Trial Title:
Clinical Trial Investigating the Chemotherapeutic Compound Treosulfan (Trecondi® Ideogen) in Myeloma Patients
NCT ID:
NCT05636787
Condition:
Multiple Myeloma
Conditions: Official terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Melphalan
Treosulfan
Conditions: Keywords:
Multiple Myeloma
Melphalan
Treosulfan
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Intervention model description:
Randomized prospective non-blinded clinical phase II trial
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Treosulfan
Description:
Efficacy of standard treatment melphalan will be compared to the combination melphalan
with treosulfan
Arm group label:
Arm B - TreoMel
Intervention type:
Drug
Intervention name:
Melphalan
Description:
Efficacy of standard treatment melphalan will be compared to the combination melphalan
with treosulfan
Arm group label:
Arm A - Mel
Arm group label:
Arm B - TreoMel
Summary:
Clinical trial investigating the chemotherapeutic compound treosulfan (Trecondi® Ideogen)
in myeloma patients.
Detailed description:
Background and rationale:
Due to demographic changes, multiple myeloma with its preferential manifestation in the
elderly population exerts increasing incidence worldwide. Since decades, autologous stem
cell transplantation (ASCT) after high-dose chemotherapy (HDCT) with melphalan is the
standard first-line consolidation option for patients with multiple myeloma considered
fit for this approach. Nevertheless, subsequent relapse despite this intensive treatment
is inevitable in most myeloma patients, emphasizing the unmet clinical need for improved
conditioning strategies to further enhance the effect of HDCT treatment.
The Inselspital in Bern represents one of the largest European centers for autologous
stem cell transplantation (ASCT) in myeloma, lymphoma and leukemia patients, and it is
the largest center in Switzerland for ASCT, with more than 150 ASCT performed annually.
In parallel, the transplant team at the Inselspital has a dedicated history of clinical
trials aiming to further improve tolerance and efficacy of HDCT with ASCT.
In a previous randomized phase 2 study performed at the department of medical oncology of
the Inselspital, the combination of the cytotoxic compound bendamustin in addition to the
standard melphalan dose as a novel HDCT regimen before autologous transplantation in 120
myeloma patients has been explored and established. This approach was successful in terms
of increased anti-myeloma efficacy, but the nephrotoxicity of high-dose bendamustin was
relevant in a significant subset of patients. This fact, ultimately, led to the propose
of a novel approach.
The present study aims to combine high-dose melphalan (Melphalan Ideogen) with treosulfan
(Trecondi® Ideogen), a well established bifunctional alkylating agent. Treosulfan has a
favorable toxicity profile, and it is used in patients with acute leukemias in the
allogeneic transplant setting as a standard approach in an increasing number of centers.
However, no study so far evaluated treosulfan combined with melphalan as high-dose
chemotherapy in patients with multiple myeloma. Consequently, this approach is unique and
novel in patients with multiple myeloma in the autologous transplant setting.
Compared to the closely related (and more known) compound busulfan, treosulfan compares
favorably in terms of decreased neurotoxicity (for busulfan, antiepileptic prophylaxis is
necessary), and it does not cause irreversible hair loss, which is often observed after
busulfan treatment. The team at the Inselspital performed a pilot study in 25 patients
with relapsed myeloma undergoing second-line HDCT/ASCT therapy. Treosulfan (14 mg/m2 i.v.
at days -4, -3, and -2) combined with standard dose melphalan (day -1) had promising
anti-myeloma activity and was well tolerated as expected from the previous studies.
Standardized measurement of treosulfan serum levels by mass spectrometry (Metabolomics,
University Institute of Clinical Chemistry, Inselspital Bern) in these patients
demonstrated consistent pharmacokinetic profiles with peak levels within the therapeutic
range and with low interindividual differences. Consequently, no modifications of the
treosulfan dosage were needed during these initial experiences. With the clinical trial
outlined in this protocol, the study team aim to gain insights into the use of treosulfan
as part of the high-dose chemotherapy regimen before ASCT in myeloma patients. The study
will be performed as an open-label, randomized phase 2 study, involving multiple
recruiting regional Swiss centers, with all high-dose treatments being performed at the
University Hospital Inselspital Bern. Patients will first undergo standardized induction
therapy (e.g. VRD regimen, with or without Daratumumab), followed by a 1:1 randomization
to two treatment arms:
Arm B, the experimental ("TreoMel") arm, combines treosulfan at three days at 14 g/m2
followed by 200 mg/m2 melphalan given on two days at 100 mg/m2. Arm A, the standard arm,
comprises standard 200 mg/m2 melphalan ("Mel"), split into two days à 100 mg/m2.
The stem cell transplantation is identical in both arms, as is the post-transplant
management.
In patients with reduced renal function (creatinine clearance <50 mL/min and ≥ 35
ml/min), the melphalan total dose will be lowered to 140 mg/m2, split into two doses at
70 mg/m2. Treosulfan will be administered in a dosage of 14 mg/m2 i.v. on days -5, -4,
and -3 in Arm A ("TreoMel"). The autologous cells will be transfused on day 0.
