Study of Idarubicin, Cytarabine, and Nivolumab in Patients With High-Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)

Sponsor
M.D. Anderson Cancer Center (Other)
Overall Status
Completed
CT.gov ID
NCT02464657
Collaborator
Bristol-Myers Squibb (Industry)
44
Enrollment
1
Location
3
Arms
58.2
Actual Duration (Months)
0.8
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The goal of this clinical research study is to find the highest tolerable dose of nivolumab that can be give in combination with idarubicin and cytarabine in patients with MDS and AML. The safety and effectiveness of this drug combination will also be studied.

This is an investigational study. Nivolumab is not FDA-approved or commercially available. Idarubicin is FDA-approved and commercially available for the treatment of patients with AML. Cytarabine is FDA approved and commercially available for treatment of patient with AML. The use of these drugs in combination is investigational. The study doctor can explain how the drugs are designed to work.

Up to 75 patients will take part in this study. All will be enrolled at MD Anderson.

Detailed Description

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you join this study. Up to 3 groups of 3 - 6 participants will be enrolled in Phase 1 of the study, and up to 70 participants will be enrolled in Phase 2.

If you are enrolled in Phase 1, the dose of nivolumab you receive will depend on when you join this study. There are 3 dose levels being tests in this part of the study: a low dose, a middle dose, and a high dose. The first group of participants will receive the middle dose level of nivolumab. If no intolerable side effects are seen, the next group will receive the highest dose level. However, if there are intolerable side effects, 3 more participants will receive the middle dose. If there are further intolerable side effects seen, the next group will receive the lowest dose of nivolumab.

If you are enrolled in Phase 2, you will receive nivolumab at the highest dose that was tolerated in Phase 1.

All participants will receive the same dose levels of idarubicin and cytarabine.

Study Drug Administration:

You will receive 1- 7 cycles of the drug combination. These cycles will be 28-35 days long.

  • On Days 1-3 of each cycle, you will receive idarubicin by vein over about 15-30 minutes.

  • On Days 1-4 of each cycle, you will receive cytarabine by vein over about 24 hours. If you are age 60 or older, you will receive the drugs on Days 1-3 only. On these days you will receive drugs to help decrease the risk of side effects.

  • On Day 24 (+/- 2 days) of each cycle, you will receive nivolumab by vein over about 1 hour.

After 2 cycles, if the disease appears to get better, you will receive nivolumab by vein about every 2 weeks for up to 1 year.

Study Visits:
At least one (1) time a week during Cycle 1 and then at least once each cycle after that:
  • You will have a physical exam.

  • Blood (about 2-3 teaspoons) will be drawn for routine tests.

You will have a bone marrow aspirate collected for cytogenetics testing between Day 21-28 of each cycle and then, if the doctor thinks it is needed, you will have this performed every 1-2 weeks after that unless a complete response is achieved. After that, you will have bone marrow collected every 3-6 months for 1 year.

After your last dose of study drug, you will have a physical exam.

Length of Study:

You may continue taking nivolumab for up to 1 year. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the follow-up visits.

Study Design

Study Type:
Interventional
Actual Enrollment :
44 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase I/II Study of Idarubicin, Cytarabine, and Nivolumab in Patients With High-Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)
Actual Study Start Date :
Jul 1, 2015
Actual Primary Completion Date :
May 7, 2020
Actual Study Completion Date :
May 7, 2020

Arms and Interventions

ArmIntervention/Treatment
Experimental: Ph 1 Nivolumab (1mg) + Idarubicin + Cytarabine

Phase I dose of Nivolumab 1 mg/kg by vein on Day 24 of a 28 day cycle. Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Phase I and Phase II dose of Solumedrol 50 mg or Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.

