Daratumumab for First Line Treatment of Transplant-ineligible Myeloma Patients Followed by Daratumumab Re-treatment at First Relapse

Studien-Informationen Einschlusskriterien Studien-Rationale Geprüfte Regime

Rekrutierend

NCT-Nummer:
NCT04656951

Studienbeginn:
Juni 2021

Letztes Update:
05.04.2022

Wirkstoff:
Daratumumab

Indikation (Clinical Trials):
Multiple Myeloma, Neoplasms, Plasma Cell

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
University of Cologne

Collaborator:
Janssen-Cilag G.m.b.H

Studienleiter

Christof Scheid, Prof. Dr.
Principal Investigator
University of Cologne

Kontakt

Christof Scheid, Prof. Dr.
Kontakt:
Phone: +49 221 478
Phone (ext.): 6296
E-Mail: c.scheid@uni-koeln.de» Kontaktdaten anzeigen

Tim Richardson, MD
Kontakt:
E-Mail: tim.richardson@uk-koeln.de» Kontaktdaten anzeigen

Studienlocations
(1 von 1)

University of Cologne
50937 Cologne
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Christof Scheid, PD Dr. med.
Phone: +49 221 478
Phone (ext.): 6296
E-Mail: c.scheid@uni-koeln.de

Tim Richardson, MD
E-Mail: tim.richardson@uk-koeln.de» Ansprechpartner anzeigen

Studien-Informationen

Detailed Description:

The aim of the study is to investigate the safety and efficacy of daratumumab added to a

standard induction regimen of bortezomib, cyclophosphamide and dexamethasone (VCD). A

secondary aim is to assess the efficacy of maintenance therapy until progression using

daratumumab in combination with bortezomib and dexamethasone. Thirdly the efficacy of a

daratumumab-containing regimen at first relapse shall be tested following a

daratumumab-containing first line regimen.

Rationale:

VCD has been established as a standard of care for first line therapy of transplant-eligible

patients in Germany. The favorable toxicity profile makes this regimen also suitable for

transplant-ineligible patients. Daratumumab has shown to be safe and efficacious in a variety

of combinations such as with VMP, Vd or Rd. Using a reduced dose of cyclophosphamide the

study shall investigate safety and efficacy of Dara-VCD in the transplant-ineligible patient

population.

Maintenance therapy has become standard of care in transplant-eligible and non-eligible

patients. However, there is uncertainty whether a single agent maintenance is sufficient or

whether a combination therapy is necessary. In this study the safety and efficacy of

maintenance with daratumumab in combination with bortezomib and dexamethasone will be assessd

with a focus on MRD negativity as a novel endpoint.

The multitude of treatment options at first relapse has generated the need to find an optimal

sequence of therapy regimens in first and second line. In particular it is unclear whether

the efficacy of daratumumab at relapse is affected by its prior use as part of the first line

treatment. Patients in this study will relapse on or after a daratumumab-containing

maintenance and shall receive DRd at first relapse. In the POLLUX study patients received DRd

but had no prior exposure to daratumumab. Therefore, patients included into the POLLUX study

can serve as an indirect control cohort for the present study. If in the present study the

PFS after DRd is similar to the PFS of the comparable cohort from the POLLUX study, the

assumption is supported that prior exposure to daratumumab does not impair the activity of a

subsequent daratumumab-containing regimen at relapse. In addition, the overall efficacy of

the whole protocol treatment will be assessed by analyzing PFS2 after relapse from study

inclusion (PFS2).

Ein-/Ausschlusskriterien

Inclusion Criteria:

1. Signed Written Informed Consent 1.1 Study participants must have signed and dated an

IEC approved written informed consent form in accordance with regulatory and

institutional guidelines. This must be obtained before the performance of any

protocol-related procedures that are not part of normal study participant care.

1.2 Study participants must be willing and able to comply with scheduled visits,

treatment schedule, laboratory tests and other requirements of the study.

2. Target Population 2.1. Untreated patients with multiple myeloma diagnosis to the IMWG

diagnostic criteria 2.2. Subject must have documented multiple myeloma as defined by

the criteria below:

- Monoclonal plasma cells in the bone marrow ≥10% at some point in their disease

history or presence of a biopsy proven plasmacytoma.

- Measurable disease as defined by any of the following:

- IgG multiple myeloma: Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or

urine M-protein level ≥200 mg/24 hours; or

- IgA, IgD, IgE, IgM multiple myeloma: serum M-protein level ≥0.5 g/dL or urine

M-protein level ≥200 mg/24 hours; or

- Light chain multiple myeloma without measurable disease in the serum or the

urine: Serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum

Immunoglobulin kappa lambda free light chain ratio.

3. ECOG ≤2

4. Not eligible for autologous transplantation

5. Age 18 years or above

6. Reproductive Status

- Women of childbearing potential (WOCBP) must use appropriate method(s) of

contraception and must agree to use adequate method to avoid pregnancy for 5

months (30 days plus the time required for durvalumab to undergo five half-lives)

after the last dose of study drug.

- Appropriate methods of contraception are:

- female sterilization or tubal ligation (at least 6 weeks prior to the

start of the study treatment),

- male sterilization (at least 6 months prior to the start of the study

treatment) and/or

- a combination of a hormonal method of contraception with a barrier

method or/and

- an intrauterine device or system

- Women of childbearing potential must have a negative serum or urine pregnancy

test (minimum sensitivity 25 IU/L or equivalent units of β-HCG) within one until

two weeks prior to the start of durvalumab at time of neoadjuvant treatment and

after surgery before starting adjuvant treatment.

