Trial document




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  DRKS00020561

Trial Description

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Title

Efficacy of Daratumumab (dara) retreatment using a histone deacytelase-inhibitor (HDACi: panobinostat) as a dara-longevity-inducing, epigenetic agent in combination with bortezomib-dexamethasone as a quadruplet in relapsed / refractory multiple myeloma (RRMM) patients

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Trial Acronym

Dara-H-VERUMM

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URL of the Trial

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Brief Summary in Lay Language

Multiple myeloma is a cancer in which malignant plasma cells proliferate and impair the growth and function of other blood cells. The malignant plasma cells typically produce more defined proteins (antibodies), which can lead to the impairment of other organ functions (such as the kidneys).
Treatment options for patients* with relapsed/refractory (recurrent/therapy-resistant) multiple myeloma are limited, especially if they have already been treated with daratumumab and relapse occurs. Therefore, the novel use of daratumumab in a 4-drug combination, based on data from previous studies, with careful dosing, represents a safe and promising approach.

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Brief Summary in Scientific Language

MM is a chronic disease that shows frequent, often multiple relapses, thus effective relapse options are needed. This is the more the case, since even after very novel Dara second- line treatment with Dara-Rd, MM-relapse will occur, thus, whether reinduction with Dara-combination treatment is feasible, will be solved in this phase 2 trial.
The FDA/EMA approved PanVD regimen for relapsed patients was chosen as the backbone therapy in this IIT study. In addition, FDA/EMA-approved Dara is combined with HDACi panobinostat-VD (Dara-PanVD), to enable long-term Dara treatment despite prior Dara treatment, to induce persistence of CD38 expression and thus longer Dara treatment duration, and to improve VD.

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Do you plan to share individual participant data with other researchers?

No

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Description IPD sharing plan:

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Organizational Data

  •   DRKS00020561
  •   2021/04/23
  •   [---]*
  •   yes
  •   Approved
  •   20-1231-AMG-ff multi, Ethik-Kommission der Albert-Ludwigs-Universität Freiburg
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Secondary IDs

  •   2020-000382-16 
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Health Condition or Problem studied

  •   C90.00 -  [generalization C90.0: Multiple myeloma]
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Interventions/Observational Groups

  •   first 8 cycles (3-week cycles): all Pt receive 4-drug combination Daratumumab (s.c. at a flat dose of 1800 mg, weekly for C1-3, every 3 weeks for C4-8) bortezomib (s.c., 1.3 mg/m2 weekly), panobinostat (p.o., 15 mg twice weekly) and dexamethasone (p.o., 40 mg weekly)
    From 9 cycles onwards (4-week cycles), randomization in maintenance therapy - Arm 1:
    daratumumab (s.c. at flat dose of 1800 mg every 4 weeks) in combination with panobinostat (p.o., 15mg every 2 weeks) and bortezomib (s.c. 1.3 mg/m2 every 2 weeks).
  •   first 8 cycles (3-week cycles): all Pt receive 4-drug combination Daratumumab (s.c. at a flat dose of 1800 mg, weekly for C1-3, every 3 weeks for C4-8) bortezomib (s.c., 1.3 mg/m2 weekly), panobinostat (p.o., 15 mg twice weekly) and dexamethasone (p.o., 40 mg weekly)
    From 9 cycles onwards (4-week cycles), randomization in maintenance therapy - Arm 2:
    daratumumab (s.c. at flat dose of 1800 mg every 4 weeks) in combination with bortezomib (s.c. 1.3 mg/m2 every 2 weeks).
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Open (masking not used)
  •   [---]*
  •   Other
  •   Treatment
  •   Parallel
  •   II
  •   No
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Primary Outcome

Response to Dara-PanVD, determined within 2 weeks after the end of cycle 8

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Secondary Outcome

Overall survival (OS), Progression-free survival (PFS), response duration, Minimal residual disease (MRD), Quality of Life (QoL), fitness assessment via R-MCI, safety (grade 3/4 toxicities under Dara-PanVD according to National cancer institute – common terminology criteria for adverse events (NCI-CTCAE) version 5.0, adverse events, serious adverse events. Early death within initial 6 + 12 months, biomarker studies before, during and at end of the study medication. Treatment longevity assessed as number of Dara-PanVD / Dara-(Pan)V cycles given.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
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Recruitment

  •   Planned
  •   2021/06/01
  •   30
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

