CPX-351 in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

Study Description

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Brief Summary:

This phase II clinical trial studies how well liposomal cytarabine-daunorubicin CPX-351 (CPX-351) works in treating patients with relapsed or refractory acute myeloid leukemia or myelodysplastic syndrome. Drugs used in chemotherapy, such as liposomal cytarabine-daunorubicin CPX-35, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing.

Condition or disease	Intervention/treatment	Phase
Adult Acute Erythroid Leukemia (M6); Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia and Acute Monocytic Leukemia (M5); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes	Drug: liposomal cytarabine-daunorubicin CPX-351; Other: laboratory biomarker analysis	Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the efficacy and safety profile of the use of CPX-351 in older patients (age 60 and older) with: higher risk of myelodysplastic syndrome (MDS) who are refractory/relapsed after prior hypomethylating (HMA) therapy; subjects greater than 75 years old with higher risk MDS who are HMA relapsed/refractory who have progressed to acute myeloid leukemia (AML)); AML with refractory/relapsed disease after prior HMA therapy for AML.

SECONDARY OBJECTIVES:

I. Determine the duration of remission following induction therapy with CPX-351.

II. Determine overall survival at 12 months. III. Determine the early induction mortality (at 60 days) following CPX-351 in this cohort following induction therapy.

OUTLINE:

INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 intravenously (IV) over 90 minutes on days 1, 3, and 5. Patients with reduced blast count not achieving a morphological leukemia free state (< 5% blasts) receive a second course of induction therapy. Patients achieving a complete remission (CR) or a CR with incomplete blood count recovery (CRi) at day 14 or after a second course of induction therapy proceed to consolidation therapy.

SECOND INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1 and 3.

CONSOLIDATION: Beginning on day 28, patients receive liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1 and 3. Patients may receive a second course after 28-75 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for up to 1 year.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	33 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase II Study of CPX-351 for Treatment of AML or Higher Risk MDS Relapsed or Refractory to Prior Therapy With Hypomethylating (HMA) Agent
Study Start Date :	February 2014
Estimated Primary Completion Date :	July 2019
Estimated Study Completion Date :	December 2019

Arms and Interventions

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Arm

Intervention/treatment

Experimental: Treatment (liposomal cytarabine-daunorubicin CPX-351); INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1, 3, and 5. Patients achieving a complete remission (CR) or a CR with incomplete blood count recovery (CRi) at day 14 proceed to consolidation therapy. Patients with reduced blast count not achieving a morphological leukemia free state (< 5% blasts) receive a second course of induction therapy liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1 and 3. Patients achieving a CR or a CRi at day 14 or after a second course of induction therapy proceed to consolidation therapy. SECOND INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1 and 3. CONSOLIDATION: Beginning on day 28, patients receive liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1 and 3. Treatment may repeat after 28-75 days in the absence of disease progression or unacceptable toxicity.

Drug: liposomal cytarabine-daunorubicin CPX-351; Given IV; Other Name: CPX-351; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

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Primary Outcome Measures :

1. Incidence of mortality assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: At day 30 ]
   To analyze the safety data, adverse events recorded using CTCAE 4.0 for each patient will reviewed and totaled, for the total number of adverse events for each adverse event compared to total group of patients (rate of outcome of each adverse event in study population).
2. Incidence of mortality assessed using the CTCAE version 4.0 [ Time Frame: At day 60 ]
   To analyze the safety data, adverse events recorded using CTCAE 4.0 for each patient will reviewed and totaled, for the total number of adverse events for each adverse event compared to total group of patients (rate of outcome of each adverse event in study population).
3. Incidence of serious adverse events as assessed by CTCAE version 4.0 [ Time Frame: Up to 4 weeks after completion of treatment ]
   To analyze the safety data, adverse events recorded using CTCAE 4.0 for each patient will reviewed and totaled, for the total number of adverse events for each adverse event compared to total group of patients (rate of outcome of each adverse event in study population).
4. Frequency of grade 3-5 adverse events as assessed by CTCAE version 4.0 [ Time Frame: Up to 4 weeks after completion of treatment ]
   To analyze the safety data, adverse events recorded using CTCAE 4.0 for each patient will reviewed and totaled, for the total number of adverse events for each adverse event compared to total group of patients (rate of outcome of each adverse event in study population).
5. Response rate (CR + CRi) following induction therapy using the European Leukemia Net classification for AML and the International Working Group guidelines for MDS [ Time Frame: Day 42 ]
   The response rate will be calculated by adding the total CR + CRi (total number of CR + CRi for AML + CR for MDS) events after up to two courses of induction therapy, and comparing it to the total number of patients undergoing induction with CPX-351.

Secondary Outcome Measures :

1. Duration of remission following induction with CPX-351 [ Time Frame: From the start of response until disease relapse or death, assessed up to 1 year ]
   Calculated by counting the number of days from the date of remission until date of disease relapse for patients who achieve a CR (and CRi for AML). The average days of remission will be calculated to determine the median duration of remission.
2. Overall survival [ Time Frame: From the date of entry into trial to death from any cause, assessed at 12 months ]
   Determined by the number of patients who are alive at 12 months compared to the number of patients who initiated into the study.
3. Early induction mortality after first induction [ Time Frame: Day 60 ]
   Calculated by determining the number of deaths within the first 60 days, using day 1 of the first induction therapy as the first day, compared to the total number of patients who have received any dose of CPX-351.

