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Anakinra: Safety and Efficacy in the Management of Fever During Neutropenia and Mucositis in ASCT (AFFECT-1)

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ClinicalTrials.gov Identifier: NCT03233776
Recruitment Status : Recruiting
First Posted : July 31, 2017
Last Update Posted : December 6, 2018
Sponsor:
Information provided by (Responsible Party):
Radboud University

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.


Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: Anakinra Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Intervention Model: Sequential Assignment
Intervention Model Description: 3+3 design
Masking: None (Open Label)
Primary Purpose: Supportive Care
Official Title: Safety and Efficacy of Interleukin-1 Inhibitor Anakinra for the Amelioration of Fever During Neutropenia and Mucositis in Patients With Multiple Myeloma Receiving an Autologous Stem Cell Transplantation After High-dose Melphalan
Actual Study Start Date : August 21, 2017
Estimated Primary Completion Date : February 2019
Estimated Study Completion Date : November 2019


Arm Intervention/treatment
Experimental: Anakinra
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
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.
Other Name: Kineret




Primary Outcome Measures :
  1. Establish the maximum tolerated dose of anakinra (MTD, 100, 200 or 300 mg). [ Time Frame: Day of admission (day -2) until discharge. Maximum period: +30 days. ]
    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).


Secondary Outcome Measures :
  1. Incidence of fever during neutropenia [ Time Frame: Day of admission (day -2) until discharge. Maximum period: +30 days. ]
  2. Incidence of mucositis-related fever [ Time Frame: Day of admission (day -2) until discharge. Maximum period: +30 days. ]
  3. Daily mean CRP level [ Time Frame: Day of admission (day -2) until discharge. Maximum period: +30 days. ]
  4. Intestinal mucositis as measured by the area-under-the-curve of reciprocal citrulline levels [ Time Frame: Day of admission (day -2) until discharge. Maximum period: +30 days. ]
  5. Clinical mucositis as determined by the daily mouth and gut scores [ Time Frame: Day of admission (day -2) until discharge. Maximum period: +30 days. ]
  6. Days with fever (≥ 38.5° C) [ Time Frame: Day of admission (day -2) until discharge. Maximum period: +30 days. ]
  7. Incidence of bloodstream infections i.e. bacteremia [ Time Frame: Day of admission (day -2) until discharge. Maximum period: +30 days. ]
  8. Length of hospital stay in days [ Time Frame: Day of admission (day -2) until discharge. Maximum period: +30 days. ]
  9. Use of systemic antimicrobial agents (incidence and duration) [ Time Frame: Day of admission (day -2) until discharge. Maximum period: +30 days. ]
  10. Use of analgesic drugs (incidence and duration) [ Time Frame: Day of admission (day -2) until discharge. Maximum period: +30 days. ]
  11. Use of total parenteral nutrition (TPN) (incidence and duration) [ Time Frame: Day of admission (day -2) until discharge. Maximum period: +30 days. ]
  12. Quality of life [ Time Frame: Baseline, at discharge (average: 23 days; maximum: after 30 days), +100 days, +1 year ]
    Quality of life according to the EORTC QLQ-C30

  13. Fatigue severity [ Time Frame: Baseline, at discharge (average: 23 days; maximum: after 30 days), +100 days, +1 year ]
    Severity of fatigue as the score measured by the validated FACIT-Fatigue scale

  14. Short term overall survival [ Time Frame: +100 days and +1 year ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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
  • History of mycobacterial infection.
  • Subjects with intrinsic disorders of the gastro-intestinal (GI) tract, including, but not limited to: Crohn's disease, ulcerative colitis, celiac disease, short bowel syndrome.
  • Subject has any concurrent medical or psychiatric condition or disease that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03233776


Contacts
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Contact: Postbus Trialbureau Hematologie-Oncologie +31 24 36 14 794 trialbureauhemat-onco@radboudumc.nl

Locations
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Netherlands
Radboud university medical center Recruiting
Nijmegen, Netherlands, 6525 GA
Contact: Postbus Trialbureau Hematologie-Oncologie    +31 24 36 14 794    trialbureauhemat-onco@radboudumc.nl   
Principal Investigator: Nicole Blijlevens, MD PhD         
Sponsors and Collaborators
Radboud University
Investigators
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Principal Investigator: Nicole Blijlevens, MD PhD Radboud University

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Responsible Party: Radboud University
ClinicalTrials.gov Identifier: NCT03233776     History of Changes
Other Study ID Numbers: SC35
First Posted: July 31, 2017    Key Record Dates
Last Update Posted: December 6, 2018
Last Verified: December 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Radboud University:
Anakinra
Mucositis
Hematopoietic stem cell transplantation
Febrile neutropenia

Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Mucositis
Neutropenia
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Mouth Diseases
Stomatognathic Diseases
Agranulocytosis
Leukopenia
Leukocyte Disorders
Interleukin 1 Receptor Antagonist Protein
Antirheumatic Agents