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

Last updated: April 4, 2022
Sponsor: University of Cologne
Overall Status: Active - Recruiting

Phase

2

Condition

Multiple Myeloma

Cancer/tumors

Bone Neoplasm

Treatment

N/A

Clinical Study ID

NCT04656951
Uni-Koeln-3946
  • Ages > 18
  • All Genders

Study Summary

Daratumumab for first line treatment of transplant-ineligible myeloma patients followed by daratumumab re-treatment at first relapse (GMMG-DADA)

Eligibility Criteria

Inclusion

Inclusion Criteria:

  1. Signed Written Informed Consent 1.1 Study participants must have signed and dated anIEC approved written informed consent form in accordance with regulatory andinstitutional guidelines. This must be obtained before the performance of anyprotocol-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 IMWGdiagnostic criteria 2.2. Subject must have documented multiple myeloma as defined bythe criteria below:
  • Monoclonal plasma cells in the bone marrow ≥10% at some point in their diseasehistory 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 orurine M-protein level ≥200 mg/24 hours; or
  • IgA, IgD, IgE, IgM multiple myeloma: serum M-protein level ≥0.5 g/dL or urineM-protein level ≥200 mg/24 hours; or
  • Light chain multiple myeloma without measurable disease in the serum or theurine: Serum immunoglobulin free light chain ≥10 mg/dL and abnormal serumImmunoglobulin kappa lambda free light chain ratio.
  1. ECOG ≤2
  2. Not eligible for autologous transplantation
  3. Age 18 years or above
  4. Reproductive Status
  • Women of childbearing potential (WOCBP) must use appropriate method(s) ofcontraception and must agree to use adequate method to avoid pregnancy for 5months (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 thestart of the study treatment),
  • male sterilization (at least 6 months prior to the start of the studytreatment) and/or
  • a combination of a hormonal method of contraception with a barriermethod or/and
  • an intrauterine device or system
  • Women of childbearing potential must have a negative serum or urine pregnancytest (minimum sensitivity 25 IU/L or equivalent units of β-HCG) within one untiltwo weeks prior to the start of durvalumab at time of neoadjuvant treatment andafter surgery before starting adjuvant treatment.
  • Women will be not be considered to be of childbearing potential if they arepost-menopausal and/or underwent surgical sterilization (bilateral oophorectomy,bilateral salpingectomy or hysterectomy). To be considered post-menopausal theappropriate age-specific requirements have to be met:
  • Women < 50 years of age would be considered post-menopausal if they have beenamenorrheic for 12 months or more following cessation of exogenous hormonaltreatments and if they have luteinizing hormone and follicle-stimulating hormonelevels in the post-menopausal range for the institution.
  • Women ≥ 50 years of age would be considered post-menopausal if they have beenamenorrheic for 12 months or more following cessation of all exogenous hormonaltreatments, had radiation-induced menopause with last menses > 1 year ago, hadchemotherapy-induced menopause with last menses > 1 year ago.
  • Women must not be breastfeeding. Men who are sexually active with WOCBP must useany contraceptive method with a failure rate of less than 1% per year. Menreceiving durvalumab and who are sexually active with WOCBP must be willing toadhere to contraception for a period of 7 month post treatment completion.

Exclusion

Exclusion Criteria:

  • Subject has received any multiple myeloma therapy previously except dexamethasone to amaximum cumulative dose of 160mg, emergency radiotherapy or surgery for symptomcontrol
  • 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 yearsbefore 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 forsubjects suspected of having COPD and subjects must be excluded if FEV1 is <50% ofpredicted normal.
  2. Known moderate or severe persistent asthma, within the past 2 years, uncontrolledasthma of any classification. Note that subjects who currently have controlledintermittent asthma or controlled mild persistent asthma are allowed to participate inthe study.
  • Use of drugs with significant interaction with or intolerance to theinvestigational 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 systemicinfection) that is likely to interfere with study procedures or results, or thatin the opinion of the investigator would constitute a hazard for participating inthis study.
  • Patients has known current symptomatic congestive heart failure (New York HeartAssociation Class III-IV), unstable angina pectoris, or cardiac arrhythmia
  • Subject has any of the following laboratory test results during the ScreeningPhase:
  • 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 × ULN)
  • Pregnant women and nursing mothers, or a women who is planning to become pregnantwhile enrolled in this study or within 3 month after the last dose of daratumumab
  • Failure to use highly-effective contraceptive methods. The followingcontraceptive methods with a Pearl Index lower than 1% are regarded ashighly-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 assafe: condom plus spermicide, simple barrier methods (vaginal pessaries,condom, female condoms), copper spirals, the rhythm method, basaltemperature method, and the withdrawal method (coitus interruptus).
  • Persons with any kind of dependency on the principal investigator or employed bythe sponsor or principal investigator
  • Legally incapictated persons
  • Subject is known or suspected of not being able to comply with the studyprotocol(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, compromisetheir well-being) or that could prevent, limit, or confound theprotocol-specified assessments.
  • Persons held in an institution by legal or official order

Study Design

Total Participants: 160
Study Start date:
June 01, 2021
Estimated Completion Date:
December 31, 2029

Study 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).

Connect with a study center

  • University of Cologne

    Cologne, 50937
    Germany

    Active - Recruiting

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