Navitoclax in Relapsed or Refractory High-Risk Myelodysplastic Syndrome

NCT05564650 | Active Not Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 22P.205JT 17450
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

This trial tests the safety, side effects, and best dose of navitoclax in combination with venetoclax and decitabine in treating patients with higher risk myelodysplastic syndrome (MDS) that has come back after initial treatment or was not responsive to initial treatment. This study will also look at the effectiveness of the treatment combination and patient's quality of life while on these medications. Navitoclax is an oral drug that works as an inhibitor of the BCL-2 family of proteins, which are often overly expressed in a wide variety of cancers and are linked to tumor drug resistance. This drug blocks some of the enzymes that keep cancer cells from dying. Venetoclax is an oral drug that works as an inhibitor of BCL-2 proteins that works very similarly to navitoclax by blocking the action of a certain proteins in the body that helps cancer cells survive which helps to kill cancer cells. Decitabine is an intravenous drug. It is a hypomethylating agent which means it interferes with deoxyribonucleic acid (DNA) methylation. DNA methylation is a major factor that regulates gene expression in cells, and an increase in DNA methylation can block the genes that regulate cell division and growth. When these genes are blocked the overall result allows or promotes cancer as there is no control over cell growth. Decitabine stops cells from making DNA and may kill cancer cells. Participation in this trial may improve the understanding of both chemotherapy response in MDS and mechanisms of resistance to current therapies.

Conditions

Recurrent Myelodysplastic Syndrome; Refractory Myelodysplastic Syndrome; Myelodysplastic Syndrome

Keywords

Myelodysplastic Syndrome; MDS; high risk MDS; HR-MDS; Relapsed or Refractory; R/R; relapsed or refractory higher-risk myelodysplastic syndrome; acute myeloid leukemia; AML; bone marrow mononuclear cells; BMMC; Navitoclax; Venetoclax; Decitabine; R/R MDS; BCL-2; BCL-XL; MCL-1; BCL-2 family; triplet therapy; dose escalation; dose expansion; Bayesian Optimal Interval (BOIN); quality of life; PROMIS-Fatigue; EORTC QLQ-C30

Outcome Measures

Primary Outcomes (2)

• Maximally Tolerated Dose (MTD) of Navitoclax in Combination with Venetoclax and Decitabine (Phase I)

  The Bayesian optimal interval (BOIN) design will be employed to find the MTD. The BOIN design is implemented in a simple way. It is more flexible and possesses superior operating characteristics that are comparable to those of the more complex model based designs.

  Within 30 days of the first dose of study treatment

• Complete Response (CR) Rate (Phase II)

  A 90% confidence interval will be computed for the CR rate by cycle 4.

  Up to cycle 4, an average of 4 months

Secondary Outcomes (11)

• Number of Dose-Limiting Toxicities (Phase I)

  Within 30 days of the first dose of study treatment

• Marrow Complete Response Rate (mCR) (Phase II)

  Up to 2 years from enrollment of the last patient

• Hematologic Improvement (HI) rate (Phase II)

  Up to 2 years from enrollment of the last patient

• Leukemia Free Survival (LFS) (Phase II)

  Up to 2 years from enrollment of the last patient

• Overall survival (OS) (Phase II)

  Up to 2 years from enrollment of the last patient

Other Outcomes (4)

• Expression levels of anti-apoptotic BCL-2 family members (Phase II)

  At baseline

• Expression levels of anti-apoptotic BCL-2 family members (Phase II)

  after triplet therapy, up to 2 years from enrollment of the last patient

• Single cell gene expression (Phase II)

  At baseline

Study Arms (1)

Treatment (navitoclax, decitabine, venetoclax)

EXPERIMENTAL

This is a single-center trial of navitoclax, venetoclax and decitabine in adult patients with R/R HR-MDS who have previously failed HMA therapy. This trial was intended to be a Phase 1/2 trial but the trial never moved forward to Phase 2. In the phase I dose escalation portion, patients will receive navitoclax in combination with standard dosing of venetoclax and decitabine. The maximally tolerated dose (MTD) will be the recommended phase II dose (RP2D). Previously, navitoclax in combination with venetoclax and chemotherapy in ALL found the MTD to 50mg of nativoclax po. In the phase II dose expansion portion, patients will receive navitoclax at the RP2D in combination with standard dose venetoclax and decitabine. Patients will continue on treatment with navitoclax, venetoclax and decitabine until relapse, dose-limiting toxicity, availability of alternate therapy or withdrawal of consent.

