Clinical trial NCT02955810 (phase 1, status: unknown status)
Conditions: multiple myeloma
ICD codes: C90.01, C90.02, C90.00
Drugs: daratumumab, cyclophosphamide, bortezomib, dexamethasone
SMILES: [H][C@@]12C[C@@H](C)[C@](O)(C(=O)CO)[C@@]1(C)C[C@H](O)[C@@]1(F)[C@@]2([H])CCC2=CC(=O)C=C[C@]12C, ClCCN(CCCl)P1(=O)NCCCO1, ClCCN(CCCl)P1(=O)NCCCO1, C[C@@H](O[C@H]1OCCN(CC2=NNC(=O)N2)[C@H]1C1=CC=C(F)C=C1)C1=CC(=CC(=C1)C(F)(F)F)C(F)(F)F
Eligibility criteria:

        Inclusion Criteria:

          -  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 is willing to
             participate in the study.

          -  Patient must be between 18 and <70 years of age.

          -  Patient must have documented diagnosis of multiple myeloma requiring treatment as per
             IMWG updated criteria for the diagnosis of multiple myeloma and measurable disease as
             defined by:

               -  Monoclonal plasma cells in the bone marrow ≥10% 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

                  ≥1.0g/dl or urine M-protein level ≥200mg/24 hours; or

               -  IgA, IgE, IgD or IgM multiple myeloma: serum M-protein level ≥0.5g/dl or urine
                  M-protein level ≥200mg/24 hours; or

               -  Light chain multiple myeloma without measurable disease in the serum or the
                  urine: serum immunoglobulin free light chain ≥10mg/dl and abnormal serum
                  immunoglobulin kappa lambda free light chain ratio.

          -  Newly diagnosed patient eligible for high dose therapy and autologous stem cell
             transplantation.

          -  Patient must have an ECOG performance status score of 0-2.

          -  Patient must have pre-treatment clinical laboratory values meeting the following
             criteria during the Screening Phase:

               -  Haemoglobin ≥7.5g/dl (≥5mmol/l); prior red blood cell [RBC] transfusion or
                  recombinant human erythropoietin use is permitted);

               -  absolute neutrophil count (ANC) ≥1.0x109/l (GCSF is permitted);

               -  AST ≤ 2.5 x upper limit of normal (ULN);

               -  ALT ≤ 2.5 x ULN;

               -  total bilirubin ≤ 1.5 x ULN (except in patients with congenital bilirubinaemia,
                  such as Gilbert syndrome, direct bilirubin ≤ 1.5 x ULN);

               -  calculated creatinine clearance ≥40ml/min/1.73m2;

               -  corrected serum calcium ≤ 14mg/dl (<3.5mmol/l); or free ionized calcium ≤6.5mg/dl
                  (≤1.6mmol/l);

               -  platelet count ≥70x109/l for patients in whom <50% of bone marrow nucleated cells
                  are plasma cells; otherwise platelet count >50x109/l (transfusions are not
                  permitted to achieve this minimum platelet count).

          -  Patients who are women of child-bearing potential or male partners of women of
             childbearing potential must agree to use adequate contraception methods from signing
             of the informed consent form until at least 4 months after the last study drug
             administration.

          -  Childbearing potential is defined as any woman who has not undergone a hysterectomy or
             bilateral oophorectomy; or has not been naturally post-menopausal for at least 12
             consecutive months (i.e. has had menses at any time in the preceding 12 consecutive
             months). The investigator or a designated associate is required to advise the patient
             how to achieve adequate birth control. Highly effective contraception is defined in
             the study as methods that achieve a failure rate of less than 1% per year when used
             consistently and correctly. Such methods include: combined (oestrogen and progestogen
             containing) hormonal contraception associated with inhibition of ovulation (oral,
             intravaginal, transdermal) progestogen-only hormonal contraception associated with
             inhibition of ovulation (oral, injectable and implantable), intrauterine device (IUD),
             intrauterine hormone -releasing system (IUS), bilateral tubal occlusion, successfully
             vasectomised partner and sexual abstinence. In addition, the use of condoms by
             patients or their partners is required unless the woman has had a hysterectomy.
             Contraception will start 4 weeks before the start of therapy, will continue during
             therapy including dose interruptions and for 4 months after the last dose of any
             component of the treatment regimen.

          -  A woman of childbearing potential must have 2 negative serum or urine pregnancy tests
             at Screening, first within 10 to 14 days prior to first dose and the second within 24
             hours prior to first dose.

          -  Patient must be willing and able to adhere to the prohibitions and restrictions
             specified in this protocol.

