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

Phase 2

Completed

Conditions: Adult Acute Myelomonocytic Leukemia (M4)
Previously Treated Myelodysplastic Syndromes
Secondary Myelodysplastic Syndromes
Adult Acute Monoblastic Leukemia and Acute Monocytic Leukemia (M5)
Adult Acute Myeloblastic Leukemia Without Maturation (M1)
Adult Acute Myeloid Leukemia With Del(5q)
de Novo Myelodysplastic Syndromes
Adult Acute Megakaryoblastic Leukemia (M7)
Adult Acute Myeloblastic Leukemia With Maturation (M2)
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)

Interventions: Drug: liposomal cytarabine-daunorubicin CPX-351

Registration Number: NCT02019069

Lead Sponsor: Rondeep Brar

Brief Summary: This phase 2 clinical trial studies how well CPX-351 (liposomal cytarabine-daunorubicin) works in treating patients with relapsed or refractory acute myeloid leukemia or myelodysplastic syndrome. Drugs used in chemotherapy, such as CPX-351, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 11

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Liposomal cytarabine-daunorubicin CPX-351	liposomal cytarabine-daunorubicin CPX-351	* 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. * 2nd INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3. * 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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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.
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.
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.
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.
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).
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.
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.