Combination Navitoclax, Venetoclax and Decitabine for Advanced Myeloid Neoplasms

NCT05455294 | Active Not Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 22-263
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 3

Brief Summary

The purpose of this research study is to test the safety of a new three drug combination of navitoclax, decitabine, and venetoclax to treat advanced myeloid malignancies. The names of the drugs involved in this study are:

• Venetoclax
• Decitabine
• Navitoclax

Conditions

Myeloid Malignancy; Myelofibrosis; Myelodysplastic Syndromes; Acute Myeloid Leukemia; Myeloproliferative Neoplasm

Keywords

Myeloid Malignancy; Myelodysplastic Syndromes; Myelofibrosis; Acute Myeloid Leukemia; Myeloproliferative Neoplasm; MDS-myeloproliferative neoplasm

Outcome Measures

Primary Outcomes (2)

• Recommended Phase 2 Dose (RP2D)

  The RP2D is the minimally safe and biologically effective dose. The minimally safe dose is the highest dose level at which \<2 of 6 participants experience a dose limiting toxicity (DLT). See subsequent primary outcome for the DLT definition. With respect to safety, the RP2D will also consider laboratory evidence of platelet recovery. Evaluation of efficacy will be done in real time prioritizing full complete response (see subsequent secondary outcome for the objective response criteria) when possible for AML/MDS/MDS-MPN and transfusion independence/blast reduction/TSS improvement/splenic reduction for myelofibrosis.

  The observation period for RP2D evaluation was the first 28 days (cycle 1) of treatment.

• Dose Limiting Toxicity (DLT)

  DLT is defined by hematologic or non-hematologic adverse event (AE) per protocol (section 5.4); A treatment-related death is a DLT; AEs are graded based on NCI CTCAE v5.0 and must be considered unrelated to the underlying disease or co-morbidity to be a DLT.

  The observation period for DLT evaluation was the first 28 days (cycle 1) of treatment.

Secondary Outcomes (3)

• Objective Response Rate (ORR)

  Bone marrow evaluation for disease response is performed end of C1, C2, every 2 cycles until CR/CRi and then every 3 cycles. Each cycle is 28 days. Time frame is indefinite as based on maximum treatment duration which is not fixed.

• Median Progression-Free Survival (PFS)

  Bone marrow evaluation for disease response is performed days 22-28 of C1, end of C2, every 2 cycles (cycle end) until CR/CRi and then every 3 cycles. Off treatment, disease is assessed every 4 months up to 2 years.

• Overall Survival (OS)

  Survival is assessed in long-term follow-up every 4 months up to 2 years.

Other Outcomes (1)

• Navitoclax Target Dose Rate

  While on study treatment for up 1 year

Study Arms (5)

Dose Level 0: Decitabine + Venetoclax + Navitoclax [AML and Non-AML]

EXPERIMENTAL

Dose Level 0 \[AML and Non-AML\] Decitabine \[intravenously (IV) preferred\] Venetoclax Cycle 1: ramp-up days 1-2 and days 3-14 absence of strong/moderate CYP3A inhibitor and reduced doses dependent on presence of moderate or strong CYP3A inhibitor Cycle 2+: dosing days 1-14 Navitoclax Cycle 1: dosing days 3-14; Cycle 2+: dosing on days 1-14 Cycle length=28 days Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.

Drug: Navitoclax; Drug: Venetoclax; Drug: Decitabine

Dose Level 1: Venetoclax + Decitabine + Navitoclax [AML and Non-AML]

EXPERIMENTAL

Dose Level 1 \[AML and Non-AML\] Decitabine \[intravenously (IV) preferred\] Cycle 1+: dosing on days 1-5 Venetoclax \[orally\] Cycle 1: ramp-up starting on day 1-2 then days 3-14 continued dosing in absence of strong/moderate CYP3A inhibitor and reduced doses dependent on presence of moderate or strong CYP3A inhibitor Cycle 2+: dosing days 1-14 Navitoclax \[orally\] Cycle 1: Dosing days 3-14 Cycle 2+: dosing on days 1-14 Cycle length=28 days Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.

