Phase 1-2 Amrubicin in Combo With Lenalidomide + Weekly Dexamethasone in Relapsed/Refractory Multiple Myeloma

Study Overview
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Brief Summary
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To assess if amrubicin is safe and useful for patients with multiple myeloma requiring additional treatment.

Detailed Description
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PRIMARY OBJECTIVES Establish the maximum tolerated dose (MTD) and toxicity profile for the combination of amrubicin with lenalidomide and dexamethasone in previously treated adult patients with multiple myeloma during Phase I Determine the combined rate of complete response (CR) and very good partial response (VGPR) for this combination in this population as defined by the International Myeloma Working Group Uniform Response Criteria (IMWGURC) SECONDARY OBJECTIVES Determine the overall response rate (CR, VGPR and PR) Assess additional evidence of ant-tumor activity as measured by duration of response (DOR), progression-free survival (PFS), time to tumor progression (TTP), and overall survival (OS)

Official Title
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A Phase 1 Study of Amrubicin in Combination With Lenalidomide and Weekly Dexamethasone in Relapsed/Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Amrubicin
* Drug: Lenalidomide
* Drug: Dexamethasone
* Drug: Aspirin
* Drug: Pegfilgrastim


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Relapsed or refractory multiple myeloma that has progressed following at least 1 prior therapy. Measurable disease defined as one of the following: Serum M-protein ≥ 1 g/dL Urine M-protein ≥ 200 mg/24 hours Received at least 1 prior line of systemic treatment that may have included lenalidomide and/or an anthracycline. No cytotoxic chemotherapy within 4 weeks prior to first dose of amrubicin. This interval may be reduced to 14 days for thalidomide, lenalidomide, bortezomib or corticosteroids, provided other entry criteria are met. Age ≥ 18 at the time of consent. Life expectancy of more than ≥ 3 months. No known central nervous system involvement by myeloma. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 at study registration during phase 1. Once safety is confirmed, ECOG performance status 0 to 2 at study registration during phase 2. No poorly-controlled intercurrent illness. Platelets > 100 x 10^9/L Hemoglobin > 8.0g/dL Absolute neutrophil count (ANC) >1.5 x 10^9/L Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x upper limit of normal (ULN) Total bilirubin ≤ 1.5 x ULN Calculated creatinine clearance ≥ 50 mL/min by Cockcroft-Gault formula. Left ventricular ejection fraction (LVEF) ≥ 50% by Echocardiogram (ECHO) or multiple gate acquisition scan (MUGA) All study participants must be registered into the mandatory RevAssist program, and be willing and able to comply with the Requirements of RevAssist. Disease-free of prior malignancies for ≥ 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 U/mL within 10 to 14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days) and must either commit to continued abstinence from heterosexual intercourse or begin 2 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. 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. Ability to understand and the willingness to sign a written informed consent document. Able to adhere to the study visit schedule and other protocol requirements. Able to take aspirin (81 or ≥ 25 mg) daily as prophylactic anticoagulation. Patients intolerant to aspirin may use warfarin or low molecular weight heparin (LMWH). Patients with previous thromboembolic event on lenalidomide or thalidomide may be started on warfarin or LMWH. Patients already taking warfarin or LMWH do not require additional aspirin.. Lactating females must agree not to breast-feed while taking lenalidomide Exclusion Criteria: Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form. Pregnant or breastfeeding females. Any concurrent severe or uncontrolled medical disease which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. Use of any other experimental drug or therapy within 28 days of first dose of amrubicin. Known hypersensitivity to thalidomide or lenalidomide. The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs. LVEF ≤ 50%. Concurrent use of other anti-cancer agents or treatments. Known positive for HIV, or infectious hepatitis, type B or C. Cranial radiotherapy ≤ 21 days prior to first dose of amrubicin; radiotherapy to all other areas ≤ 7 days prior to first dose of amrubicin.

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: Amrubicin + Lenalidomide + Dexamethasone<br>Amrubicin will be given intravenously on Day 1 of each 3-week cycle beginning with 40 mg/m2, for a maximum of 4 cycles. Concurrent therapeutic medications: Lenalidomide: 10 or 15 mg daily by mouth, Days 1 to 14 Dexamethasone: 40 mg weekly by mouth (Days 1, 8, and 15) Other drugs: Aspirin: 81 or 325 mg daily oral Pegfilgrastim subcutaneous on Day 2 | Drug: Amrubicin<br>* 40, 60, or 80 mg/m2 intravenous (IV)<br>* Other names: SM-5887;Drug: Lenalidomide<br>* 15 mg daily by mouth<br>* Other names: Revlimid;Drug: Dexamethasone<br>* 40 mg weekly by mouth<br>* Other names: Dexpak Taperpak;Drug: Aspirin<br>* 81 or 325 mg daily by mouth<br>* Other names: acetylsalicylic acid;Drug: Pegfilgrastim<br>* 6 mg subcutaneous on Day 2<br>* Other names: PEG-GCSF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rates After Amrubicin + Lenalidomide + Dexamethasone, Per International Myeloma Working Group Uniform Response Criteria | Modified International Myeloma Working Group Uniform Response Criteria: Complete (CR)= Negative for monoclonal protein (MP) in urine (U) and serum (S) + No tissue plasmacytomas (PC) + <5% plasma cells (PCs) in marrow (M) Stringent CR (sCR)= CR with normal light chain ratio+ no PCs in M Near CR (nCR)= CR, except MP persists in U and S Partial (PR)= S MP ≤50%, + U MP ≤90% or <200 mg/24 hours (hr) Very Good PR (VGPR)= in S MP ≤90%, + U MP <100 mg/24 hr Minimal (MR)= S MP ≤51-75%, + If light chain is excreted, reduced 50-89%/24 hr that is also >200 mg/24 hr, + No increase in lytic bone lesions Progressive disease (PD)= any of: S MP ≥125% and/or ≥+0.5 g/dL, U MP ≥125% and/or ≥+200 mg/24 hr New or increased bone lesions/PC S calcium >11.5 mg/dL (attributed to increased PCs) PD after CR/sCR= Reappearance of S or U MP ≥5% clonal PCs in M New PC, lytic bone lesions, hypercalcemia Stable Disease (SD)= Not CR, VGPR, MR, PR, or PD | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) |  | 140 days | 
| Progression-free Survival (PFS) | Progression-free survival (PFS) is alive and free from progression, per the modified International Myeloma Working Group Uniform Response Criteria, defined as any of: Serum monoclonal protein ≥ 125% baseline and/or ≥ +0.5 g/dL from baseline, Urine monoclonal protein ≥ 125% baseline and/or ≥ +200 mg/24 hour from baseline New or increased bone lesions or plasmacytomas Serum calcium > 11.5 mg/dL (attributed to increased plasma cells) | 9 months | 
| Time-to-next Treatment |  | 9 months |