The primary objective is to evaluate the safety and efficacy of anakinra in patients with multiple myeloma receiving high-dose melphalan (HDM) in the preparation for an autologous hematopoietic stem cell transplantation (SCT). Secondary objectives…
ID
Source
Brief title
Condition
- Haematopoietic neoplasms (excl leukaemias and lymphomas)
- Gastrointestinal inflammatory conditions
- Body temperature conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
-Establish the safety of anakinra as well as the maximum tolerated dose (MTD).
Secondary outcome
- Incidence of fever during neutropenia
- Incidence of mucositis-related fever
- Maximum CRP level on day +9-10
- 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 ((* 38.2° C)
- Days with fever (* 38.5° C)
- Mean daily morning temperature
- Area under the curve of daily morning temperature
- Incidence of bloodstream infections i.e. bacteremia
- Type of bloodstream infections
- Incidence of persistently positive blood cultures on day +4
- Quality of life according to the EORTC QLQ-C30
- Severity of fatigue as the score measured by the validated FACIT-Fatigue scale
- Short term overall survival (100 days and 1 year)
- 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)
Background summary
Mucosal barrier injury (MBI) of the mouth (oral mucositis) and gut (intestinal
mucositis) is an important side effect of treatment with intensive chemotherapy
and radiotherapy. The occurrence of mucositis is a major risk factor for fever
during neutropenia (febrile neutropenia, FN) and the development of bloodstream
infections (BSI) with microbes residing at the integument. These complications
often require dose reductions or cause delay in and even cessation of
treatment, all precluding optimal treatment for patients with cancer with a
lower chance for cure. Currently, however, there are no effective strategies to
prevent or treat mucositis. Therefore, there is an unmet need for effective
treatment and prevention strategies for mucositis and fever during neutropenia.
Cytokines that belong to the interleukin-1 family are involved in multiple
inflammatory and immune responses, but also play a crucial role in the
pathogenesis of mucositis. Inhibition of the IL-1 pathway has proven to be
effective in a number of IL-1 mediated diseases, such as rheumatoid arthritis
(RA), gout and Cryopyrin-associated Periodic Syndromes (CAPS). Recently,
studies in murine models of chemotherapy-induced mucositis demonstrated that
anakinra, a recombinant human interleukin-1 receptor antagonist, significantly
ameliorated intestinal mucositis. Therefore, we hypothesize that inhibition of
the IL-1 pathway, in patients receiving intensive chemotherapy in the context
of hematopoietic stem cell transplantation, can decrease the incidence of
intestinal mucositis and consequently fever during neutropenia.
Study objective
The primary objective is to evaluate the safety and efficacy of anakinra in
patients with multiple myeloma receiving high-dose melphalan (HDM) in the
preparation for an autologous hematopoietic stem cell transplantation (SCT).
Secondary objectives are the gathering of blood and microbiota samples for
translational research.
Study design
A single center dose finding phase IIa study with a traditional 3+3 design
Intervention
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.
Study burden and risks
Burden associated with participation:
Subjects will receive study treatment with anakinra intravenously once daily.
As compared to standard treatment outside study context, three times a week
additional blood tests will be obtained (total volume 100 mL), as well as stool
samples and oral swabs twice a week. Also, from day +4 until day +12,
additional blood cultures will be obtained (total volume 120 mL). Finally,
subjects will be asked to complete a number of questionnaires (2
questionnaires, both on 4 time points) related to quality of life and fatigue
severity.
Risks associated with the investigated product:
The impact of anakinra on mucositis and therewith the expected reduced
incidence of fever and infections has not been established yet. Being an
anti-inflammatory drug the signs of infections may be masked and the
immunosuppressive effects may increase the risk for infections. In addition,
neutropenia and headache are documented side effects of anakinra. However, in
previous studies in SCT recipients the use of anakinra was not accompanied by
untoward side effects and no detrimental effects of engraftment post-SCT have
occurred.
Geert Grooteplein Zuid 8
Nijmegen 6525GA
NL
Geert Grooteplein Zuid 8
Nijmegen 6525GA
NL
Listed location countries
Age
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 inhibitor, such as anakinra, rilonacept or canakinumab, within three months prior to baseline visit
- Treatment with TNF 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-004419-11-NL |
| CCMO | NL59679.091.16 |