Acute Myeloid Leukemia Clinical Trial

BLAST MRD AML-2: BLockade of PD-1 Added to Standard Therapy to Target Measurable Residual Disease in Acute Myeloid Leukemia 2- A Randomized Phase 2 Study of Anti-PD-1 Pembrolizumab in Combination With Azacitidine and Venetoclax as Frontline Therapy in Unfit Patients With Acute Myeloid Leukemia

Summary

This phase II trial studies how well azacitidine and venetoclax with or without pembrolizumab work in treating older patients with newly diagnosed acute myeloid leukemia. Chemotherapy drugs, such as azacitidine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. 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. 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. Giving azacitidine and venetoclax with pembrolizumab may increase the rate of deeper/better responses and reduce the chance of the leukemia coming back in patients with newly diagnosed acute myeloid leukemia compared to conventional therapy of azacitidine and venetoclax alone.

View Full Description

Full Description

PRIMARY OBJECTIVE:

I. Assess the percentage of patients with minimal residual disease (MRD) negative complete remission (CR) (MRD-CR) or complete remission with incomplete count recovery (MRD-CRi) with azacitidine (AZA) + venetoclax (VEN) with pembrolizumab during the first 6 cycles and compare to control arm.

SECONDARY OBJECTIVES:

I. Assess the investigator-assessed rates of CR/CRi/partial remission (PR)/morphological leukemia free state (MLFS) as defined per the modified International Working Group (IWG) 2003 response criteria with AZA + VEN with pembrolizumab, as well as rates of MRD negative MLFS.

II. Rates of complete remission with partial count recovery (CRh) and hematologic improvement (HI) to red blood cells and platelets.

III. Assess time to MRD negativity and duration of MRD negative state, event free survival (EFS), relapse free survival (RFS), calculated as the time from initial treatment to either disease relapse or death, duration of response (DOR, defined as the time from first CR/CRi to the date of the first documented relapse or death, whichever occurs first) and overall survival (OS).

IV. Assess the proportion of patients who develop severe toxicity.

EXPLORATORY OBJECTIVES:

I. MRD assessment by duplex sequencing (DS) and comparing DS and multiparameter flow cytometry for MRD detection as an exploratory biomarker.

II. Assessment of immune-checkpoint expression and dynamic change of immune cell subsets in response to the combination of checkpoint-inhibition and backbone combination in acute myeloid leukemia (AML).

III. High-throughput sequencing of the T-cell receptor (TCR) Vb CDR3 regions on flow cytometrically sorted t-cell subsets to assess the effect of immunotherapy on the diversity of the t-cell repertoire and assess for correlation to clinical outcomes.

IV. Investigation of protein signatures and ribonucleic acid (RNA) signatures associated with response and efficacy using O-link cytokine panel and RNA-sequencing (seq), respectively.

V. Determination of mutational load by whole exome sequencing to assess for correlation with clinical outcomes, immune infiltrating profile, and T cell repertoire diversity and clonality.

VI. Profiling of deoxyribonucleic acid (DNA) methylation patterns before and after treatment to assess for correlation to response to treatment.

VII. Correlate gut microbiome at baseline and changes in the microbiome with clinical response, both in standard chemotherapy and immunotherapy/chemotherapy therapy settings.

VIII. MRD assessment using duplex sequencing strategy for circulating cell-free tumor DNA and correlation with long-term outcomes.

IX: Exploring different thresholds of MRD negativity using flow cytometry aside from the 0.1% level that will be used for the primary endpoint purposes (e.g. 0.01%).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I (AZA + VEN):

INDUCTION THERAPY PHASE: Patients receive azacitidine intravenously (IV) over 10-40 minutes or subcutaneously (SC) on days 1-7 or days 1-5 in week 1 and 1-2 in week 2. Patients also receive venetoclax orally (PO) on days 1-28 of cycle 1 and days 1-21 or 1-28 of subsequent cycles. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY PHASE: Patients receive azacitidine IV over 10-40 minutes or SC on days 1-7 or days 1-5 in week 1 and 1-2 in week 2. Patients also receive venetoclax PO on days 1-28 of cycle 1 and days 1-21 or 1-28 of subsequent cycles. Cycles repeat every 28 days for up to 3 years in the absence of disease progression or unacceptable toxicity. After completion of 24 cycles, patients who respond to treatment or have stable disease (SD) may continue treatment per physician discretion.

