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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

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ClinicalTrials.gov Identifier: NCT04284787
Recruitment Status : Suspended (pending amendment approval)
First Posted : February 26, 2020
Last Update Posted : November 13, 2020
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief 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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome Secondary Acute Myeloid Leukemia Therapy-Related Acute Myeloid Leukemia Drug: Azacitidine Biological: Pembrolizumab Drug: Venetoclax Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 76 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: BLockade of PD-1 Added to Standard Therapy to Target Measurable Residual Disease in Acute Myeloid Leukemia 2 (BLAST MRD AML-2): A Randomized Phase 2 Study of the Venetoclax, Azacitidine, and Pembrolizumab (VAP) Versus Venetoclax and Azacitidine as First Line Therapy in Older Patients With Acute Myeloid Leukemia (AML) Who Are Ineligible or Who Refuse Intensive Chemotherapy
Actual Study Start Date : August 3, 2020
Estimated Primary Completion Date : August 1, 2021
Estimated Study Completion Date : August 1, 2021


Arm Intervention/treatment
Active Comparator: Arm I (AZA, VEN)

INDUCTION THERAPY PHASE: Patients receive azacitadine IV over 10-40 minutes or SCon days 1-7 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 azacitadine IV over 10-40 minutes or SC on days 1-7 and 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 SD may continue treatment per physician discretion.

Drug: Azacitidine
Given IV or SC
Other Names:
  • 5 AZC
  • 5-AC
  • 5-Azacytidine
  • 5-AZC
  • Azacytidine
  • Azacytidine, 5-
  • Ladakamycin
  • Mylosar
  • Onureg
  • U-18496
  • Vidaza

Drug: Venetoclax
Given PO
Other Names:
  • ABT-0199
  • ABT-199
  • ABT199
  • GDC-0199
  • RG7601
  • Venclexta
  • Venclyxto

Experimental: 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, azacitadine IV over 10-40 minutes or SC on days 1-7, 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, azacitadine IV over 10-40 minutes or SC on days 1-7, 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 azacitadine and venetoclax per physician discretion.

Drug: Azacitidine
Given IV or SC
Other Names:
  • 5 AZC
  • 5-AC
  • 5-Azacytidine
  • 5-AZC
  • Azacytidine
  • Azacytidine, 5-
  • Ladakamycin
  • Mylosar
  • Onureg
  • U-18496
  • Vidaza

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Drug: Venetoclax
Given PO
Other Names:
  • ABT-0199
  • ABT-199
  • ABT199
  • GDC-0199
  • RG7601
  • Venclexta
  • Venclyxto




Primary Outcome Measures :
  1. Percentage of patients with minimal residual disease negative complete remission (MRD-CR) or MRD-complete remission with incomplete count recovery (Cri) with azacitadine (AZA) + venetoclax (VEN) with MK-3475 (pembrolizumab) [ Time Frame: Up to 6 cycles (each cycle is 28 days) ]

Secondary Outcome Measures :
  1. Proportion of patients who develop severe toxicity [ Time Frame: Up to cycle 2 (each cycle is 28 days) ]

Other Outcome Measures:
  1. Biomarkers or serial measurements of biomarkers associated with response outcomes [ Time Frame: Baseline up to 3 years ]
    A univariate logistic regression will be selected to assess baseline biomarkers associated with response outcomes. The dynamic changes of PD-L1/ PD-1 expressions, concentration of cytokine, and ribonucleic acid (RNA) sequencing (seq)/T-cell receptor (TCR) seq etc. will be monitored. The measurements of biomarkers in changes over time from baseline to several time-points will be performed by using generalized linear mixed effects modeling with a Benjamini-Hochberg correction to control for false discovery rates.