Biological: Navitoclax; Drug: Venetoclax; Drug: Decitabine; Procedure: Bone Marrow Biopsy; Procedure: Biospecimen Collection; Other: Laboratory Biomarker Analysis; Other: Quality-of-Life Assessment

Interventions

Navitoclax BIOLOGICAL

Given PO

Also known as: 923564-51-6, A-855071.0, ABT-263, BcI-2 Family Protein Inhibitor ABT-263

Treatment (navitoclax, decitabine, venetoclax)

Venetoclax DRUG

Given PO

Also known as: 1257044-40-8, 4-(4-((2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(1H-pyrrolo(2,3-b)pyridin-5-yloxy)benzamide, ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto

Treatment (navitoclax, decitabine, venetoclax)

Decitabine DRUG

Given IV

Also known as: 2'-Deoxy-5-azacytidine, 2353-33-5, 4-Amino-1-(2-deoxy-beta-D-erythro-pentofuranosyl)-1,3,5-triazin-2(1H)-one, 5-Aza-2'-deoxycytidine, 5-Aza-2'deoxycytidine, 5-Aza-2-deoxycytidine, 5-Azadeoxycytidine, Dacogen, Decitabine for Injection, Deoxyazacytidine, Dezocitidine

Treatment (navitoclax, decitabine, venetoclax)

Bone Marrow Biopsy PROCEDURE

Undergo bone marrow biopsy

Also known as: Biopsy of Bone Marrow, Biopsy, Bone Marrow

Treatment (navitoclax, decitabine, venetoclax)

Biospecimen Collection PROCEDURE

Undergo collection of blood

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Treatment (navitoclax, decitabine, venetoclax)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (navitoclax, decitabine, venetoclax)

Quality-of-Life Assessment OTHER

Ancillary studies

Also known as: Quality of Life Assessment

Treatment (navitoclax, decitabine, venetoclax)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provide signed and dated informed consent form
• Willing to comply with all study procedures and be available for the duration of the study
• Male or female, aged 18 years or older
• Must have myelodysplastic syndrome with Revised International Prognostic Score (IPSS-R) of at least 3 and have been previously treated with hypomethylating agent (HMA) (azacitidine or decitabine) and venetoclax for at least 2 cycles. Patients in the phase I portion of the trial may be enrolled if they have not received venetoclax with HMA therapy
• Prior hematopoietic stem cell transplant will be allowed if 90 or more days has passed since the date of transplant to day 1 of cycle 1 and patients are no longer taking immunosuppressive agents
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
• Must be able to swallow pills whole
• Creatinine clearance \>= 40 mL/min, calculated with the use of the 24-hour creatinine clearance or modified Cockcroft-Gault equation
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =\< 2.5 x upper limit of normal (ULN)
• Total bilirubin =\< 1.5 x ULN (or =\< 3 x ULN for patients with documented Gilbert syndrome)
• Coagulation: activated partial thromboplastin time (aPTT) and international normalized ratio (INR) =\< 1.5 x ULN
• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
• Not a woman of childbearing potential (WOCBP)
• A WOCBP who agrees to follow contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment. Approved methods are detailed below
• Hormonal Methods: levonorgestrel-releasing intrauterine system (e.g., Mirena, registered trademark), implants, hormone shot or injection, combined pill, minipill, patch

You may not qualify if:

• Active, uncontrolled systemic infection. Patients on prophylactic antibiotics are NOT excluded
• Uncontrolled human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infections defined as detectable viral load
• History of any active malignancy within the past 2 years prior to screening, with the exception of:
• Adequately treated carcinoma in situ of the uterine cervix
• Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin
• Asymptomatic prostate
• Subject requiring a medication that interferes with coagulation or platelet function - except for low dose aspirin (up to 100 mg daily) and prophylactic dose low molecular weight heparin (LMWH). Subjects prescribed these medications prior to enrollment should discontinue at least 3 days prior to C1D1. If they are not able to discontinue these medications, subjects will be excluded
• White blood cells (WBC) \> 25,000 cells/microL. Hydroxyurea therapy to reduce WBC count prior to enrollment is NOT excluded
• Malabsorption syndrome or other condition precluding enteral medication administration
• Subjects treated concomitantly with CYP2C8 substrates, CYP2C9 substrates, CYP3A inhibitors, CYP3A inducers and P-glycoprotein inhibitors are allowed. Venetoclax dosing must be adjusted. Pregnancy or lactation or intending to become pregnant during the study
• Pregnancy or lactation or intending to become pregnant during the study
• Known allergic reactions to components of the study product(s)
• Treatment with another investigational drug or other intervention within 2 weeks of planned cycle 1 day 1 (C1D1)

Sponsors & Collaborators

• Thomas Jefferson University: lead
• AbbVie: collaborator

Study Sites (1)

Sidney Kimmel Cancer Center at Thomas Jefferson University

Philadelphia, Pennsylvania, 19107, United States

Location

MeSH Terms

Conditions

Myelodysplastic Syndromes; Recurrence; Leukemia, Myeloid, Acute

Interventions

navitoclax; venetoclax; Decitabine; Injections; Biopsy; Specimen Handling

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Azacitidine; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Drug Administration Routes; Drug Therapy; Therapeutics; Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Gina Keiffer, MD

  Thomas Jefferson University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 19, 2022
• First Posted: October 3, 2022
• Study Start: January 12, 2023
• Primary Completion: May 3, 2024
• Study Completion (Estimated): May 8, 2026
• Last Updated: December 8, 2025

Record last verified: 2025-12

Locations

US (1)