Eligibility Criteria

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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:

• Ability to understand and voluntarily give informed consent
• Age ≥ 60

• Pathological diagnosis of AML (by WHO criteria) or higher risk MDS (includes int-2 and high risk MDS by IPSS) along with one of the following:

  • Patients with de novo or secondary MDS with progression/refractoriness after HMA treatment who have not transformed to AML
  • Patients with MDS and prior HMA treatment for MDS who transform to AML
  • Patients with AML who are refractory/relapsed after HMA therapy for their AML are eligible
• Life expectancy > 1 month
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Able to adhere to the study visit schedule and other protocol requirements

• Laboratory values fulfilling the following:

  • Serum creatinine < 2.0 mg/dL
  • Serum total bilirubin ≤ 2.5 mg/dL. Note, patients with Gilbert's syndrome may have elevated bilirubin at baseline prior to diagnosis with AML or MDS. Patients with Gilbert's syndrome are included if their total bilirubin is ≤ 2 times their baseline total bilirubin.
  • Serum alanine aminotransferase or aspartate aminotransferase < 3 times ULN
• Cardiac ejection fraction ≥ 45% by echocardiography (transthoracic echocardiography) or MUGA scan
• Patients with second malignancies may be eligible at discretion of PI given acute life threatening nature of untreated AML or higher risk MDS. Patients maintained on long-term non-chemotherapy treatment, e.g., hormonal therapy, are also eligible.

Exclusion Criteria:

• Patients who have previously undergone allogeneic hematopoietic stem cell transplant will be excluded from this study
• Patients who have previously had > 368 mg/m2 cumulative dose of daunorubicin or > 368 mg/m2 daunorubicin-equivalent anthracycline therapy (for example, from prior treatment of solid tumors). See appendix for anthracycline equivalence table.
• Acute promyelocytic leukemia [t(15;17)]
• Any serious medical condition, laboratory abnormality or psychiatric illness that would prevent obtaining informed consent
• Patients who have had conventional intensive cytotoxic induction chemotherapy for treatment of specifically MDS or AML are excluded.
• Patients who have not previously been treated with HMA therapy will be excluded
• Clinical evidence of active CNS leukemia
• Patients with evidence of uncontrolled current myocardial impairment (e.g. unstable ischemic heart disease, uncontrolled arrhythmia, symptomatic valvular dysfunction not controlled on medical therapy, uncontrolled hypertensive heart disease, and uncontrolled congestive heart failure)
• Active and uncontrolled infection. Patients with an active infection receiving treatment and hemodynamically stable for 48 hours may be entered into the study
• Known active uncontrolled HIV or hepatitis C infection
• Known hypersensitivity to cytarabine, daunorubicin or liposomal products
• Known history of Wilson's disease or other copper-related disorders
• Other medical or psychiatric illness or organ dysfunction or laboratory abnormality which in the opinion of the investigator would compromise the patient's safety or interfere with data interpretation

• Laboratory abnormalities:

  • Serum creatinine ≥ 2.0 mg/dL
  • Serum total bilirubin > 2.5 mg/dL. Note, patients with Gilbert's syndrome may have elevated bilirubin at baseline prior to diagnosis with AML or MDS. Patients with Gilbert's syndrome are excluded if their total bilirubin is > 2 times their baseline total bilirubin.
  • Serum alanine aminotransferase or aspartate aminotransferase > 3 times ULN

Contacts and Locations

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Contacts

Contact: Jack Taw	650-723-2781	jtaw@stanford.edu

Locations

United States, California
Stanford University, School of Medicine	Recruiting
Stanford, California, United States, 94305
Contact: Jack Taw 650-723-1269 jtaw@stanford.edu
Principal Investigator: Rondeep Brar, MD

Sponsors and Collaborators

Rondeep Brar

National Cancer Institute (NCI)

Investigators

Principal Investigator:	Rondeep Brar, MD	Stanford University

More Information

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Responsible Party:	Rondeep Brar, Clinical Assistant Professor, Stanford University
ClinicalTrials.gov Identifier:	NCT02019069 History of Changes
Other Study ID Numbers:	HEM0036; NCI-2013-01982 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 4593; HEM0036 ( Other Identifier: Stanford University Hospitals and Clinics ); P30CA124435 ( U.S. NIH Grant/Contract ); 28524 ( Other Identifier: Stanford IRB Number )
First Posted:	December 24, 2013
Last Update Posted:	May 14, 2018
Last Verified:	May 2018

Additional relevant MeSH terms:

Syndrome; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Preleukemia; Leukemia, Monocytic, Acute; Leukemia, Myelomonocytic, Acute; Leukemia, Megakaryoblastic, Acute; Leukemia, Erythroblastic, Acute; Disease; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases	Hematologic Diseases; Precancerous Conditions; Myeloproliferative Disorders; 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