Description:
This phase Ib trial studies the side effects and best dose of pembrolizumab and how well it
works in combination with decitabine in treating patients with acute myeloid leukemia or
myelodysplastic syndrome that is newly-diagnosed, has come back, or does not respond to
treatment. 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. Drugs used in chemotherapy, such as decitabine, work in different ways to
stop the growth of cancer cells, either by killing the cells, by stopping them from dividing,
or by stopping them from spreading. This trial may help doctors find the best dose of
pembrolizumab that can be safely given in combination with decitabine, and to determine what
side effects are seen with this treatment.
Title
- Brief Title: Pembrolizumab and Decitabine in Treating Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome That Is Newly-Diagnosed, Recurrent, or Refractory
- Official Title: Phase 1b Study of Pembrolizumab and Decitabine Combination Therapy in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome
Clinical Trial IDs
- ORG STUDY ID:
19107
- SECONDARY ID:
NCI-2019-03153
- SECONDARY ID:
19107
- NCT ID:
NCT03969446
Conditions
- Acute Myeloid Leukemia
- High Risk Myelodysplastic Syndrome
- Recurrent Acute Myeloid Leukemia
- Recurrent High Risk Myelodysplastic Syndrome
- Refractory Acute Myeloid Leukemia
- Refractory High Risk Myelodysplastic Syndrome
- Secondary Acute Myeloid Leukemia
- Therapy-Related Acute Myeloid Leukemia
Interventions
| Drug | Synonyms | Arms |
|---|
| Decitabine | 5-Aza-2'-deoxycytidine, Aza-TdC, Dacogen, Decitabine for Injection, Deoxyazacytidine, Dezocitidine | Cohort I (pembrolizumab, decitabine) |
| Pembrolizumab | Keytruda, Lambrolizumab, MK-3475, SCH 900475 | Cohort I (pembrolizumab, decitabine) |
Purpose
This phase Ib trial studies the side effects and best dose of pembrolizumab and how well it
works in combination with decitabine in treating patients with acute myeloid leukemia or
myelodysplastic syndrome that is newly-diagnosed, has come back, or does not respond to
treatment. 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. Drugs used in chemotherapy, such as decitabine, work in different ways to
stop the growth of cancer cells, either by killing the cells, by stopping them from dividing,
or by stopping them from spreading. This trial may help doctors find the best dose of
pembrolizumab that can be safely given in combination with decitabine, and to determine what
side effects are seen with this treatment.
Detailed Description
PRIMARY OBJECTIVES:
I. Assess the safety and tolerability of pembrolizumab in combination with decitabine, by
evaluation of toxicities including: type, frequency, severity, attribution, time course and
duration.
II. Determine the maximum tolerated dose(s)/schedule (MTD) and phase 2 recommended dose(s)/
schedule (RP2D) of the combination for acute myeloid leukemia (AML) and high-risk
myelodysplastic syndrome (MDS).
III. Obtain preliminary estimate of complete remission (CR/CR with incomplete hematologic
recovery [CRi]) rate.
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 cohorts.
COHORT I: Patients with AML 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 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 are followed up for 30 days, then every 3 and 6
months for up to 2 years.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Cohort I (pembrolizumab, decitabine) | Experimental | Patients with AML 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. | |
| 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. | |
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 of 0-1
- Histologically confirmed AML or MDS with the following characteristics
- Patients diagnosed with AML by World Health Organization (WHO) classification, meeting
one of following criteria:
- Age 60 or older, newly diagnosed, untreated, who are unwilling to undergo or not
candidates for conventional induction chemotherapy with cytarabine/anthracyclines
- Age 60 or older with relapsed or refractory disease
- Adult patients < 60 with previously untreated high-risk disease (complex
karyotype, inv(3) or t(3;3), t(6;9), monosomal karyotype, therapy-related and
secondary disease) that are unwilling to undergo or not candidates for
conventional induction chemotherapy with cytarabine/anthracyclines and/or
allogeneic stem cell transplantation
- Adult patients < 60 with refractory/relapsed AML who are otherwise not candidates
for allogeneic stem cell transplantation
- Patients with extramedullary disease who meet one of the above criteria may be
included
- Patients with a diagnosis of MDS as per WHO Classification that meets one of the
following treatment history criteria
- Newly diagnosed high-risk MDS (International Prognostic Scoring System [IPSS]:
intermediate 2 and high risk)
- Refractory to or relapsed after previous therapies
- Human leukocyte antigen (HLA)-DR15-positive MDS that has failed immunosuppressive
therapies
- Must have a life expectancy of >= 3 months
- Fully recovered (=< grade 1) from the acute toxic effects (except alopecia) of prior
anti-cancer therapy
- 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
- Total bilirubin =< 1.5 x upper limit of normal (ULN) (unless has Gilbert?s disease)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN or =<
5 x ULN