Drug: Navitoclax; Drug: Venetoclax; Drug: Decitabine

Dose Level 2: Venetoclax + Decitabine + Navitoclax [AML]

EXPERIMENTAL

Dose Level 2 \[AML\] Decitabine \[intravenously (IV) preferred\] Cycle 1+: dosing on days 1-5 Venetoclax \[orally\] Cycle 1: ramp-up on day 1-2, days 3-21 continued dosing in absence of strong/moderate CYP3A inhibitor and reduced doses dependent on presence of moderate or strong CYP3A inhibitor Cycle 2+: dosing on days 1-21 Navitoclax \[orally\] Cycle 1: dosing on days 3-14 Cycle 2+: dosing on days 1-14 Cycle length=28 days Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.

Drug: Navitoclax; Drug: Venetoclax; Drug: Decitabine

Dose Level -1: Venetoclax + Decitabine + Navitoclax [Non-AML]

EXPERIMENTAL

Dose Level -1 \[Non-AML\] Decitabine \[intravenously (IV) preferred\] Cycle 1+:dosing \[intravenously (IV) preferred\] on days 1-3 Venetoclax \[orally\] Cycle 1: ramp-up of starting day 1-2 then days 3-7 continued dosing in absence of strong/moderate CYP3A inhibitor and reduced doses dependent on presence of moderate or strong CYP3A inhibitor Cycle 2+: dosing on days 1-7 Navitoclax \[orally\] Cycle 1: Dosing days 3-14 Cycle 2+: continued dosing on days 1-14 Cycle length=28 days Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.

Drug: Navitoclax; Drug: Venetoclax; Drug: Decitabine

Recommended Phase 2 Dose Level: Venetoclax + Decitabine + Navitoclax [AML and Non-AML]

EXPERIMENTAL

RP2D \[AML and Non-AML\] Decitabine \[intravenously (IV) preferred\] To be determined based on dose escalation design. Venetoclax \[orally\] To be determined based on dose escalation design. Navitoclax \[orally\] To be determined based on dose escalation design. Cycle length=28 days Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.

Drug: Navitoclax; Drug: Venetoclax; Drug: Decitabine

Interventions

Navitoclax DRUG

See Arm Description

Also known as: ABT-263

Dose Level -1: Venetoclax + Decitabine + Navitoclax [Non-AML]; Dose Level 0: Decitabine + Venetoclax + Navitoclax [AML and Non-AML]; Dose Level 1: Venetoclax + Decitabine + Navitoclax [AML and Non-AML]; Dose Level 2: Venetoclax + Decitabine + Navitoclax [AML]; Recommended Phase 2 Dose Level: Venetoclax + Decitabine + Navitoclax [AML and Non-AML]

Venetoclax DRUG

See Arm Description

Also known as: Venclexta

Dose Level -1: Venetoclax + Decitabine + Navitoclax [Non-AML]; Dose Level 0: Decitabine + Venetoclax + Navitoclax [AML and Non-AML]; Dose Level 1: Venetoclax + Decitabine + Navitoclax [AML and Non-AML]; Dose Level 2: Venetoclax + Decitabine + Navitoclax [AML]; Recommended Phase 2 Dose Level: Venetoclax + Decitabine + Navitoclax [AML and Non-AML]

Decitabine DRUG

See Arm Description

Also known as: Dacogen

Dose Level -1: Venetoclax + Decitabine + Navitoclax [Non-AML]; Dose Level 0: Decitabine + Venetoclax + Navitoclax [AML and Non-AML]; Dose Level 1: Venetoclax + Decitabine + Navitoclax [AML and Non-AML]; Dose Level 2: Venetoclax + Decitabine + Navitoclax [AML]; Recommended Phase 2 Dose Level: Venetoclax + Decitabine + Navitoclax [AML and Non-AML]

Eligibility Criteria

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

You may qualify if:

