Leukemia, Myeloid, Acute
Conditions
Brief summary
This is an open label study to assess the suitability of CPX-351 as first intensive therapy in elderly (age ≥60 years) patients with AML. Patients may have received prior AML treatment with non-intensive regimens, e.g. hypomethylating agents, low dose Ara C or lenolidomide, but may not have received intensive AML treatment with anthracyclines and/or cytarabine prior to enrollment on this trial. The outcome of elderly patients following intensive treatment with CPX-351 will be measured by clinical endpoints for efficacy and safety and by biological/functional response.
Interventions
DRUGCPX-351
Cytarabine:Daunorubicin Liposome Injection
Sponsors
Jazz Pharmaceuticals
Weill Medical College of Cornell University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Ability to understand and voluntarily give informed consent * Age≥60 years at the time of study treatment * Pathological diagnosis of AML according to WHO criteria (with \>20% blasts in the peripheral blood or bone marrow) including: * De novo AML with normal karyotype or adverse karyotypes (including patients with karyotypic abnormalities characteristic of MDS) * Secondary AML: transformed from prior MDS or MPN, confirmed by bone marrow documentation of prior antecedent hematologic disorder * Therapy-related AML: t-AML, requires documented history of prior cytotoxic therapy or ionizing radiotherapy for an unrelated disease * Performance status \>50% KPS, ECOG 0-2 * Laboratory values fulfilling the following: * Serum creatinine \< 2.5 mg/dL * Serum total bilirubin \< 2.5 mg/dL, * Serum alanine aminotransferase or aspartate aminotransferase \< 3 times the ULN * Patients with elevated liver enzymes and serum creatinine values secondary to AML are eligible after discussion with PI * Cardiac ejection fraction ≥ 50% by echocardiography or MUGA * Patients with history of second malignancies in remission may be eligible if there is clinical evidence of disease stability off cytotoxic chemotherapy, documented by imaging, tumor marker studies, etc., at screening. Patients maintained on long-term non-chemotherapy treatment, e.g., hormonal therapy, are eligible.
Exclusion criteria
* Acute promyelocytic leukemia \[t(15;17)\] * Clinical evidence of active CNS leukemia * Prior intensive chemotherapy for AML with anthracycline/cytarabine-based regimens and/ or prior HSCT. Patients may have been treated with commercially available or investigational hypomethylating agents (e.g. decitabine, azacitidine, SGI-110), lenalidomide, or low-dose cytarabine (not to exceed 20 mg/m2 daily for 14 days for ≤ 6 cycles) * Prior treatment including HMA, systemic chemotherapy, surgery, or radiation therapy must have been completed at least 7 days before start of study treatment or after discussion with PI. Treatment with investigational agents must have been completed at least 14 days prior to study drug treatment. Hydroxyurea is permitted for control of blood counts before the start of study treatment. Toxicities associated with prior therapies must have recovered to grade 1 or less prior to start of study treatment. * Patients with prior cumulative anthracycline exposure of greater than 368 mg/m2 daunorubicin (or equivalent). * Any serious medical condition, laboratory abnormality or psychiatric illness that would prevent obtaining informed consent * Patients with myocardial impairment of any cause (e.g. cardiomyopathy, ischemic heart disease, significant valvular dysfunction, hypertensive heart disease, and congestive heart failure) resulting in heart failure by New York Heart Association Criteria (Class III or IV staging) * Active or uncontrolled infection. Patients with an infection receiving treatment (antibiotic, antifungal or antiviral treatment) may be entered into the study but must be afebrile and hemodynamically stable for ≥72 hrs. * Patients with current or recent evidence of invasive fungal infection (blood or tissue culture); patients with recent fungal infection must have a subsequent negative cultures to be eligible * Known HIV (new testing not required) or evidence of active hepatitis B or C infection (with rising transaminase values) * Hypersensitivity to cytarabine, daunorubicin or liposomal products * History of Wilson's disease or other copper-metabolism disorder * History of prior bone marrow or solid organ transplantation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Efficacy | 2.5 Years | Overall survival is measured from the date of registration to death from any cause. Patients not known to have died will be censored on the date they were last known to be alive. Patients were followed for 2.5 years. |
