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CPX-351 and Enasidenib in Treating Patients With Relapsed Acute Myeloid Leukemia Characterized by IDH2 Mutation

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ClinicalTrials.gov Identifier: NCT03825796
Recruitment Status : Recruiting
First Posted : January 31, 2019
Last Update Posted : April 23, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Jonsson Comprehensive Cancer Center

Brief Summary:
This phase II trial studies how well CPX-351 and enasidenib work in treating patients with acute myeloid leukemia characterized by IHD2 mutation that has come back. Drugs used in chemotherapy, such as CPX-351, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Enasidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving CPX-351 and enasidenib may work better in treating patients with acute myeloid leukemia.

Condition or disease Intervention/treatment Phase
Blasts 5 Percent or More of Bone Marrow Nucleated Cells IDH2 Gene Mutation Recurrent Acute Myeloid Leukemia Drug: Enasidenib Mesylate Drug: Liposome-encapsulated Daunorubicin-Cytarabine Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To estimate the remission rate (defined as complete remission [CR]/ CR with incomplete hematologic recovery [CRi]) of the combination of liposome-encapsulated daunorubicin-cytarabine (CPX-351) plus enasidenib mesylate (enasidenib) in adults with relapsed acute myeloid leukemia (AML) characterized by a 2-hydroxyglutarate (2-HG) producing IDH2 mutations that include IDH2^R172 and IDH2^R140.

SECONDARY OBJECTIVES:

I. To evaluate persistent severe hematologic toxicity at induction day 60 in patients with a morphologic leukemia-free state (bone marrow blasts < 5%).

II. To evaluate delayed CR/CRi with enasidenib maintenance in participants with stable disease after induction with CPX-351.

IV. To evaluate 30- and 60-day survival. V. To evaluate CPX-351 plus enasidenib as a bridge to allogeneic hematopoietic stem cell transplantation (HSCT).

EXPLORATORY OBJECTIVES:

I. To determine the co-existing mutations that are present with the IDH2 mutation and describe those that are present in patients who achieve CR/CRi.

II. To determine the depth of molecular response to induction by minimal residual disease (MRD) using next generation sequencing.

III. To estimate the subclinical cardiotoxicity of CPX-351 as measured by troponin I, electrocardiography (ECG), and echocardiography.

OUTLINE:

INDUCTION: Patients receive liposome-encapsulated daunorubicin-cytarabine intravenously (IV) over 90 minutes on days 1, 3, and 5, and enasidenib mesylate orally (PO) on days 10-60 in the absence of disease progression or unacceptable toxicity. Patients whose bone marrow is not hypoplastic with no excess blasts receive re-induction including liposome-encapsulated daunorubicin-cytarabine IV on days 1 and 3, and enasidenib mesylate PO on days 8-60 in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Patients < 60 years receive cytarabine twice daily (BID) on days 1, 3, and 5, and patients >= 60 years receive cytarabine IV once daily on days 1-5. Patients also receive enasidenib mesylate PO on days 6-55. Treatment repeats every 28-55 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients who maintain CR/CRi after completion of consolidation therapy undergo allogeneic HSCT at the discretion of the treating physician.

MAINTENANCE: Patients receive enasidenib mesylate PO daily in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days, then periodically thereafter.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: CPX-351 Plus Enasidenib for Relapsed Acute Myelogenous Leukemia Characterized by the IDH2 Mutation
Actual Study Start Date : April 12, 2019
Estimated Primary Completion Date : January 1, 2021
Estimated Study Completion Date : January 1, 2022


Arm Intervention/treatment
Experimental: Treatment (CPX-351, enasidenib mesylate)
Open label, single arm, non-randomized
Drug: Enasidenib Mesylate
Given PO
Other Names:
  • 2-Methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4-yl]amino}-1,3,5-triazin-2-yl)amino]propan-2-ol Methanesulfonate
  • 2-Propanol, 2-Methyl-1-((4-(6-(trifluoromethyl)-2-pyridinyl)-6-((2-(trifluoromethyl)-4-pyridinyl)amino)-1,3,5-triazin-2-yl)amino)-, Methanesulfonate (1:1)
  • AG-221 Mesylate
  • CC-90007
  • Enasidenib Methanesulfonate
  • Idhifa

Drug: Liposome-encapsulated Daunorubicin-Cytarabine
Given IV
Other Names:
  • CPX-351
  • Cytarabine-Daunorubicin Liposome for Injection
  • Liposomal AraC-Daunorubicin CPX-351
  • Liposomal Cytarabine-Daunorubicin
  • Liposome-encapsulated Combination of Daunorubicin and Cytarabine
  • Vyxeos




Primary Outcome Measures :
  1. Rate of complete remission (CR)/CR with incomplete hematologic recovery (CRi) after induction therapy [ Time Frame: Up to day 60 ]

Secondary Outcome Measures :
  1. Proportion of patients with persistent grade 4 hematologic toxicity per Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 [ Time Frame: At day 60 ]
    The proportion along with the exact 95% confidence interval will reported.

  2. Proportion of patients who achieve CR/CRi during maintenance therapy [ Time Frame: Up to 2 years ]
    This is calculated only among patients who had stable disease after induction therapy and have received maintenance enasidenib monotherapy.

  3. Time to return of normal hematopoiesis [ Time Frame: From day 1 of induction assessed up to 2 years ]
    Defined as time from day 1 of induction to absolute neutrophil count (ANC) >= 1000/uL and platelet count >= 100,000/uL. The median time to return of normal hematopoiesis will be reported along with the corresponding range.

  4. Overall survival [ Time Frame: From day 1 of induction therapy, assessed at day 30 and 60 ]
    Will be estimated using Kaplan-Meier methods. The survival estimate at these two time points will be reported along with a 95% confidence interval.

