Safety, Efficacy, and Pharmacokinetics of Continuous Subcutaneous Lenalidomide in Multiple Myeloma (MM)

Study Overview
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Brief Summary
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Primary Objective • Assess the safety and tolerability of low-dose lenalidomide administered by continuous subcutaneous (SC) infusion (STAR-LLD) in combination with dexamethasone and a proteasome inhibitor (PI). Secondary Objectives To assess the immunologic activity of natural killer (NK) cells and T cells for innate and humoral immunity. To establish the pharmacokinetic (PK) profile of STAR-LLD at a defined infusion rate targeting steady-state blood concentrations. To determine pharmacodynamic (PD) changes with STAR-LLD in a panel of biomarkers associated with clinical response to lenalidomide. Evaluate changes in efficacy indicators including objective response rate (ORR), progression-free survival (PFS), and duration of response (DOR). Exploratory Objective To assess the impact of STAR-LLD on patient reported symptoms and outcomes. Primary Endpoints The grade, frequency, and relationship of treatment-emergent adverse events (TEAEs) including adverse events of special interest (AESIs): (gastrointestinal [GI] toxicity, fatigue, hematologic toxicity, rash (non-infusion site). The observation of dose-limiting toxicities (DLTs) of STAR-LLD during Cycle 1. Secondary Endpoints Immune profiles, functional assays for NK cell activation and antigen specific T-cell activity. Blood concentrations of lenalidomide at on Day 1 and at steady state. Changes in biomarkers during treatment. Rate of complete response, very good partial response (VGPR), partial response (PR), stable disease (SD), and progressive disease. Determination of ORR, PFS, and DOR

Official Title
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A Protocol to Assess the Safety, Efficacy, and Pharmacokinetics of Continuous Subcutaneous Administration of Low-dose Lenalidomide (STAR-LLD) for the Treatment of Multiple Myeloma (MM)