| 30-Day Mortality Rate | 30 Days | Mortality rate at Day 30 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate (CR, CRp, CRi, and CR+CRp+CRi) | 30 days post-treatment, up to 3 months post-baseline | The number of patients who achieve response will be divided by the number of patients in the efficacy population to determine response rate. |
| Change in Relationship of Cognitive Function to Treatment Response and OS, Event-free Survival and Morphologic Leukemia Free State as Measured by the MOCA | Screening through 30 days post-treatment, up to 3 months post-baseline | The Montreal Cognitive Assessment (MOCA) is a 30-point test which assesses several cognitive domains. Possible total scores range from 0 to 30. The results can be interpreted as follows: normal cognition: 26-30 points, mild cognitive impairment: 18-25 points, moderate cognitive impairment: 10-17 points, and severe cognitive impairment: under 10 points. |
| Change in Relationship of Cognitive Function to Treatment Response and OS, Event-free Survival and Morphologic Leukemia Free State as Measured by the Blessed Orientation-Memory-Concentration Test | Screening through 30 days post-treatment, up to 3 months post-baseline | The Blessed Orientation-Memory-Concentration Test is designed to evaluate older patients for early dementia. Possible total scores range from 0 (all items answered correctly) to 28 (all items answered incorrectly). |
| Incidence of Adverse Events | Through treatment completion, an average of 1 year | Adverse events included neutropenic fever, transient episodes of pericarditis, febrile neutropenia, streptococcus bacteremia, hypotensive episode, severe diffuse cerebral dysfunction, UTI (klebsiella pneumonia), anorexia with malnutrition, hypophosphatemia, hypokalemia, purple macules, elevated ALT, hypoalbuminemia, hyperbilirubinemia, syncope, joint pain, transaminitis, bacteremia, typhlitis, VRE bacteremia, Osteomyelitis, Decreased LVEF, GI adenovirus, Acute kidney injury, pulmonary edema, neutropenia, bronchospasm, bone pain, urinary incontinence, c. difficile infection, mucositis, and vaginal pain. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CPX-351 (Cytarabine:Daunorubicin) Injection Dosing for first induction: CPX-351
• CPX-351 at 100u/m2 will be administered on study days 1, 3 and 5
Dosing for second induction:
• CPX-351 at 100 u/m2 will be administered on days 1 and 3
Dosing for consolidation:
• CPX-351 at 65 u/m2 will be administered on days 1 and 3
CPX-351: Cytarabine:Daunorubicin Liposome Injection | 30 |
| Total | 30 |
Baseline characteristics
| Characteristic | CPX-351 (Cytarabine:Daunorubicin) Injection |
|---|---|
| Age, Continuous | 70.98 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 10 Participants |
| Newly Diagnosed AML Patients Aged ≥ 60 Years | 30 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 9 Participants |
| Race (NIH/OMB) White | 15 Participants |
| Region of Enrollment United States | 30 Participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 23 / 30 |
| other Total, other adverse events | 30 / 30 |
| serious Total, serious adverse events | 14 / 30 |
Outcome results
Primary
30-Day Mortality Rate
Mortality rate at Day 30
Time frame: 30 Days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CPX-351 (Cytarabine:Daunorubicin) Injection | 30-Day Mortality Rate | 2 Participants |
Primary
Primary Efficacy
Overall survival is measured from the date of registration to death from any cause. Patients not known to have died will be censored on the date they were last known to be alive. Patients were followed for 2.5 years.
Time frame: 2.5 Years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CPX-351 (Cytarabine:Daunorubicin) Injection | Primary Efficacy | 7 Participants |
Secondary
Change in Relationship of Cognitive Function to Treatment Response and OS, Event-free Survival and Morphologic Leukemia Free State as Measured by the Blessed Orientation-Memory-Concentration Test
The Blessed Orientation-Memory-Concentration Test is designed to evaluate older patients for early dementia. Possible total scores range from 0 (all items answered correctly) to 28 (all items answered incorrectly).