ARM II (AZA + VEN + PEMBROLIZUMAB):

INDUCTION THERAPY PHASE: Patients receive pembrolizumab IV over 30 minutes on day 8 of cycle 1 and every 3 weeks in cycle 2-6, azacitidine IV over 10-40 minutes or SC on days 1-7 or days 1-5 in week 1 and 1-2 in week 2, and venetoclax PO on days 1-28 of cycle 1 and days 1-21 or 1-28 of subsequent cycles. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY PHASE: Patients receive pembrolizumab IV over 30 minutes on day 8 of cycle 1 and every 3 weeks in cycle 2-6, azacitidine IV over 10-40 minutes or SC on days 1-7 or days 1-5 in week 1 and 1-2 in week 2, and venetoclax PO on days 1-28 of cycle 1 and days 1-21 or 1-28 of subsequent cycles. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. After completion of 24 cycles, patients who respond to treatment or have SD may continue treatment with azacitidine and venetoclax per physician discretion.

After completion of study treatment, patients are followed up every 6 months for up to 3 years

View Eligibility Criteria

Eligibility Criteria

Inclusion Criteria:

Newly diagnosed and pathologically-confirmed, previously untreated AML as defined by World Health Organization (WHO) criteria. Bone marrow biopsy, or aspirate or peripheral blood that were obtained up to 3 weeks before signing consent are allowed for purposes of confirming AML diagnosis for eligibility purposes. Secondary AML arising from prior myelodysplastic syndrome (MDS), as long as they have not received more than full cycle of hypomethylating agent therapy for MDS, and therapy related (t)-AML are also allowed. AML arising from prior antecedent hematologic disorders defined as MDS, mycoplasma pneumoniae (MPN), or aplastic anemia are allowed. Note 1: Patients must have evidence of bone marrow involvement on aspirate or biopsy. Patients with only extramedullary disease and no bone marrow involvement will be excluded. Note 2: Every effort should be made to get an aspirate for central flow assessment at screening and all subsequent required time points, but in cases where an aspirate cannot be collected-including dry taps-the patient will not be excluded and assessments will be performed on peripheral blood (PB) which should be collected at every time that bone marrow (BM) is collected. Note 3: Some patients with AML require initiation of therapy quickly after diagnosis, and full metaphase karyotype results in some centers can take 2-3 weeks to result. To avoid this issue being an impediment to accrual to study or to cause delays in initiation of therapy in patients who need fast initiation of therapy, we allow use of karyotype and/or fluorescence in situ hybridization (FISH) results on samples from blood or marrow that were obtained up to 3 weeks before signing consent for purposes of eligibility and stratification. In any case, results from FISH or karyotype should exclude presence of core-binding factor (CBF) abnormalities by time of randomization
Age >= 60 years
Patients who are ineligible for intensive chemotherapy according to treating physician's assessment or who refuse intensive chemotherapy
Eastern Cooperative Oncology Group (ECOG) performance status of 0-3
Prior use of lenalidomide, erythropoiesis-stimulating agents (ESAs), and growth factors is allowed if used to treat prior MDS. AML must be previously untreated except for hydroxyurea, or all-trans retinoic acid (ATRA) for suspicion of APL but both should be discontinued prior to initiation of study therapy. Hypomethylating agents are not allowed to have been used for AML therapy. If hypomethylating agent therapy was used for prior MDS or MPN therapy then it should not have exceeded one full cycle. Note: One dose of prophylactic intrathecal therapy is allowed during or before screening if a lumbar puncture is performed to rule out central nervous system (CNS) involvement
Hydroxyurea or leukopheresis are allowed for management of hyperleukocytosis, as well as ATRA, before initiation of study therapy. White blood cell (WBC) count must be < 25 x 10^9/L to start on study therapy per venetoclax label. Hydroxyurea and ATRA may be administered up to one day prior to start of study treatment
Intermediate-risk or poor risk AML as well as favorable risk by National Comprehensive Cancer Network (NCCN)/European LeukemiaNet (ELN) with the exception of "good-risk" cytogenic profile (i.e., for eligibility patient should lack the presence of t(8;21), (inv[16] or t[16;16]), or t(15;17) by full cytogenetics or FISH). Clarification: We allow use of karyotype and/or FISH results (as well as FLT3 results) on samples from blood or marrow that were obtained up to 3 weeks before signing consent for purposes of eligibility and stratification. Adverse karyotype can be determined based on FISH results (e.g., loss of chromosome 7 or 5 or 3 or more abnormalities) based on the specific probes used in the FISH. If results of full metaphase karyotype are not available and the available FISH results do not suggest an adverse karyotype, and there is a need to initiate therapy before those full results are available, then the patient can be stratified into the unknown/intermediate NCCN cytogenetic group for randomization purposes. In any case, results from FISH or karyotype should show that CBF abnormalities are NOT present by at time of randomization as the presence of CBF abnormalities is an exclusion factor

Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (CrCl) >= 60 mL/min for patient with creatinine levels > 1.5 x institutional ULN

