Clinical Trials

Understanding the molecular basis of cancer is a critical step toward devising the most effective treatment of the patient as an individual. The promise of molecular targeted therapeutics and personalized cancer care has been demonstrated in breast and lung cancer and chronic myeloid leukemia. However, similar examples of success in multiple myeloma have not been achieved despite extensive basic research as well as clinical advances. What is well understood is that myeloma is a heterogeneous disease with great genetic and epigenetic complexity.22, 23 Therefore, there remains a critical need to understand myeloma patient biology in the context of current patient care.24 The objective of this longitudinal study is to identify patient subgroups and phenotypes defined by molecular profiling and clinical features. These profiles will enable a better understanding of mechanisms of disease, drug response and patient relapse. Ultimately the study is intended to drive successful drug development and patient care in multiple myeloma.

BT062 is an antibody-drug conjugate designed to bind and destroy Myeloma cells. The study drug is being given in multiple doses with standard Multiple Myeloma treatments, lenalidomide and dexamethasone, to test how well the treatments are tolerated and work together. This study is a dose escalation study with the purpose to find out the highest dose of BT062 that a subject can tolerate in combination with lenalidomide and dexamethasone.

The main purpose is to test the safety and tolerability of SNS01-T. The first group of patients with relapsed or refractory multiple myeloma will be given a relatively low dose. If tolerated, a second group will receive a higher dose. If tolerated by the second group, a third and then a fourth group will receive higher doses. Treatment-related adverse events (side effects), changes in vital signs, physical examination, and laboratory values will be monitored. Patients will receive twice weekly infusions for 6 weeks and then will be followed monthly for 6 months. A secondary purpose is to explore whether SNS01-T is an effective treatment for multiple myeloma, mantle cell lymphoma and diffuse large B cell lymphoma.

PRIMARY OBJECTIVES:

     I. Determine the maximum tolerated dose (MTD) of bortezomib in combination with pomalidomide and dexamethasone.

     II. To evaluate the hematologic response rate (PR, VGPR, or CR) of pomalidomide, bortezomib and dexamethasone in patients with relapsed or refractory myeloma.

     SECONDARY OBJECTIVES:

     I. Time to progression.

     II. To assess the toxicity of pomalidomide, bortezomib and dexamethasone in this patient population.

     OUTLINE : This is a phase I, dose-escalation study of bortezomib followed by a phase II study. Patients receive oral pomalidomide on days 1-21; bortezomib IV on days 1, 8,15, 22; and oral dexamethasone on days 1, 8, 15, 22 . Treatment  repeats every 28 days for 8 courses. Patients then receive maintenance therapy comprising oral pomalidomide on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6 months.

PRIMARY OBJECTIVES:

     I. To compare the stringent complete response (sCR) rate after 12 cycles among arms.

     SECONDARY OBJECTIVES:

     I. To compare progression-free and overall survival among arms. II. To describe the adverse event profile of each arm.

     TERTIARY OBJECTIVES:

     I. To compare sCR after 6 cycles and 24 cycles and quality of life among arms.

     OUTLINE: Patients are randomized to 1 of 3 treatment arms.

     ARM A: Patients receive bortezomib subcutaneously (SC) on days 1 and 15 of courses 1-12 and day 1 of courses 13-24.

     ARM B: Patients receive bortezomib SC as in Arm A, cyclophosphamide orally (PO) on days 1 and 15 of courses 1-12 and day 1 of courses 13-24, and dexamethasone PO on days 1 and 15 of courses 1-12 and day 1 of courses 13-24.

     ARM C: Patients receive bortezomib SC as in Arm A and lenalidomide PO once daily (QD) on days 1-28.

     In all arms, treatment continues every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

     After completion of study treatment, patients are followed up every 6 months for 3 years.

The primary purpose of this dose escalation study is to estimate the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of LGH447 as a single agent when administered orally once daily to adult patients with Multiple Myeloma (MM).

PRIMARY OBJECTIVES:

     I. To establish the maximum tolerated dose of carfilzomib given in combination with oral cyclophosphamide and thalidomide and dexamethasone. (Phase I) II. In newly diagnosed myeloma to evaluate the response rate (CR, nCR, and VGPR) to carfilzomib given in combination with oral cyclophosphamide and thalidomide and dexamethasone after four 28 day cycles. (Phase II)

     SECONDARY OBJECTIVES:

     I. Determine the overall response rate (CR, nCR, PR) after 4, 8, 12 cycles. II. Determine the duration of progression-free and overall survival for patients receiving this regimen.

     III. To evaluate the incidence of toxicities for this regimen. IV. To evaluate the ability to successfully collect peripheral blood stem cells following four months of combination therapy.

     OUTLINE: This is a phase I, dose escalation study of carfilzomib followed by a phase II study.

     Patients receive carfilzomib IV on days 1, 2, 8, 9, 15, and 16; oral cyclophosphamide on days 1, 8, and 15; oral dexamethasone on days 1, 8, 15, and 22; and oral thalidomide on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

     After completion of study treatment, patients are followed at 3 months, then every 3 months for 1 year, and then every 6 months for up to 3 years.