Time frame: Screening through 30 days post-treatment, up to 3 months post-baseline
Population: 9 subjects did not complete the Blessed Orientation-Memory-Concentration Test and they were excluded from analysis for this measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CPX-351 (Cytarabine:Daunorubicin) Injection | Change in Relationship of Cognitive Function to Treatment Response and OS, Event-free Survival and Morphologic Leukemia Free State as Measured by the Blessed Orientation-Memory-Concentration Test | Blessed Orientation-Memory-Concentration Test (baseline) | 3.45 score on a scale | Standard Deviation 2.87 |
| CPX-351 (Cytarabine:Daunorubicin) Injection | Change in Relationship of Cognitive Function to Treatment Response and OS, Event-free Survival and Morphologic Leukemia Free State as Measured by the Blessed Orientation-Memory-Concentration Test | Blessed Orientation-Memory-Concentration Test (30 days post-treatment) | 2 score on a scale | Standard Deviation 2.27 |
Secondary
Change in Relationship of Cognitive Function to Treatment Response and OS, Event-free Survival and Morphologic Leukemia Free State as Measured by the MOCA
The Montreal Cognitive Assessment (MOCA) is a 30-point test which assesses several cognitive domains. Possible total scores range from 0 to 30. The results can be interpreted as follows: normal cognition: 26-30 points, mild cognitive impairment: 18-25 points, moderate cognitive impairment: 10-17 points, and severe cognitive impairment: under 10 points.
Time frame: Screening through 30 days post-treatment, up to 3 months post-baseline
Population: 9 subjects did not complete the MOCA and they were excluded from analysis for this measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CPX-351 (Cytarabine:Daunorubicin) Injection | Change in Relationship of Cognitive Function to Treatment Response and OS, Event-free Survival and Morphologic Leukemia Free State as Measured by the MOCA | Montreal Cognitive Assessment (baseline) | 24.72 score on a scale | Standard Deviation 2.85 |
| CPX-351 (Cytarabine:Daunorubicin) Injection | Change in Relationship of Cognitive Function to Treatment Response and OS, Event-free Survival and Morphologic Leukemia Free State as Measured by the MOCA | Montreal Cognitive Assessment (30 days post-treatment) | 25.79 score on a scale | Standard Deviation 2.99 |
Secondary
Complete Response Rate (CR, CRp, CRi, and CR+CRp+CRi)
The number of patients who achieve response will be divided by the number of patients in the efficacy population to determine response rate.
Time frame: 30 days post-treatment, up to 3 months post-baseline
Population: 14 subjects were excluded from analysis for this measure due to treatment failure (progressive disease or non-evaluable).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CPX-351 (Cytarabine:Daunorubicin) Injection | Complete Response Rate (CR, CRp, CRi, and CR+CRp+CRi) | Complete remission (CR) | 11 Participants |
| CPX-351 (Cytarabine:Daunorubicin) Injection | Complete Response Rate (CR, CRp, CRi, and CR+CRp+CRi) | Complete remission with incomplete recovery (CRi) | 5 Participants |
Secondary
Incidence of Adverse Events
Adverse events included neutropenic fever, transient episodes of pericarditis, febrile neutropenia, streptococcus bacteremia, hypotensive episode, severe diffuse cerebral dysfunction, UTI (klebsiella pneumonia), anorexia with malnutrition, hypophosphatemia, hypokalemia, purple macules, elevated ALT, hypoalbuminemia, hyperbilirubinemia, syncope, joint pain, transaminitis, bacteremia, typhlitis, VRE bacteremia, Osteomyelitis, Decreased LVEF, GI adenovirus, Acute kidney injury, pulmonary edema, neutropenia, bronchospasm, bone pain, urinary incontinence, c. difficile infection, mucositis, and vaginal pain.
Time frame: Through treatment completion, an average of 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CPX-351 (Cytarabine:Daunorubicin) Injection | Incidence of Adverse Events | 56 events |