Aflibercept for Relapsed Multiple Myeloma

Study Overview
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Brief Summary
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This phase II trial is studying the side effects and how well aflibercept works in treating patients with stage II or stage III multiple myeloma that has relapsed or not responded to previous treatment. Aflibercept may be able to carry cancer-killing substances directly to multiple myeloma cells. It may also stop the growth of multiple myeloma by blocking blood flow to the cancer.

Detailed Description
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OBJECTIVES: I. To evaluate the safety and efficacy of VEGF Trap (aflibercept) in patients with relapsed or refractory, stage II or III multiple myeloma (MM). II. To perform correlative studies in order to evaluate the angiogenic properties of tissue from patients during the course of treatment with VEGF Trap. OUTLINE: This is a multicenter study. Patients receive aflibercept intravenously (IV) over 1 hour on day 1. Treatment repeats every 2 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed for 60 days and then periodically thereafter.

Official Title
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A Phase 2 Study of Aflibercept for the Treatment of Relapsed or Refractory Multiple Myeloma

Conditions
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Stage II Multiple Myeloma, Stage III Multiple Myeloma

Intervention / Treatment
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* Biological: aflibercept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed multiple myeloma Stage II or III disease according to Salmon-Durie staging criteria Relapsed or refractory disease Progressive disease Measurable disease, defined by ≥ 1 of the following criteria: Serum M protein ≥ 1.0 g/dL by serum protein electrophoresis Free light chain measurement > 200 mg/dL Urinary M protein excretion ≥ 200 mg/24 hours Must have received ≥ 2 prior therapies* for multiple myeloma that meet the following criteria: Antimyeloma therapeutic regimen consisting of ≥ 1 complete course of single-agent or combination-agent therapy, or a planned series of treatments (e.g., 3-4 courses of induction therapy followed by a stem cell harvest procedure followed by conditioning high-dose therapy supported by stem cell transplantation) Antimyeloma regimen is discontinued because of the development of resistant disease or severe therapy-related toxicity Individual antimyeloma regimen will be considered to have been discontinued when all agents of the regimen have been permanently stopped A prior regimen will not be considered to have been discontinued for the modification of drug doses, or if less than all the agents of a combination regimen have been discontinued, or if the regimen has been halted temporarily for the development of a plateau phase of myeloma Maintenance therapy will not be considered an additional regimen If new agents are added to an existing regimen, presumably because of tumor resistance, the old regimen will be considered to have ended and a new regimen to have started No evidence of central nervous system (CNS) disease, including primary brain tumor or brain metastasis Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2 OR Karnofsky PS 60-100% Life expectancy > 12 weeks White blood cell (WBC) ≥ 3,000/mm^3 Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 75,000/mm^3 Bilirubin ≤ 1.5 times upper limit of normal (ULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times ULN Creatinine ≤ 2.0 mg/dL OR creatinine clearance ≥ 60 mL/min No albuminuria only Urine protein: creatinine ratio < 1 OR 24-hour urine protein with an albumin level < 500 mg Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for ≥ 6 months after completion of study therapy Exclusion criteria: No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies No known history of allergic reactions attributed to compounds of similar chemical or biological composition to other agents used in the study No serious or nonhealing wound, ulcer, or bone fracture No significant traumatic injury within the past 28 days No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days No clinically significant cardiovascular disease No prothrombin time (PT) or international normalized ratio (INR) > 1.5 (unless patient is on full-dose warfarin) No evidence of bleeding diathesis or coagulopathy No uncontrolled intercurrent illness that would limit compliance with study requirements, including ongoing or active infection No psychiatric illness or social situations that would limit study compliance No concurrent major surgery No concurrent immunosuppressive agents (including steroids) No other concurrent investigational agents

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: Treatment (antiangiogenesis therapy)<br>Patients receive aflibercept IV over 1 hour on day 1. Treatment repeats every 2 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. | Biological: aflibercept<br>* Given IV<br>* Other names: Zaltrap;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (Complete [CR] and Partial Response [PR]) | A 95% confidence interval was intended to be estimated via binomial proportions, but was not computed due to small sample size. Criteria for Response from EBMT, IBMTR, ABMTR: Complete Response:Complete absence of monoclonal protein by immunofixation for a minimum of 6 weeks; Near Complete Response:Absence of serum paraprotein by standard serum/urine protein electrophoresis without disappearance of monoclonal spike by immunofixation; Partial Response:Sustained decrease in production rate of monoclonal serum protein to 50% or less of pretreatment value; Stable Disease: No significant change from baseline; Progression of Disease:Patients with a > or = 25% rise in production rate, new/increased size of lytic lesions/plasmacytomas/progressive marrow plasmacytosis; Symptomatic Deterioration:Patients with deterioration of health requiring discontinuation of treatment w/out objective evidence of disease progression. | At baseline and every 4 weeks during study treatment until treatment discontinuation due to disease progression, unacceptable toxicities and/or patient withdrawal. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae. | Time from first treatment day until objective or symptomatic progression, assessed up to 6 months | 
| Overall Survival (OS) | Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae. | Time from first treatment day until death, assessed up to 6 months | 
| Toxicities | Toxicities will be assessed and graded according to Common Terminology Criteria for Adverse Events (CTCAE) v. 3.0 terminology. Exact 95% confidence intervals around the toxicity proportions will be calculated to assess the precision of the obtained estimates. | up to 6 months | 
| Tissue Expression Patterns of VEGFR Subtypes | The change in the prevalence/expression of these markers between pre-and-post treatment samples will be analyzed by McNemar's test. Ninety-five percent confidence intervals will be calculated to assess the precision of the obtained estimates for all laboratory correlates. | At baseline and post-treatment (1 week after 2nd dose and end of study) | 
| The Apoptotic State of Tumor Neovasculature | The change in the prevalence/expression of these markers between pre-and-post treatment samples will be analyzed by McNemar's test. Ninety-five percent confidence intervals will be calculated to assess the precision of the obtained estimates for all laboratory correlates. | At baseline and post-treatment (1 week after 2nd dose and end of study) | 
| Proangiogenic Factors Such as VEGF | The change in the prevalence/expression of these markers between pre-and-post treatment samples will be analyzed by McNemar's test. Ninety-five percent confidence intervals will be calculated to assess the precision of the obtained estimates for all laboratory correlates. | At baseline, before every course for 3 months, and then every 3 months during treatment for the first year | 
| Circulating Endothelial Progenitors | The change in the prevalence/expression of these markers between pre-and-post treatment samples will be analyzed by McNemar's test. Ninety-five percent confidence intervals will be calculated to assess the precision of the obtained estimates for all laboratory correlates. | At baseline, before every course for 3 months, and then every 3 months during treatment for the first year |