Anakinra: Safety and Efficacy in the Management of Fever During Neutropenia and Mucositis in ASCT

NCT03233776 | Completed Phase 2 DMC

• 1 other identifier: SC35
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

Oral and intestinal mucositis are major risk factors for the occurrence of fever during neutropenia and bloodstream infections after intensive chemo- and radiotherapy. These complications often require dose reductions or cause delay of treatment, and thereby interfere with optimal anticancer treatment. Currently, there are no effective strategies to prevent or treat mucositis and the related complications. The pro-inflammatory cytokine interleukin-1β (IL-1β) has shown pivotal in the pathogenesis of mucositis and recently, it has been established in murine models that IL-1 inhibition significantly ameliorates chemotherapy-induced intestinal mucositis. In this phase IIa study the safety, maximum tolerated dose and efficacy of anakinra, a recombinant human IL-1 receptor antagonist, will be determined in adult patients with multiple myeloma who receive high-dose melphalan (HDM) in the preparation for an autologous hematopoietic stem cell transplantation (ASCT) and are at high risk for experiencing mucositis and fever during neutropenia (FN). After establishing the optimal dose, a pivotal double-blind randomized placebo-controlled multicenter phase IIb trial will be planned to establish efficacy.

Conditions

Multiple Myeloma

Keywords

Anakinra; Mucositis; Hematopoietic stem cell transplantation; Febrile neutropenia

Outcome Measures

Primary Outcomes (1)

• Establish the maximum tolerated dose of anakinra (MTD, 100, 200 or 300 mg).

  In this study, using a traditional 3+3 design, 3 doses of anakinra will be examined: 100, 200 and 300 mg. The first cohort of patients will start with 100 mg. Escalation to the next dose cohort(s) is based on the occurrence of dose limiting toxicities (DLTs). The definition of a DLT is: an opportunistic infection, a SUSAR, severe non-hematological toxicity grade 3-4, or the occurrence of primary graft failure or prolonged neutropenia (neutrophils have not been \>0.5 x10\^9/l on one single day, assessed on day +21, and counting from day 0).

  Day of admission (day -2) until discharge. Maximum period: +30 days.

Secondary Outcomes (14)

• Incidence of fever during neutropenia

  Day of admission (day -2) until discharge. Maximum period: +30 days.

• Incidence of mucositis-related fever

  Day of admission (day -2) until discharge. Maximum period: +30 days.

• Daily mean CRP level

  Day of admission (day -2) until discharge. Maximum period: +30 days.

• Intestinal mucositis as measured by the area-under-the-curve of reciprocal citrulline levels

  Day of admission (day -2) until discharge. Maximum period: +30 days.

• Clinical mucositis as determined by the daily mouth and gut scores

  Day of admission (day -2) until discharge. Maximum period: +30 days.

Study Arms (1)

Anakinra

EXPERIMENTAL

Dosage form: intravenous. Dosage: either 100 mg, 200 mg or 300 mg. Frequency: once daily. Duration: 15 days (day -2 until day +12).

Drug: Anakinra

Interventions

Anakinra DRUG

Subjects will be treated with a daily dose of anakinra, intravenously, starting on day -2, until day +12 (day 0 is day of SCT). Predefined doses are 100 mg , 200 mg and 300 mg.

Also known as: Kineret

Anakinra

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Aged ≥ 18 years
• Diagnosed with multiple myeloma
• Scheduled to receive an autologous SCT after myeloablative therapy with high-dose melphalan
• Managed with a central venous catheter (triple- or quadruple lumen)
• Is able and willing to participate
• Has provided written informed consent
• Has a negative tuberculosis Quantiferon test
• Has negative serology for active hepatitis B and C
• Has negative serology for HIV
• Has no known hypersensitivity to Escherichia coli derived products or any components of anakinra
• Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation (during treatment with study medication), and for 30 days after the last dose.

You may not qualify if:

• Inability to understand the nature and extent of the trial and the procedures required
• Enrolment in any other investigational treatment study or use of an investigational agent during the stem cell transplantation (this means studies in multiple myeloma regarding induction or maintenance treatment are permitted).
• Women who are pregnant or nursing
• Diagnosed with amyloidosis or light-chain deposition disease
• ALT or AST greater than 2.0 x upper limit of normal (ULN) of the local laboratories values.
• Bilirubin levels greater than 2.0 x upper limit of normal (ULN) of the local Laboratories values, except for benign non-malignant indirect hyperbilirubinemia such as Gilbert syndrome
• Impaired renal function with eGFR \<40 ml/min
• Received a live vaccine during the 3 months prior to baseline visit
• Recent use of IL-1 antagonist, such as anakinra, rilonacept or canakinumab, within three months prior to baseline visit
• Treatment with TNFα inhibiting agents (such as etanercept, adalimumab, infliximab, certolizumab and golimumab).
• Uncontrolled bacterial or viral infections, or fungal infections, at the start of therapy
• Documented colonization with highly resistant microorganisms (HRMOs, in Dutch: BRMO's), prior to registration, or detected during screening procedures
• Documented colonization with methicillin-resistant Staphylococcus aureus (MRSA), prior to registration
• Subjects who are not able to receive antibacterial prophylaxis with quinolones (because of hypersensitivity)
• Subjects with an active solid malignancy prior to registration, with the exception of cutaneous basal or squamous cell carcinomas

Sponsors & Collaborators

• Radboud University Medical Center: lead

Study Sites (1)

Radboud university medical center

Nijmegen, 6525 GA, Netherlands

Location

Related Publications (1)

• Wardill HR, de Mooij CEM, Da Silva Ferreira AR, Havinga H, Harmsen HJM, van der Velden WJFM, van Groningen LFJ, Tissing WJE, Blijlevens NMA. Supporting the gastrointestinal microenvironment during high-dose chemotherapy and stem cell transplantation by inhibiting IL-1 signaling with anakinra. Sci Rep. 2022 May 11;12(1):6803. doi: 10.1038/s41598-022-10700-3.

  PMID: 35546555 DERIVED

MeSH Terms

Conditions

Multiple Myeloma; Mucositis; Febrile Neutropenia

Interventions

Interleukin 1 Receptor Antagonist Protein

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Mouth Diseases; Stomatognathic Diseases; Neutropenia; Agranulocytosis; Leukopenia; Cytopenia; Leukocyte Disorders

Intervention Hierarchy (Ancestors)

Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Study Officials

• Nicole Blijlevens, MD PhD

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: SUPPORTIVE CARE
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 3+3 design

Study Record Dates

• First Submitted: July 19, 2017
• First Posted: July 31, 2017
• Study Start: August 21, 2017
• Primary Completion: April 2, 2020
• Study Completion: April 2, 2020
• Last Updated: November 18, 2024

Record last verified: 2020-11

Locations

NL (1)