- Women will be not be considered to be of childbearing potential if they are

post-menopausal and/or underwent surgical sterilization (bilateral oophorectomy,

bilateral salpingectomy or hysterectomy). To be considered post-menopausal the

appropriate age-specific requirements have to be met:

- Women < 50 years of age would be considered post-menopausal if they have been

amenorrheic for 12 months or more following cessation of exogenous hormonal

treatments and if they have luteinizing hormone and follicle-stimulating hormone

levels in the post-menopausal range for the institution.

- Women ≥ 50 years of age would be considered post-menopausal if they have been

amenorrheic for 12 months or more following cessation of all exogenous hormonal

treatments, had radiation-induced menopause with last menses > 1 year ago, had

chemotherapy-induced menopause with last menses > 1 year ago.

- Women must not be breastfeeding. Men who are sexually active with WOCBP must use

any contraceptive method with a failure rate of less than 1% per year. Men

receiving durvalumab and who are sexually active with WOCBP must be willing to

adhere to contraception for a period of 7 month post treatment completion.

Exclusion Criteria:

- Subject has received any multiple myeloma therapy previously except dexamethasone to a

maximum cumulative dose of 160mg, emergency radiotherapy or surgery for symptom

control

- Participation in other interventional clinial trials

- Subject has known meningeal involvement of multiple myeloma.

- Subject has a history of malignancy (other than multiple myeloma) within 3 years

before the date of Screening.

Subject has either of the following:

1. Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in

1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for

subjects suspected of having COPD and subjects must be excluded if FEV1 is <50% of

predicted normal.

2. Known moderate or severe persistent asthma, within the past 2 years, uncontrolled

asthma of any classification. Note that subjects who currently have controlled

intermittent asthma or controlled mild persistent asthma are allowed to participate in

the study.

- Use of drugs with significant interaction with or intolerance to the

investigational product

- Subject is known to be seropositive for human immunodeficiency virus (HIV)

- active hepatitis B (defined by a positive test for hepatitis B surface antigen

[HBsAg] or positive HBV DNA)

- Subject has any concurrent medical condition or disease (eg, active systemic

infection) that is likely to interfere with study procedures or results, or that

in the opinion of the investigator would constitute a hazard for participating in

this study.

- Patients has known current symptomatic congestive heart failure (New York Heart

Association Class III-IV), unstable angina pectoris, or cardiac arrhythmia

- Subject has any of the following laboratory test results during the Screening

Phase:

- Absolute neutrophil count ≤1.0 × 109/L;

- Platelet count <50 × 109/L

- Aspartate aminotransferase (AST) or alanine aminotransferase level (ALT)

≥2.5 times the upper limit of normal (ULN)

- Alkaline phosphatase level ≥2.5 × ULN

- Total bilirubin level ≥1.5 × ULN, (except for Gilbert Syndrome: direct

bilirubin 1.5 × ULN)

- Pregnant women and nursing mothers, or a women who is planning to become pregnant

while enrolled in this study or within 3 month after the last dose of daratumumab

- Failure to use highly-effective contraceptive methods. The following

contraceptive methods with a Pearl Index lower than 1% are regarded as

highly-effective:

- Oral hormonal contraception ('pill')

- Dermal hormonal contraception

- Vaginal hormonal contraception (NuvaRing®)

- Contraceptive plaster

- Long-acting injectable contraceptives

- Implants that release progesterone (Implanon®)

- Tubal ligation (female sterilisation)

- Intrauterine devices that release hormones (hormone spiral)

- Double barrier methods This means that the following are not regarded as

safe: condom plus spermicide, simple barrier methods (vaginal pessaries,

condom, female condoms), copper spirals, the rhythm method, basal

temperature method, and the withdrawal method (coitus interruptus).

- Persons with any kind of dependency on the principal investigator or employed by

the sponsor or principal investigator

- Legally incapictated persons

- Subject is known or suspected of not being able to comply with the study

protocol(eg, because of alcoholism, drug dependency, or psychological disorder)

or the subject has any condition for which, in the opinion of the investigator,

participation would not be in the best interest of the subject (eg, compromise

their well-being) or that could prevent, limit, or confound the

protocol-specified assessments.

- Persons held in an institution by legal or official order

Studien-Rationale

Primary outcome:

1. Efficacy of induction therapy with daratumumab, bortezomib, cyclophosphamide and dexamethasone (DVCd) (Time Frame - 24 weeks):
Proportion of patients achieving a very good partial remission (VGPR) or better after 8 cycles of DVCd

Secondary outcome:

1. Assessment of the efficacy of maintenance therapy until progression using daratumumab in combination with bortezomib and dexamethasone. (Time Frame - open):
Proportion of patients with no detectable minimal residual disease as best response to maintenance therapy using daratumumab in combination with bortezomib and dexamethasone

2. Assessment of the efficacy of a daratumumab-containing regimen at first relapse, following a daratumumab-containing first line regimen. (Time Frame - up to 48 months (from first progression/relapse until second progression/relapse or death, whichever occurs first (PFS-R)):
Progression free survival from first relapse (PFS-R)

Geprüfte Regime

Daratumumab (Darzalex):
Daratumumab added to induction regimen of bortezomib, cyclophosphamide and dexamethasone (VCD), to bortezomib and dexamethasone during maintenance and to lenalidomide and dexamethasone at progression/relapse.

Quelle: ClinicalTrials.gov

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