Clinical trial NCT02626481 (phase 2, status: active, not recruiting)
Conditions: multiple myeloma
ICD codes: C90.01, C90.02, C90.00
Drugs: daratumumab, 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, 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:

          1. Must be able to understand and voluntarily sign an informed consent form

          2. Must be able to adhere to the study visit schedule and other protocol requirements

          3. Age ≥18 years

          4. Life expectancy > 6 months

          5. Patients must have relapsed myeloma, and previously treated with Bortezomib,
             Lenalidomide, and Pomalidomide treatment, and being resistant or refractory to
             Bortezomib and Lenalidomide and Pomalidomide treatment, defined as follows:

             5.1. Any number of prior therapies 5.2. Patients must have Progressive Disease as
             defined by the IMWG as one of the following (Kyle, 2009):

             Increase of 25% from lowest response value in any one or more of the following:

               -  Serum M-component (absolute increase must be ≥ 0.5 g/100 ml)b and/or Urine
                  M-component (absolute increase must be ≥ 200 mg per 24 h) and/or

               -  Only in patients without measurable serum and urine M-protein levels: the
                  difference between involved and uninvolved

               -  FLC levels (absolute increase must be > 10 mg/l). Bone marrow plasma cell
                  percentage (absolute % must be ≥ 10%)

               -  Definite development of new bone lesions or soft tissue plasmacytomas or definite
                  increase in the size of existing bone lesions or soft tissue plasmacytomas

               -  Development of hypercalcemia (corrected serum calcium > 11.5 mg/100 ml) that can
                  be attributed solely to the plasma cell proliferative disorder 5.3. Patients must
                  have undergone prior treatment with Bortezomib and Lenalidomide and Pomalidomide:

               -  They must have received at least two cycles of therapy

               -  Either at diagnosis or relapse

               -  Either in separate regimens or within the same regimen

               -  The line of treatment with Bortezomib and/or Lenalidomide and/or Pomalidomide
                  does not need to be the very last line of prior therapy

          6. Patients must have a clearly detectable and quantifiable monoclonal M-component value:

             IgG (serum M-component > 10g/l) IgA (serum M-component >5g/l) IgD (serum M-component >
             0.5g/l) Light chain (serum M-component >1g/l or Bence Jones > 200mg/24H) In patients
             without measurable serum and urine M-protein levels when the absolute serum FreeLight
             chain (sFLC) is ≥100 mg/l and an abnormal sFLC K/λ ratio (<0.26 and >1.65) is found
             (Dispenzieri, 2008).

          7. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2

          8. Adequate bone marrow function within 5 days prior to 1st drug intake (cycle1, day 1,
             C1D1), without transfusion nor growth factor support within 5 days prior to 1st drug
             intake , defined as:

             Absolute neutrophils ≥ 1000/mm3 Platelets ≥ 50000/mm3 Haemoglobin ≥ 8.5g/dl

          9. Adequate organ function defined as:

             Serum creatinine clearance (Cockcroft-Gault formula) ≥30 ml/min Serum SGOT or SGPT <
             3.0 X upper limit of normal (ULN) Serum total bilirubin < 2.0 mg/dL

         10. Wash out period of at least 2 weeks from previous antitumor therapy or any
             investigational treatment or 5 half-lives from previous antibodies.

         11. Women who are partners of men and of childbearing potential must be practicing one of
             the following methods of birth control: subcutaneous hormonal implant, levonorgestrel
             releasing intra-uterine system, medroxyprogesterone acetate depot, tubal
             sterilization, ovulation inhibitory progesterone only pills, or sexual intercourse
             with a vasectomized male partner (vasectomy must be confirmed by 2 negative semen
             analyses). Or women will commit to absolute and continuous abstinence confirmed to her
             physician on a monthly basis. Childbearing potential*. Contraception will start during
             therapy including dose interruptions, for 4 months after discontinuation of
             Daratumumab.