• years or older
• Subjects must have a diagnosis of one of the following:
• Myelofibrosis in accelerated phase (AP-MF), defined by WHO as 10-19% blasts in either bone marrow or blood. There is no requirement for prior therapy.
• Myelofibrosis in blast phase (BP-MF), defined as ≥ 20% blasts in either bone marrow or blood. There is no requirement for prior therapy.
• Untreated secondary AML (s-AML), which includes subjects with therapy-related disease or known antecedent MDS or MDS/MPN. All these subjects must be ineligible or not recommended for any available approved therapy as determined by the treating provider. For subjects with known antecedent MDS or MDS/MPN, they must have received prior HMA therapy (minimum number of cycles are not required in this setting).
• MDS/MPN overlap syndromes (e.g. CMML) with ≥ 5% blasts in either bone marrow or blood. No requirements for prior therapy.
• MDS with excess blasts defined as ≥ 5% blasts in either bone marrow or blood must be ineligible for any available approved therapy including intensive chemotherapy and immediate allogeneic stem cell transplant per treating investigator and must meet at least one of the following criteria: 1) persistent disease despite prior exposure to venetoclax plus HMA for at least 3 cycles, 2) disease progression per IWG 2006 criteria on venetoclax plus HMA or on M15-954 protocol, or 3) persistent disease after at least four cycles of any HMA-based therapy.
• ECOG performance status ≤ 2 (see Appendix A)
• Baseline platelet count ≥ 25 x 109/L
• Subjects must have adequate organ function as defined below:
• Aspartate transaminase (AST) and alanine transaminase (ALT) \< 3 x ULN
• Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)
• Subject must have adequate renal function as demonstrated by a creatinine clearance ≥ 45 mL/min; calculated by the Cockcroft Gault formula
• aPTT ≤ 1.5 x ULN
• INR ≤ 1.5 x ULN

You may not qualify if:

• Subject cannot have had prior navitoclax or any BCL-XL therapy. Otherwise, there are no restrictions on any other prior therapies. Prior venetoclax is allowed.
• Subject is eligible and willing to receive intensive chemotherapy for their specific disease.
• Anti-leukemic therapy within 14 days of first day of study treatment except for hydroxyurea. If on hydroxyurea, then subject needs to be off hydroxyurea at least 3 days prior to first dose of study treatment. If on venetoclax, then a wash-out period of at least five times the half-life of the treatment.
• Subject with known and active concurrent malignancy requiring treatment. Subjects with basal or squamous skin cancers or carcinomas in situ are allowed. Exception: hormonal or topical therapies are allowed.
• Subject has known active/uncontrolled HIV and on contraindicated medication due to drug-drug CYP inducer interaction. HIV testing is not required.
• Subject has known and active CNS involvement with AML.
• Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:
• Uncontrolled and/or active systemic infection (viral, bacterial or fungal). Controlled infections are allowed.
• Chronic, active hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate. Subjects that have prior HCV that has been definitively treated with negative HCV viral load prior to study initiation and no evidence of cirrhosis are allowed to participate.
• Recent diagnosis of myocardial infarction or worse heart failure within the last six months.
• Treatment with any moderate or strong CYP3A inducers (see Appendix D for examples) within 7 days prior to the first dose of study drug.
• Administration or consumption of any of the following within 3 days prior to the first dose of study drug:
• Grapefruit or grapefruit products
• Seville oranges (including marmalade containing Seville oranges)
• Star fruit

Sponsors & Collaborators

• Jacqueline Garcia, MD: lead
• AbbVie: collaborator

Study Sites (3)

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

MeSH Terms

Conditions

Myelodysplastic Syndromes; Primary Myelofibrosis; Leukemia, Myeloid, Acute; Myeloproliferative Disorders

Interventions

navitoclax; venetoclax; Decitabine

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; 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

Study Officials

• Jacqueline S Garcia, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Model Details: This is a Phase 1 study with a dose escalation design and an expansion cohort.

Study Record Dates

• First Submitted: July 5, 2022
• First Posted: July 13, 2022
• Study Start: July 18, 2022
• Primary Completion: April 17, 2024
• Study Completion (Estimated): December 31, 2026
• Last Updated: January 28, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Locations

US (3)