Drug: Nivolumab
Phase I Starting Dose of Nivolumab: 1 mg/kg by vein on Day 24 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I.
Other Names:
  • BMS-936558
  • Opdivo
  • Drug: Idarubicin
    Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle.
    Other Names:
  • Idamycin
  • Drug: Cytarabine
    Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle.
    Other Names:
  • Ara-C
  • Cytosar
  • DepoCyt
  • Cytosine Arabinosine Hydrochloride
  • Drug: Solu-medrol
    Phase I and Phase II dose of Solu-medrol 50 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.
    Other Names:
  • Methylprednisolone
  • Depo-Medrol
  • Medrol
  • Drug: Dexamethasone
    Phase I and Phase II dose of Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.
    Other Names:
  • Decadron
  • Experimental: Ph 1 Nivolumab (3 mg) + Idarubicin + Cytarabine

    Phase I dose of Nivolumab 3 mg/kg by vein on Day 24 of a 28 day cycle. Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Phase I and Phase II dose of Solumedrol 50 mg or Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.

    Drug: Nivolumab
    Phase I Starting Dose of Nivolumab: 1 mg/kg by vein on Day 24 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I.
    Other Names:
  • BMS-936558
  • Opdivo
  • Drug: Idarubicin
    Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle.
    Other Names:
  • Idamycin
  • Drug: Cytarabine
    Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle.
    Other Names:
  • Ara-C
  • Cytosar
  • DepoCyt
  • Cytosine Arabinosine Hydrochloride
  • Drug: Solu-medrol
    Phase I and Phase II dose of Solu-medrol 50 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.
    Other Names:
  • Methylprednisolone
  • Depo-Medrol
  • Medrol
  • Drug: Dexamethasone
    Phase I and Phase II dose of Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.
    Other Names:
  • Decadron
  • Experimental: Ph 2 Nivolumab (3 mg) + Idarubicin + Cytarabine

    Phase II dose of Nivolumab 3 mg/kg by vein on Day 24 of a 28 day cycle. Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Phase I and Phase II dose of Solumedrol 50 mg or Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.

    Drug: Nivolumab
    Phase I Starting Dose of Nivolumab: 1 mg/kg by vein on Day 24 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I.
    Other Names:
  • BMS-936558
  • Opdivo
  • Drug: Idarubicin
    Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle.
    Other Names:
  • Idamycin
  • Drug: Cytarabine
    Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle.
    Other Names:
  • Ara-C
  • Cytosar
  • DepoCyt
  • Cytosine Arabinosine Hydrochloride
  • Drug: Solu-medrol
    Phase I and Phase II dose of Solu-medrol 50 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.
    Other Names:
  • Methylprednisolone
  • Depo-Medrol
  • Medrol
  • Drug: Dexamethasone
    Phase I and Phase II dose of Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.
    Other Names:
  • Decadron
  • Outcome Measures

    Primary Outcome Measures

    1. Maximum Tolerated Dose (MTD) of Nivolumab [28 days]

      MTD is highest dose level in which <2 patients of 6 develop first cycle dose-limiting toxicity (DLT).

    Secondary Outcome Measures

    1. Event-Free Survival (EFS) [56 days]

      EFS defined as time from the treatment start till treatment failure, relapse, or death whichever comes first. Event Free Survival will be presented by median EFS, which is the time point at which the cumulative survival drops below 50%. If there is no median survival (not reached), it means the cumulative survival was more than 50%.

    2. Relapse Free Survival [Up to 2 years and10 Months]

      Relapse-free survival was defined as the time from treatment response to date of relapse or death, whichever occurred first.

    3. Overall Survival [Up to 2 years and 10 Months]

      Overall survival was defined as the time from the start of treatment to death or date of last follow-up.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. Diagnosis of 1) AML (WHO classification definition of >/= 20% blasts), or 2) high risk MDS (defined as the presence of 10% blasts).

    2. Patients aged 18 to 60 years are eligible. Patients older than 60 who are deemed fit to receive intensive chemotherapy by the treating physician are eligible after discussion with the PI.

    3. In the Phase I portion, patients with relapsed or refractory AML/MDS are also eligible, as per the treating physician's discretion.

    4. For the Phase II portion of the study, patients must be chemo-naive, i.e. not have received any prior chemotherapy (except hydrea or one dose of ara-C </= 2g) for AML or MDS. They could have received hypomethylator agents, transfusions, hematopoietic growth factors or vitamins. Temporary prior measures such as apheresis or hydrea or one dose of ara-C </= 2g in order to safely control hyperleucocytosis prior to enrollment.