  2. Biomarkers or serial measurements of biomarkers associated with survival outcomes [ Time Frame: Baseline up to 3 years ]
    The Kaplan-Meier method and log-rank test will be used to estimate the distribution of survival between/among different marker strata. Univariate or Multivariate cox proportional hazard models will be employed to explore the significance of biomarkers on survival outcomes, while adjusting for the potential prognostic factors. The interaction effects between treatment and biomarkers also will be evaluated. Serial measurements of biomarkers will be estimated at baseline, end of induction, post-cycle 1, 2, 4, and 6, every 3 months during maintenance, one year, and end of treatment when applicable. Landmark analysis or joint modeling will be used to assess serial measurements of biomarkers dynamical impacts on survival outcomes, where appropriate.

  3. Biomarkers effects between treatment arms [ Time Frame: Up to 3 years ]
    The associations between treatment arms and baseline biomarkers will be evaluated using Chi-squared test/ Fisher's exact test, analysis of variance (ANOVA) and the Mann-Whitney U tests as appropriate. Trajectory trends of the changes in markers' values or status across the measurement time will be explored using generalized linear mixed models. The bar plots and trajectory time plots will visually show the differences over time between treatment arms. The associations between markers and the demographic/prognostic factors will also be assessed using the similar statistical methods.

  4. Correlations between biomarkers [ Time Frame: Up to 3 years ]
    The correlations between biomarkers will be evaluated using Pearson/Spearman rank-order correlation coefficients, Chi-squared/Fisher's exact tests, and Wilcoxon rank sun / Kruskal-Wallis tests as appropriate. A scatter plot, boxplot, and mosaic plot will also be generated for visualization. The multiplicity of the endpoints will be adjusted using the correction of Benjamini and Hochberg.

  5. MRD assessment [ Time Frame: Up to 3 years ]
    Library preparation, sequencing, and analysis will be performed with TwinStrand's optimized workflow, and TwinStrand's bioinformatics core will perform all analyses related to assay output.

  6. Cytokine panel analysis [ Time Frame: At day 30 (after administration of pembrolizumab and count recovery) and after cycles 2, 4, and 6 (each cycle is 28 days) ]
    IFN-gamma+/CD3+/ CD4+ or IFN-gamma+/CD3+/CD8+ events will be gated and percentages of the total CD4+ and CD8+ T cells will be determined. Will compare levels of leukemia specific T-cell.

  7. Expression of PD-1, PD-L1 in acute myeloid leukemia (AML) bone marrow (BM) [ Time Frame: At day 14 and at time of count recovery ]
    An association of clinical response with the expression of PD-L1 AML BM cells will be assessed by a Pearson chi-square test on a 2x2 table of frequencies.

  8. Dynamic change of immune subsets [ Time Frame: Baseline up to cycle 6 (each cycle is 28 days) ]
    Statistical analyses of the frequency of CD8+, CD4+, Foxp3 regulatory T cells (Tregs), CD8+/Foxp3+ Tregs, central memory T cell (TCM)/effector memory T cell re-expressed CD45RA (TEMRA), effector memory T cell (TEM)/TEMRA, the percentage of Ki67 and GzmB in PD-1+, Eomes+ CD8 T cells to compare changes over time from baseline to several time-points will be performed by using mixed effects modeling with a Benjamini-Hochberg correction to control for false discovery rates.



Information from the National Library of Medicine

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Ages Eligible for Study:   60 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as hepatitis C [HCV] ribonucleic acid [RNA] [qualitative] is detected) infection. Note: testing for hepatitis B and Hepatitis C is not required unless mandated by a local health authority
  • 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 MK-3475 (pembrolizumab) or any of its excipients, or other agents used in this study
  • 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 MK-3475 (pembrolizumab) 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 MK-3475 (pembrolizumab), breastfeeding should be discontinued if the mother is treated with MK-3475 (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 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04284787


Locations
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United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Amer M Zeidan Yale University Cancer Center LAO
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04284787    
Other Study ID Numbers: NCI-2020-01016
NCI-2020-01016 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10334 ( Other Identifier: Yale University Cancer Center LAO )
10334 ( Other Identifier: CTEP )
UM1CA186689 ( U.S. NIH Grant/Contract )
First Posted: February 26, 2020    Key Record Dates
Last Update Posted: November 13, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Pembrolizumab
Azacitidine
Venetoclax
Antineoplastic Agents, Immunological
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors