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

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

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

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Amrubicin; Drug: Lenalidomide; Drug: Dexamethasone; Drug: Aspirin; Drug: Pegfilgrastim

Detailed Description

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)

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Amrubicin + Lenalidomide + Dexamethasone; 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; 40, 60, or 80 mg/m2 intravenous (IV); Other Names: SM-5887; Drug: Lenalidomide; 15 mg daily by mouth; Other Names: CC-5013; Revlimid; Drug: Dexamethasone; 40 mg weekly by mouth; Other Names: Decadron; Dexamethasone Intensol; Dexpak Taperpak; Drug: Aspirin; 81 or 325 mg daily by mouth; Other Names: acetylsalicylic acid; Drug: Pegfilgrastim; 6 mg subcutaneous on Day 2; Other Names: Neulasta; PEG-GCSF

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Michaela Liedtke
• Collaborators: Celgene Corporation
• Investigators: Principal Investigator: Michaela Liedtke, Stanford University

Publications and helpful links

General Publications

• Dinner S, Dunn TJ, Price E, Coutre SE, Gotlib J, Berube C, Kaufman GP, Medeiros BC, Liedtke M. A phase I, open-label, dose-escalation study of amrubicin in combination with lenalidomide and weekly dexamethasone in previously treated adults with relapsed or refractory multiple myeloma. Int J Hematol. 2018 Sep;108(3):267-273. doi: 10.1007/s12185-018-2468-5. Epub 2018 May 25.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2011
• Primary Completion (Actual): July 1, 2016
• Study Completion (Actual): July 1, 2017

Study Registration Dates

• First Submitted: May 16, 2011
• First Submitted That Met QC Criteria: May 17, 2011
• First Posted (Estimate): May 18, 2011

Study Record Updates

• Last Update Posted (Actual): September 18, 2018
• Last Update Submitted That Met QC Criteria: September 17, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Antineoplastic Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Aspirin; Dexamethasone; Dexamethasone acetate; BB 1101; Lenalidomide; Amrubicin
• Other Study ID Numbers: IRB-19092 (Other Identifier: Stanford IRB); AR_MM_PI_007 (Other Identifier: Celgene Corporation); SU-05062011-7711 (Other Identifier: Stanford University); HEMMYL0018 (Other Identifier: OnCore ID)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No