Creatinine clearance (CrCl) should be calculated per institutional standard
Glomerular filtration rate (GFR) can also be used in place of creatinine or CrCl
Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for patients with total bilirubin levels > 1.5 x ULN
Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN OR =< 5 x ULN for patients with liver metastases

Patients who are human immunodeficiency virus (HIV) positive may participate IF they meet the following eligibility requirements:

They must be stable on their anti-retroviral regimen, and they must be healthy from an HIV perspective
Patients must have an undetectable HIV viral load
Patients with a known history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
Patients who have undergone major surgery must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
Female patients of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). Female patients of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication. Male patients who have a female partner of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy. NOTE: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient
Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible

Exclusion Criteria:

Patients with core binding factor (CBF)-AML and acute promyelocytic leukemia (APL)
Received a prior anti-cancer monoclonal antibodies (mAb) within 4 weeks prior to study registration or have not recovered (recovery defined as baseline or =< grade 1) from adverse events (AEs) due to agents administered more than 4 weeks earlier
Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
Patients who have had chemotherapy, targeted small molecule therapy (aside from imatinib, dasatinib, or nilotinib, hydroxyurea, or ATRA), or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
Left ventricular ejection fraction < 50% as determined by either echocardiogram or multi-gated acquisition (MUGA)

Patients who have not recovered from AEs due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of =< grade 2 neuropathy and alopecia

NOTE: 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
Patients currently participating and receiving study therapy or have participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment are ineligible
History of hypersensitivity to pembrolizumab (MK-3475) or any of its excipients, or other agents used in this study

Current use of systemic corticosteroids or immunosuppressive agents

EXCEPTION: Low doses of steroids (e.g., < 10 mg of prednisone or equivalent dose of other steroid), used for treatment of non-hematologic medical condition (e.g., chronic adrenal insufficiency) inhaled corticosteroids, or topical steroids are permitted

Other active primary malignancy (other than non-melanomatous skin cancer or carcinoma in situ of the cervix) requiring treatment or limiting expected survival to =< 2 years

NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment (other than hormonal therapy for their cancer)
Patient with known active CNS disease and/or carcinomatous meningitis before study enrollment. Assessment of the cerebrospinal fluid (CSF) is not required to enroll in the study unless there is clinical suspicion for CNS involvement. However, if CSF assessment is performed for any reason, there should be no evidence of active leukemia in the CSF as per investigator judgement. Up to one dose of prophylactic intrathecal chemotherapy is allowed prior to study enrollment. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of protocol treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to protocol treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
Patients who received prior allogenic transplant
Patient with a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
Patient with a diagnosis of immunodeficiency or receiving high dose systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of treatment
Patient with active autoimmune disease except for patients with hypothyroidism and vitiligo that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
Patient with a known history of non-infectious pneumonitis that required the use of steroids or current non-infectious pneumonitis
Patient with active uncontrolled infection
Patient with a known history of active TB (Bacillus tuberculosis)
Patients with uncontrolled intercurrent illness
Patients with psychiatric illness/social situations that would limit compliance with study requirements
Pregnant women are excluded from this study because pembrolizumab (MK-3475) is humanized antibody with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with pembrolizumab, breastfeeding should be discontinued if the mother is treated with pembrolizumab. These potential risks may also apply to other agents used in this study
Patients with no bone marrow involvement (i.e., those with only extramedullary disease)
Patients who received prior hypomethylating agent (HMA) therapy for more than one full cycle in treatment for prior MDS. Patient must not have received HMA therapy for treatment of AML

Patients that received a live vaccine within 30 days of planned start of study therapy

NOTE: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
Patients with active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment. Patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from participation

Study is for people with:

Acute Myeloid Leukemia

Phase:

Phase 2

Estimated Enrollment:

76

Study ID:

NCT04284787

Recruitment Status:

Recruiting

Sponsor:

National Cancer Institute (NCI)

Check Your Eligibility

Let’s see if you might be eligible for this study.

What is your age and gender ?

