Pembrolizumab and Decitabine With or Without Venetoclax in Treating Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome That Is Newly-Diagnosed, Recurrent, or Refractory

NCT03969446 | Recruiting Phase 1 DMC FDA Drug

• 3 other identifiers: 19107NCI-2019-03153P30CA033572
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 1

Brief Summary

This phase Ib trial studies the side effects and best dose of pembrolizumab and how well it works in combination with decitabine with or without venetoclax in treating patients with acute myeloid leukemia or myelodysplastic syndrome that is newly-diagnosed, has come back (recurrent), or does not respond to treatment (refractory). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Decitabine is in a class of medications called hypomethylation agents. It works by helping the bone marrow produce normal blood cells and by killing abnormal cells in the bone marrow. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. This trial may help doctors find the best dose of pembrolizumab that can be safely given in combination with decitabine with or without venetoclax, and to determine what side effects are seen with this treatment.

Conditions

Acute Myeloid Leukemia; Myelodysplastic Syndrome; Recurrent Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia; Refractory Myelodysplastic Syndrome; Recurrent Myelodysplastic Syndrome

Outcome Measures

Primary Outcomes (3)

• Incidence of adverse events

  Will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome.

  Up to 2 years

• Maximum-tolerated dose (MTD)

  Will be based on the assessment of dose-limiting toxicities (DLTs) during cycle 1 and NCI CTCAE version 5.0. Standard 3+3 design rules will govern enrollment and dose de-escalation. In each arm, the dose level that produces =\< 1/6 DLTs will be declared the MTD.

  Up to day 42

• Response to treatment

  Will obtain preliminary estimates of complete remission (CR)+CR with incomplete hematologic recovery (CRi). Patients will have their response classified according to modified Cheson, 2006 criteria (myelodysplastic syndrome cohort) and Dohner et al., 2017 criteria (acute myeloid leukemia cohort). Rates and 95% Clopper-Pearson binomial confidence interval will be calculated for the complete remission rate (patients that have confirmed CR/CRi). Response rates will also be explored based on number/type of prior therapy(ies).

  Up to 2 years

Secondary Outcomes (3)

• Response duration

  From date of first documented response (CR + CRi) to documented disease relapse or death whichever occurs first, assessed up to 2 years

• Overall survival

  From date of first dose of study drug to date of death from any cause, assessed up to 2 years

• Progression-free survival

  From date of first dose of study drug to first documented disease relapse/progression or death from any cause, whichever occurs first, assessed up to 2 years

Other Outcomes (3)

• Change in PD-1, PD-L1, and PD-L2 levels

  Baseline up to 2 years

• Change in T cell subset distribution

  Baseline up to 2 years

• Change in T cell receptor repertoire

  Baseline up to 2 years

Study Arms (3)

Cohort I Arm I (pembrolizumab, decitabine)

EXPERIMENTAL

Patients receive pembrolizumab IV over 30 minutes on days 1 and 22 and decitabine IV over 1 hour on days 1-10. Patients who achieve a CR receive decitabine on days 1-5. Treatment repeats every 42 days for up to 8 cycles or 1 year from start of therapy, whichever comes first, in the absence of disease progression or unacceptable toxicity.

Drug: Decitabine; Biological: Pembrolizumab

Cohort I Arm II (pembrolizumab, decitabine, venetoclax)

EXPERIMENTAL

Patients with pembrolizumab IV over 30 minutes on days 1 and 22 and decitabine IV over 1 hour on days 1-10 or 1-5. Patients who achieve a CR receive decitabine on days 1-5. Patients also receive venetoclax PO QD on days 1-14. Treatment repeats every 42 days for up to 8 cycles or 1 year from start of therapy, whichever comes first, in the absence of disease progression or unacceptable toxicity.

Drug: Decitabine; Biological: Pembrolizumab; Drug: Venetoclax

Cohort II (pembrolizumab, decitabine)

EXPERIMENTAL

Patients with MDS receive pembrolizumab IV over 30 minutes on days 1 and 22 and decitabine over 1 hour on days 1-5. Treatment repeats every 42 days for up to 8 cycles or 1 year from start of therapy, whichever comes first, in the absence of disease progression or unacceptable toxicity.

