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

Primary Purpose

Aggressive Systemic Mastocytosis, Mast Cell Leukemia, Systemic Mastocytosis

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Brentuximab vedotin
Sponsored by
Jason Robert Gotlib
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Aggressive Systemic Mastocytosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • Stanford University, School of Medicine
  • MD Anderson Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Brentuximab vedotin

Arm Description

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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.
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.
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.
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.
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.
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.
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

Full Information

First Posted
March 5, 2013
Last Updated
January 9, 2019
Sponsor
Jason Robert Gotlib
Collaborators
Seagen Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01807598
Brief Title
Brentuximab Vedotin in Treating Patients With Advanced Systemic Mastocytosis or Mast Cell Leukemia
Official Title
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)
Study Type
Interventional

2. Study Status

Record Verification Date
January 2019
Overall Recruitment Status
Completed
Study Start Date
September 2013 (undefined)
Primary Completion Date
September 2017 (Actual)
Study Completion Date
September 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Jason Robert Gotlib
Collaborators
Seagen Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Aggressive Systemic Mastocytosis, Mast Cell Leukemia, Systemic Mastocytosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
10 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Brentuximab vedotin
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Brentuximab vedotin
Other Intervention Name(s)
Adcetris, anti-CD30 antibody-drug conjugate, anti-CD30 ADC, SGN-35
Primary Outcome Measure Information:
Title
Overall Response Rate (ORR) Per Consensus International Response Criteria (Rate of Complete or Partial Remissions or Clinical Improvement)
Description
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
Time Frame
Up to 1 year
Secondary Outcome Measure Information:
Title
Brentuximab Vedotin Toxicity
Description
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.
Time Frame
Up to 1 year
Title
Percent Change of CD30 Expression on Neoplastic Mast Cells
Description
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.
Time Frame
Baseline and up to 1 year
Title
Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) Total Symptom Score
Description
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.
Time Frame
Up to 1 year
Title
Quality of Life (QoL) Score Using a Modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF)
Description
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.
Time Frame
Up to 1 year
Title
Duration of Response (DOR)
Description
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.
Time Frame
Up to 1 year
Title
Time to Response (TTR)
Description
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.
Time Frame
Up to 1 year
Title
Progression-free Survival (PFS)
Description
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
Time Frame
Up to 1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jason Gotlib
Organizational Affiliation
Stanford University Hospitals and Clinics
Official's Role
Principal Investigator
Facility Information:
Facility Name
Stanford University, School of Medicine
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
31350306
Citation
Gotlib J, Baird JH, George TI, Langford C, Reyes I, Abuel J, Perkins C, Schroeder K, Bose P, Verstovsek S. A phase 2 study of brentuximab vedotin in patients with CD30-positive advanced systemic mastocytosis. Blood Adv. 2019 Aug 13;3(15):2264-2271. doi: 10.1182/bloodadvances.2019000152.
Results Reference
derived

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

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