Recruitment

Recruitment Status
Completed
Estimated Enrollment
43

Inclusion Criteria

Serum creatinine =< 1.5 x ULN or 24-hour clearance >= 50 ml/min
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
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
...
Serum creatinine =< 1.5 x ULN or 24-hour clearance >= 50 ml/min
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
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
Recovered from toxicity of previous chemotherapy (excludes grade 1 neurotoxicity and hematological toxicity)
Absolute neutrophil count >= 1500/uL
Patients should have received single autologous stem cell transplantation 60-120 days prior to enrollment to the trial
Platelet count >= 80,000/uL
NOTE: For patients with no relapse prior to transplant, measurable disease at the time of diagnosis
Willingness to return to the Mayo Clinic enrolling institution for follow-up
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN or =< 5 x ULN if liver involvement
Hemoglobin >= 9.0 g/dL
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
Serum monoclonal protein >= 1.0 g/dL
Plasma creatine phosphokinase (CK) < 1.5 x ULN
Patients must be willing to provide biological samples as required by the study
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
Patients should have received the autologous SCT within 12 months of their diagnosis of myeloma to be eligible for the study
Serum total bilirubin =< 1.5 x ULN (upper limit of normal)
>= 200 mg of monoclonal protein in the urine on 24 hour electrophoresis
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])
Diagnosis of symptomatic multiple myeloma (MM)
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
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)

Exclusion Criteria

Patients unwilling or unable to comply with the protocol
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)
A past medical history of clinically significant ECG abnormalities or a family history of prolonged QT-interval syndrome
...
Patients unwilling or unable to comply with the protocol
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)
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)
Fridericia QT (QTcF) > 450 msec for males and > 470 msec for females on the screening electrocardiogram (ECG)
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
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
Angina pectoris within 3 months
Patients with evidence of disease progression post SCT at the time of consideration for the study enrollment will not be included
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
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
Barrier method of contraception: condom or occlusive cap (diaphragm or cervical vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
Patients who have previously been treated with systemic LDE225 or with other hedgehog pathway inhibitors
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)
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
Note: hormonal contraception methods (e.g. oral, injected, implanted) are not allowed
Patients with concurrent uncontrolled medical conditions that may interfere with their participation in the study or potentially affect the interpretation of the study data
Major surgery within 4 weeks prior to registration
Known allergies to any of the components of the investigational treatment regimen or required ancillary treatments
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
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 unable to take oral drugs or with lack of physical integrity of the upper gastrointestinal tract or known malabsorption syndromes
Prior allogeneic bone marrow/peripheral blood stem cell transplant
Acute myocardial infarction within 3 months
Other co-morbidity, which would interfere with patient's ability to participate in the trial, e.g. uncontrolled infection, uncompensated lung disease
Seroreactivity for human immunodeficiency virus (HIV), human T-lymphotropic virus type I (HTLV I) or II, hepatitis B virus (HBV), hepatitis C virus (HCV)
Placement of a non-hormonal intrauterine device (IUD) or non-hormonal intrauterine system (IUS)
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
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
Other active malignancy requiring therapy; EXCEPTIONS: non-melanotic skin cancer or carcinoma-in-situ of the cervix
Requirement for anticoagulation with warfarin

Summary

Conditions
  • Recurrent Plasma Cell Myeloma
  • Refractory Plasma Cell Myeloma
Type
Interventional
Phase
Phase 2
Design
  • Allocation: N/A
  • Intervention Model: Single Group Assignment
  • Masking: None (Open Label)
  • Primary Purpose: Treatment

Participation Requirements

Age
Between 18 years and 125 years
Gender
Both males and females

Description

PRIMARY OBJECTIVES: I. To assess the complete response (CR) rate with lenalidomide and sonidegib (LDE225) maintenance following an upfront single autologous stem cell transplant (SCT). SECONDARY OBJECTIVES: I. To assess the toxicity of lenalidomide and LDE225 when used as maintenance therapy in pati...