Drug: Decitabine; Biological: Pembrolizumab

Interventions

Pembrolizumab BIOLOGICAL

Given IV

Also known as: Keytruda, Lambrolizumab, MK-3475, SCH 900475

Cohort I Arm I (pembrolizumab, decitabine); Cohort I Arm II (pembrolizumab, decitabine, venetoclax); Cohort II (pembrolizumab, decitabine)

Venetoclax DRUG

Given PO

Also known as: ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto

Cohort I Arm II (pembrolizumab, decitabine, venetoclax)

Decitabine DRUG

Given IV

Also known as: 5-Aza-2'-deoxycytidine, Dacogen, Decitabine for Injection, Deoxyazacytidine, Dezocitidine

Cohort I Arm I (pembrolizumab, decitabine); Cohort I Arm II (pembrolizumab, decitabine, venetoclax); Cohort II (pembrolizumab, decitabine)

Eligibility Criteria

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

You may qualify if:

• Documented informed consent of the participant and/or legally authorized representative
• Agreement to allow the use of archival blood samples and marrow from diagnostic tumor biopsies. If unavailable, exceptions may be granted with study principal investigator (PI) approval
• Eastern Cooperative Oncology Group (ECOG) status =\< 1
• Histologically confirmed AML (not including acute promyelocytic leukemia) or MDS
• Patients with the following diagnoses
• Refractory/relapsed AML by World Health Organization (WHO) classification, who are not candidates for allogeneic stem cell transplantation or potentially curative chemotherapy (Extramedullary disease is allowed).
• MDS by WHO Classification who have failed to respond or relapsed after previous therapies
• Must have a life expectancy of \>= 3 months
• Fully recovered (=\< grade 1) from the acute toxic effects (except alopecia) or complications of prior anti-cancer therapy, including surgery
• Cannot be a candidate for allogeneic hematopoietic cell transplantation (alloHCT) within 90 days of starting treatment on the protocol and should be off pembrolizumab for at least 30 days to become eligible for alloHCT post-protocol therapy
• White blood cells (WBC) =\< 25 x 10\^9/L prior to initiation of venetoclax. Cytoreduction with hydroxyurea prior to treatment and/or during cycles 1 and/or 2 may be required
• Total bilirubin =\< 2 x upper limit of normal (ULN) (unless has Gilbert's disease)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 x ULN
• Creatinine clearance of \> 30 mL/min per 24-hour urine test or the Cockcroft-Gault formula
• International normalized ratio (INR) OR prothrombin time (PT) =\< 1.5 x ULN

You may not qualify if:

• Previous allogeneic cell transplantation
• Previous treatment with pembrolizumab
• Previously refractory to treatment with decitabine + venetoclax (i.e. progressed through therapy without first attaining at least a partial response)
• Systemic steroid therapy or any other form of immunosuppressive medication
• Received a live-virus or live-attenuated virus vaccination within 30 days of planned treatment start. Administration of killed vaccines is allowed
• Prior treatment with any other anti-programmed cell death protein-1 (anti-PD-1), or PD ligand-1 (PD-L1) or PD ligand-2 (PD-L2) agent or an antibody targeting other immuno-regulatory receptors or mechanisms
• Prior therapy with an anti-CD137, anti-CTLA-4 antibody (including ipilimumab), denosumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
• Current or planned use of other investigational agents, antineoplastic, biological or chemotherapeutic agents during the study treatment period, or within 4 weeks or five half-lives, whichever is shorter, prior to day 1 of protocol therapy with the following exception:
• Hydroxyurea is allowed prior to treatment with venetoclax and through cycle 2 for control of rapidly progressing leukemia
• Strong or moderate CYP3A4 inducers within 14 days prior to day 1 of venetoclax
• Grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or star fruit consumed within 3 days prior to the first dose of venetoclax
• Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=\<2 weeks of radiotherapy) to non-central nervous system (CNS) disease
• Concurrent use of corticosteroids (exception: nasal or topical corticosteroids or physiologic levels for steroid replacement are allowed)
• Granulocyte-macrophage colony-stimulating factor (GMCSF) or granulocyte colony stimulating factor (GCSF) within 7 days prior to start of study treatment
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent

Sponsors & Collaborators

• City of Hope Medical Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

City of Hope Medical Center

Duarte, California, 91010, United States

RECRUITING

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Interventions

Decitabine; Injections; pembrolizumab; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases

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

Study Officials

• Vaibhav Agrawal

  City of Hope Medical Center

  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

Study Record Dates

• First Submitted: May 28, 2019
• First Posted: May 31, 2019
• Study Start: May 4, 2020
• Primary Completion (Estimated): July 4, 2027
• Study Completion (Estimated): July 4, 2027
• Last Updated: March 5, 2026

Record last verified: 2026-03

Locations

US (1)