Acute Megakaryoblastic Leukemia, Myelofibrosis, Primary Myelofibrosis
Conditions
Brief summary
The purpose of this study is to evaluate the safety of alisertib and its effect, bad and/or good, on acute megakaryoblastic leukemia (AMKL) or myelofibrosis (MF). The study drug, alisertib, is an investigational drug. An investigational drug is one that has not been approved by the U.S. Food and Drug Administration (FDA). Alisertib has shown evidence in the lab that it may have an effect on a type of cell that produces platelets. This cell is called a megakaryocyte and it is known to be defective (doesn't work well) in both AMKL and MF.
Detailed description
PRIMARY OBJECTIVES: I. Determine the safety profile of alisertib in patients with acute megakaryoblastic leukemia (AMKL) and in patients with myelofibrosis (MF). SECONDARY OBJECTIVES: I. Determine preliminary efficacy of alisertib in both populations. TERCIARY OBJECTIVES: I. Describe pharmacodynamics (PD) effects of alisertib in peripheral blood and/or bone marrow samples. II. Evaluate the relationship between biomarker expression levels and response to alisertib. III. Evaluate reduction in splenomegaly by palpation (MF arm only). IV. Evaluate improvement in MF symptoms (MF arm only), as assessed by the Myeloproliferative Neoplasm Symptom Assessment form (MPN-SAF). V. Assess change in bone marrow fibrosis in patients in the MF arm. OUTLINE: Patients receive alisertib orally (PO) twice daily (BID) on days 1-7. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at approximately 30 days and 6 months.
Interventions
DRUGAlisertib
Given PO
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPharmacological Study
Correlative studies
Sponsors
The Leukemia and Lymphoma Society
Millennium Pharmaceuticals, Inc.
National Cancer Institute (NCI)
Northwestern University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* AMKL PATIENTS: Patients must have a confirmed diagnosis of relapsed/refractory acute megakaryoblastic leukemia (AMKL), as defined by World Health Organization (WHO) criteria * AMKL PATIENTS: Patients must have an Eastern Cooperative Oncology Group (ECOG) status 0-2 * AMKL PATIENTS: Total bilirubin =\< 1.5 x upper limit of normal (ULN) * AMKL PATIENTS: Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =\< 2.5 x ULN * AMKL PATIENTS: Creatinine \< 1.5 x ULN or calculated creatinine clearance \> 30 ml/min * AMKL PATIENTS: Prothrombin time (PT) and partial thromboplastin time (PTT) =\< 1.5 x ULN * AMKL PATIENTS: Absolute neutrophil count (ANC) \>= 1500/mm\^3 * AMKL PATIENTS: Platelets \>= 100,000/mm\^3 * AMKL PATIENTS: Hemoglobin \> 9 g/dL * AMKL PATIENTS: Patients must have estimated life expectancy of 6 months or greater * AMKL PATIENTS: Female patients of child-bearing potential (FOCBP) must have a negative serum beta-human chorionic gonadotropin (HCG) pregnancy test within 7 days prior to registration; NOTE: a FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: * Has not undergone a hysterectomy or bilateral oophorectomy * Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for \> 12 months) * AMKL PATIENTS: Female patients must meet at least one of the following conditions: * Must be post-menopausal for at least 1 year prior to registration (not of childbearing potential) * Must be surgically sterilized * Willing to use an acceptable method of birth control (i.e. hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study * AMKL PATIENTS: Male patients, even if surgically sterilized (status post-vasectomy) agrees to use an acceptable method for contraception during the entire study treatment period through 4 months after the last dose of alisertib * AMKL PATIENTS: Patients must be able to understand and willing to sign a written informed consent * MF PATIENTS: Patients must have a confirmed diagnosis of myelofibrosis (MF), as defined by WHO criteria * MF PATIENTS: Patients must be intermediate I risk or beyond and meet the following: * In need of treatment * Intolerant or refractory to ruxolitinib (or other investigational Janus kinase \[JAK\]-inhibitors) OR unlikely to benefit from ruxolitinib * Ineligible for stem cell transplantation * MF PATIENTS: Patients must have an ECOG status 0-2 * MF PATIENTS: Direct bilirubin \< 1.5 x ULN * MF PATIENTS: ALT/AST =\< 2.5 x ULN * MF PATIENTS: Creatinine \< 1.5 x ULN or calculated creatinine clearance \> 30 ml/min * MF PATIENTS: PT and PTT =\< 1.5 x ULN * MF PATIENTS: ANC \>= 1500/mm\^3 * MF PATIENTS: Platelets \>= 100,000/mm\^3 * MF PATIENTS: Patients must have estimated life expectancy of 6 months or greater * MF PATIENTS: Female patients of child-bearing potential (FOCBP) must have a negative serum beta-HCG pregnancy test within 7 days prior to registration * MF PATIENTS: Female patients must meet at least one of the following conditions: * Must be post-menopausal for at least 1 year prior to registration (not of childbearing potential) * Must be surgically sterilized * Willing to use an acceptable method of birth control (i.e. hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study * MF PATIENTS: Male patients, even if surgically sterilized (i.e. status post-vasectomy) agrees to use an acceptable method for contraception during the entire study treatment period through 4 months after the last dose of alisertib * MF PATIENTS: Patients must be able to understand and willing to sign a written informed consent
