Clinical Trials /

High Dose Cytarabine Followed by Pembrolizumab in Relapsed/Refractory AML

NCT02768792

Description:

Rationale:The purpose of this research study is to test the effectiveness of the standard high dose cytarabine (HiDAC) on days 1 through 5 followed by a single dose of pembrolizumab on day 14 as induction therapy in patients with relapsed and refractory acute myeloid leukemia (AML). Patients who achieve a response to treatment will continue on the study drug (pembrolizumab) every 3 weeks for up to 2 years maintenance therapy. Purpose:This is a study about a new investigative drug, pembrolizumab (MK-3475) that is being studied in a clinical research trial together with standard chemotherapy (HiDAC) in relapsed and refractory AML. The study will also explore the association between potential immune biomarkers and clinical outcomes with pembrolizumab; therefore all patients will have blood and bone marrow samples collected before and after treatment to determine the dynamic nature of immune signatures pre and post-treatment.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: High Dose Cytarabine Followed by Pembrolizumab in Relapsed/Refractory AML
  • Official Title: LCCC 1522: Phase 2 Study of High Dose Cytarabine Followed by Pembrolizumab in Relapsed and Refractory Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: LCCC 1522
  • NCT ID: NCT02768792

Conditions

  • Acute Myeloid Leukemia, in Relapse

Interventions

DrugSynonymsArms
pembrolizumab,KEYTRUDA, MK-3475open-label, multicenter, single-arm

Purpose

Rationale:The purpose of this research study is to test the effectiveness of the standard high dose cytarabine (HiDAC) on days 1 through 5 followed by a single dose of pembrolizumab on day 14 as induction therapy in patients with relapsed and refractory acute myeloid leukemia (AML). Patients who achieve a response to treatment will continue on the study drug (pembrolizumab) every 3 weeks for up to 2 years maintenance therapy. Purpose:This is a study about a new investigative drug, pembrolizumab (MK-3475) that is being studied in a clinical research trial together with standard chemotherapy (HiDAC) in relapsed and refractory AML. The study will also explore the association between potential immune biomarkers and clinical outcomes with pembrolizumab; therefore all patients will have blood and bone marrow samples collected before and after treatment to determine the dynamic nature of immune signatures pre and post-treatment.

Detailed Description

      Primary Objective

      1. Estimate the objective overall rate of CR (CR+CRi) for age-adjusted HiDAC (age <60 years:
      2 gm/m2 IV Q12hours days 1-5; age >60 years: 1.5 gm/m2 IV Q12hours days 1-5) followed by
      pembrolizumab 200 mg IV on day 14 in relapsed and refractory AML patients

      Secondary Objectives

        1. Estimate the rate of unacceptable toxicity associated with HiDAC followed by
           pembrolizumab as induction therapy

        2. Estimate the objective overall response rates (PR+CR+CRi) for HiDAC followed by
           pembrolizumab.

        3. Characterize the toxicity associated with HiDAC followed by pembrolizumab as induction
           therapy

        4. Characterize the toxicity associated with pembrolizumab 200 mg IV Q3weeks when used as
           monotherapy maintenance after an initial response to induction phase HiDAC followed by
           pembrolizumab

        5. Estimate the relapse-free survival (RFS) and progression-free survival (PFS) of patients
           receiving maintenance pembrolizumab

        6. Estimate the overall survival (OS) of patients who received induction phase treatment.
    

Trial Arms

NameTypeDescriptionInterventions
open-label, multicenter, single-armOtherPembrolizumab 200 mg is administered IV once as monotherapy, 14 days after the initiation of HiDAC salvage induction chemotherapy. Patients who have a response (i.e., PR/CR/CRi) to induction phase will receive maintenance pembrolizumab at 200 mg IV every 3 weeks for up to 2-years of maintenance therapy (i.e., beginning on day 1 of maintenance). Patients who are ineligible for pembrolizumab administration by day 21 will be removed from the study.
  • pembrolizumab,

Eligibility Criteria

        Inclusion Criteria:

          1. Willing and able to provide written informed consent for the trial

          2. > 18 years and < 70 years of age on day of signing informed consent

          3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1

          4. Have histologically or cytologically confirmed recurrent AML as defined by ≥5 %
             myeloblasts in the bone marrow aspirate and or biopsy.

          5. Must have received at least 1 cycle of induction therapy for front-line AML including
             cytarabine continuous infusion + anthracycline +/- cladribine or etoposide for 1 or 2
             cycles, or liposomal cytarabine and daunorubicin (CPX-351), or high dose cytarabine
             with or without fludarabine, cladribine or clofarabine, > 4 cycles of
             azacitidine/decitabine or the equivalent experimental therapy (the latter as confirmed
             by the PI)

          6. Cytoreduction allowed with hydroxyurea and/or leukapheresis for up to 14 days prior to
             D1 of treatment under LCCC1522. Patients must be off hydroxyurea for > 12 hours prior
             to D1 of treatment under LCCC1522

          7. Demonstrate adequate organ function as defined below. All screening labs should be
             performed within 14 days of D1 of treatment under LCCC1522.

