Ibrutinib in Treating Patients With Advanced Systemic Mastocytosis

Jason Robert Gotlib

Status and phase

Terminated

Phase 2

Conditions

Systemic Mastocytosis

Mast Cell Leukemia

Aggressive Systemic Mastocytosis

Treatments

Drug: Ibrutinib

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT02415608

HEMMPD0021 (Other Identifier)

P30CA124435 (U.S. NIH Grant/Contract)

IRB-31815

NCI-2014-02341 (Registry Identifier)

Details and patient eligibility

About

This phase 2 trial studies ibrutinib to see how well it works in treating patients with systemic (affecting the entire body) mastocytosis that has spread to other parts of the body and usually cannot be cured or controlled with treatment (advanced). Systemic mastocytosis is a disease in which too many mast cells (a type of immune system cell) are found throughout the body. Mast cells give off chemicals such as histamine that can cause flushing (a hot, red face), itching, abdominal cramps, muscle pain, nausea, vomiting, diarrhea, low blood pressure, and shock. Ibrutinib may stop the growth of mast cells by blocking some of the enzymes needed for cell growth.

Full description

PRIMARY OBJECTIVE:

Evaluate the response rate to ibrutinib in patients with advanced systemic mastocytosis (SM) (aggressive systemic mastocytosis [ASM] or mast cell leukemia [MCL], or SM-associated hematologic non-mast cell disorder [AHNMD]) by the end of 6 cycles (6 months).

SECONDARY OBJECTIVES:

Evaluate the tolerability and safety profile of ibrutinib in patients with advanced SM. Evaluate the pharmacokinetic (PK) profile of ibrutinib in a subset of patients with advanced SM. Evaluate changes in histopathology (blood and bone marrow) of patients with advanced SM in response to ibrutinib therapy. Evaluate changes in mastocytosis related symptom scores and quality-of-life (QOL) using a modified Myeloproliferative Neoplasm Symptom Assessment Form (MPNSAF). Evaluate the duration of response (DoR) and time to response (TTR). Evaluate progression-free survival (PFS) and overall survival.

OUTLINE:

Patients receive ibrutinib orally (PO) once daily (QD) on days 1 to 28. Treatment repeats every 28 days for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients achieving an unconfirmed or confirmed clinical improvement (CI), partial response (PR), or complete response (CR) by the end of course 6 will be permitted to continue maintenance courses of ibrutinib on an ongoing basis until loss of response/progressive disease, or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 6 months thereafter.

Enrollment

4 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

INCLUSION CRITERIA

Diagnosis of systemic mastocytosis per 2008 World Health Organization (WHO) criteria. Those with advanced systemic mastocytosis (ASM); mast cell leukemia (MCL); or systemic mastocytosis-associated hematological clonal non-mast cell lineage disease (SM-AHNMD) required to have at least 1 organ damage finding
Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 3.0 x upper limit of normal (ULN); if considered related to ASM/MCL ≤ 5 x ULN
Estimated creatinine clearance ≥ 30 mL/min (Cockcroft-Gault)
Total bilirubin ≤ 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin); if considered related to ASM/MCL ≤ 3 x ULN
Female subjects must be of non-reproductive potential, or if of childbearing potential must have a negative serum pregnancy test upon study entry
Must agree to use highly effective methods of birth control
Written informed consent
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3
Life expectancy > 12 weeks

EXCLUSION CRITERIA

Received any investigational agent, chemotherapy, interferon-alpha, or 2-chlorodeoxyadenosine (2-CdA, cladribine) within 30 days prior to day 1; or monoclonal antibody ≤ 6 weeks prior to first administration of study treatment (patients with an AHNMD with progressive leukocytosis who require control of their counts are permitted to receive hydroxyurea)
Diagnosis of AHNMD requiring immediate cytoreductive therapy or targeted drugs (eg, acute myeloid leukemia [AML])
History of other malignancies, except:
- Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before the first dose of study drug, and at low risk for recurrence
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- Adequately treated carcinoma in situ without evidence of disease
Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc., or chronic administration [> 14 days] of > 10 mg/day of prednisone) within 28 days of the first dose of study drug
Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug
Systemic treatment for infection completed ≤ 14 days before the first dose of study drug
Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4), grade 0 or 1, or to the levels dictated in the inclusion/exclusion criteria with the exception of alopecia
Known bleeding disorders (eg, severe von Willebrand's disease) or severe hemophilia
History of stroke or intracranial hemorrhage within 6 months prior to enrollment
Known history of human immunodeficiency virus (HIV) or
Active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV)
Major surgery within 4 weeks of first dose of study drug
Any life-threatening illness, medical condition, or organ system dysfunction that could compromise the subject's safety or put the study outcomes at undue risk
Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization
Unable to swallow capsules or malabsorption syndrome
Disease significantly affecting gastrointestinal function
Resection of the stomach or small bowel
Symptomatic inflammatory bowel disease
Ulcerative colitis
Partial or complete bowel obstruction
Requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor
Lactating or pregnant
Unwilling or unable to participate in all required study evaluations and procedures
Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations)
Known hypersensitivity to any excipient contained in the drug
Received hematopoietic growth factor support within 14 days of day 1 of ibrutinib (Jehovah's witnesses may be given an erythropoiesis-stimulating agent before and during the trial in lieu of red blood cell transfusions but anemia and/or red blood cell (RBC) transfusion dependence cannot be used for response assessment in these patients)
Presence of the factor interacting with poly(A) polymerase alpha (PAPOLA) and cleavage and polyadenylation specific factor 1 (CPSF1) (FIP1L1)-platelet-derived growth factor receptor, alpha polypeptide (PDGFRalpha) fusion even with resistance to imatinib (such patients are no longer defined as systemic mastocytosis by the WHO)
Received any treatment with ibrutinib prior to study entry
The concomitant use of warfarin or other vitamin K antagonists unless felt to be of significant clinical need; low molecular weight heparin or other anticoagulants may be used instead if anticoagulation is required