Exclusion criteria
* Patients who have received treatment with clinically significant enzyme inducers (such as enzyme inducing antiepileptic drugs phenytoin, carbamazepine, or phenobarbital, or rifampin, rifabutin, rafapentine, or St. John's wort) within 14 days prior to registration are not eligible * Patients who have received any investigational products, antineoplastic therapies, or radiotherapy within 14 days prior to registration are not eligible; NOTE: patients actively receiving hydroxyurea are eligible and may continue to receive hydroxyurea through cycle 1 of protocol treatment * Patients who have received prior administration of an Aurora A kinase targeted agent (including alisertib) are not eligible * Patients who have received corticosteroids within 7 days prior registration are not eligible, UNLESS the patient has been taking a continuous dose of no more than 15 mg/day of prednisone for at least 1 month prior; NOTE: low dose steroid use for control of nausea and vomiting will be allowed; topical steroid use and inhaled steroids are also permitted * Patients who are candidates (eligible and willing) for standard and/or potentially curative treatments are not eligible * Patients who have had received radiation therapy to more than 25% of the bone marrow are not eligible (whole pelvic radiation is considered to be over 25%) * Patients who have had major surgery within one month (28 days) prior to registration are not eligible * Patients who have had prior allogenic bone marrow or organ transplantation are not eligible * Patients who have had grade 2 or higher diarrhea, despite optimal antidiarrheal supportive care, within 7 days prior to registration are not eligible * Patients who have had grade 2 or higher peripheral neuropathy within 14 days prior to registration are not eligible * Patients who have had a myocardial infarction within 6 months (24 weeks) prior to registration are not eligible * Patients who have class III or IV heart failure (as defined by the New York Heart Association), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities are not eligible * Patients who have known gastrointestinal (GI) disease or GI procedures which could interfere with the oral absorption or tolerance of alisertib are not eligible; examples include (but are not limited to) partial gastrectomy, history of small intestine surgery, and celiac disease * Patients who have a known history of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness (such as severe chronic obstructive pulmonary disease or requirement for supplemental oxygen) are not eligible * Patients who have a requirement for constant administration of proton pump inhibitor, histamine-2 (H2) antagonist, or pancreatic enzymes are not eligible; intermittent usage of antacids or H2 antagonists are allowed * Patients who have a systemic infection requiring intravenous (IV) antibiotic therapy within 14 days prior to registration (or other severe infection) are not eligible * Patients who are known human immunodeficiency virus (HIV) positive are not eligible * Patients who are known hepatitis B surface antigen positive are not eligible * Patients who have known or suspected active hepatitis C infections are not eligible; NOTE: patients who are hepatitis C surface antigen positive are eligible * Female patients who are pregnant or breast feeding are not eligible * Patients who have a severe acute or chronic medical or psychiatric condition, including uncontrolled diabetes, malabsorption, resection of the pancreas or upper small bowel, requirement for pancreatic enzymes, any condition that would modify small bowel absorption of oral medications, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for enrollment in this study are not eligible * Patients who have symptomatic central nervous system (CNS) involvement are not eligible * Patients who have been diagnosed or treated for another malignancy within 3 years prior to registration are not eligible aside from these exceptions: completely resected basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy * Patients who are unable to swallow oral medication or are unwilling to comply with the administration requirements are not eligible * Patients who require administration of myeloid growth factors or platelet transfusions within 14 days prior to registration are not eligible
