| Eligibility |
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/? 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)
|