Submit

There are 27 Locations for this study

See Locations Near You

Yale University
New Haven Connecticut, 06520, United States More Info
Site Public Contact
Contact
203-785-5702
[email protected]
Rory M. Shallis
Principal Investigator
MedStar Georgetown University Hospital
Washington District of Columbia, 20007, United States More Info
Site Public Contact
Contact
202-444-2223
Kimberley Doucette
Principal Investigator
Northwestern University
Chicago Illinois, 60611, United States More Info
Site Public Contact
Contact
312-695-1301
[email protected]
Shira N. Dinner
Principal Investigator
HaysMed University of Kansas Health System
Hays Kansas, 67601, United States More Info
Site Public Contact
Contact
785-623-5774
Kenneth Byrd
Principal Investigator
University of Kansas Cancer Center
Kansas City Kansas, 66160, United States More Info
Site Public Contact
Contact
913-588-3671
[email protected]
Kenneth Byrd
Principal Investigator
Lawrence Memorial Hospital
Lawrence Kansas, 66044, United States More Info
Site Public Contact
Contact
785-505-2800
[email protected]
Kenneth Byrd
Principal Investigator
Olathe Health Cancer Center
Olathe Kansas, 66061, United States More Info
Site Public Contact
Contact
913-355-8000
[email protected]
Kenneth Byrd
Principal Investigator
University of Kansas Cancer Center-Overland Park
Overland Park Kansas, 66210, United States More Info
Site Public Contact
Contact
913-588-3671
[email protected]
Kenneth Byrd
Principal Investigator
Ascension Via Christi - Pittsburg
Pittsburg Kansas, 66762, United States More Info
Site Public Contact
Contact
620-235-7900
[email protected]
Kenneth Byrd
Principal Investigator
Salina Regional Health Center
Salina Kansas, 67401, United States More Info
Site Public Contact
Contact
785-452-7038
[email protected]
Kenneth Byrd
Principal Investigator
University of Kansas Health System Saint Francis Campus
Topeka Kansas, 66606, United States More Info
Site Public Contact
Contact
785-295-8000
Kenneth Byrd
Principal Investigator
University of Kansas Hospital-Westwood Cancer Center
Westwood Kansas, 66205, United States More Info
Site Public Contact
Contact
913-588-3671
[email protected]
Kenneth Byrd
Principal Investigator
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore Maryland, 21287, United States More Info
Site Public Contact
Contact
410-955-8804
[email protected]
Ivana Gojo
Principal Investigator
Siteman Cancer Center at West County Hospital
Creve Coeur Missouri, 63141, United States More Info
Site Public Contact
Contact
800-600-3606
[email protected]
Geoffrey L. Uy
Principal Investigator
Truman Medical Centers
Kansas City Missouri, 64108, United States More Info
Site Public Contact
Contact
816-404-4375
Kenneth Byrd
Principal Investigator
University of Kansas Cancer Center - North
Kansas City Missouri, 64154, United States More Info
Site Public Contact
Contact
913-588-3671
[email protected]
Kenneth Byrd
Principal Investigator
University of Kansas Cancer Center - Lee's Summit
Lee's Summit Missouri, 64064, United States More Info
Site Public Contact
Contact
913-588-3671
[email protected]
Kenneth Byrd
Principal Investigator
University of Kansas Cancer Center at North Kansas City Hospital
North Kansas City Missouri, 64116, United States More Info
Site Public Contact
Contact
913-588-3671
[email protected]
Kenneth Byrd
Principal Investigator
Washington University School of Medicine
Saint Louis Missouri, 63110, United States More Info
Site Public Contact
Contact
800-600-3606
[email protected]
Geoffrey L. Uy
Principal Investigator
Siteman Cancer Center-South County
Saint Louis Missouri, 63129, United States More Info
Site Public Contact
Contact
800-600-3606
[email protected]
Geoffrey L. Uy
Principal Investigator
Siteman Cancer Center at Christian Hospital
Saint Louis Missouri, 63136, United States More Info
Site Public Contact
Contact
800-600-3606
[email protected]
Geoffrey L. Uy
Principal Investigator
Siteman Cancer Center at Saint Peters Hospital
Saint Peters Missouri, 63376, United States More Info
Site Public Contact
Contact
800-600-3606
[email protected]
Geoffrey L. Uy
Principal Investigator
Dartmouth Hitchcock Medical Center
Lebanon New Hampshire, 03756, United States
Wake Forest University at Clemmons
Clemmons North Carolina, 27012, United States More Info
Site Public Contact
Contact
888-716-9259
Daniel R. Reed
Principal Investigator
Wake Forest Baptist Health - Wilkes Medical Center
Wilkesboro North Carolina, 28659, United States More Info
Site Public Contact
Contact
888-716-9253
Daniel R. Reed
Principal Investigator
Wake Forest University Health Sciences
Winston-Salem North Carolina, 27157, United States More Info
Site Public Contact
Contact
336-713-6771
Daniel R. Reed
Principal Investigator
University of Oklahoma Health Sciences Center
Oklahoma City Oklahoma, 73104, United States

How clear is this clinincal trial information?

Study is for people with:

Acute Myeloid Leukemia

Phase:

Phase 2

Estimated Enrollment:

76

Study ID:

NCT04284787

Recruitment Status:

Recruiting

Sponsor:


National Cancer Institute (NCI)

How clear is this clinincal trial information?

×

Introducing, the Journey Bar

Use this bar to access information about the steps in your cancer journey.