             Serum creatinine ≤1.5 X upper limit of normal (ULN) OR Measured or calculated
             creatinine clearance (GFR can also be used in place of creatinine or CrCl)-- ≥60
             mL/min for subject with creatinine levels > 1.5 X institutional ULN Serum total
             bilirubin ≤ 1.5 X ULN unless due to Gilbert's Disease, hemolysis or leukemic
             infiltration OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5
             ULN Aspartate Aminotransferase (AST)(SGOT) and Alanine Aminotransferase (ALT) (SGPT) ≤
             5 X ULN International Normalized Ratio (INR) or Prothrombin Time (PT)- ≤1.5 X ULN
             unless subject is receiving anticoagulant therapy as long as PT or PTT is within
             therapeutic range of intended use of anticoagulants or patient has disseminated
             intravascular coagulation deemed by investigator to be due to leukemia Activated
             Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving
             anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
             of anticoagulants or patient has disseminated intravascular coagulation deemed by
             investigator to be due to leukemia

          8. Female subject of childbearing potential should have a negative urine or serum
             pregnancy within 72 hours prior to receiving the first dose of HiDAC treatment and
             again prior to D1 of pembrolizumab treatment. If the urine test is positive or cannot
             be confirmed as negative, a serum pregnancy test will be required.

          9. Female subjects of childbearing potential should be willing to use adequate method of
             contraception for the course of the study through 120 days after the last dose of
             study medication. Subjects of childbearing potential are those who have not been
             surgically sterilized or have not been free from menses for > 1 year. The two birth
             control methods can be two barrier methods or a barrier method plus a hormonal method
             to prevent pregnancy. Subjects should start using birth control from the screening
             visit throughout the study period up to 120 days after the last dose of study therapy.

             Note: Abstinence is acceptable if this is the usual lifestyle preferred contraception
             for the subject.

         10. Male subjects must agree to use an adequate method of contraception starting with D1
             of HiDAC 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 subject.

         11. As determined by the enrolling physician or protocol designee, ability of the patient
             to understand and comply with study procedures

        Exclusion Criteria:

          1. Is currently participating in or has participated in a study of an investigational
             agent or using an investigational device within 4 weeks of the first dose of
             treatment.

          2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 7 days prior to the first dose of HiDAC
             treatment. Note: use of steroid eye drops starting at the time of HiDAC administration
             is allowed.

          3. Has a known history of active Bacillus Tuberculosis (TB)

          4. Hypersensitivity to pembrolizumab or any of its excipients

          5. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not
             recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents
             administered more than 4 weeks earlier.

          6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
             within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
             baseline) from adverse events due to a previously administered agent. Note: Subjects
             with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the
             study.

             Note: If subject received major surgery, they must have recovered adequately from the
             toxicity and/or complications from the intervention prior to starting therapy.

          7. Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
             skin that has undergone potentially curative therapy, or in situ cervical cancer that
             has undergone potentially curative therapy.

          8. Has known active central nervous system (CNS) leukemia; subjects with previously
             treated CNS disease may participate provided they are stable (without evidence of
             active disease by imaging for at least 4 weeks prior to the first dose of 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 D1
             of treatment.

          9. Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment.

         10. Has evidence of interstitial lung disease or a history of ( non-infectious)
             pneumonitis that required steroids or current pneumonitis.

         11. Has 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.

         12. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial

         13. Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the pre-screening or screening visit
             through 120 days after the last dose of trial treatment

         14. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or
             anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including
             ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation
             or checkpoint pathways)

         15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

         16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., hepatitis C
             virus (HCV) RNA qualitative is detected).

         17. Has received a live vaccine within 30 days prior to the first dose of trial treatment
             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

         18. Has uncontrolled intercurrent illness including, but not limited to, active and
             uncontrolled infection, symptomatic congestive heart failure, unstable angina
             pectoris, and uncontrolled symptomatic cardiac arrhythmia. Patients with infection
             under active treatment and controlled with antibiotics are eligible.

         19. Diagnosed with acute promyelocytic leukemia (APL, M3)

         20. Receipt of previous allogeneic stem cell transplant; receipt of previous autologous
             transplant for AML or non-AML condition is allowed

             -
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The rate of CR for age-adjusted HiDAC followed by pembrolizumab 200mg on day 14.
Time Frame:45 days
Safety Issue:
Description:Estimate of the objective overall rate of CR (CR+CRi) for age-adjusted HiDAC. The rate of CR+CRi as defined by the International European LeukemiaNet Guidelines in AML.

Secondary Outcome Measures

Measure:Rate of unacceptable toxicity
Time Frame:Day 14 until 2 years complete on study treatment
Safety Issue:
Description:number of drug-related grade 3 non-hematologic toxicity (with exception of infusion reactions, rash, fever, infection, nausea, fatigue, and anorexia) persisting for >7 days with supportive care, or any drug-related non-hematologic grade >4 toxicity (excluding infection). Toxicity will be classified and graded according to National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE, version 4.0
Measure:objective overall response rates (partial remission + complete remission + complete remission with incomplete blood count recovery) for HiDAC followed by pembrolizumab
Time Frame:45 days
Safety Issue:
Description:PR+CR+CRi as determined by International European LeukemiaNet Guidelines in AML
Measure:Relapse-free survival (RFS of patients receiving maintenance pembrolizumab
Time Frame:2 years
Safety Issue:
Description:RFS will be defined as time from day 1 of CR/CRi to relapse or death from any cause.
Measure:Progression-free survival (PFS) of patients receiving maintenance pembrolizumab.
Time Frame:7 years
Safety Issue:
Description:PFS will be defined as time from day 1 of response (i.e., PR/CR/CRi) to progression or death from any cause.
Measure:Overall survival (OS) of patients who received induction phase of treatment.
Time Frame:7 years
Safety Issue:
Description:OS is defined as time from day 1 of treatment until date of last known follow up or death of any cause

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:UNC Lineberger Comprehensive Cancer Center

Last Updated

September 2, 2019