PRIMARY OBJECTIVES: I. To assess the complete response (CR) rate with lenalidomide and sonidegib (LDE225) maintenance following an upfront single autologous stem cell transplant (SCT). SECONDARY OBJECTIVES: I. To assess the toxicity of lenalidomide and LDE225 when used as maintenance therapy in patients post autologous SCT. II. To determine the progression-free survival rate at 1 and 2 years post autologous SCT. III. To evaluate progression-free survival and overall survival. TERTIARY OBJECTIVES: I. To determine the proportion of patients achieving a minimal residual disease (MRD) negative status. OUTLINE: Patients receive sonidegib orally (PO) once daily (QD) on days 1-28 and lenalidomide PO QD on days 1-21. Treatment repeats every 28 days for up to 18 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve stringent complete response (sCR), CR, very good partial response (VGPR), partial response (PR), minor response (MR), or stable disease (SD) (or unconfirmed [u]sCR, uCR, uVGPR, uPR, uMR) continue treatment in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 90 days for up to 3 years.

Inclusion Criteria

Serum creatinine =< 1.5 x ULN or 24-hour clearance >= 50 ml/min
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
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
...
Serum creatinine =< 1.5 x ULN or 24-hour clearance >= 50 ml/min
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
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
Recovered from toxicity of previous chemotherapy (excludes grade 1 neurotoxicity and hematological toxicity)
Absolute neutrophil count >= 1500/uL
Patients should have received single autologous stem cell transplantation 60-120 days prior to enrollment to the trial
Platelet count >= 80,000/uL
NOTE: For patients with no relapse prior to transplant, measurable disease at the time of diagnosis
Willingness to return to the Mayo Clinic enrolling institution for follow-up
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN or =< 5 x ULN if liver involvement
Hemoglobin >= 9.0 g/dL
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
Serum monoclonal protein >= 1.0 g/dL
Plasma creatine phosphokinase (CK) < 1.5 x ULN
Patients must be willing to provide biological samples as required by the study
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
Patients should have received the autologous SCT within 12 months of their diagnosis of myeloma to be eligible for the study
Serum total bilirubin =< 1.5 x ULN (upper limit of normal)
>= 200 mg of monoclonal protein in the urine on 24 hour electrophoresis
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])
Diagnosis of symptomatic multiple myeloma (MM)
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
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)

Exclusion Criteria

Patients unwilling or unable to comply with the protocol
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)
A past medical history of clinically significant ECG abnormalities or a family history of prolonged QT-interval syndrome
...
Patients unwilling or unable to comply with the protocol
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)
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)
Fridericia QT (QTcF) > 450 msec for males and > 470 msec for females on the screening electrocardiogram (ECG)
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
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
Angina pectoris within 3 months
Patients with evidence of disease progression post SCT at the time of consideration for the study enrollment will not be included
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
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
Barrier method of contraception: condom or occlusive cap (diaphragm or cervical vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
Patients who have previously been treated with systemic LDE225 or with other hedgehog pathway inhibitors
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)
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
Note: hormonal contraception methods (e.g. oral, injected, implanted) are not allowed
Patients with concurrent uncontrolled medical conditions that may interfere with their participation in the study or potentially affect the interpretation of the study data
Major surgery within 4 weeks prior to registration
Known allergies to any of the components of the investigational treatment regimen or required ancillary treatments
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
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 unable to take oral drugs or with lack of physical integrity of the upper gastrointestinal tract or known malabsorption syndromes
Prior allogeneic bone marrow/peripheral blood stem cell transplant
Acute myocardial infarction within 3 months
Other co-morbidity, which would interfere with patient's ability to participate in the trial, e.g. uncontrolled infection, uncompensated lung disease
Seroreactivity for human immunodeficiency virus (HIV), human T-lymphotropic virus type I (HTLV I) or II, hepatitis B virus (HBV), hepatitis C virus (HCV)
Placement of a non-hormonal intrauterine device (IUD) or non-hormonal intrauterine system (IUS)
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
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
Other active malignancy requiring therapy; EXCEPTIONS: non-melanotic skin cancer or carcinoma-in-situ of the cervix
Requirement for anticoagulation with warfarin

Tracking Information

NCT #
NCT02086552
Collaborators
  • National Cancer Institute (NCI)
  • Novartis Pharmaceuticals
Investigators
  • Principal Investigator: Francis Buadi Mayo Clinic
  • Francis Buadi Mayo Clinic
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