    5. Serum biochemical values with the following limits unless considered due to leukemia: ---Creatinine </= 1.5 mg/dl --- total bilirubin </= 1.5 mg/dL, unless increase is due to hemolysis or congenital disorder --- transaminases (SG PT) </= 2.5 x upper limit of normal (ULN).

    6. Ability to take oral medication.

    7. Ability to understand and provide signed informed consent.

    8. Baseline test of ejection fraction must be >/= 50%.

    9. Performance status < 3, unless directly related to disease process as determined by the Principal Investigator.

    Exclusion Criteria:
    1. Subjects with APL.

    2. Any coexisting medical condition that in the judgment of the treating physician is likely to interfere with study procedures or results.

    3. Nursing women, women of childbearing potential with positive urine pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception (such as birth control pills, IUD, diaphragm, abstinence, or condoms by their partner) over the entire course of the study. --- Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug. --- Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab. --- Women must not be breastfeeding.

    4. Continued:Men who are sexually active with WOCBP must use acceptable birth control methods. Acceptable birth control methods include: oral or injectable hormonal birth control, intrauterine devices(IUDS), and double barrier methods (for example a condom in combination with spermicide). Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception.

    5. Cardiac disease: Congestive heart failure > class II NYHA. Patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months.

    6. History of cardiac ventricular arrhythmias requiring anti-arrhythmic therapy within past 3 months.

    7. Thrombotic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.

    8. Pulmonary hemorrhage/bleeding event > CTCAE Grade 2 within 4 weeks of first dose of study drug.

    9. Major surgery, open biopsy or significant traumatic injury within 4 weeks of first study drug.

    10. Active clinically serious and uncontrolled infection > CTCAE Grade 2 uncontrolled with antibiotics.

    11. Patients should be excluded if they have an active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.

    12. Patients should be excluded if they are known to be positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.

    13. Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).

    14. History of allergy to study drug components.

    15. Prior immune checkpoint targeting drugs (e.g., anti PD1, and PDL1, anti-kir, anti CD137...etc)

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1University of Texas MD Anderson Cancer CenterHoustonTexasUnited States77030

    Sponsors and Collaborators

    • M.D. Anderson Cancer Center
    • Bristol-Myers Squibb

    Investigators

    • Principal Investigator: Farhad Ravandi-Kashani, MD, M.D. Anderson Cancer Center

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    M.D. Anderson Cancer Center
    ClinicalTrials.gov Identifier:
    NCT02464657
    Other Study ID Numbers:
    • 2014-0907
    • NCI-2015-01258
    First Posted:
    Jun 8, 2015
    Last Update Posted:
    Oct 7, 2021
    Last Verified:
    Sep 1, 2021

    Study Results

    Participant Flow

    Recruitment DetailsRecruitment Period: July 2015 - June 2018
    Pre-assignment Detail
    Arm/Group TitlePh 1 - Nivolumab (1mg) + Idarubicin + CytarabinePh 1 - Nivolumab (3mg) + Idarubicin + CytarabinePh 2 - Nivolumab + Idarubicin + Cytarabine
    Arm/Group DescriptionPhase I starting dose of Nivolumab 1 mg/kg by vein on Day 24 of a 28 day cycle. Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Phase I and Phase II dose of Solumedrol 50 mg or Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Nivolumab: Phase I Starting Dose of Nivolumab: 1 mg/kg by vein on Day 24 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Idarubicin: Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Cytarabine: Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Solu-medrol: Phase I and Phase II dose of Solu-medrol 50 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Dexamethasone: Phase I and Phase II dose of Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.Phase I starting dose of Nivolumab 3 mg/kg by vein on Day 24 of a 28 day cycle. Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Phase I and Phase II dose of Solumedrol 50 mg or Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Nivolumab: Phase I Starting Dose of Nivolumab: 1 mg/kg by vein on Day 24 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Idarubicin: Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Cytarabine: Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Solu-medrol: Phase I and Phase II dose of Solu-medrol 50 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Dexamethasone: Phase I and Phase II dose of Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.Phase II dose of Nivolumab 3 mg/kg by vein on Day 24 of a 28 day cycle. Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Phase I and Phase II dose of Solumedrol 50 mg or Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Nivolumab: Phase I Starting Dose of Nivolumab: 1 mg/kg by vein on Day 24 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Idarubicin: Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Cytarabine: Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Solu-medrol: Phase I and Phase II dose of Solu-medrol 50 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Dexamethasone: Phase I and Phase II dose of Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.
    Period Title: Overall Study
    STARTED3239
    COMPLETED3239
    NOT COMPLETED000

