SL-401 in Patients with Advanced, High Risk Myeloproliferative Neoplasms
There are 2 parts to this study: Part 1 (dose escalation) and Part 2 (dose expansion). The goal of Part 1 of this clinical research study is to find the highest tolerable dose of SL-401 that can be given to patients with either myelofibrosis (MF), chronic myelomonocytic leukemia (CMML), advanced systemic mastocytosis (SM), or advanced symptomatic primary eosinophilic disorder (PED). The goal of Part 2 of this research study is to learn if the dose found in Part 1 can help to control the disease. The safety of this drug will be studied in both parts of this study.
Disease Group: Myeloproliferative Diseases
Treatment Agent: SL-401
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Stemline Therapeutics, Inc.
Primary Objective: The primary objectives of the study are to determine the maximum tolerated dose (MTD) or the maximum tested dose at which multiple dose-limiting toxicities (DLTs) are not observed of SL-401 and to characterize the safety profile of SL-401. An additional primary objective for the Stage 2 portion of the study is a preliminary assessment of overall response rates associated with SL-401 in each of the 4 evaluated myeloproliferative neoplasms (MPN). Secondary Objectives: The secondary objectives for both study stages are to characterize the anti-tumor activity (including response rates, components of the response criteria, duration of response [DUR], progression-free survival (PFS), and overall survival [OS]), pharmacokinetics (PK) and immunogenicity of SL-401. Exploratory Objectives: Exploratory objectives are to characterize expression of interleukin-3 receptor (IL-3R)/CD123 (and other potentially relevant stem cell and disease markers) on myeloid malignant cells and associated cell populations in the and bone marrow (when feasible), to evaluate potential changes in IL-3R/CD123 (and other potentially relevant marker) expressing populations over time, and preliminary correlation of baseline IL-3R/CD123 (and other potentially relevant marker) expression and clinical efficacy (including response rates).
IRB Review and Approval Date: 07/02/2015
Recruitment Status: Open
Projected Accrual: 78-102
1) The patient is 18 years old or older.
2) The patient has an Eastern Cooperative Oncology Group (ECOG) performance score of 0-2.
3) The patient has adequate baseline organ function, including cardiac, renal, and hepatic function: Left Ventricular Egection Fraction (LVEF) >/= institutional lower limit of normal as measured by multigated acquisition scan or 2-dimensional (2-D) Echocardiogram (ECHO) within 28 days prior to start of therapy and no clinically significant abnormalities on a 12-lead electrocardiogram (ECG). Serum creatinine </= 1.5 mg/dL (or </= 114 µmol/L). Serum albumin >/= 3.2 g/dL (or >/= 32 g/L) in the absence of receipt of (IV) albumin within the previous 72 hours. Bilirubin </= 1.5 mg/dL (or </= 26 µmol/L). Aspartate Transaminase (AST) and Alanine Transaminase (ALT) </= 2.5 times the upper limit of normal (ULN). Creatine phosphokinase (CPK) </= 2.5 times the ULN.
4) If a woman of child bearing potential (WOCBP), the patient has a negative serum or urine pregnancy test within 1 week prior to SL-401 treatment (intervals shorter than 1 week are acceptable, if required by institutional guidelines).
5) The patient has signed informed consent prior to initiation of any study-specific procedures or treatment.
6) The patient is able to adhere to the study visit schedule and other protocol requirements, including follow-up for response assessments.
7) The patient (either male or female) agrees to use acceptable contraceptive methods for the duration of time in the study, and to continue to use acceptable contraceptive methods for 2 months after the last SL-401 infusion.
8) Patient has an Absolute Neutrophil Count (ANC) >/= 0.5×10^9/L.
9) INCLUSION CRITERIA SPECIFIC TO PATIENTS WITH MF (STAGES 1 AND 2)
10) Patient has a diagnosis of either Primary Myelofibrosis (PMF), post-polycythermia vera (pPV) MF, or post-essential thrombocythemia (pET) MF.
11) Patient has a Dynamic International Prognostic Scoring System (DIPSS-plus) score of either 2-3 (intermediate-2 risk) or >/= 4 (high risk). Patient must have >/=2 of the following: Age >65 years. Hb <10 g/dL. Leukocyte count >25×10^9/L. Circulating (peripheral blood) blasts >/= 1%. Constitutional symptoms, defined as either weight loss >10% during prior 6 months or fever (>37.5°C) or night sweats not attributable to other etiologies persisting for >1 month. Platelet count <100×10^9/L. Unfavorable karyotype (complex karyotype, or abnormalities that include +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p-, or 11q23 rearrangement). Red blood cell (RBC) transfusion dependence (defined as transfusion of =6 units of packed red blood cells (pRBCs) during 12 weeks prior to study enrollment for an Hb <8.5 g/dL in the absence of bleeding or treatment-induced anemia. [It should be noted that patients who are transfusion-dependent will also have a hemoglobin <10 g/dL and hence accrue 2 points in scoring]).
12) Patient has symptomatic MF which is considered refractory to, resistant to, or relapsed following prior ruxolitinib or other Janus Kinase (JAK) inhibitor therapy by the Investigator. Patients who are not candidates for JAK inhibitor therapy (because of baseline Absolute Neutrophil Count [ANC] <1×10^9/L or platelets <100×10^9/L or other reasons are eligible provided that all other entry criteria are met).
13) Patient is not an immediate candidate for allogeneic Stem Cell Transplantation (SCT).
14) Patient has a peripheral blood blast count <20%.
15) Patient discontinued JAK inhibitors (ruxolitinib or others) or any investigational anti-MF therapy at least 14 days prior to study entry, unless specified below.
16) Patient discontinued any other anti-MF therapy at least 28 days prior to study entry, including interferon, thalidomide, lenalidomide, or cytotoxic therapies.
17) INCLUSION CRITERIA SPECIFIC TO PATIENTS WITH CMML.
18) Patient has a diagnosis of CMML involving each of the following: Peripheral blood monocytosis (>/=1×10^9/L) that cannot be attributed to infectious, autoimmune/connective-tissue or other non-neoplastic etiologies. Absence of Philadelphia chromosome t(9,22), as assessed per cytogenetic profile (BM) or BCR-ABL1 fusion oncogene by either Fluorescence In Situ Hybridization (FISH) or PCR (blood or BM). For patients with evidence of eosinophilia, absence of Platelet-derived Growth Factor Receptor (PDGFR)-a or PDGFR-ß gene re-arrangements defined specifically as: The absence of FIPL1-PDGFRA fusion gene (by reverse transcription [RT]-PCR or interphase/metaphase FISH) on evaluation of peripheral blood or BM (i.e., FISH for the CHIC2 deletion [4q12]), and the absence of 5q33 translocation on cytogenetic analysis of BM aspirate/biopsy (i.e., PDGFRB rearrangement).
19) #19 CONTINUED...Less than 20% blasts and promonocytes in both peripheral blood and BM. Dysplasia involving 1 or more myeloid lineage on BM evaluation. (If dysplasia is absent or minimal, diagnosis of CMML is appropriate if the above 4 criteria are met, and an acquired, clonal or molecular genetic abnormality is present in the hematopoietic cells, AND/OR if the monocytosis has persisted for >/= 3 months and other non-neoplastic etiologies have been excluded.
20) Patient has CMML-1 that is refractory to, resistant to, or relapsed following at least three 4-week cycles of a prior hypomethylating agent (azacytidine, decitabine), OR has CMML-2 (10-19% BM blasts or 5-19% circulating blasts) regardless of prior hypomethylating agent therapy.
21) Patient is not an immediate candidate for allogeneic SCT.
22) Patient discontinued any investigational anti-CMML therapy at least 14 days prior to study entry.
23) Patient discontinued any hypomethylating agents at least 28 days prior to study entry.
24) INCLUSION CRITERIA SPECIFIC TO PATIENTS WITH ADVANCED SM (STAGES 1 AND 2)
25) Patient has SM, defined as the presence of multifocal dense infiltrates of mast cells (MCs) (>15 MCs in aggregate) detected in BM and/or other extracutaneous organs, and at least one of the following: In biopsy sections of BM or other extracutaneous organs, >25% of the MCs in the infiltrate are spindle-shaped, have atypical morphologic features OR >25% of MCs on the BM aspirate smear are immature or atypical. Detection of an activating point mutation at codon 816 in KIT in BM, blood or another extracutaneous organ. MCs in BM, blood, or other extracutaneous organ express CD2 and/or CD25 in addition to normal mast cell markers. Serum total tryptase persistently (i.e., >1 documented assessment) >20ng/ml (unless there is an associated clonal myeloid disorder, in which case this parameter is not valid).
Criteria truncated, please contact Prinicipal Investigator's office for full criteria
1) Patient has persistent clinically significant toxicities Grade >/=
2 from previous chemotherapy not readily controlled by supportive
measures (excluding alopecia, nausea, and fatigue).
2) Patient has received treatment with chemotherapy, wide-field radiation, or biologic therapy within 14 days of study entry.
3) Patient has received treatment with another investigational agent within 14 days of study entry or concurrent treatment with another investigational agent.
4) Patient has previously received treatment with SL-401 or has a known hypersensitivity to any components of the drug product.
5) Patient has an active malignancy and/or cancer history (excluding myeloproliferative disorders and concomitant myeloid malignancies as specified in the inclusion criteria) that can confound the assessment of the study endpoints. Patients with a past cancer history (within 2 years of entry) and/or ongoing active malignancy or substantial potential for recurrence must be discussed with the Sponsor before study entry. Patients with the following neoplastic diagnoses are eligible: non-melanoma skin cancer, carcinoma in situ (including superficial bladder cancer), cervical intraepithelial neoplasia, or organ-confined prostate cancer with no evidence of progressive disease.
6) Patient has clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association Class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction, unstable angina, or stroke within 6 months prior to study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication).
7) Patient has uncontrolled, clinically significant pulmonary disease (e.g., chronic obstructive pulmonary disease, pulmonary hypertension) that, in the Investigator’s opinion, would put the patient at significant risk for pulmonary complications during the study.
8) Patient has known active or suspected disease involvement of the central nervous system (CNS). If suspected due to clinical findings, CNS disease should be ruled out with relevant imaging and/or examination of cerebrospinal fluid.
9) Patient is receiving immunosuppressive therapy, with the exception of corticosteroids as specified in the inclusion criteria and tacrolimus, for treatment or prophylaxis of graft-versus-host disease (GVHD). If the patient has been on immunosuppressive treatment or prophylaxis for GVHD, the treatment(s) must have been discontinued at least 14 days prior to study drug and there must be no evidence of Grade >/= 2 GVHD.
10) Patient has uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, disseminated intravascular coagulation, or psychiatric illness that would limit compliance with study requirements.
11) Patient is pregnant or breast feeding.
12) Patient has known human immunodeficiency virus (HIV).
13) Patient has evidence of active or chronic Hepatitis B or Hepatitis C infection.
14) Patient is oxygen-dependent.
15) Patient has any medical condition that in the Investigator’s opinion place the patient at an unacceptably high risk for toxicities.
16) EXCLUSION CRITERIA SPECIFIC TO PATIENTS WITH MF (STAGES 1 AND 2)
17) Patient is Philadelphia chromosome-positive t(9,22), as assessed per cytogenetic profile (BM) or has BCR-ABL1 fusion oncogene by either fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR) (blood or BM).
18) Patient requires corticosteroid therapy at a dose of >10 mg prednisone per day (or equivalent).
19) Patient requires ongoing hydroxyurea therapy. (Hydroxyurea for the management of highly proliferative disease may be allowed with the approval of the Sponsor and Medical Monitor.)
20) Patient received splenic irradiation within 6 months prior to study entry.
21) Patient had prior leukemic transformation of MF.
22) EXCLUSION CRITERIA SPECIFIC TO PATIENTS WITH CMML.
23) Patient requires corticosteroid therapy at a dose of >10 mg prednisone per day (or equivalent).
24) EXCLUSION CRITERIA SPECIFIC TO PATIENTS WITH ADVANCED, SYMPTOMATIC PED (STAGES 1 AND 2)
25) Patient has imatinib-sensitive gene re-arrangements, mutations/translocations defined as any of the following: FIPL1-PDGFRA fusion gene (gene re-arrangement); 5q33 translocation (PDGFRB fusion gene (gene-rearrangement); BCR-ABL mutations (t[9,22]/Philadelphia chromosome).
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