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

Primary Purpose

Multiple Myeloma

Status
Completed
Phase
Phase 2
Locations
Netherlands
Study Type
Interventional
Intervention
Anakinra
Sponsored by
Radboud University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional supportive care trial for Multiple Myeloma focused on measuring Anakinra, Mucositis, Hematopoietic stem cell transplantation, Febrile neutropenia

Eligibility Criteria

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

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.

Sites / Locations

  • Radboud university medical center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Anakinra

Arm Description

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

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

Incidence of fever during neutropenia
Incidence of mucositis-related fever
Daily mean CRP level
Intestinal mucositis as measured by the area-under-the-curve of reciprocal citrulline levels
Clinical mucositis as determined by the daily mouth and gut scores
Days with fever (≥ 38.5° C)
Incidence of bloodstream infections i.e. bacteremia
Length of hospital stay in days
Use of systemic antimicrobial agents (incidence and duration)
Use of analgesic drugs (incidence and duration)
Use of total parenteral nutrition (TPN) (incidence and duration)
Quality of life
Quality of life according to the EORTC QLQ-C30
Fatigue severity
Severity of fatigue as the score measured by the validated FACIT-Fatigue scale
Short term overall survival

Full Information

First Posted
July 19, 2017
Last Updated
November 23, 2020
Sponsor
Radboud University Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT03233776
Brief Title
Anakinra: Safety and Efficacy in the Management of Fever During Neutropenia and Mucositis in ASCT
Acronym
AFFECT-1
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
Study Type
Interventional

2. Study Status

Record Verification Date
November 2020
Overall Recruitment Status
Completed
Study Start Date
August 21, 2017 (Actual)
Primary Completion Date
May 7, 2019 (Actual)
Study Completion Date
August 1, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Radboud University Medical Center

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Myeloma
Keywords
Anakinra, Mucositis, Hematopoietic stem cell transplantation, Febrile neutropenia

7. Study Design

Primary Purpose
Supportive Care
Study Phase
Phase 2
Interventional Study Model
Sequential Assignment
Model Description
3+3 design
Masking
None (Open Label)
Allocation
N/A
Enrollment
9 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Anakinra
Arm Type
Experimental
Arm Description
Dosage form: intravenous. Dosage: either 100 mg, 200 mg or 300 mg. Frequency: once daily. Duration: 15 days (day -2 until day +12).
Intervention Type
Drug
Intervention Name(s)
Anakinra
Other Intervention Name(s)
Kineret
Intervention Description
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.
Primary Outcome Measure Information:
Title
Establish the maximum tolerated dose of anakinra (MTD, 100, 200 or 300 mg).
Description
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).
Time Frame
Day of admission (day -2) until discharge. Maximum period: +30 days.
Secondary Outcome Measure Information:
Title
Incidence of fever during neutropenia
Time Frame
Day of admission (day -2) until discharge. Maximum period: +30 days.
Title
Incidence of mucositis-related fever
Time Frame
Day of admission (day -2) until discharge. Maximum period: +30 days.
Title
Daily mean CRP level
Time Frame
Day of admission (day -2) until discharge. Maximum period: +30 days.
Title
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.
Title
Clinical mucositis as determined by the daily mouth and gut scores
Time Frame
Day of admission (day -2) until discharge. Maximum period: +30 days.
Title
Days with fever (≥ 38.5° C)
Time Frame
Day of admission (day -2) until discharge. Maximum period: +30 days.
Title
Incidence of bloodstream infections i.e. bacteremia
Time Frame
Day of admission (day -2) until discharge. Maximum period: +30 days.
Title
Length of hospital stay in days
Time Frame
Day of admission (day -2) until discharge. Maximum period: +30 days.
Title
Use of systemic antimicrobial agents (incidence and duration)
Time Frame
Day of admission (day -2) until discharge. Maximum period: +30 days.
Title
Use of analgesic drugs (incidence and duration)
Time Frame
Day of admission (day -2) until discharge. Maximum period: +30 days.
Title
Use of total parenteral nutrition (TPN) (incidence and duration)
Time Frame
Day of admission (day -2) until discharge. Maximum period: +30 days.
Title
Quality of life
Description
Quality of life according to the EORTC QLQ-C30
Time Frame
Baseline, at discharge (average: 23 days; maximum: after 30 days), +100 days, +1 year
Title
Fatigue severity
Description
Severity of fatigue as the score measured by the validated FACIT-Fatigue scale
Time Frame
Baseline, at discharge (average: 23 days; maximum: after 30 days), +100 days, +1 year
Title
Short term overall survival
Time Frame
+100 days and +1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nicole Blijlevens, MD PhD
Organizational Affiliation
Radboud University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Radboud university medical center
City
Nijmegen
ZIP/Postal Code
6525 GA
Country
Netherlands

12. IPD Sharing Statement

Citations:
PubMed Identifier
35546555
Citation
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.
Results Reference
derived

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

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