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

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)

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

Study Overview

• Status: Completed
• Conditions: Systemic Mastocytosis; Mast Cell Leukemia; Aggressive Systemic Mastocytosis
• Intervention / Treatment: Drug: Brentuximab vedotin

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University, School of Medicine
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Brentuximab vedotin; 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; Other Names: Adcetris; SGN-35; anti-CD30 antibody-drug conjugate; anti-CD30 ADC

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Jason Robert Gotlib
• Collaborators: Seagen Inc.
• Investigators: Principal Investigator: Jason Gotlib, Stanford University Hospitals and Clinics

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: September 1, 2013
• Primary Completion (Actual): September 1, 2017
• Study Completion (Actual): September 1, 2017

Study Registration Dates

• First Submitted: March 5, 2013
• First Submitted That Met QC Criteria: March 6, 2013
• First Posted (Estimate): March 8, 2013

Study Record Updates

• Last Update Posted (Actual): January 29, 2019
• Last Update Submitted That Met QC Criteria: January 9, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Immune System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Hypersensitivity; Neoplasms, Connective Tissue; Immune Complex Diseases; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia; Mastocytosis; Mastocytosis, Systemic; Leukemia, Mast-Cell; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Brentuximab Vedotin; Immunoconjugates
• Other Study ID Numbers: IRB-25727 (Other Identifier: Stanford IRB); NCI-2013-00537 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); 107011 (Other Identifier: Organon); HEMMPD0016 (Other Identifier: OnCore)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No