This study will be conducted as a standard Phase 1b, open-label, multi-center study of
patients with relapsed and/or refractory Myeloma who have received at least two prior
therapeutic treatments or regimens. Throughout the Phase I portion of this study, a standard
3+3 dose escalation design will be utilized. Two dosing cohorts will evaluate escalating
doses SAR650984 (5mg/kg and 10 mg/kg Day 1 and 15 of each 28-day cycle) with standard dose
Carfilzomib (20-27 mg/mg2). Once a safe dose is established, an expansion cohort will further
evaluate safety and begin to assess activity of this combination (SAR650984 (5mg/kg or 10
mg/kg Day 1 and 15 of each 28-day cycle) with standard dose Carfilzomib).
During the dose escalation portion of the study, the DLT period will be the first cycle (28
days) or from Day 1 through Day 28 of initial study treatment.
Expansion Phase Cohort An expansion cohort will begin once the MTD of SAR650984 plus standard
dose Carfilzomib is established. The Expansion Cohort will enroll 18 patients for additional
safety and preliminary efficacy data of SAR650984 plus Carfilzomib at the MTD.
- Males or females, age 18 years or older.
- Diagnosis of MM and documentation of treatment with an IMiD® and proteasome inhibitor.
Must have had 2 prior regimens/lines of therapy but there is no maximum number of
prior regimens and prior autologous bone marrow transplant is acceptable if > 12 weeks
from transplantation. A line of therapy is defined as a course of therapy that is not
interrupted by progressive disease. For example, induction therapy, autologous stem
cell transplantation, and maintenance therapy without intervening progressive disease
is one line of therapy.
- Confirmed evidence of relapse/disease progression from immediately prior MM therapy or
refractory to the immediately prior treatment. Refractory disease is defined as those
who are non-responsive (< minimal response) on active therapy or experience disease
progression within 60 days after the discontinuation of therapy. Relapsed disease is
defined as achievement of at least a minimal response followed by disease progression
on therapy or within 60 days of discontinuing active therapy.
- Patients may have received prior Carfilzomib (sensitive, relapsed and refractory all
eligible) but must be > 4 weeks from last dosing of Carfilzomib. In the expansion
cohort, at least 10 patients will be required to be refractory to Carfilzomib
(refractory defined as having evidence of disease progression while receiving
Carfilzomib or within 60 days of stopping Carfilzomib therapy).
- Patients must have measurable disease defined as at least one of the following:
- Serum M-protein ≥0.5 g/dl (≥5 g/l)
- Urine M-protein ≥200 mg/24 h
- Serum FLC assay: Involved FLC level ≥10 mg/dl (≥100 mg/l) and an abnormal serum free
light chain ratio (<0.26 or >1.65)
- Quantitative immunoglobulin > 500mg/dL, only for IgA and IgD myeloma when the protein
electrophoresis under-represents disease burden.
- Biopsy proven plasmacytoma (should be measured within 28 days prior to initial
investigational agent dosing).
- Subject has an ECOG ≤ 2 performance status OR Karnofsky ≥ 60% performance status.
- Females of childbearing potential (FCBP) - A female of childbearing potential is a
sexually mature woman who: 1) has not undergone a hysterectomy or bilateral
oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive
months may be included if the patient is not pregnant by a negative serum β-human
chorionic gonadotropin (β-hCG) pregnancy test result obtained during screening.
Pregnancy testing is not required for post-menopausal or surgically sterilized women.
FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex
condom during sexual contact with a FCBP even if they have had a successful vasectomy.
Females must agree to avoid pregnancy during the study and must agree to use a
medically acceptable method of birth control as determined by the study doctor while
participating in the study and for at least 12 weeks after the last dose of study
- Voluntary written informed consent before performance of any study-related procedure
not part of routine medical care with the understanding that consent may be withdrawn
by the subject at any time without prejudice to future medical care.
- Ability to understand the purpose and risks of the study and provide signed and dated
informed consent and authorization to use protected health information (in accordance
with national and local subject privacy regulations).
Inclusion Clinical Laboratories Criteria
- The following laboratory results must be met within 7 days of study drug (treatment)
- Absolute neutrophil count (ANC) > 1,000 cells/dL (1.0 x 10e9/L) (Growth factor cannot
be used within the previous 7 days)
- Hemoglobin ≥ 8.0 g/dl (without transfusion within the previous 7 days).
- Platelet count > 50,000 cells/dL (50 x 10e9/L)
- Creatinine clearance ≥ 30 mL/min (Cockcroft-Gault equation)
- Serum SGOT/AST or SGPT/ALT < 2.5 x upper limit of normal (ULN)
- Total bilirubin ≤ 1.5 x ULN
- Serum calcium (corrected for albumin) level at or below the ULN range (treatment of
hypercalcemia is allowed and subject may enroll if hypercalcemia returns to normal
with standard treatment) prior to study therapy initiation.
- Left ventricular ejection fraction; LVEF ≥40% (By echocardiogram or MUGA testing).
- Diagnosed or treated for another malignancy within 3 years of enrollment, with the
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
the skin, an in situ malignancy, low-risk prostate cancer after curative therapy or
complete resection of other advanced malignancy with the expectation that the patient
has received curative therapy.
- Patient has received other investigational drugs with 21 days before enrollment (or
must be > than four half-lives of the experimental agent). No prior SAR650984
anti-CD38 antibody therapy allowed.
- History of significant cardiovascular disease unless the disease is well-controlled or
history of myocardial infarction in the past 6 months. Significant cardiac diseases
includes second/third degree heart block; significant conduction abnormalities,
significant ischemic heart disease; QTc interval > 480 msec at baseline (using
Bazett's formula and read by local cardiologist); poorly controlled hypertension;
congestive heart failure of New York Heart Association (NYHA) Class II or worse
(slight limitation of physical activity; comfortable at rest, but ordinary physical
activity results in fatigue, palpitation, or dyspnea) and inability to tolerate
intravenous hydration necessary for study therapy administration.
- Prior peripheral stem cell transplant within 12 weeks of the first dose of study
- Daily requirement for corticosteroids (>10 mg prednisone QD or equivalent)
- Patients with evidence of significant mucosal or internal bleeding
- Prior radiation therapy or chemotherapy within 2 weeks or major surgical procedure
within 4 weeks of the first dose of study treatment.
- Known active infection requiring parenteral or oral anti-infective treatment, once a
patient has completed antibiotics and symptoms of infection have resolved to <Grade 2,
they are then considered eligible from an infection standpoint.
- Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or
confuse follow-up evaluation.
- Any medical conditions that, in the Investigator's opinion, would impose excessive
risk to the patient. Examples of such conditions include any pre-existing kidney
disease (acute or chronic, unless renal insufficiency is felt to be secondary to MM),
hypertension, active seizure disorder or pulmonary diseases that would impose
excessive risk to the patient.
- Patient has hypersensitivity to any of the components of study therapy including
required prophylactic medications.
- Known HIV seropositivity or active hepatitis B or C viral infection
- Neuropathy ≥Grade 3 or painful neuropathy ≥Grade 2 (National Cancer Institute Common
Terminology Criteria for Adverse Events [NCI CTCAE] v4.03)
- Gastro-intestinal abnormalities, including bowel obstruction, inability to take oral
medication, requirement for intravenous (IV) alimentation, active peptic ulcer or
prior surgical procedures or bowel resection affecting absorption.