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety Profile of Alisertib Per NCI's Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. | From time of treatment to 6 months post discontinuation (range of cycles attempted 1 to 29, median 7.5 cycles, 1 Cycle = 21 days) | Adverse events will be defined as those included in CTCAE v 4.0. The AEs that were determined to be at least possibly related to study drug and graded 3, 4, 5 are included here. Grade 1 (mild): the event causes discomfort without disruption of normal daily activities. Grade 2 (moderate): the event causes discomfort that affects normal daily activities. Grade 3 (severe): the event makes the patient unable to perform normal daily activities or significantly affects his/her clinical status. Grade 4 (Life-threatening): the patient was at risk of death at the time of the event. Grade 5 (fatal): the event caused death. All patients who received at least 1 dose of alisertib were considered evaluable for this endpoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response to Treatment | Baseline to up to 6 months after the last dose of treatment | Serial blood and/or bone marrow samples will be collected at specific timepoints for each disease to determine response to alisertib treatment. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Changes in Pharmacodynamic Effects of Alisertib | Baseline to up to 6 months after the last dose of treatment | Serial blood and/or bone marrow samples will be collected at specific timepoints. Flow cytometry, colony forming assays, AURKA autophosphorylation assays, and in vitro cultures of patient specimens to assess the effect of MLN8237 on megakaryocytes and other hematopoietic cells will be measured. |
| Changes in Biomarker Expression Levels | Baseline to up to 6 months after the last dose of treatment | To evaluate the relationship between biomarker expression levels and response. Biomarkers will include a) genes encoding key enzymes in Aurora kinase signaling, b) markers of cellular aneuploidy and apoptosis, and c) markers of megakaryocytic differentiation. |
| Change in Bone Marrow Fibrosis (MF Patients) | Screening and up to 54 weeks | Assess change in bone marrow fibrosis in patients in the MF arm. Bone marrow will be assessed at screening and after cycle 6 in this population. |
| Changes in Splenomegaly by Palpation (MF Patients) | Baseline to up to 6 months after the last dose of treatment | To evaluate reduction in splenomegaly by palpation in the MF arm. Patients will be examined for splenomegaly by palpation once per cycle and change from baseline will be calculated over time. |
| Changes in MF Symptoms Assessed by the MPN-SAF (Myeloproliferative Neoplasm Symptom Assessment Form) Score (MF Patients) | Once per cycle (1 cycle=21 days) | To evaluate improvement in MF symptoms in the MF arm, changes in symptom scores over time will be calculated. |
Countries
United States
Participant flow
Recruitment details
The study opened for accrual on October 09, 2015 with an accrual goal of 24 patients. The first patient started treatment July 05, 2016. The study closed to further accrual on November 02, 2017 with total accrual having been met.
Participants by arm
| Arm | Count |
|---|---|
| Alisertib 50 mg BID Patients receive alisertib PO BID on days 1-7. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Alisertib: Administered orally 50 mg BID on days 1-7 of each cycle; one cycle is defined as 21 days (days 8-21 will be rest days). Patients may continue to receive cycles of alisertib until progression of disease or unacceptable toxicity.
Laboratory Biomarker Analysis: Correlative studies
Pharmacological Study: Correlative studies | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Continued Treatment Cycles 2 Through 6 | Adverse Event | 2 |
| Continued Treatment Cycles 2 Through 6 | Lack of Efficacy | 2 |
| Continued Treatment Cycles 2 Through 6 | Progressive Disease | 4 |
| Continued Treatment Cycles 2 Through 6 | Withdrawal by Subject | 2 |
| Follow-up Period (6 Months) | Death | 4 |
| Follow-up Period (6 Months) | Lost to Follow-up | 2 |
| Follow-up Period (6 Months) | Withdrawal by Subject | 5 |
| Registered for Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Alisertib 50 mg BID |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 18 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 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 | 1 Participants |
| Race (NIH/OMB) White | 22 Participants |
| Refractory Acute Megakaryoblastic Leukemia or Myelofibrosis Myelofibrosis | 24 Participants |
| Refractory Acute Megakaryoblastic Leukemia or Myelofibrosis Refractory Acute Megakaryoblastic Leukemia | 0 Participants |
| Region of Enrollment United States | 24 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 5 / 24 |
| other Total, other adverse events | 24 / 24 |
| serious Total, serious adverse events | 8 / 24 |
Outcome results
Primary
Safety Profile of Alisertib Per NCI's Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.
