Sonidegib and Lenalidomide After Stem Cell Transplant in Treating Patients With Multiple Myeloma
Condition: Recurrent Plasma Cell Myeloma; Refractory Plasma Cell Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Laboratory Biomarker Analysis; Lenalidomide; Sonidegib
Intervention description: Correlative studies; Given PO; Given PO
Intervention MeSH terms: Lenalidomide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 28.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies how well sonidegib and lenalidomide after stem cell transplant
      works in treating patients with multiple myeloma. Sonidegib and lenalidomide may stop the
      growth of cancer cells by blocking some of the enzymes needed for cell growth and may delay
      multiple myeloma from coming back after a stem cell transplant.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Absolute neutrophil count >= 1500/uL

          -  Platelet count >= 80,000/uL

          -  Hemoglobin >= 9.0 g/dL

          -  Serum total bilirubin =< 1.5 x ULN (upper limit of normal)

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN or =<
             5 x ULN if liver involvement

          -  Plasma creatine phosphokinase (CK) < 1.5 x ULN

          -  Serum creatinine =< 1.5 x ULN or 24-hour clearance >= 50 ml/min

          -  Diagnosis of symptomatic multiple myeloma (MM)

          -  Patients should have received single autologous stem cell transplantation 60-120 days
             prior to enrollment to the trial

          -  Patients should have received the autologous SCT within 12 months of their diagnosis
             of myeloma to be eligible for the study

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2

          -  Recovered from toxicity of previous chemotherapy (excludes grade 1 neurotoxicity and
             hematological toxicity)

          -  Voluntary written informed consent before performance of any study-related procedure
             not part of normal medical care, with the understanding that the subject may withdraw
             consent at any time without prejudice to future medical care

          -  Willingness to return to the Mayo Clinic enrolling institution for follow-up

          -  Measurable disease of multiple myeloma at the time of baseline values for disease
             assessment as defined by at least one of the following:

               -  Serum monoclonal protein >= 1.0 g/dL

               -  >= 200 mg of monoclonal protein in the urine on 24 hour electrophoresis

               -  Serum immunoglobulin free light chain (involved free light chain [FLC]) >=10
                  mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio

                    -  NOTE: For patients with no relapse prior to transplant, measurable disease
                       at the time of diagnosis

                    -  NOTE: For patients who have had a disease relapse prior to transplant,
                       measurable disease at the time of the most recent relapse immediately prior
                       to transplant; NOTE: if the patient had treatment for the relapsed disease
                       prior to transplant, the patient must have measurable disease at the time of
                       relapse prior to this therapy

          -  Patients may have a history of current or previous deep vein thrombosis or pulmonary
             embolism but must be willing to initiate prophylaxis with low molecular weight heparin

          -  Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy
             test with a sensitivity of at least 50 mIU/mL within 10-14 days prior to and again
             within 24 hours of starting lenalidomide and LDE225 and must either commit to
             continued abstinence from heterosexual intercourse or begin TWO acceptable methods of
             birth control, one highly effective method and one additional effective method AT THE
             SAME TIME, at least 28 days before she starts taking lenalidomide and LDE225; 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; all
             patients must be counseled at a minimum of every 28 days about pregnancy precautions
             and risks of fetal exposure; a female of childbearing potential is any woman,
             regardless of sexual orientation or whether they have undergone tubal ligation, who
             meets the following criteria: has not undergone a hysterectomy or bilateral
             oophorectomy; or has not been naturally postmenopausal for at least 24 consecutive
             months (i.e., has had menses at any time in the preceding 24 consecutive months)

          -  Sexually active males must be willing to use a condom (even if they have undergone a
             prior vasectomy) while having intercourse, while taking lenalidomide and for 4 weeks
             after stopping treatment

          -  Patient enrolling to this study must agree to register to the mandatory REVLIMID Risk
             Evaluation and Mitigation Strategy (REMS [TM]) program, and be willing and able to
             comply with the requirements of (REVLIMID REMS [TM])

          -  Patients must be willing to provide biological samples as required by the study

        Exclusion Criteria:

          -  Prior allogeneic bone marrow/peripheral blood stem cell transplant

          -  Patients with evidence of disease progression post SCT at the time of consideration
             for the study enrollment will not be included

          -  Impaired cardiac function or clinically significant heart disease, including any one
             of the following:

               -  Angina pectoris within 3 months

               -  Acute myocardial infarction within 3 months

               -  Fridericia QT (QTcF) > 450 msec for males and > 470 msec for females on the
                  screening electrocardiogram (ECG)

               -  A past medical history of clinically significant ECG abnormalities or a family
                  history of prolonged QT-interval syndrome

               -  Other clinically significant heart disease (e.g. congestive heart failure,
                  uncontrolled hypertension, history of labile hypertension, or history of poor
                  compliance with an antihypertensive regimen)

          -  Seroreactivity for human immunodeficiency virus (HIV), human T-lymphotropic virus type
             I (HTLV I) or II, hepatitis B virus (HBV), hepatitis C virus (HCV)