    Baseline Characteristics

    Arm/Group TitlePh 1 - Nivolumab (1mg) + Idarubicin + CytarabinePh 1 - Nivolumab (3mg) + Idarubicin + CytarabinePh 2 - Nivolumab + Idarubicin + CytarabineTotal
    Arm/Group DescriptionPhase I dose of Nivolumab 1 mg/kg by vein on Day 24 of a 28 day cycle. Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Phase I and Phase II dose of Solumedrol 50 mg or Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Nivolumab: Phase I Starting Dose of Nivolumab: 1 mg/kg by vein on Day 24 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Idarubicin: Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Cytarabine: Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Solu-medrol: Phase I and Phase II dose of Solu-medrol 50 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Dexamethasone: Phase I and Phase II dose of Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.Phase I dose of Nivolumab 3 mg/kg by vein on Day 24 of a 28 day cycle. Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Phase I and Phase II dose of Solumedrol 50 mg or Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Nivolumab: Phase I Starting Dose of Nivolumab: 1 mg/kg by vein on Day 24 of a 28 day cycle.Phase II dose of Nivolumab 3 mg/kg by vein on Day 24 of a 28 day cycle. Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Phase I and Phase II dose of Solumedrol 50 mg or Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Nivolumab: Phase I Starting Dose of Nivolumab: 1 mg/kg by vein on Day 24 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Idarubicin: Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Cytarabine: Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Solu-medrol: Phase I and Phase II dose of Solu-medrol 50 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Dexamethasone: Phase I and Phase II dose of Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.Total of all reporting groups
    Overall Participants323944
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    3
    100%
    2
    100%
    38
    97.4%
    43
    97.7%
    >=65 years
    0
    0%
    0
    0%
    1
    2.6%
    1
    2.3%
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    51
    63
    54
    54
    Sex: Female, Male (Count of Participants)
    Female
    2
    66.7%
    1
    50%
    24
    61.5%
    27
    61.4%
    Male
    1
    33.3%
    1
    50%
    15
    38.5%
    17
    38.6%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    1
    33.3%
    0
    0%
    3
    7.7%
    4
    9.1%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    0
    0%
    1
    2.6%
    1
    2.3%
    White
    2
    66.7%
    2
    100%
    33
    84.6%
    37
    84.1%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    2
    5.1%
    2
    4.5%
    Region of Enrollment (participants) [Number]
    United States
    3
    100%
    2
    100%
    39
    100%
    44
    100%

    Outcome Measures

    1. Primary Outcome
    TitleMaximum Tolerated Dose (MTD) of Nivolumab
    DescriptionMTD is highest dose level in which <2 patients of 6 develop first cycle dose-limiting toxicity (DLT).
    Time Frame28 days

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitlePh 1 - Nivolumab (1mg) + Idarubicin + CytarabinePh 1 - Nivolumab (3mg) + Idarubicin + Cytarabine
    Arm/Group DescriptionPhase I dose of Nivolumab 1 mg/kg by vein on Day 24 of a 28 day cycle. Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Phase I and Phase II dose of Solumedrol 50 mg or Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Nivolumab: Phase I Starting Dose of Nivolumab: 1 mg/kg by vein on Day 24 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Idarubicin: Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Cytarabine: Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Solu-medrol: Phase I and Phase II dose of Solu-medrol 50 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Dexamethasone: Phase I and Phase II dose of Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.Phase I dose of Nivolumab 3 mg/kg by vein on Day 24 of a 28 day cycle. Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Phase I and Phase II dose of Solumedrol 50 mg or Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Nivolumab: Phase I Starting Dose of Nivolumab: 1 mg/kg by vein on Day 24 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Idarubicin: Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Cytarabine: Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Solu-medrol: Phase I and Phase II dose of Solu-medrol 50 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Dexamethasone: Phase I and Phase II dose of Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.
    Measure Participants32
    Number [mg/kg]
    NA
    3
    2. Secondary Outcome
    TitleEvent-Free Survival (EFS)
    DescriptionEFS defined as time from the treatment start till treatment failure, relapse, or death whichever comes first. Event Free Survival will be presented by median EFS, which is the time point at which the cumulative survival drops below 50%. If there is no median survival (not reached), it means the cumulative survival was more than 50%.
    Time Frame56 days

