EMN19: Daratumumab Combined With Bortezomib, Cyclophosphamide and Dexamethasone for the Treatment of Multiple Myeloma Patients Presenting With Extramedullary Disease

Sponsor

European Myeloma Network (Other)

Overall Status

Recruiting

CT.gov ID

NCT04166565

Collaborator

Janssen, LP (Industry)

Enrollment

Locations

Arm

Anticipated Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This trial will try to establish the feasibility and efficacy of the combination of DaraVCD in Multiple Myeloma (MM) patients presenting with extramedullary disease (EMD). The study will be conducted as a Phase II trial.

Forty patients will be included in the study cohort. All patients will be followed closely for toxicities and response assessment. After completion of treatment, patients will be followed every 6 months for survival until 5 years after enrolment

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma Extramedullary Plasmacytoma	Drug: Daratumumab Drug: Bortezomib Drug: Cyclophosphamide Drug: Dexamethasone	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Daratumumab Combined With Bortezomib, Cyclophosphamide and Dexamethasone for the Treatment of Multiple Myeloma Patients Presenting With Extramedullary Disease. The ANTARES Study

Actual Study Start Date :

Oct 31, 2019

Anticipated Primary Completion Date :

Dec 1, 2021

Anticipated Study Completion Date :

Dec 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Daratumumab/bortezomib/cyclophospamide/dexamethasone (daraVCD) Daratumumab 16 mg/kg will be administered by i.v. infusion. Daratumumab will be administered weekly in Cycles 1 and 2, then every 2 weeks for Cycles 3-6, and thereafter every month up to 36 months. Bortezomib 1.5 mg/m2 bortezomib will be administered by a subcutaneous injection once weekly (Days 1, 8, 15 and 22) in all cycles. Cyclophosphamide 300 mg/m2 will be administered as a p.o. or i.v. weekly dose (Days 1, 8, 15, and 22) in every 28-day cycle (maximum weekly dose 500 mg). Dexamethasone will be administered on Days 1, 2, 8, 9, 15, 16, 22 and 23 in all cycles. On daratumumab infusion days dexamethasone may be administered i.v. or p.o. approximately 1 hour before the daratumumab infusion. On days when daratumumab is not administered, dexamethasone is to be administered p.o.	Drug: Daratumumab Daratumumab 16 mg/kg will be administered by i.v. infusion. Daratumumab will be administered weekly in Cycles 1 and 2, then every 2 weeks for Cycles 3-6, and thereafter every month up to 36 months. Drug: Bortezomib Bortezomib 1.5 mg/m2 bortezomib will be administered by a subcutaneous injection once weekly (Days 1, 8, 15 and 22) in all cycles. Other Names: Velcade Drug: Cyclophosphamide Cyclophosphamide 300 mg/m2 will be administered as a p.o. or i.v. weekly dose (Days 1, 8, 15, and 22) in every 28-day cycle (maximum weekly dose 500 mg). Dexamethasone will be administered on Days 1, 2, 8, 9, 15, 16, 22 and 23 in all cycles. On daratumumab infusion days dexamethasone may be administered i.v. or p.o. approximately 1 hour before the daratumumab infusion. On days when daratumumab is not administered, dexamethasone is to be administered p.o. Drug: Dexamethasone Dexamethasone will be administered on Days 1, 2, 8, 9, 15, 16, 22 and 23 in all cycles. On daratumumab infusion days dexamethasone may be administered i.v. or p.o. approximately 1 hour before the daratumumab infusion. On days when daratumumab is not administered, dexamethasone is to be administered p.o.

Arm

Intervention/Treatment

Experimental: Daratumumab/bortezomib/cyclophospamide/dexamethasone (daraVCD)

Daratumumab 16 mg/kg will be administered by i.v. infusion. Daratumumab will be administered weekly in Cycles 1 and 2, then every 2 weeks for Cycles 3-6, and thereafter every month up to 36 months. Bortezomib 1.5 mg/m2 bortezomib will be administered by a subcutaneous injection once weekly (Days 1, 8, 15 and 22) in all cycles. Cyclophosphamide 300 mg/m2 will be administered as a p.o. or i.v. weekly dose (Days 1, 8, 15, and 22) in every 28-day cycle (maximum weekly dose 500 mg). Dexamethasone will be administered on Days 1, 2, 8, 9, 15, 16, 22 and 23 in all cycles. On daratumumab infusion days dexamethasone may be administered i.v. or p.o. approximately 1 hour before the daratumumab infusion. On days when daratumumab is not administered, dexamethasone is to be administered p.o.