               -  Criteria for women of childbearing potential :

        This protocol defines a female of childbearing potential as a sexually mature woman who:

          1. has not undergone a hysterectomy or bilateral oophorectomy or

          2. has not been naturally postmenopausal (amenorrhea following cancer therapy does not
             rule out childbearing potential) for at least 24 consecutive months (ie, has had
             menses at any time in the preceding 24 consecutive months) 12. A woman of childbearing
             potential must have 2 negative serum or urine pregnancy tests at Screening, first
             within 28 days prior to dosing and the second within 48 hours prior to dosing, and
             remain on a highly effective method of birth control. The two methods of reliable
             contraception must include one highly effective method and one additional effective
             (barrier) method. FCBP must be referred to a qualified provider of contraceptive
             methods if needed. The following are examples of highly effective and additional
             effective methods of contraception:

               -  Highly effective methods:

                    -  Intrauterine device (IUD)

                    -  Hormonal (birth control pills, injections, implants)

                    -  Tubal ligation

                    -  Partner's vasectomy

               -  Additional effective methods:

                    -  Male condom

                    -  Diaphragm

                    -  Cervical Cap 13. Serum (urine in the case where serum is not possible in a
                       timely manner) pregnancy test to be performed for all women of childbearing
                       potential regularly during the study,. In addition, a pregnancy test may be
                       done at any time during the study at the discretion of the investigator if a
                       subject misses a period or has unusual menstrual bleeding.

                       14. A woman of childbearing potential must remain on a highly effective
                       method of birth control. Contraception must begin 4 weeks before initiating
                       treatment with Daratumumab, during therapy, during dose interruptions and
                       continuing for 4 months following discontinuation of Daratumumab. Reliable
                       contraception is indicated even where there has been a history of
                       infertility, unless due to hysterectomy.

                       15. A man who has not had a vasectomy and who is sexually active with a
                       woman of childbearing potential must agree to use a barrier method of birth
                       control eg, condom with spermicidal foam/gel/film/cream/suppository, and all
                       men must also not donate sperm during the study, for 4 months following
                       discontinuation of Daratumumab. The exception to this restriction is that if
                       the subject's female partner is surgically sterile, a second method of birth
                       control is not required.

                       16. Subjects affiliated with an appropriate social security system.

        Exclusion Criteria:

          1. Target disease exceptions:

               -  Solitary bone/solitary extramedullary plasmocytoma

               -  Patients with non-secretory MM and non-measurable MM

               -  Evidence of central nervous system (CNS) involvement

          2. Medical history and Concurrent disease:

             o Subjects with prior (≤ 5 years) or concurrent invasive malignancies except the
             following: Adequately treated basal cell or squamous cell skin cancer Incidental
             finding of low grade (Gleason 3+3 or less) prostate cancer Any cancer from which the
             subject has been disease free for at least 3 years.

               -  Subject with known/underlying medical conditions that, in the investigator's
                  opinion would make the administration of the study drug hazardous (ie:
                  uncontrolled diabetes or uncontrolled coronary artery disease)

               -  Any uncontrolled or severe cardiovascular or pulmonary disease determined by the
                  investigator including:

             NYHA functional classification III or IV congestive heart failure LVEF ( Left
             Ventricular Ejection Fraction) ≥45% Uncontrolled angina, hypertension or arrhythmia
             Myocardial infarction in the past 6 months

               -  Subjects with grade 2 or greater peripheral neuropathy (as per NCI-CTCAEv4.0)

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

               -  Known positive for HIV or active hepatitis B or C.

               -  Subjects with psychiatric illnesses or social situations that would preclude them
                  understanding the informed consent, study compliance or the ability to tolerate
                  study procedures and/or study therapy

               -  Subjects with 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 subjects must be
                  excluded if FEV1 <50% of predicted normal.

               -  Subjects with a history of moderate or severe persistent asthma within the past 2
                  years (see appendix), or with uncontrolled asthma of any classification at the
                  time of screening (Note that subjects who currently have controlled intermittent
                  asthma or controlled mild persistent asthma are allowed in the study).

          3. Physical and laboratory test findings:

               -  Patients on dialysis or with a Creatinine clearance < 30mL/min

               -  SGOT or SGPT >3ULN

          4. Prohibited prior therapies

               -  Prior local irradiation within two weeks before first dose

               -  Previous anti-CD38 therapy.

          5. Allergies and Adverse Drug Reaction:

             o Hypersensitivity to Dexamethasone that would prohibit treatment with study therapy

          6. Refusal to consent or protected by a legal regime (guardianship, trusteeship)