Adverse events will be defined as those included in CTCAE v 4.0. The AEs that were determined to be at least possibly related to study drug and graded 3, 4, 5 are included here. Grade 1 (mild): the event causes discomfort without disruption of normal daily activities. Grade 2 (moderate): the event causes discomfort that affects normal daily activities. Grade 3 (severe): the event makes the patient unable to perform normal daily activities or significantly affects his/her clinical status. Grade 4 (Life-threatening): the patient was at risk of death at the time of the event. Grade 5 (fatal): the event caused death. All patients who received at least 1 dose of alisertib were considered evaluable for this endpoint.
Time frame: From time of treatment to 6 months post discontinuation (range of cycles attempted 1 to 29, median 7.5 cycles, 1 Cycle = 21 days)
Population: Data was collected from all patients for the primary endpoint until May 2018 when it was determined there was sufficient data collected for primary endpoint analysis and primary endpoint was determined to be met. At the time of data cut off, 7 patients remained on active treatment and range of cycles completed by patients was 1-29 (median 7.5 cycles). No further data was collected after May 2018 for primary outcome measure purposes.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Alisertib 50 mg BID | Safety Profile of Alisertib Per NCI's Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. | Neutropenia Grade 3 | 5 Participants |
| Alisertib 50 mg BID | Safety Profile of Alisertib Per NCI's Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. | Neutropenia Grade 4 | 5 Participants |
| Alisertib 50 mg BID | Safety Profile of Alisertib Per NCI's Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. | Febrile Neutropenia Grade 3 | 1 Participants |
| Alisertib 50 mg BID | Safety Profile of Alisertib Per NCI's Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. | Lymphocytopenia Grade 3 | 9 Participants |
| Alisertib 50 mg BID | Safety Profile of Alisertib Per NCI's Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. | Thrombocytopenia Grade 3 | 5 Participants |
| Alisertib 50 mg BID | Safety Profile of Alisertib Per NCI's Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. | Thrombocytopenia Grade 4 | 2 Participants |
| Alisertib 50 mg BID | Safety Profile of Alisertib Per NCI's Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. | Anemia Grade 3 | 5 Participants |
| Alisertib 50 mg BID | Safety Profile of Alisertib Per NCI's Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. | Vertigo Grade 3 | 1 Participants |
| Alisertib 50 mg BID | Safety Profile of Alisertib Per NCI's Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. | Diarrhea Grade 3 | 1 Participants |
| Alisertib 50 mg BID | Safety Profile of Alisertib Per NCI's Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. | Alanine aminotransferase increased Grade 3 | 1 Participants |
| Alisertib 50 mg BID | Safety Profile of Alisertib Per NCI's Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. | Creatinine increased Grade 3 | 1 Participants |
Secondary
Response to Treatment
Serial blood and/or bone marrow samples will be collected at specific timepoints for each disease to determine response to alisertib treatment.
Time frame: Baseline to up to 6 months after the last dose of treatment
Other Pre-specified
Change in Bone Marrow Fibrosis (MF Patients)
Assess change in bone marrow fibrosis in patients in the MF arm. Bone marrow will be assessed at screening and after cycle 6 in this population.
Time frame: Screening and up to 54 weeks
Other Pre-specified
Changes in Biomarker Expression Levels
To evaluate the relationship between biomarker expression levels and response. Biomarkers will include a) genes encoding key enzymes in Aurora kinase signaling, b) markers of cellular aneuploidy and apoptosis, and c) markers of megakaryocytic differentiation.
Time frame: Baseline to up to 6 months after the last dose of treatment
Other Pre-specified
Changes in MF Symptoms Assessed by the MPN-SAF (Myeloproliferative Neoplasm Symptom Assessment Form) Score (MF Patients)
To evaluate improvement in MF symptoms in the MF arm, changes in symptom scores over time will be calculated.
Time frame: Once per cycle (1 cycle=21 days)
Other Pre-specified
Changes in Pharmacodynamic Effects of Alisertib
Serial blood and/or bone marrow samples will be collected at specific timepoints. Flow cytometry, colony forming assays, AURKA autophosphorylation assays, and in vitro cultures of patient specimens to assess the effect of MLN8237 on megakaryocytes and other hematopoietic cells will be measured.
Time frame: Baseline to up to 6 months after the last dose of treatment
Other Pre-specified
Changes in Splenomegaly by Palpation (MF Patients)
To evaluate reduction in splenomegaly by palpation in the MF arm. Patients will be examined for splenomegaly by palpation once per cycle and change from baseline will be calculated over time.
Time frame: Baseline to up to 6 months after the last dose of treatment