Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase, Primary Myelofibrosis, Secondary Myelofibrosis
Conditions
Brief summary
This phase II trial studies how well second mitochondrial-derived activator of caspases (SMAC) mimetic LCL161 (LCL161) works in treating patients with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocytosis myelofibrosis. SMAC mimetic LCL161 may help control the growth of abnormal cells by promoting apoptosis (programmed cell death).
Detailed description
PRIMARY OBJECTIVES: I. To determine the efficacy of LCL161 as therapy for primary myelofibrosis (PMF), post-polycythemia vera (PV) myelofibrosis (MF) and post-essential thrombocytosis (ET) MF. II. To determine the objective response which is defined as CR (complete remission) + PR (partial remission) + CI (clinical improvement) after three cycles of treatment. SECONDARY OBJECTIVES: I. To determine the safety of LCL161 as therapy for PMF, post-PV MF and post-ET MF. II. To determine time to response and response duration. III. To assess changes in symptom burden as assessed by Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) and M.D. Anderson Symptom Inventory (MDASI) questionnaires. EXPLORATORY OBJECTIVE: I. To assess the mechanisms of action of LCL161 in patients with MF; these studies will include the analysis of baculoviral IAP repeat containing 2 (cIAP1), X-linked inhibitor of apoptosis, E3 ubiquitin protein ligase (XIAP), and poly (adenosine diphosphate \[ADP\]-ribose) polymerase 1 (PARP) protein levels which will be determined by western blot (actin as loading control) and will be measured at baseline and at beginning of each cycle for first 3 cycles and at end of study. OUTLINE: Patients receive SMAC mimetic LCL161 orally (PO) on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days.
Interventions
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERQuestionnaire Administration
Ancillary studies
Given PO
Sponsors
National Cancer Institute (NCI)
Novartis Pharmaceuticals
M.D. Anderson Cancer Center
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
* Patients must provide written informed consent * Willing and able to comply with scheduled visits, treatment plan and laboratory tests * Patient is able to swallow and retain oral medication * Must be diagnosed with treatment requiring PMF or post ET/PV MF with intermediate-1, intermediate -2 or high risk disease according to the International Working Group (IWG) prognostic scoring system, or if with low risk disease then with symptomatic splenomegaly that is \>= 5 cm below left costal margin by physical exam * Patients who are not candidates for, intolerant, or relapsed/refractory to ruxolitinib * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * Absolute neutrophil count (ANC) \>= 0.5 x 10\^9/L (1500/mm\^3) * Serum direct bilirubin =\< 2.0 x ULN (upper limit of normal) * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x ULN, except for patients with MF involvement of the liver who must have AST and ALT =\< 5 x ULN * Serum creatinine =\< 1.5 x ULN * Treatment-related toxicities from prior therapies must have resolved to grade =\< 1 * At least 2 weeks from prior MF-directed treatment (till the start of study drug)
Exclusion criteria
* Any concurrent severe and/or uncontrolled medical conditions that could increase the patient's risk for toxicity while in the study or that could confound discrimination between disease- and study treatment-related toxicities * Impaired cardiac function or clinically significant cardiac diseases, including any of the following: history or presence of ventricular tachyarrhythmia; presence of unstable atrial fibrillation (ventricular response \> 100 beats per minute \[bpm\]); patients with stable atrial fibrillation are eligible, provided they do not meet any of the other cardiac
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Response | After 3 courses of Therapy | Will be defined as complete remission (CR), partial remission (PR), or clinical improvement (CI) after 3 courses of treatment according to International Working Group (IWG) consensus criteria for myelofibrosis. Complete remission (CR): bone marrow blasts \<5%, hemoglobin \>/= 10, absolute neutrophil count (ANC) \>/= 1000, platelets \>/= 100, \<2% immature myeloid cell, spleen and liver not palpable. Partial Response (PR): CR plus one or more of the following: ANC \>/= 1000, decreased platelets by 50%, hemoglobin \>/= 8.5 but \< 10, \<2% immature myeloid cells. Clinical improvement (CI): hemoglobin increase of 2g/dl, transfusion independence or reduction splenomegaly and/or hepatomegaly \>/= 50%, \>/=50% reduction in MPN-SAF TSS |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | Up to 7 years 5 Months | duration of response is defined as the date at which the subject's objective status is first noted to be a CR or PR to the date progression is documented (if one has occurred) or to the date of last follow-up (for those subjects who have not progressed). |
| Time to Response | Up to 7 years 5 months | The time to response is defined as the time from study registration to the first date at which the subject's objective status was classified as a response (CR or PR). In subjects who do not achieve a response, time to response will be censored at the subject's last evaluation date. The distribution for each of these event-time variables (duration of response and time to response) will be estimated by Kaplan-Meier curves. |
| Overall Survival | Up to 7 years 5 months | Time from date of treatment start until date of death due to any cause or last Follow-up. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (SMAC Mimetic LCL161) Patients receive SMAC mimetic LCL161 PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Laboratory Biomarker Analysis: Correlative studies
Questionnaire Administration: Ancillary studies
Smac Mimetic LCL161: Given PO | 50 |
| Total | 50 |
Baseline characteristics
| Characteristic | Treatment (SMAC Mimetic LCL161) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 37 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants |
| Age, Continuous | 72 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 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 | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) White | 42 Participants |
| Region of Enrollment United States | 50 participants |
| Sex: Female, Male Female | 22 Participants |
| Sex: Female, Male Male | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 50 |
| other Total, other adverse events | 50 / 50 |
| serious Total, serious adverse events | 33 / 50 |
Outcome results
Primary
Number of Participants With a Response
Will be defined as complete remission (CR), partial remission (PR), or clinical improvement (CI) after 3 courses of treatment according to International Working Group (IWG) consensus criteria for myelofibrosis. Complete remission (CR): bone marrow blasts \<5%, hemoglobin \>/= 10, absolute neutrophil count (ANC) \>/= 1000, platelets \>/= 100, \<2% immature myeloid cell, spleen and liver not palpable. Partial Response (PR): CR plus one or more of the following: ANC \>/= 1000, decreased platelets by 50%, hemoglobin \>/= 8.5 but \< 10, \<2% immature myeloid cells. Clinical improvement (CI): hemoglobin increase of 2g/dl, transfusion independence or reduction splenomegaly and/or hepatomegaly \>/= 50%, \>/=50% reduction in MPN-SAF TSS
Time frame: After 3 courses of Therapy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (SMAC Mimetic LCL161) | Number of Participants With a Response | 15 Participants |
Secondary
Duration of Response
duration of response is defined as the date at which the subject's objective status is first noted to be a CR or PR to the date progression is documented (if one has occurred) or to the date of last follow-up (for those subjects who have not progressed).
Time frame: Up to 7 years 5 Months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (SMAC Mimetic LCL161) | Duration of Response | 31.5 Months |
Secondary
Overall Survival
Time from date of treatment start until date of death due to any cause or last Follow-up.
Time frame: Up to 7 years 5 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (SMAC Mimetic LCL161) | Overall Survival | 34 Months |
Secondary
Time to Response
The time to response is defined as the time from study registration to the first date at which the subject's objective status was classified as a response (CR or PR). In subjects who do not achieve a response, time to response will be censored at the subject's last evaluation date. The distribution for each of these event-time variables (duration of response and time to response) will be estimated by Kaplan-Meier curves.
Time frame: Up to 7 years 5 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (SMAC Mimetic LCL161) | Time to Response | 1.4 Months |