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Lenalidomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ≥18 years at the time of informed consent. Autologous stem cell transplant (ASCT) ineligible. SARS -CoV2 virus (COVID)-19 negative. A prior diagnosis of MM as defined by International Myeloma Working Group (IMWG) criteria (Appendix 7). Documented measurable disease following first line therapy defined as: Serum monoclonal protein ≥1.0 g/dL by protein electrophoresis. ≥200 mg/24 hours of monoclonal protein in the urine on 24-hour electrophoresis. Serum free light chain (SFLC) ≥10 mg/dL AND abnormal serum kappa to lambda free light chain (FLC) ratio. Intended to be treated in 2nd line or greater with lenalidomide, dexamethasone, and a PI. Proteasome inhibitor sensitive defined as progression free for > 6 months from cessation of PI or never received a prior PI. Progression per IMWG criteria on the most recent line of therapy. Eastern Cooperative Oncology Group (ECOG-Appendix 1) performance status ≤2 (patients with a performance status of 3 based solely on bone pain secondary to MM may be eligible following consultation and approval by the Medical Monitor). Willing to comply with the protocol defined Lenalidomide Pregnancy Risk Minimization Plan for the prevention of pregnancy (Appendix 5). Females of childbearing potential (FCBP) must have a medically supervised negative serum or urine pregnancy test 4-14 days prior to planned start of treatment and again 24 hours prior to initiation of study medication. All FCBP must agree to either commit to continued abstinence from sexual intercourse or begin TWO acceptable methods of birth control AT THE SAME TIME, at least 28 days before receiving the first dose of STAR-LLD. FCBP must also agree to ongoing pregnancy testing. Males must agree to use a latex or synthetic condom during sexual contact with a FCBP from the time of starting study treatment through 28 days after the last dose, even if they have had a vasectomy. Able to take anti-thrombotic prophylaxis. The following laboratory results must be met during screening: ANC ≥1,000 cells/mm3 (1.0 x 109/L). Platelet count ≥75,000 cells/mm3 (75 x 109/L). Hemoglobin ≥8.0 g/dL (red blood cell (RBC) transfusions are permitted prior to initiation of study drug if hemoglobin is stable for 72 hours). Total bilirubin ≤1.5 x upper limit of normal (ULN), or patient diagnosed with Gilberts syndrome with a total bilirubin <5.0 x ULN that has been reviewed and approved by the Medical Monitor. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 x ULN. Calculated creatinine clearance ≥60 mL/min. Appendix 4 Negative pregnancy test for FCBP (must be obtained within 4-14 days before the initiation of study drug. The following criteria must be met within 72 hours prior to first administration of continuous infusion STAR-LLD: ANC ≥1,000 cells/mm3 (1.0 x 109/L). Platelet count ≥75,000 cells/mm3 (75 x 109/L). Hemoglobin ≥8.0 g/dL (RBC transfusions are permitted prior to initiation of study drug if hemoglobin is stable for 72 hours). Calculated creatinine clearance ≥60 mL/min. Appendix 4 Negative pregnancy test for FCBP (must be obtained within 24 hours of first dose of study drug). Able and willing to receive percutaneous ambulatory therapy. Has an in-home care partner willing to receive training from a nurse for assistance with pump management. Exclusion Criteria: Pregnant or breastfeeding. Received an ASCT. Venous thromboembolism within 12 months of starting treatment on study. Patients with active hepatitis B or C or human immunodeficiency virus (HIV) positive and on active therapy for those viral illnesses. Currently taking any investigational therapy for the treatment of MM. A 28-day washout prior to Cycle 1 Day 1 is required for any previous investigational therapy. Received a prior treatment line containing lenalidomide and failed to achieve an objective response (CR, VGPR or PR). Discontinued a prior line of treatment due to intolerability to lenalidomide. Concomitant use of strong CYP3A inducers (see https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-3). Concurrent clinically significant amyloidosis or plasma cell leukemia or POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes). Known active infection requiring systemic anti-infective treatment (prophylactic treatment is permitted). Prior malignancies within the previous 3 years, other than previously treated squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix or breast or another malignancy that is considered cured with minimal risk of recurrence (e.g., very low and low risk prostate cancer in active surveillance). Prior major surgical procedure or radiation therapy within 4 weeks of the initiation of STAR-LLD (this does not include limited course of radiation used for management of bone pain within 7 days of initiation of STAR-LLD). Any other condition that precludes adequate understanding, cooperation, and compliance with study procedures or any condition that could pose a risk to the patient's safety, as per the Investigator's judgment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study ARM1 - Vld (Velcade-lenalidomide-dexamethasone)<br>Bortezomib SC at 1.3 mg/m2 on Days 1, 8, 15, and 22 of each 28-day cycle Lenalidomide 400 mcg/hr continuously for 28 of 28-day cycle Dexamethasone 40mg orally on Days 1, 8, 15 and 22 of each 28-day cycle (age 75 or over 20 mg. | Drug: Lenalidomide<br>* Low-dose lenalidomide continuous SC infusion (STAR-LDD) in combination with bortezomib and dexamethasone<br>* Other names: Dexamethasone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the safety and tolerability of low-dose lenalidomide administered by continuous subcutaneous (SC) infusion (STAR-LLD) in combination with dexamethasone and a proteasome inhibitor (PI). | Based on the incidence of adverse events associated with the use of the drug | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the immunologic activity of natural killer (NK) cells and T cells for innate and humoral immunity. | Measure changes in T cell and NK cell function/exhaustion over the study by flow cytometry | 12 months | 
| To establish the pharmacokinetic (PK) profile of STAR-LLD at a defined infusion rate targeting steady-state blood concentrations. | Meaured vs predicted blood concentrations of lenalidomide during the infusion and at steady state | 12 months | 
| To determine pharmacodynamic (PD) changes with STAR-LLD in a panel of biomarkers associated with clinical response to lenalidomide. | Evaluate desirable changes in immune cells activity over therapy | 12 months | 
| Evaluate changes in efficacy indicators including objective response rate (ORR), progression-free survival (PFS), and duration of response (DOR). | An ORR of 60% is representative of patients being retreated with PI and Len | 12 months |