          -  Other active malignancy requiring therapy; EXCEPTIONS: non-melanotic skin cancer or
             carcinoma-in-situ of the cervix

          -  Any of the following:

               -  Pregnant or nursing (lactating) women, where pregnancy is defined as the state of
                  a female after conception and until the termination of gestation, confirmed by a
                  positive human chorionic gonadotropin (hCG) laboratory test (> 5 mIU/mL)

               -  Patients who are not willing to apply highly effective contraception during the
                  study and through the duration as defined below after the final dose of study
                  treatment

               -  Women of child-bearing potential, defined as all women physiologically capable of
                  becoming pregnant, must use highly effective contraception during the study and
                  through 6 months after the final dose of study treatment; highly effective
                  contraception is defined as either:

                    -  Total abstinence: when this is in line with the preferred and usual
                       lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation,
                       symptothermal, post-ovulation methods) and withdrawal are not acceptable
                       methods of contraception

                    -  Sterilization: patient has had surgical bilateral oophorectomy (with or
                       without hysterectomy) or tubal ligation at least six weeks before taking
                       study treatment; in case of oophorectomy alone, only when the reproductive
                       status of the woman has been confirmed by follow up hormone level assessment

                    -  Male partner sterilization (with the appropriate post-vasectomy
                       documentation of the absence of sperm in the ejaculate); (for female study
                       patients, the vasectomized male partner should be the sole partner for that
                       patient)

                    -  Use a combination of the following (both a+b):

                         -  Placement of a non-hormonal intrauterine device (IUD) or non-hormonal
                            intrauterine system (IUS)

                         -  Barrier method of contraception: condom or occlusive cap (diaphragm or
                            cervical vault caps) with spermicidal foam/gel/film/cream/vaginal
                            suppository

                    -  Note: hormonal contraception methods (e.g. oral, injected, implanted) are
                       not allowed

                    -  Note: woman are considered post-menopausal and not child bearing potential
                       if they have had 12 months of natural (spontaneous) amenorrhea with an
                       appropriate clinical profile (e.g. age appropriate, history of vasomotor
                       symptoms) or six months of spontaneous amenorrhea with serum follicle
                       stimulating hormone (FSH) levels > 40 mIU/mL and estradiol < 20 pg/mL or
                       have had surgical bilateral oophorectomy (with or without hysterectomy) at
                       least six weeks ago; in the case of oophorectomy alone, only when the
                       reproductive status of the woman has been confirmed by follow up hormone
                       level assessment is she considered not of child bearing potential

               -  Male patient must use highly effective (double barrier) methods of contraception
                  (e.g., spermicidal gel plus condom) for the entire duration of the study, and
                  continuing using contraception and refrain from fathering a child for 6 months
                  following the study drug; a condom is required to be used also by vasectomized
                  men as well as during intercourse with a male partner in order to prevent
                  delivery of the study treatment via seminal fluid

               -  Sexually active males who are unwilling to use a condom during intercourse while
                  taking drug and for 6 months after stopping investigational medications and agree
                  not to father a child in this period

          -  Other co-morbidity, which would interfere with patient's ability to participate in the
             trial, e.g. uncontrolled infection, uncompensated lung disease

          -  Concurrent chemotherapy, radiotherapy, or any ancillary therapy for treatment of
             multiple myeloma; NOTE: bisphosphonates are considered to be supportive care rather
             than therapy, and are thus allowed while on protocol treatment

          -  Known allergies to any of the components of the investigational treatment regimen or
             required ancillary treatments

          -  Major surgery within 4 weeks prior to registration

          -  Patients with concurrent uncontrolled medical conditions that may interfere with their
             participation in the study or potentially affect the interpretation of the study data

          -  Patients unable to take oral drugs or with lack of physical integrity of the upper
             gastrointestinal tract or known malabsorption syndromes

          -  Patients who have previously been treated with systemic LDE225 or with other hedgehog
             pathway inhibitors

          -  Patients who have neuromuscular disorders (e.g. inflammatory myopathies, muscular
             dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy) or are on
             concomitant treatment with drugs that are recognized to cause rhabdomyolysis, such as
             5-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) inhibitors (statins), clofibrate and
             gemfibrozil, and that cannot be discontinued at least 2 weeks prior to starting LDE225
             treatment; NOTE: if it is essential that the patient stays on a statin to control
             hyperlipidemia, only pravastatin may be used with extra caution

          -  Patients who have taken part in an experimental drug study =< 4 weeks prior to
             registration

          -  Patients who are receiving treatment with medications known to be moderate and strong
             inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4
             (CYP3A4)/cytochrome P450, family 3, subfamily A, polypeptide 5 (5) or drugs
             metabolized by cytochrome P450, family 2, subfamily B, polypeptide 6 (CYP2B6) or
             cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9) that have narrow
             therapeutic index, and that cannot be discontinued before starting treatment with
             LDE225

          -  Patients unwilling or unable to comply with the protocol

          -  Requirement for anticoagulation with warfarin