.

8. Women of childbearing potential must have a negative pregnancy test before enrollment. Male participants and women of childbearing potential must agree to use highly effective contraception during the study and for at least 6 months after the last dose of study treatment.

**Exclusion Criteria:**

1. Acute promyelocytic leukemia (APL), characterized by t(15;17) translocation or positivity for the PML-RARα fusion gene.
2. Active or symptomatic central nervous system leukemia.
3. Use of strong CYP3A4 inhibitors (e.g., voriconazole or posaconazole) or strong CYP3A4 inducers (e.g., rifampin or carbamazepine) within 7 days before the first dose of study treatment when these medications cannot be replaced. Participants requiring strong CYP3A4 inhibitors for fungal infection prophylaxis or treatment may be enrolled if no suitable alternative is available, provided that palbociclib and venetoclax doses are adjusted according to the study protocol. However, strong CYP3A4 inhibitors are prohibited during venetoclax dose ramp-up.
4. Previous treatment with venetoclax, another BCL-2 inhibitor, or a CDK4/6 inhibitor resulting in intolerable toxicity.
5. Severe gastrointestinal disorders that may significantly impair oral drug absorption, such as Crohn's disease or severe ulcerative colitis, or inability to swallow oral tablets or capsules.
6. Severe, active, and uncontrolled systemic infection, including bacterial, fungal, or viral infection; positive testing for human immunodeficiency virus (HIV); or active hepatitis B or hepatitis C infection.
7. History of congenital or acquired long QT syndrome; current use of medications known to prolong the QT interval that cannot be discontinued (e.g., amiodarone, sotalol, or methadone); or myocardial infarction, unstable angina, severe arrhythmia, or New York Heart Association (NYHA) Class III-IV heart failure within the preceding 6 months.
8. History of another malignancy, except for adequately treated nonmelanoma skin cancer, cervical carcinoma in situ, or similar conditions, with a disease-free interval of less than 2 years.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Palbociclib, All-Trans Retinoic Acid, and Venetoclax

Drug: Palbociclib; Palbociclib will be administered orally on Days 1-21 of each 28-day treatment cycle. During Phase Ib, three dose levels will be evaluated using a standard 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D). During Phase II, palbociclib will be administered at the established RP2D in combination with all-trans retinoic acid and venetoclax.; Drug: All-trans retinoic acid; All-trans retinoic acid (ATRA) will be administered orally at a dose of 25 mg/m² on Days 1-28 of each 28-day treatment cycle, in combination with palbociclib and venetoclax.; Drug: Venetoclax; Venetoclax will be administered orally with a dose ramp-up of 100 mg on Day 1, 200 mg on Day 2, and 400 mg daily from Day 3 onward. Treatment duration will range from 14 to 28 days per 28-day cycle, depending on hematologic recovery and myelosuppression, with dose adjustments according to the study protocol.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Dose-Limiting Toxicities (DLTs) During Phase Ib	The proportion of participants experiencing dose-limiting toxicities (DLTs) during the first 28-day treatment cycle in Phase Ib. DLTs will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0, and include Grade 4 or higher hematologic toxicity lasting more than 7 days with bone marrow hypoplasia or Grade 3 or higher nonhematologic toxicity that does not resolve with optimal supportive care.	During the first 28-day treatment cycle (Days 1-28)
Overall Response Rate (ORR) During Phase II	The proportion of participants in Phase II who achieve complete remission (CR), complete remission with incomplete hematologic recovery (CRi), or partial remission (PR). Treatment response will be assessed by bone marrow examination according to the response criteria specified in the study protocol.	At the end of each 28-day treatment cycle, until disease progression or treatment discontinuation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (MTD) During Phase Ib	The highest evaluated dose level of palbociclib in combination with all-trans retinoic acid and venetoclax that is considered tolerable based on dose-limiting toxicities observed during the Phase Ib 3+3 dose-escalation stage.	During the first 28-day treatment cycle (Days 1-28)
Recommended Phase II Dose (RP2D)	The recommended Phase II dose of palbociclib in combination with all-trans retinoic acid and venetoclax, determined based on the dose-limiting toxicity findings and overall safety and tolerability during Phase Ib.	From initiation of study treatment through completion of the Phase Ib dose-escalation stage, assessed up to 6 months.
Incidence and Severity of Adverse Events (AEs)	The number and percentage of participants experiencing adverse events (AEs) and serious adverse events (SAEs), including their severity and relationship to study treatment. Adverse events will be graded according to NCI CTCAE version 5.0.	From the first dose of study treatment through 30 days after the last dose, assessed up to 12 months.
Complete Remission (CR) and Complete Remission With Incomplete Hematologic Recovery (CRi) Rate	The proportion of participants achieving CR or CRi. CR is defined as bone marrow blasts below 5%, absence of peripheral blood blasts and extramedullary disease, absolute neutrophil count above 1.0 × 10^9/L, and platelet count above 100 × 10^9/L. CRi meets the bone marrow criteria for CR but with incomplete neutrophil or platelet recovery.	At the end of each 28-day treatment cycle, until disease progression or treatment discontinuation
Measurable Residual Disease (MRD) Negativity Rate	The proportion of participants achieving MRD negativity among those with CR or CRi. MRD will be assessed by multiparameter flow cytometry, with MRD negativity defined as a level below 0.1%.	At the end of each 28-day treatment cycle in participants achieving CR or CRi
Event-Free Survival (EFS)	Time from study enrollment to the first occurrence of disease progression, relapse, or death from any cause. Participants without an event will be censored at the date of their last disease assessment.	From the date of study enrollment to the first occurrence of disease progression, relapse, or death from any cause, whichever occurs first, assessed up to 24 months.
Overall Survival (OS)	Time from study enrollment to death from any cause. Participants who are alive at the time of analysis will be censored at the date they were last known to be alive.	From the date of study enrollment to death from any cause, assessed up to 24 months.
Duration of Response (DOR)	Time from the first documented CR or CRi to disease relapse or death from any cause, whichever occurs first, among participants achieving CR or CRi.	From the date of first documented CR or CRi to disease relapse or death from any cause, whichever occurs first, assessed up to 24 months.

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital of Nanchang University

Study record dates

Study Major Dates

• Study Start (Estimated): November 1, 2026
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: October 28, 2026
• First Submitted That Met QC Criteria: November 3, 2026
• First Posted (Actual): November 9, 2026

Study Record Updates

• Last Update Posted (Actual): November 9, 2026
• Last Update Submitted That Met QC Criteria: November 3, 2026
• Last Verified: October 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Organic Chemicals; Retinoids; Carotenoids; Polyenes; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Pigments, Biological; Biological Factors; Diterpenes; Vitamin A; Tretinoin; venetoclax; palbociclib
• Other Study ID Numbers: 2025efyC03

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No