Patients will be stratified 1) according to the myeloma remission status as assessed
based on the last available remission status: complete (CR) and very good partial
remission (VGPR) versus partial remission (PR), minimal remission (MR), no change (NC)
and progressive disease (PD); and 2) according to renal function: Renal function:
creatinine clearance ≥ 50 ml/min versus < 50 ml/min.
Based on a previous cohort of 122 myeloma patients at the Inselspital (2010-2013), a CR1
rate in the standard (Mel) arm of 50% is anticipate.
The primary endpoint is to show an improvement of the CR rate after ASCT (before
initiation of maintenance treatment) in the standard arm A using melphalan only ("Mel")
from 50% to 65% in the experimental arm B combining treosulfan and melphalan ("TreoMel").
Therefore, the study is considered successful if the experimental treosulfan/melphalan
arm is superior by 15% points. With a statistical power of 80% and one-tailed
significance level of 5%, 60 patients are required for cohorts A and B each. Thus, the
total number of patients for the trial needed amounts to 120 patients. As the yearly
number of myeloma patients undergoing HDCT/ASCT therapy at the Inselspital Bern is close
to 80 patients, the recruitment of a sufficient number of patients in the planned study
duration of 36 months appears feasible.
Patients can be included with a diagnosis of multiple myeloma after standard first-line
induction therapy, commonly being the VRD regimen with or without additional daratumumab.
In the case of refractory myeloma, one or several additional alternative induction
regimens can be applied before the study treatment. Further preconditions are clinical
fitness for HDCT/ASCT and age of at least 18 years, ECOG less than 3, and creatinine
clearance of at least 35 mL/min or more (for additional incl./excl. criteria see the
entire protocol).
The measurement of the endpoints of the study will be as follows: Primary endpoint is the
complete remission (CR) rate after ASCT (before initiation of maintenance treatment)
following measurement of myeloma parameters in the peripheral blood including M-gradient,
quantitative immunoglobulins, kappa/lambda light chain ratio, and immunofixation.
Secondary endpoints are: time to neutrophil and thrombocyte engraftment, progression-free
and overall survival, toxicities, infectious complications, hospitalization duration,
minimal residual disease (MRD) load determined by next-generation immunophenotyping.
Treosulfan serum levels will be assessed by pharmacokinetic drug monitoring based on mass
spectrometry. Bone marrow punction for defining the response will be performed in all
patients after neutrophil engraftment before hospital discharge around 15 days after
ASCT. Bone marrow analyses comprise cytomorphology, histopathology, and flow cytometry at
a sensitivity level of 10(-5) for MRD assessment.
The trial will be performed at the Department of Oncology at the Inselspital, University
Hospital Bern. The CTU of the University of Bern will perform the on-site monitoring of
the study.
Criteria for eligibility:
Criteria:
Inclusion criteria:
1. Eligible are myeloma patients after standard first-line induction treatment.
Additional induction regimens in refractory myeloma patients are allowed.
2. Patients must be considered fit for subsequent consolidation with high-dose
chemotherapy with autologous stem cell transplantation.
3. Patients must be aged 18-75 years.
4. Patients must have an ECOG <3.
5. Patients must have a creatinine clearance ≥35 ml/min.
6. Patients must have an LVEF ≥40% within three months prior to start of study HDCT.
7. Patients must have given voluntary written informed consent.
Exclusion criteria:
1. Patients with an uncontrolled acute infection.
2. Patients with a transplantation comorbidity index (HCTCI) > 6 points.
3. Patients with concurrent active malignant disease with the exception of
basalioma/spinalioma of the skin or early-stage cervix carcinoma, or early-stage
prostate cancer. Previous treatment for other malignancies (not listed above) must
have been terminated at least 6 months before registration and no evidence of active
disease may be documented since then.
4. Patients with major coagulopathy or bleeding disorder.
5. Patients with other medical conditions that could potentially interfere with the
completion of treatment according to this protocol or that would impair tolerance to
therapy or prolong hematological recovery.
6. Lack of patient cooperation to allow study treatment as outlined in this protocol.
7. Known pregnancy or lactating female patients. The pregnancy test could be omitted
from the screening visit and postponed to the study treatment if indicated (a
pregnancy test in female patients of child-bearing potential is not mandatory since
patients are already under induction chemotherapy or mobilization chemotherapy, and
pregnancy was excluded before starting induction chemotherapy; if, however, a
pregnancy test is clinically indicated, it can be done either during screening or
before the start of study treatment).
Patient not willing to implement adequate contraceptive measures (hormonal treatment
p.o. or i.m., intra-uterine surgical devices, or latex condoms) to avoid pregnancy
during study treatment and for 12 additional months.
8. Use of any anti-cancer investigational agents within 14 days prior to the expected
start of trial treatment.
9. Contraindications and hypersensitivity to any of the active chemotherapy compounds.
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Departement of Medical Oncology, University Hospital Berne
Address:
City:
Berne
Zip:
3010
Country:
Switzerland
Status:
Recruiting
Contact:
Last name:
Thomas Pabst, MD
Phone:
+41 31 632 84 30
Email:
thomas.pabst@insel.ch
Start date:
June 6, 2023
Completion date:
April 2028
Lead sponsor:
Agency:
Insel Gruppe AG, University Hospital Bern
Agency class:
Other
Source:
Insel Gruppe AG, University Hospital Bern
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05636787