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitlePh 2 Nivolumab (3mg) + Idarubicin + Cytarabine
    Arm/Group DescriptionPhase II dose of Nivolumab 3 mg/kg by vein on Day 24 of a 28 day cycle. Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Phase I and Phase II dose of Solumedrol 50 mg or Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Nivolumab: Phase I Starting Dose of Nivolumab: 1 mg/kg by vein on Day 24 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Idarubicin: Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Cytarabine: Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Solu-medrol: Phase I and Phase II dose of Solu-medrol 50 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Dexamethasone: Phase I and Phase II dose of Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.
    Measure Participants39
    Median (95% Confidence Interval) [Months]
    NA
    3. Secondary Outcome
    TitleRelapse Free Survival
    DescriptionRelapse-free survival was defined as the time from treatment response to date of relapse or death, whichever occurred first.
    Time FrameUp to 2 years and10 Months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitlePh 2 - Nivolumab (3mg) + Idarubicin + Cytarabine
    Arm/Group DescriptionPhase II dose of Nivolumab 3 mg/kg by vein on Day 24 of a 28 day cycle. Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Phase I and Phase II dose of Solumedrol 50 mg or Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Nivolumab: Phase I Starting Dose of Nivolumab: 1 mg/kg by vein on Day 24 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Idarubicin: Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Cytarabine: Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Solu-medrol: Phase I and Phase II dose of Solu-medrol 50 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Dexamethasone: Phase I and Phase II dose of Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.
    Measure Participants39
    Median (95% Confidence Interval) [Months]
    18.54
    4. Secondary Outcome
    TitleOverall Survival
    DescriptionOverall survival was defined as the time from the start of treatment to death or date of last follow-up.
    Time FrameUp to 2 years and 10 Months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitlePh 2 Nivolumab (3mg) + Idarubicin + Cytarabine
    Arm/Group DescriptionPhase II dose of Nivolumab 3 mg/kg by vein on Day 24 of a 28 day cycle. Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Phase I and Phase II dose of Solumedrol 50 mg or Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Nivolumab: Phase I Starting Dose of Nivolumab: 1 mg/kg by vein on Day 24 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Idarubicin: Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Cytarabine: Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Solu-medrol: Phase I and Phase II dose of Solu-medrol 50 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Dexamethasone: Phase I and Phase II dose of Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.
    Measure Participants39
    Median (95% Confidence Interval) [Months]
    18.54

