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

PRIMARY OBJECTIVES:

Determine efficacy of CPX-351 by measuring the response rate as the sum of complete response (CR) and complete remission with incomplete count recovery (CRi) 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:

1. Determine the safety of CPX-351, as the frequency of Grade 3 to 5 SAEs
2. Determine the duration of remission (DOR) following induction therapy with CPX-351.
3. Determine overall survival (OS) at 12 months.
4. Determine the early induction mortality (at 30 and 60 days) following CPX-351 following induction therapy.

OUTLINE:

Patients receive liposomal cytarabine-daunorubicin CPX-351 intravenously (IV) at a dose of 65 units/m2/day over 90 minutes on days 1, 3, and 5 of each induction cycle.

* 1st INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV at a dose of 65 units/m2/day 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
* 2nd INDUCTION: Patients with reduced blast count not achieving a morphological leukemia free state (< 5% blasts) receive the 2nd course of induction therapy. Patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3. Patients achieving a complete remission (CR) or a CR with incomplete blood count recovery (CRi) after the 2nd course of induction therapy proceed to consolidation therapy.
* CONSOLIDATION: Beginning on day 28, patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.

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

• liposomal cytarabine-daunorubicin CPX-351 (Drug), also known as CPX-351: Given IV

Primary outcomes

• Response Rate (RR) [Day 42]: The response rate was determined as the sum of complete response calculated by adding the total complete response (CR) and complete response with incomplete count recovery (CRi). The outcome is reported as the total number without dispersion. * CR = less than 5% blasts; no blasts with auer rods; and no persistence of extramedullary disease, with blood count recovery to platelets ≥ 100,000/uL and ANC > 1000/uL, with transfusion independence. * CRi = all the parameters for CR, but platelets < 100,000/uL and/or ANC ≤ 1000/uL.

Secondary outcomes

• Complete Response With Incomplete Count Recovery (CRi) [Day 42]: Complete response (CR) with incomplete count recovery (CRi) was determined as the number of participants who achieved CRi after induction therapy. The outcome is reported as the total number or participants without dispersion. * CR = less than 5% blasts; no blasts with auer rods; and no persistence of extramedullary disease, with blood count recovery to platelets ≥ 100,000/uL and ANC > 1000/uL, with transfusion independence. * CRi = all the parameters for CR, but platelets < 100,000/uL and/or ANC ≤ 1000/uL.
• Complete Response (CR) [Day 42]: Complete response (CR) was determined the number of participants who achieved CR by Day 42 after induction treatment. The outcome is reported as the total number of participants without dispersion. • CR = less than 5% blasts; no blasts with auer rods; and no persistence of extramedullary disease, with blood count recovery to platelets ≥ 100,000/uL and ANC > 1000/uL, with transfusion independence.
• Duration of Remission (DOR) Following Induction With CPX-351 [Up to 1 year]: Duration of remission (DOR) was assessed as the length of time from documented complete response (CR) or complete response with incomplete count recovery (CRi) until documented lost of response, relapse, or death. The outcome is reported as the median with full range. * CR = less than 5% blasts; no blasts with auer rods; and no persistence of extramedullary disease, with blood count recovery to platelets ≥ 100,000/uL and ANC > 1000/uL, with transfusion independence. * CRi = all the parameters for CR, but platelets < 100,000/uL and/or ANC ≤ 1000/uL. For patients remaining alive, duration of remission (DOR) is reported as the length of time from documented complete response (CR) or complete response with incomplete count recovery (CRi) until the most recent assessment.
• Overall Survival (OS) [At 12 months]: Overall survival (OS) was assessed as the number of participants remaining alive 12 months, starting from date of entry into trial. The outcome is reported as the number of participants (without dispersion).
• Early Induction Mortality (Day 30 After 1st Induction) [30 days]: Early induction mortality was assessed as the number of participants who died within 30 days of completing the 1st cycle of CPX-351 (1st induction). The outcome is reported as the number of participants without dispersion.
• Mortality at Day 60 After 1st Induction [60 days]: Mortality at Day 60 after 1st induction was assessed as the number of participants who died within 60 days of completing the 1st cycle of CPX-351 (1st induction). The outcome is reported as the number of participants without dispersion.
• Participants Experiencing of Serious Adverse Events [Up to 4 weeks after completion of treatment]: Serious adverse events per participant were assessed as serious adverse events per 21CFR§312.32 that were Grade 3 or greater, and independent of relationship to CPX-351. The outcome is reported as the number of participants that experienced any defined SAE, a number without dispersion.
• Serious Adverse Events [Up to 4 weeks after completion of treatment]: Serious adverse events were assessed as serious adverse events per 21CFR§312.32 that were Grade 3 or greater, and independent of relationship to CPX-351. The outcome is reported as the total number of the defined SAEs, a number without dispersion.

Sex: All, ages: 60 Years to any

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

Participant flow

Outcome results

• Response Rate (RR) (Primary), Count of participants, Participants: Liposomal Cytarabine-daunorubicin CPX-351 3
• Complete Response With Incomplete Count Recovery (CRi) (Secondary), Count of participants, Participants: Liposomal Cytarabine-daunorubicin CPX-351 1
• Complete Response (CR) (Secondary), Count of participants, Participants: Liposomal Cytarabine-daunorubicin CPX-351 2
• Duration of Remission (DOR) Following Induction With CPX-351 (Secondary), Median, days: Liposomal Cytarabine-daunorubicin CPX-351 185 (25 to 329)
• Overall Survival (OS) (Secondary), Count of participants, Participants: Liposomal Cytarabine-daunorubicin CPX-351 1
• Early Induction Mortality (Day 30 After 1st Induction) (Secondary), Count of participants, Participants: Liposomal Cytarabine-daunorubicin CPX-351 2
• Mortality at Day 60 After 1st Induction (Secondary), Count of participants, Participants: Liposomal Cytarabine-daunorubicin CPX-351 3
• Participants Experiencing of Serious Adverse Events (Secondary), Count of participants, Participants: Liposomal Cytarabine-daunorubicin CPX-351 5
• Serious Adverse Events (Secondary), Number, Adverse events: Liposomal Cytarabine-daunorubicin CPX-351 8

Adverse events

Time frame: Up to 4 weeks after completion of treatment]

Serious adverse events by term

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2017-02-28)

• Rondeep Brar, MD, Principal investigator, Stanford University

NIH grants: P30CA124435