Drug: Daratumumab

Daratumumab 16 mg/kg will be administered by i.v. infusion. Daratumumab will be administered weekly in Cycles 1 and 2, then every 2 weeks for Cycles 3-6, and thereafter every month up to 36 months.

Drug: Bortezomib

Bortezomib 1.5 mg/m2 bortezomib will be administered by a subcutaneous injection once weekly (Days 1, 8, 15 and 22) in all cycles.

Other Names:

Velcade

Drug: Cyclophosphamide

Cyclophosphamide 300 mg/m2 will be administered as a p.o. or i.v. weekly dose (Days 1, 8, 15, and 22) in every 28-day cycle (maximum weekly dose 500 mg). Dexamethasone will be administered on Days 1, 2, 8, 9, 15, 16, 22 and 23 in all cycles. On daratumumab infusion days dexamethasone may be administered i.v. or p.o. approximately 1 hour before the daratumumab infusion. On days when daratumumab is not administered, dexamethasone is to be administered p.o.

Drug: Dexamethasone

Dexamethasone will be administered on Days 1, 2, 8, 9, 15, 16, 22 and 23 in all cycles. On daratumumab infusion days dexamethasone may be administered i.v. or p.o. approximately 1 hour before the daratumumab infusion. On days when daratumumab is not administered, dexamethasone is to be administered p.o.

Outcome Measures

Primary Outcome Measures

CR or better [5 years]
the proportion of patients who achieved CR or better

Secondary Outcome Measures

Duration of Response [5 years]
defined as time, in months, from initial response (PR or better) until the date of a disease progression event
Progression Free Survival [5 years]
Progression Free Survival
Overall Response Rate [5 years]
defined as the proportion of patients who will achieve PR or better, as per IMWG criteria
Overall Survival [5 years]
Safety (Adverse Events) [5 years]
Adverse Events of the investigational combination treatment

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Confirmed diagnosis of Multiple Myeloma(MM) (IMWG consensus guidelines)
Newly diagnosed or relapsed (patients should have received a maximum of one line of prior therapy) patients presenting with extramedullary disease (EMD) of the skin, liver, lungs, central nervous system, lymph nodes or other tissues, but not solely paraskeletal plasmacytoma (expanding soft tissue masses)* detected by physical exam and confirmed (when required) by Weight Bearing CT/MRI/PET-CT and/or biopsy**. Documentation of plasma cell infiltration is highly recommended unless it requires invasive surgical intervention such as intracerebral infiltration of plasmacytomas.

*Note: patients with only paraosseous extension of MM forming soft tissue plasmacytomas are not eligible

**Note: An additional radiologic assessment at screening is not required to confirm EMD. Documentation in terms of physician's/pathologist's report and/or radiologic assessments performed within 42 days of C1D1 will suffice for the purposes of eligibility. All patients however will undergo a baseline radiologic assessment at C1D1 for response purposes.

Patients with one prior line of therapy must have:

achieved a response (PR or better based on investigator's determination of response by the IMWG criteria) to at least one prior regimen.
documented evidence of PD based on Investigator's determination of response as defined by the IMWG criteria on or after the last line of treatment.

Age ≥ 18 years
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Note: for patients with central nervous system (CNS) involvement, an ECOG performance status >2 is also acceptable
Each patient must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. Patients must be willing and able to adhere to the prohibitions and restrictions specified in this protocol, as referenced in the ICF.
Patient must have measurable disease of MM as defined by the below criteria:

IgG MM: Serum M protein level ≥1.0 g/dL or urine M protein level ≥200 mg/24 hours, or
IgA, IgD, IgE, IgM MM: Serum M-protein level ≥0.5 g/dL or urine M-protein level ≥200 mg/24 hours; or
Light chain MM, for patients without measurable disease in the serum or urine: Serum immunoglobulin free light chain (FLC) ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio.

Reproductive Status

Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test at screening. Females are not of childbearing potential if they have been in natural menopause for at least 24 consecutive months, or have had a hysterectomy and/or bilateral oophorectomy
Women must not be breastfeeding
WOCBP must agree to follow instructions for reliable methods of birth control. This includes one highly effective (< 1% failure rate per year) form of contraception (tubal ligation, intrauterine device (IUD), combined or progestogen only hormonal contraception associated with inhibition of ovulation [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner's vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks before the start of treatment and continue for the duration of study treatment and for 3 months after cessation of daratumumab or 12 months after cessation of cyclophosphamide, whichever is longer.
Males who are sexually active must always use a latex or synthetic condom during any sexual contact with females of reproductive potential, even if they have undergone a successful vasectomy. They must also agree to follow instructions for methods of contraception for 4 weeks before the start of study treatment, for the duration of study treatment, and for 3 months after cessation of daratumumab or 6 months after cessation of cyclophosphamide, whichever is longer.
Female patients must not donate eggs for up to 3 months after cessation of daratumumab or 12 months after cessation of cyclophosphamide, whichever is longer.
Male patients must not donate sperm for up to 3 months after cessation of daratumumab or 6 months after cessation of cyclophosphamide, whichever is longer.
Azoospermic males and WOCBP who are not heterosexually active are exempt from contraceptive requirements. However, WOCBP will still undergo pregnancy testing as described above.