    Adverse Events

    Time FrameUp to 2 years 10 months
    Adverse Event Reporting Description
    Arm/Group TitlePh 1 Nivolumab (1mg) + Idarubicin + CytarabinePh 1 Nivolumab (3mg) + Idarubicin + CytarabinePh 2 Nivolumab (3mg) + Idarubicin + Cytarabine
    Arm/Group DescriptionPhase I dose of Nivolumab 1 mg/kg by vein on Day 24 of a 28 day cycle. Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Phase I and Phase II dose of Solumedrol 50 mg or Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Nivolumab: Phase I Starting Dose of Nivolumab: 1 mg/kg by vein on Day 24 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Idarubicin: Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Cytarabine: Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Solu-medrol: Phase I and Phase II dose of Solu-medrol 50 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Dexamethasone: Phase I and Phase II dose of Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.Phase I dose of Nivolumab 3 mg/kg by vein on Day 24 of a 28 day cycle. Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Phase I and Phase II dose of Solumedrol 50 mg or Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Nivolumab: Phase I Starting Dose of Nivolumab: 1 mg/kg by vein on Day 24 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Idarubicin: Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Cytarabine: Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Solu-medrol: Phase I and Phase II dose of Solu-medrol 50 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Dexamethasone: Phase I and Phase II dose of Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.Phase II dose of Nivolumab 3 mg/kg by vein on Day 24 of a 28 day cycle. Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Phase I and Phase II dose of Solumedrol 50 mg or Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Nivolumab: Phase I Starting Dose of Nivolumab: 1 mg/kg by vein on Day 24 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. Idarubicin: Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Cytarabine: Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Solu-medrol: Phase I and Phase II dose of Solu-medrol 50 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. Dexamethasone: Phase I and Phase II dose of Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.
    All Cause Mortality
    Ph 1 Nivolumab (1mg) + Idarubicin + CytarabinePh 1 Nivolumab (3mg) + Idarubicin + CytarabinePh 2 Nivolumab (3mg) + Idarubicin + Cytarabine
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total0/3 (0%) 0/2 (0%) 4/39 (10.3%)
    Serious Adverse Events
    Ph 1 Nivolumab (1mg) + Idarubicin + CytarabinePh 1 Nivolumab (3mg) + Idarubicin + CytarabinePh 2 Nivolumab (3mg) + Idarubicin + Cytarabine
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total1/3 (33.3%) 0/2 (0%) 32/39 (82.1%)
    Blood and lymphatic system disorders
    Blood and Lymphatic system disorder0/3 (0%) 00/2 (0%) 02/39 (5.1%) 2
    Neutropenic Fever0/3 (0%) 00/2 (0%) 028/39 (71.8%) 50
    Ear and labyrinth disorders
    Middle ear inflammation0/3 (0%) 00/2 (0%) 01/39 (2.6%) 1
    Gastrointestinal disorders
    Colitis0/3 (0%) 00/2 (0%) 02/39 (5.1%) 2
    Diarrhea0/3 (0%) 00/2 (0%) 03/39 (7.7%) 3
    Ileocolitis/typhlitis0/3 (0%) 00/2 (0%) 01/39 (2.6%) 1
    Nausea0/3 (0%) 00/2 (0%) 01/39 (2.6%) 1
    Pancreatitis0/3 (0%) 00/2 (0%) 02/39 (5.1%) 3
    General disorders
    Abdominal Pain0/3 (0%) 00/2 (0%) 01/39 (2.6%) 1
    Fever0/3 (0%) 00/2 (0%) 011/39 (28.2%) 12
    Headache0/3 (0%) 00/2 (0%) 02/39 (5.1%) 2
    Neck Pain0/3 (0%) 00/2 (0%) 01/39 (2.6%) 1
    Pelvic Pain1/3 (33.3%) 10/2 (0%) 00/39 (0%) 0
    Hepatobiliary disorders