1. Male or female patients ≥18 years of age
2. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
3. Patients with a confirmed diagnosis of multiple myeloma (in line with the
revised IMWG criteria) who have received Dara-Rd as relapse treatment
in 2nd line and have documented evidence of PD based on the investigator’s determination of response as defined by the IMWG
uniform response criteria.
(Patients who have received a prior autologous bone marrow transplant
and otherwise meet the inclusion criteria are eligible for this study)
4. Must have measurable disease defined by at least 1 of the following 3
measurements:
- Serum M-protein ≥0.5 g/dL
- Urine M-protein ≥200 mg/24 hours OR
- Serum Free Light Chain (FLC) >100 mg/L of involved FLC
5. Laboratory test results within these ranges:
- White blood cell count ≥2 x 109/L
- Absolute neutrophil (ANC) count ≥0.5 x 109/L
- Platelet count ≥75 x 109/L
- Hemoglobin >8 g/dL
- Calculated creatinine clearance (according to MDRD) ≥30
mL/minute
- Total bilirubin ≤1.5 x upper limit of normal (ULN)
- AST and ALT ≤2.5 x ULN
- Corrected serum calcium level <3.5 mmol/L (<14 mg/dL)
6. Women of childbearing potential (WOCBP) must have 2 negative serum
pregnancy tests, one 10-14 days prior to start of the study drugs and one
within 24 hours prior to the start of study drugs. Women must not be
breastfeeding. WOCBP must agree to follow instructions for methods of
contraception for 4 weeks before the start of treatment with study drugs,
for the duration of treatment with study drugs, and for a total of 3 months
after cessation of the last study drug. Males who are sexually active with
WOCBP must use during the duration of the study and up to 3 months
afterwards a latex or synthetic condom during any sexual contact with
females of reproductive potential, even if they have undergone a
successful vasectomy.
Patients must abstain from donating blood, semen, or sperm during
participation in the study
7. Written informed consent obtained according to international guidelines
and local laws;
8. Ability to understand the nature of the trial and comply with the trialrelated
procedures.

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Exclusion Criteria

1. Plasma cell leukemia, and/or extensive EM relapse (=multiple, large
sites); entirely refractory MM disease, documented systemic light-chain
amyloidosis, MM involving the central nervous system
2. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy,
monoclonal protein, and skin changes)
3. Waldenström’s macroglobulinemia or IgM myeloma
4. Clinical signs of meningeal involvement of multiple myeloma
5. Chronic obstructive pulmonary disease (COPD) with a forced expiratory
volume in 1 second (FEV1) <50% of predicted. (FEV1 testing is required
during screening)
6. Patients that are eligible for autologous stem cell transplantation (aSCT)
7. Known intolerance to or contraindication for the use of bortezomib, or
refractory to bortezomib (defined as progressive disease according to
IMWG criteria
8. Known intolerance to or contraindication for the use of daratumumab,
panobinostat, and dexamethasone or any of the other ingredients in the
study treatment formulations (known hypersensitivity to the active
substances or any of the excipients)
9. Life expectancy of <4 months
10. Major surgery within 4 weeks prior to cycle 1 day 1
11. Subject is known to be seropositive for human immunodeficiency virus
(HIV) or has active hepatitis (type A, B or hepatitis C)
12. Any serious underlying medical condition, such as:
- serious active viral, bacterial, or uncontrolled systemic fungal
infection (including SARS-CoV-2)
- severe cognitive disorders
- severe ventricular arrhythmia
13. Participation in any other interventional clinical trial within the last 30
days before the start of this trial
14. Any prior or concurrent malignancy other than multiple myeloma.
Exceptions include patients who have been disease-free for at least five
years before study entry or patients with adequately treated and
completely resected basal cell or squamous cell skin cancer, in situ
cervical, breast or prostate cancer
15. Patient without legal capacity who is unable to understand the nature,
significance and consequences of the trial
16. Known or persistent abuse of medication, drugs or alcohol; Subject is
known or suspected of not being able to comply with study protocol
17. Current or planned pregnancy, nursing period
18. Failure to use one of the following safe methods of contraception: intrauterine
device; intrauterine hormone-releasing system ( IUS), hormonal
contraception in combination with a mechanical method of
contraception, bilateral tubal occlusion, sexual abstinence
Women of childbearing potential can only participate in this study if the risk
of becoming pregnant is absolutely minimized.

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Addresses

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    • Universitätsklinikum Freiburg
    • Hugstetter Str. 55
    • 79106  Freiburg
    • Germany
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    •   [---]*
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    • Janssen-Cilag GmbH
    • Mr.  Dr.  Englisch 
    • Johnson & Johnson Platz 1
    • 41470  Neuss
    • Germany
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    • UNIVERSITÄTSKLINIKUM FREIBURGMedical Department, Hematology, Oncology & Stem cell transplantationClinical Cancer Research Group / Sektion Klinische Forschung
    • Ms.  Prof. Dr.  Monika  Engelhardt 
    • Hugstetterstr. 55
    • 79106  Freiburg
    • Germany
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    • UNIVERSITÄTSKLINIKUM FREIBURGMedical Department, Hematology, Oncology & Stem cell transplantationClinical Cancer Research Group / Sektion Klinische Forschung
    • Ms.  Prof. Dr.  Monika  Engelhardt 
    • Hugstetterstr. 55
    • 79106  Freiburg
    • Germany
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Sources of Monetary or Material Support

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    • Janssen-Cilag GmbH
    • Mr.  Dr.  Englisch 
    • Johnson & Johnson Platz 1
    • 41470  Neuss
    • Germany
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Status

  •   Recruiting planned
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Trial Publications, Results and other Documents

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* This entry means the parameter is not applicable or has not been set.