Exclusion Criteria:

Solitary plasmacytoma
Paraosseous extension of MM forming soft tissue plasmacytomas only (without EMD).
Previous therapy with any anti-CD38 or anti-CS1 monoclonal antibody
Patients refractory to bortezomib based regimens (PD on or within 60 days of completion of bortezomib OR failure to achieve at least a minimal response [MR]) as the prior line of therapy
Patients who have Bortezomib or Daratumumab hypersensitivity
Patients who have active or chronic infections
Patients who have received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic half-lives of the treatment, whichever is longer, before Cycle 1 Day 1 (C1D1). The only exception is emergency use of a short course of corticosteroids (equivalent of dexamethasone 40 mg/day for a maximum of 4 days) for palliative treatment before C1D1.
Previous autologous stem cell transplant (ASCT) within 12 weeks before C1D1.
Previous allogenic stem cell transplant (alloSCT) regardless of timing.
Patient has received radiotherapy within 14 days from C1D1. NOTE: Urgent localized radiotherapy for Spinal Cord Compression or Central Nervous System Involvement is allowed.
Patient has 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 patients suspected of having COPD and patients must be excluded if FEV1 <50% of predicted normal
Patient has known moderate or severe persistent asthma within the past 2 years (see) or currently has uncontrolled asthma of any classification. Note: Patients who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study).
Severe cardiovascular disease (arrhythmias [CTCAE Grade 3 or higher] requiring chronic treatment, congestive heart failure [New York Heart Association (NYHA) Class III - IV] or symptomatic ischemic heart disease);
Severe pulmonary dysfunction (CTCAE grade 3-4, see appendix D);
Severe neurological or psychiatric disease;
Significant hepatic dysfunction (serum bilirubin or transaminases ≥ 3 times the upper limit of normal (ULN)) unless related to hepatic involvement with MM.

Note: Patients with Gilbert Syndrome are not excluded provided that direct bilirubin is ≤2 x ULN.

Significant renal dysfunction (creatinine clearance <30 ml/min after rehydration) Note: refer to Appendix F for creatinine clearance calculation;
Significant bone marrow suppression as evidenced by any of the below laboratory tests during screening:

Absolute neutrophil count ≤1.0 × 109/L;
Hemoglobin level ≤7.5 g/dL (≤4.65 mmol/L); transfusions are not allowed to reach this level
Platelet count ≤75 × 109/L in patients in whom <50% of bone marrow nucleated cells are plasma cells and platelet count ≤50 × 109/L in patients in whom ≥50% of bone marrow nucleated cells are plasma cells; transfusions are NOT allowed to reach this level

Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, active systemic infection, uncontrolled hypertension, cancer, etc.) that is likely to interfere with the study procedures/results or which, in the opinion of the investigator, would constitute a hazard for participating in this study.
History of active malignancy during the past 5 years with the exception of basal carcinoma of the skin or stage 0 cervical carcinoma;
Any of the following:

Known active hepatitis A
Patient is seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Patients with resolved infection (ie, patients who are positive for antibodies to hepatitis B core antigen [antiHBc] and/or antibodies to hepatitis B surface antigen [antiHBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded.

EXCEPTION: Patients with serologic findings suggestive of HBV vaccination (antiHBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.

o Known to be seropositive for hepatitis C (except in the setting of a sustained virologic response, defined as aviremia at least 12 weeks after completion of antiviral therapy).

Patient known to be HIV-positive;
Current participation in another clinical trial
Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule

Contacts and Locations

Locations

	Site	City	Country
1	University of Athens	Athens	Greece
2	Anticancer Hospital of Thessaloniki	Thessaloníki	Greece
3	University of Bologna	Bologna	Italy
4	Univerity of Turin	Torino	Italy
5	Ankara University	Ankara	Turkey
6	Dokuz Eylul University	Balçova	Turkey
7	Erciyes University	Kayseri	Turkey
8	Marmara University	Pendik	Turkey