    Cholecyctitis0/3 (0%) 00/2 (0%) 02/39 (5.1%) 2
    Elevated Liver Enzymes0/3 (0%) 00/2 (0%) 02/39 (5.1%) 2
    Infections and infestations
    Catheter related infection0/3 (0%) 00/2 (0%) 01/39 (2.6%) 1
    Infection0/3 (0%) 00/2 (0%) 05/39 (12.8%) 6
    Lung Infection0/3 (0%) 00/2 (0%) 06/39 (15.4%) 6
    Pneumonitis0/3 (0%) 00/2 (0%) 01/39 (2.6%) 1
    Sepsis0/3 (0%) 00/2 (0%) 01/39 (2.6%) 1
    Injury, poisoning and procedural complications
    fall0/3 (0%) 00/2 (0%) 01/39 (2.6%) 1
    Investigations
    Thrombocytopenia0/3 (0%) 00/2 (0%) 01/39 (2.6%) 1
    Metabolism and nutrition disorders
    Dehydration0/3 (0%) 00/2 (0%) 01/39 (2.6%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms0/3 (0%) 00/2 (0%) 01/39 (2.6%) 1
    Nervous system disorders
    Intracranial Hemorrhage0/3 (0%) 00/2 (0%) 01/39 (2.6%) 1
    Syncope0/3 (0%) 00/2 (0%) 01/39 (2.6%) 1
    Reproductive system and breast disorders
    Vatinal Hemorrhage0/3 (0%) 00/2 (0%) 01/39 (2.6%) 1
    Respiratory, thoracic and mediastinal disorders
    Respiratory Failure0/3 (0%) 00/2 (0%) 01/39 (2.6%) 1
    Upper Respiratory Infection0/3 (0%) 00/2 (0%) 02/39 (5.1%) 2
    Bilateral Pulmonary Nodules0/3 (0%) 00/2 (0%) 01/39 (2.6%) 1
    Vascular disorders
    Thromboembolic Event0/3 (0%) 00/2 (0%) 01/39 (2.6%) 1
    Other (Not Including Serious) Adverse Events
    Ph 1 Nivolumab (1mg) + Idarubicin + CytarabinePh 1 Nivolumab (3mg) + Idarubicin + CytarabinePh 2 Nivolumab (3mg) + Idarubicin + Cytarabine
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total3/3 (100%) 2/2 (100%) 32/39 (82.1%)
    Blood and lymphatic system disorders
    Neutropenic Fever3/3 (100%) 52/2 (100%) 68/39 (20.5%) 12
    Leukocytosis0/3 (0%) 00/2 (0%) 02/39 (5.1%) 2
    Gastrointestinal disorders
    Abdominal Pain0/3 (0%) 00/2 (0%) 09/39 (23.1%) 10
    Anorexia0/3 (0%) 00/2 (0%) 03/39 (7.7%) 3
    Diarrhea0/3 (0%) 02/2 (100%) 215/39 (38.5%) 24
    Mucositis0/3 (0%) 00/2 (0%) 09/39 (23.1%) 11
    Nausea0/3 (0%) 00/2 (0%) 09/39 (23.1%) 14
    Vomiting0/3 (0%) 00/2 (0%) 08/39 (20.5%) 8
    General disorders
    Fever0/3 (0%) 01/2 (50%) 12/39 (5.1%) 2
    Oral Pain0/3 (0%) 00/2 (0%) 02/39 (5.1%) 2
    Infections and infestations
    Infection1/3 (33.3%) 10/2 (0%) 04/39 (10.3%) 5
    Pneumonitis0/3 (0%) 01/2 (50%) 11/39 (2.6%) 1
    Sepsis0/3 (0%) 00/2 (0%) 02/39 (5.1%) 2
    Investigations
    Alanine Aminotransferase Increased0/3 (0%) 00/2 (0%) 05/39 (12.8%) 5
    Aspartate Aminotransferase Increased0/3 (0%) 00/2 (0%) 02/39 (5.1%) 2
    Blood Bilirubin Increased0/3 (0%) 00/2 (0%) 02/39 (5.1%) 2
    Neutrophil Count Decreased0/3 (0%) 00/2 (0%) 02/39 (5.1%) 4
    Thrombocytopenia0/3 (0%) 00/2 (0%) 07/39 (17.9%) 13
    Leukopenia0/3 (0%) 00/2 (0%) 08/39 (20.5%) 12
    Metabolism and nutrition disorders
    Hyperglycemia0/3 (0%) 00/2 (0%) 02/39 (5.1%) 3
    Hypocalcemia0/3 (0%) 01/2 (50%) 11/39 (2.6%) 1
    Hypokalemia0/3 (0%) 00/2 (0%) 02/39 (5.1%) 2
    Hypomagnesemia0/3 (0%) 00/2 (0%) 02/39 (5.1%) 2
    Skin and subcutaneous tissue disorders
    Erythmea0/3 (0%) 00/2 (0%) 02/39 (5.1%) 2
    Rash0/3 (0%) 00/2 (0%) 09/39 (23.1%) 10
    Vascular disorders
    Hypotension1/3 (33.3%) 11/2 (50%) 12/39 (5.1%) 2

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/TitleDr. Farhad Ravandi-Kashani, MD/Professor
    OrganizationThe University of Texas MD Anderson Cancer Center
    Phone(713)745-0394
    Emailfravandi@mdanderson.org
    Responsible Party:
    M.D. Anderson Cancer Center
    ClinicalTrials.gov Identifier:
    NCT02464657
    Other Study ID Numbers:
    • 2014-0907
    • NCI-2015-01258
    First Posted:
    Jun 8, 2015
    Last Update Posted:
    Oct 7, 2021
    Last Verified:
    Sep 1, 2021