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

• Status: Suspended
• Trial end date: 2022-08-01
• Target enrollment: 0
• Participant gender: All

Summary

This phase II trial studies how well azacitidine and venetoclax chemotherapy with or without pembrolizumab work in treating older patients with newly diagnosed acute myeloid leukemia. Chemotherapy drugs, such as azacitidine and venetoclax, 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. 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 chemotherapy 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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: National Cancer Institute (NCI)
• Treatments: Azacitidine; Pembrolizumab; Venetoclax

Criteria

Inclusion Criteria:

• Newly diagnosed and pathologically-confirmed, previously untreated AML as defined by World Health Organization (WHO) criteria. Secondary AML (myelodysplastic syndrome [MDS]/AML, therapy related [t]-AML) is also allowed. High risk MDS (excess blasts [EB]2 with > 10% blasts) is excluded, but AML arising from prior MDS is allowed. Note: 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. Every effort should be made to get an aspirate for central flow assessment at screening and all subsequent required time points, but in cases were 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

• 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 =< 2 (Karnofsky >= 60%)

• Prior use of lenalidomide, erythropoiesis-stimulating agents (ESAs), and growth factors is allowed if used to treat prior MDS. AML must be previously untreated

• Hydroxyurea is allowed for hyperleukocytosis. White blood cell (WBC) count must be < 25 x 10^4/L to start on study therapy per venetoclax label. Hydroxyurea 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 European LeukemiaNet (ELN) with the exception of "good-risk" cytogenic profile (i.e. lack of the presence of t(8;21), (inv[16] or t[16;16]), or t(15;17) by cytogenetics or fluorescence in situ hybridization [FISH])

• 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 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 received 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 as for the course of the study through 120 days after the last dose of study medication. Male patients 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 all-trans retinoic acid [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., < 0.5 mg/kg/day, absolute maximum 40 mg/day of prednisone or equivalent dose of other steroid), 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. 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. 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 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 (MK-3475), breastfeeding should be discontinued if the mother is treated with pembrolizumab (MK-3475). 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 antecedent MDS

• 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