Phase 1b Study of Pembrolizumab, Decitabine +/- Venetoclax Combination Therapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome
Overview
- Phase
- Phase 1
- Intervention
- Decitabine
- Conditions
- Acute Myeloid Leukemia
- Sponsor
- City of Hope Medical Center
- Enrollment
- 54
- Locations
- 1
- Primary Endpoint
- Response to treatment
- Status
- Recruiting
- Last Updated
- last month
Overview
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.
Detailed Description
PRIMARY OBJECTIVES: I. Assess the safety and tolerability of pembrolizumab combined with decitabine, with or without the addition of venetoclax (treatment cohorts 1 and 2), by evaluation of toxicities including: type, frequency, severity, attribution, time course and duration. (ACUTE MYELOID LEUKEMIA \[AML\] ARM) II. Assess the safety and tolerability of pembrolizumab combined with decitabine, by evaluation of toxicities including: type, frequency, severity, attribution, time course and duration. (MYELODYSPLASTIC SYNDROME \[MDS\] ARM) III. Determine the maximum tolerated dose(s)/schedule (MTD) and recommended phase 2 dose(s)/ schedule (RP2D) within each treatment arm/cohort. III. Obtain preliminary estimates of complete remission (CR/CR with incomplete hematologic recovery \[CRi\]) rate(s) within each treatment arm/cohort. SECONDARY OBJECTIVES: I. Obtain estimates of remission duration and survival probabilities (overall and progression-free) at 2 years. II. Explore the possible association between pre-treatment PD-1, PD-L1, and PD-L2 and clinical response. III. Evaluate change in PD-1, PD-L1, PD-L2 levels as a result of the combination therapy. IV. Explore the possible association between specific T cell subsets (e.g. CD4 T regulatory cells, T naive, effector and memory cells), other immunological correlatives (e.g. T-cell receptor \[TCR\] repertoire analysis) including post-treatment changes, and clinical response to combination therapy. OUTLINE: Patients are assigned to 1 of 2 arms. ARM I: Patients with AML are assigned to 1 of 2 cohorts. COHORT I: Patients receive pembrolizumab intravenously (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. COHORT II: 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 orally (PO) once daily (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. ARM II: 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. After completion of study treatment, patients who have discontinued therapy and have not progressed are followed up at 6, 12, and 24 months post-start of treatment. Patients who progress during treatment are followed up every 3 months for 2 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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
Exclusion Criteria
- •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
Arms & Interventions
Cohort I Arm I (pembrolizumab, decitabine)
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.
Intervention: Decitabine
Cohort I Arm I (pembrolizumab, decitabine)
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.
Intervention: Pembrolizumab
Cohort I Arm II (pembrolizumab, decitabine, venetoclax)
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.
Intervention: Decitabine
Cohort I Arm II (pembrolizumab, decitabine, venetoclax)
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.
Intervention: Pembrolizumab
Cohort I Arm II (pembrolizumab, decitabine, venetoclax)
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.
Intervention: Venetoclax
Cohort II (pembrolizumab, decitabine)
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.
Intervention: Decitabine
Cohort II (pembrolizumab, decitabine)
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.
Intervention: Pembrolizumab
Outcomes
Primary Outcomes
Response to treatment
Time Frame: Up to 2 years
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).
Incidence of adverse events
Time Frame: Up to 2 years
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.
Maximum-tolerated dose (MTD)
Time Frame: Up to day 42
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.
Secondary Outcomes
- 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)