  5. Proportion of patients who go on to receive allogeneic hematopoietic stem cell transplantation (HSCT) after achieving CR/CRi [ Time Frame: Up to 2 years ]
    Will be reported along with an exact 95% confidence interval.

  6. Proportion of echocardiogram findings with left ventricular ejection fraction reduction by >= 25% [ Time Frame: Up to 2 years ]

Other Outcome Measures:
  1. Proportion of patients who have a particular co-occurring mutation with an allelic frequency >= 10% along with the IDH2 mutation, and have achieved CR/CRi [ Time Frame: Up to 2 years ]
    Will be reported along with an exact 95% confidence interval.

  2. Proportion of patients who achieved CR/CRi then achieve minimal residual disease negativity based on Invivoscribe assay [ Time Frame: Up to 2 years ]
  3. Proportion of abnormal troponin levels without concurrent elevated creatinine [ Time Frame: Up to 2 years ]
  4. Proportion of abnormal electrocardiogram (ECG) findings (new T-wave inversions or new ST segment abnormalities) [ Time Frame: Up to 2 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Bone marrow blasts >= 5% that develops after CR/CRi in patient with prior history of AML, no restriction on prior number of relapses or regimens
  • AML characterized by the IDH2 gene mutation, without requirement for a particular allelic frequency
  • Patients previously treated with IDH2 inhibitor can be enrolled
  • At least a 3-month duration of CR/CRi prior to relapse
  • Relapses after allogeneic HSCT are included with a minimum of 3 from the date of allogeneic HSCT
  • Up to 1 cycle of hypomethylating agent monotherapy at time of relapse is allowed, must be discontinued at least 14 days prior to start of salvage induction
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Serum total bilirubin < 2.0 mg/dL, unless considered due to Gilbert?s disease or leukemic involvement
  • Aspartate aminotransferase (AST), alanine aminotransferase (ALT) < 3 times the upper limit of normal, unless considered due to leukemic involvement
  • Alkaline phosphatase < 3 times the upper limit of normal, unless considered due to leukemic involvement
  • Serum creatinine =< 2.0 mg/dL, or creatinine clearance > 40 mL/min based on Cockcroft-Gault glomerular filtration rate (GFR)
  • Females of reproductive potential as well as fertile men and their partners who are female of reproductive potential must agree to abstain from sexual intercourse or to use two highly effective forms of contraception from the time of giving informed consent, during the study, and for four months (females and males) following the last dose of IDH inhibitor. A highly effective form of contraception is defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, double-barrier method (eg, synthetic condoms, diaphragm or cervical cap with spermicidal foam, cream, or gel) or male partner sterilization

Exclusion Criteria:

  • Concurrent FLT3 mutation that the treating physician deems necessary to treat with FLT3-targeted therapy; whereas, patients with FLT3-mutated AML not treated with FLT3-targeted therapy can be enrolled
  • Inability to swallow medications or history of gastrointestinal (GI) malabsorptive disease
  • Active malignancy that would limit survival by less than two years
  • New York Heart Association class III or VI
  • Left ventricular ejection fraction < 40%
  • History of coronary stent placement that require mandatory continuation of dual-antiplatelet therapy
  • Baseline QT corrected interval based on Fridericia?s formula (QTcF) interval > 450 ms
  • History of Wilson?s disease or other copper handling disorders
  • Hypersensitivity to cytarabine, daunorubicin, or liposomal products
  • Active hepatitis B with surface antibody positivity (participants with hepatitis B core antibody positivity can be enrolled if given concurrent entecavir)
  • Hepatitis C immnuoglobulin (Ig)G antibody positivity, unless received curative hepatitis C therapy and now with hepatitis C ribonucleic acid (RNA) undetectable
  • Active invasive fungal infection
  • Active bacterial or viral infection manifesting as fevers or hemodynamic instability within the past 72 hours
  • Lifetime cumulative daunorubicin-equivalent anthracycline dose > 368 mg/m^2
  • Pregnant or breast feeding

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): NCT03825796


Contacts
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Contact: Caspian Oliai 310-206-8477x30870 ext 30870 COliai@mednet.ucla.edu

Locations
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United States, California
UCLA / Jonsson Comprehensive Cancer Center Recruiting
Los Angeles, California, United States, 90095
Contact: Gary J. Schiller    310-206-5755    GSchiller@mednet.ucla.edu   
Principal Investigator: Gary J. Schiller         
University of California Davis Comprehensive Cancer Center Not yet recruiting
Sacramento, California, United States, 95817
Contact: Gary J. Schiller       GSchiller@mednet.ucla.edu   
Principal Investigator: Gary J. Schiller         
University of California San Diego Not yet recruiting
San Diego, California, United States, 92103
Contact: Gary J. Schiller       GSchiller@mednet.ucla.edu   
Principal Investigator: Gary J. Schiller         
University of California San Francisco Not yet recruiting
San Francisco, California, United States, 94143
Contact: Gary J. Schiller       GSchiller@mednet.ucla.edu   
Principal Investigator: Gary J. Schiller         
Sponsors and Collaborators
Jonsson Comprehensive Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Gary Schiller UCLA / Jonsson Comprehensive Cancer Center

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Responsible Party: Jonsson Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT03825796     History of Changes
Other Study ID Numbers: 18-001416
NCI-2018-02998 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
18-001416 ( Other Identifier: UCLA / Jonsson Comprehensive Cancer Center )
P30CA016042 ( U.S. NIH Grant/Contract )
First Posted: January 31, 2019    Key Record Dates
Last Update Posted: April 23, 2019
Last Verified: April 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Daunorubicin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors