Brentuximab Vedotin in Treating Patients With Advanced Systemic Mastocytosis or Mast Cell Leukemia

Study Overview
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Brief Summary
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This pilot clinical trial studies brentuximab vedotin in treating patients with advanced systemic mastocytosis or mast cell leukemia. Monoclonal antibodies, such as brentuximab vedotin, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them

Detailed Description
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Brentuximab vedotin is an antibody with a covalently attached toxin. The antibody portion targets the protein CD30 on the surface of cells, and the toxin acts against those cells. PRIMARY OBJECTIVES: I. To evaluate the response rate to SGN-35 (brentuximab vedotin) in patients with tumor necrosis factor receptor superfamily, member 8 (CD30+) advanced systemic mastocytosis (SM) (ASM or mast cell leukemia [MCL] with or without an associated hematological clonal non-mast cell lineage disease [AHNMD]). SECONDARY OBJECTIVES: I. To evaluate the tolerability and safety profile of SGN-35 in patients with SM. II. To evaluate expression of CD30 on neoplastic mast cells before and during therapy with SGN-35. III. To evaluate changes in mastocytosis related symptom scores and quality of life (QOL) using a modified Myeloproliferative Neoplasm Symptom Assessment Form (MPNSAF). IV. To evaluate the duration of response (DoR) and time to response (TTR). V. To evaluate progression-free survival (PFS). OUTLINE: Patients receive brentuximab vedotin intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6 weeks for 1 year and then every 12 weeks thereafter.

Official Title
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A Study of Brentuximab Vedotin (SGN-35) in CD30-Positive Systemic Mastocytosis With or Without an Associated Hematological Clonal Non-Mast Cell Lineage Disease (AHNMD)

Conditions
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Aggressive Systemic Mastocytosis, Mast Cell Leukemia, Systemic Mastocytosis

Intervention / Treatment
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* Drug: Brentuximab vedotin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Eastern Cooperative Oncology Group (ECOG) performance status of 0-3 Life expectancy > 12 weeks Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN), if caused by ASM/MCL =< 5 x ULN Serum direct bilirubin =< 1.5 x ULN; if considered related to ASM/MCL =< 3 x ULN Serum creatinine =< 2.0 mg/dL A diagnosis of systemic mastocytosis (SM) per 2008 World Health Organization (WHO) Criteria Neoplastic mast cells must express CD30 by immunohistochemistry or flow cytometry At least one of the eligible organ damage findings as defined by the international consensus response criteria Females of childbearing potential and males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug Females of childbearing potential must have a negative serum or urine beta-human chorionic gonadotropin (hCG) pregnancy test result within 7 days prior to the first dose of SGN-35 Females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy Exclusion Criteria: Unwilling or unable to comply with the protocol Any other concurrent severe known disease (except carcinoma in-situ) or concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, or active uncontrolled infection) which could compromise participation in the study History of another primary malignancy that has not been in remission for at least 3 years (the following are exempt from the 3-year limit: non-melanoma skin cancer, fully excised melanoma in situ [stage 0], curatively treated localized prostate cancer, and cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Papanicolaou [PAP] smear) Cardiovascular disease including congestive heart failure grade III or IV according to the New York Heart Association (NYHA) classification, left ventricular ejection fraction of < 50%, myocardial infarction within previous 6 months or poorly controlled hypertension Pregnant or lactating Neuropathy greater than or equal to grade 2 Known hypersensitivity to any excipient contained in the drug formulation Confirmed diagnosis of human immunodeficiency virus (HIV) infection or active viral hepatitis Presenting with an AHNMD requiring immediate cytoreductive therapy or targeted drugs (eg, AML) Received any investigational agent, chemotherapy, interferon-alfa, or 2-chlorodeoxyadenosine (2-CdA, cladribine) within 30 days prior to Day 1 Received hematopoietic growth factor support within 14 days of Day 1 of SGN-35 Use of prednisone (or equivalent corticosteroid dose) for SM up to 10 mg/day or its equivalent is allowed, but it cannot have been started during screening; patients who are on prednisone up to 10 mg/day for medical problems unrelated to SM are also permitted on study Presence of FIP1L1-PDGFR-alpha fusion even with resistance to imatinib Received any treatment with SGN-35 prior to study entry Any surgical procedure within 14 days of Day 1, excluding central venous catheter placement or other minor procedures (eg, skin biopsy)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Brentuximab vedotin<br>Subjects receive a 30-minute IV infusion of brentuximab vedotin once every 21 days for 8 courses, in the absence of disease progression or unacceptable toxicity. | Drug: Brentuximab vedotin<br> <br> * Other names: SGN-35;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) Per Consensus International Response Criteria (Rate of Complete or Partial Remissions or Clinical Improvement) | Overall response rate (ORR) is sum of complete response (CR); partial response (PR); and clinical improvement (CI) in 1 year, ie, ORR=CR+PR+CI. The outcome is the number of participants without dispersion. CR is following with response duration(RD) ≥12 weeks (wk) No mast cell disease Tryptase <20 ng/mL Neutrophils ≥1x10e9/L with normal differential Hemoglobin ≥11 g/dL Platelets ≥100x10e9/L No hepatosplenomegaly No systemic mastocytosis(SM)-related organ damage PR is following with RD ≥12wk Neither CR or progressive disease(PD) Neoplastic mast cells reduced ≥50% Tryptase reduced ≥50% 1+ disease finding resolved CI is following with RD ≥12wk Neither CR; PR; or PD 1+ of findings above Stable disease (SD) Not CR, PR, Cl, or PD Progressive disease (PD) Any of: Worsening organ damage Doubling of laboratory abnormality New transfusion dependence of ≥4 units red cells or platelets at 8wk •+ ≥100% in transfusions for 8wk 10-cm+ splenomegaly | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brentuximab Vedotin Toxicity | Toxicity was assessed as the number of adverse events considered possibly, probably, or definitely-related to treatment with brentuximab vedotin. The outcome is reported as the total number of related events, a number without dispersion, and the number of related events (without dispersion) considered to be either a hematologic toxicity or non-hematologic toxicity. | Up to 1 year | 
| Percent Change of CD30 Expression on Neoplastic Mast Cells | The presence of the CD30 marker (epitope) on neoplastic (cancerous) mast cells in core bone marrow biopsy samples was assessed by immunohistochemical methods, before and after brentuximab vedotin treatment. CD30 is a member of the TNF-receptor (TNF-R) superfamily, and is a transmembrane glycoprotein receptor that is normally at very low levels on the surface of activated T-cells. Overexpression of the CD30 marker is indicative of T-cell lymphoproliferative disorders and neoplastic mast cells, and the effect of a particular treatment on CD30 expression may be related to the efficacy of that treatment. The outcome is reported as the median percentage change in the level of CD30 detected, reported with full range. | Baseline and up to 1 year | 
| Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) Total Symptom Score | The clinical effect of patient symptoms associated with systemic mastocytosis or mast cell leukemia were assessed with the patient-reported outcome survey entitled Myeloproliferative Neoplasm Symptom Assessment Form with Mast Cell Disorder Symptoms [(MPN-SAF(MCD)]. The MPN-SAF(MCD) is a 36-question survey, with possible responses ranged from 0 to 10, with 0 indicating not present or no effect; 1 meaning present but most favorable; and 10 meaning worst imaginable (least favorable). Total range is 0 to 360, with 0 being best possible, and 360 being worst possible. Total symptom score is calculated as the sum of the individual survey scores reported at baseline and after treatment, with lower numbers indicating less effect, and larger numbers indicated greater effect. The outcome is reported as mean score value with dispersion. | Up to 1 year | 
| Quality of Life (QoL) Score Using a Modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) | Overall quality of life (QoL) was assessed by a single specific question from the 36-question Myeloproliferative Neoplasm Symptom Assessment Form with Mast Cell Disorder Symptoms [(MPN-SAF(MCD)] survey. Possible responses for theQoL question range from 0 to 10, with 0 indicating as good as it can be (most favorable), and 10 meaning as bad as it can be (least favorable). The QoL score was obtained at baseline and after treatment. The outcome is reported as mean score with dispersion. | Up to 1 year | 
| Duration of Response (DOR) | Duration of response (DOR) is defined as the time from the start of the first confirmed response until the date of the first documented and confirmed disease progression or death due to ASM or MCL. For participants with a confirmed clinical response, the outcome was to be reported as the median DOR with standard deviation. | Up to 1 year | 
| Time to Response (TTR) | Time to response (TTR) is defined as the time from the date of start of treatment to the date of first confirmed response. For participants with a confirmed clinical response, the outcome was to be reported as the median TTR with standard deviation. | Up to 1 year | 
| Progression-free Survival (PFS) | Progression-free survival (PFS) is defined as the time from the date of start of treatment until disease progression; death; or initiation of new therapy. The outcome is reported as the mean number of days of PFS, with 95% confidence interval. Progressive disease (PD) is any of the following: Worsening of any organ damage Doubling of any laboratory abnormality New transfusion dependence of ≥ 4 units red cells or platelets at 8 wk ≥ 100% increase in transfusions for 8 wk 10-cm+ splenomegaly | Up to 1 year |