- Creatinine clearance of >= 60 mL/min per 24 hour urine test or the Cockcroft-Gault
formula
- International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN
- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN
- Left ventricular ejection fraction (LVEF) >= 50%
- Corrected QT (QTc) =< 480 ms, Note: electrocardiogram (ECG) to be performed within 14
days prior to day 1 of protocol therapy
- Seronegative for human immunodeficiency virus (HIV) antigen (Ag)/antibody (Ab) combo,
hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigen negative),
and syphilis (rapid plasma reagin [RPR]) (within 28 days prior to day 1 of protocol
therapy)
- If positive, hepatitis C ribonucleic acid (RNA) quantitation must be performed
- Meets other institutional and federal requirements for infectious disease titer
requirements
- Note: Infectious disease testing to be performed within 28 days prior to day 1 of
protocol therapy
- Women of childbearing potential (WOCBP): negative urine or serum pregnancy test
- Agreement by males and females of childbearing potential to use an effective birth
control method of low user dependency or abstain from heterosexual activity from 4
weeks prior to first dose of treatment throughout the study treatment period and 3
(males) to 4 (females) months from the last dose of treatment
- Childbearing potential is defined as not being surgically sterilized (men and
women) or have not been free from menses for > 1 year (women only)
- Also, male subjects should refrain from sperm donation from the start of treatment
throughout the study treatment period and for 6 months following the last dose of
treatment
Exclusion Criteria:
- Previous allogeneic cell transplantation for at least 1 year (yr) prior, have no
history of graft versus host disease (GVHD) and been off all immunosuppression for at
least 3 months
- Previous treatment with pembrolizumab
- Systemic steroid therapy or any other form of immunosuppressive medication
- Received a live-virus vaccination within 30 days of planned treatment start
- 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, or concurrent biological,
chemotherapy, or radiation therapy during the study treatment period, or within 4
weeks prior to day 1 of protocol therapy
- Systemic cytotoxic chemotherapy, antineoplastic biologic therapy, or major surgery
within 4 weeks prior to day 1 of protocol therapy
- Concurrent use of corticosteroids (exception: nasal or topical corticosteroids or
physiologic levels for steroid replacement are allowed)
- Concurrent use of granulocyte-macrophage colony-stimulating factor (GMCSF) or
granulocyte colony stimulating factor (GCSF), or 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
- Severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb)
- Active central nervous system (CNS) disease
- History of (non-infectious) pneumonitis that required steroids or has current
pneumonitis
- Active autoimmune disease that has required systemic treatment in the past 2 years
(replacement therapies for hormone deficiencies are allowed)
- Uncontrolled active infection requiring therapy
- Seronegative for HIV Ag/Ab combo, HCV, active HBV (surface antigen negative), and
syphilis (RPR).
- If positive, hepatitis C RNA quantitation must be performed
- Known history of active TB (Bacillus tuberculosis)
- History of deep venous thrombosis (DVT) or pulmonary embolism
- Symptomatic ascites or pleural effusion
- Clinically significant uncontrolled illness
- Females only: Pregnant or breastfeeding
- Any other condition that would, in the investigator?s judgment, contraindicate the
patient?s participation in the clinical study due to safety concerns with clinical
study procedures
- Prospective participants who, in the opinion of the investigator, may not be able to
comply with all study procedures (including compliance issues related to
feasibility/logistics)
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Incidence of adverse events |
| Time Frame: | Up to 2 years |
| Safety Issue: | |
| Description: | 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. |
Secondary Outcome Measures
| Measure: | Response duration |
| Time Frame: | From date of first documented response (CR + CRi) to documented disease relapse or death whichever occurs first, assessed up to 2 years |
| Safety Issue: | |
| Description: | Will be estimated using the product-limit method of Kaplan and Meier. |
| Measure: | Overall survival |
| Time Frame: | From date of first dose of study drug to date of death from any cause, assessed up to 2 years |
| Safety Issue: | |
| Description: | Will be estimated using the product-limit method of Kaplan and Meier. |
| Measure: | Progression-free survival |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | Will be estimated using the product-limit method of Kaplan and Meier. |
| Measure: | Change in PD-1, PD-L1, and PD-L2 levels |
| Time Frame: | Baseline up to 2 years |
| Safety Issue: | |
| Description: | |
| Measure: | Change in T cell subset distribution |
| Time Frame: | Baseline up to 2 years |
| Safety Issue: | |
| Description: | |
| Measure: | Change in T cell receptor repertoire |
| Time Frame: | Baseline up to 2 years |
| Safety Issue: | |
| Description: | |
Details
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | City of Hope Medical Center |
Last Updated
August 11, 2021