Multiple Myeloma (MM) affects approximately 20,000 Americans annually and remains an incurable hematologic malignancy characterized by frequent early response followed by universal treatment relapse necessitating multiple sequential therapeutic regimens. Until recently, few effective therapies existed. Several novel agents for MM have now become available including the immunomodulatory drugs thalidomide, lenalidomide, as well as the proteasome inhibitor, bortezomib. Each of these agents is undergoing extensive clinical evaluation in combination with other therapies to produce unprecedented response rates in newly diagnosed and relapsed MM. Lenalidomide has proven to be a highly effective treatment agent, particularly when used in combination with dexamethasone but is renally excreted and little information is available about its use in myeloma patients with impaired kidney function (20% have renal failure at some time after diagnosis). Defining a safe and effective dose of lenalidomide to use is a critical step in MM treatment.

     OUTLINE: This is a Phase I, dose-escalation study of lenalidomide followed by a Phase II study. Patients are stratified according to degree of renal dysfunction (moderate [creatinine clearance 30-60 mL/min] vs severe [creatinine clearance <30 mL/min and does not require dialysis] vs end-stage renal disease [creatinine clearance <30 mL/min and requires dialysis]).

     Patients receive oral lenalidomide on days 1-21 and low-dose oral dexamethasone 40 mg on days 1, 8, 15, and 22. There is a 7 day rest (days 22-28) from lenalidomide. Each cycle is 28 days and repeated in the absence of disease progression or unacceptable toxicity.

     Patients enrolled in the phase II portion of the study will undergo blood sample collection periodically for pharmacokinetic analysis of lenalidomide (Mayo Clinic sites only).

     After completion of study treatment, patients are followed every 6 months for up to 3 years.

PRIMARY OBJECTIVES: I. To determine the confirmed overall response rate (>= partial response [PR]) of MLN9708 (proteasome inhibitor MLN9708), used as a single agent in patients with relapsed multiple myeloma, who are proteasome inhibitor naive (including bortezomib) naive OR have received less than 6 cycles of therapy with bortezomib and had a better than PR with no progression at the time of discontinuation. SECONDARY OBJECTIVES: I. To determine the overall response rate of MLN9708 in combination with dexamethasone, when dexamethasone is added to MLN9708 for lack of response or for progression. II. To determine the event free survival and overall survival among patients with relapsed myeloma following treatment with MLN9708 with dexamethasone added for lack of response or progression. OUTLINE: Patients receive MLN9708 orally (PO) on days 1, 8 and 15. Patients with lack of minor response by the end of the second course or lack of partial response by the end of the fourth course also receive dexamethasone PO on days 1, 2, 8, 9, 15, and 16. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6 or 12 months for 2 years.

PRIMARY OBJECTIVES:

     I. Study the risk of grade 3-4 non-hematologic adverse events in patients with asymptomatic high-risk smoldering multiple myeloma treated with lenalidomide. (Phase II) II. Compare the progression-free survival (PFS) of patients with asymptomatic high-risk smoldering multiple myeloma treated with lenalidomide versus observation alone. (Phase III)

     SECONDARY OBJECTIVES:

     I. Assess the response of patients treated with lenalidomide. (Phase II) II. Determine and compare the response rate, time to progression, 1-year PFS probability, and the overall survival of patients treated with lenalidomide versus observation alone. (Phase III) III. Estimate the incidence of adverse events of these regimens in these patients. (Phase III)

     TERTIARY OBJECTIVES:

     I. Describe the cohort in terms of GEP and cytogenetic risk classification and evaluate baseline immune and MRI parameters. (Phase II) II. Evaluate the impact of therapy within GEP-defined risk groups and GEP as a prognostic marker. (Phase III) III. Study the effects of lenalidomide on laboratory markers of immune function. (Phase III) IV. Study the prognostic value of MRI-detected asymptomatic bone disease on clinical outcome. (Phase III V. Evaluate the prognostic effect of baseline high-risk cytogenetic abnormalities on clinical outcome. (Phase III)

     QUATERNARY OBJECTIVES:

     I. To compare QOL change between treatment and observation arms based on the functional (FWB) and physical (PWB) well-being components of the FACT-General (G) patient-reported outcome (PRO) measure from registration (prior to initiation of treatment) up to cycle 24.

     II. To examine the impact of differential treatment response (PFS), if observed, on QOL based on the FACT FWB+PWB up to cycle 48.

     III. To obtain prospective data on Myeloma specific QOL attributes, utilizing and evaluating the Multiple Myeloma Subscale (MMS).

     OUTLINE: This is a multicenter study.

     PHASE II: Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

     PHASE III: Patients are randomized to 1 of 2 treatment arms.

     ARM I: Patients receive lenalidomide PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

     ARM II: Patients receive standard of care and undergo observation in the absence of disease progression.

     Peripheral blood, bone marrow aspirate, and bone marrow core biopsy samples are collected for gene expression profiling, immune function, and cytogenetic abnormalities. Patients complete the Functional Assessment of Cancer Therapy (FACT) Physical Well-Being (PWB), and FACT Functional Well-Being (FWB) questionnaires at baseline and periodically during study.

     After completion of study therapy, patients are followed up periodically for 10 years.