        Exclusion Criteria:

          -  Patient has received daratumumab or other anti-CD38 therapies previously.

          -  Patient has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined
             significance, or smoldering multiple myeloma. Monoclonal gammopathy of undetermined
             significance is defined by presence of serum M-protein < 3g/dl; absence of criteria
             consistent with active/symptomatic multiple myeloma as per IMWG criteria. Smoldering
             multiple myeloma is defined as asymptomatic multiple myeloma with absence of related
             organ or tissue impairment (ROTI) end organ damage.

          -  Patient has a diagnosis of Waldenstrom's macroglobulinemia or other conditions in
             which IgM M-protein is present in the absence of a clonal plasma cell infiltration
             with lytic bone lesions.

          -  Patient has prior or current systemic therapy or stem cell transplantation for any
             plasma cell dyscrasia, with the exception of an emergency use of a short course
             (equivalent of dexamethasone 40mg/day for a maximum 4 days) of corticosteroids before
             treatment.

          -  Patient has peripheral neuropathy or neuropathy grade 2 or higher, as defined by the
             National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)
             version 4.0.

          -  Patient has had any prior or concurrent invasive malignancy (other than multiple
             myeloma) within 5 years of screening period except adequately treated basal cell or
             squamous cell carcinoma of the skin, carcinoma in situ of the cervix, localized
             prostate adenocarcinoma diagnosed ≥3 years and without evidence of biochemical
             failure, or other cancer for which the patient has undergone potentially curative
             therapy and has no evidence of that disease for ≥10 years.

          -  Patient has had radiation therapy within 14 days prior to start of study treatment.

          -  Patient has had plasmapheresis within 28 days of registration.

          -  Patient is exhibiting clinical signs of meningeal involvement of multiple myeloma.

          -  10. a) 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.

             b) Patient has known moderate or severe persistent asthma within the past 2 years, or
             currently has uncontrolled asthma of any classification. (Note that patients who
             currently have controlled intermittent asthma or controlled mild persistent asthma are
             allowed in the study).

          -  Patient is known to be seropositive for or active human immunodeficiency virus (HIV)
             or known to have active hepatitis B or hepatitis C.

          -  Patient has any concurrent medical or psychiatric condition or disease (e.g. active
             systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary
             disease) that is likely to interfere with the study procedures or results, or that in
             the opinion of the investigator, would constitute a hazard for participating in this
             study.

          -  Patient has clinically significant cardiac disease, including:

               -  myocardial infarction within 1 year before registration, or an unstable or
                  uncontrolled disease/condition related to or affecting cardiac function (e. g.
                  unstable angina, congestive heart failure, New York Heart Association Class
                  IIIIV), OR

               -  cardiac arrhythmia (NCI-CTCAE Version 4.0 Grade ≥ 2) or clinically significant
                  ECG abnormalities, and

               -  screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's
                  formula (QTcF) >470 msec.

          -  Patient has known allergies, hypersensitivity, or intolerance to boron or mannitol,
             corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer
             to the DARA Investigator's Brochure), or known sensitivity to mammalian-derived
             products.

          -  Patient has plasma cell leukaemia (according to WHO criterion: ≥20% of cells in the
             peripheral blood with an absolute plasma cell count of more than 2x109/l) or POEMS
             syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin
             changes).

          -  Patient is known or suspected of not being able to comply with the study protocol
             (e.g. because of alcoholism, drug dependency, or psychological disorder). Patient has
             any condition for which, in the opinion of the investigator, participation would not
             be in the best interest of the patient (e.g. compromise the well-being) or that could
             prevent, limit, or confound the protocol-specified assessments.

          -  Patient is a woman who is pregnant, or breast-feeding, or planning to become pregnant
             while participating in this study or within 4 months after the last dose of any
             component of the treatment regimen. Or, patient is a man who plans to father a child
             while included in this study or within 4 months after the last dose of any component
             of the treatment regimen.

          -  Patient has had major surgery within 2 weeks before registration or will not have
             fully recovered from surgery, or has surgery planned during the time the patient is
             expected to participate in the study. Kyphoplasty is not considered major surgery.

          -  Patient has received an investigational drug (including investigational vaccines) or
             used an invasive investigational medical device within 4 weeks before registration or
             is currently enrolled in an interventional investigational study.

          -  Patient has contraindication to the use of any components of the treatment regimen,
             per the Summary of Product Characteristics.

          -  Incidence of gastrointestinal disease that may significantly alter the absorption of
             oral drugs.