Filgrastim in Treating Patients With Bortezomib-, Carfilzomib-, or IMID-Refractory Multiple Myeloma

A Pilot Study of G-CSF to Disrupt the Bone Marrow Microenvironment in Bortezomib-, Carfilzomib-, or IMID-Refractory Multiple Myeloma

Based on the pre-clinical data the investigators hypothesize that G-CSF treatment in patients with multiple myeloma will generate a 'hostile' bone marrow microenvironment for myeloma cells, depriving them of key support signals and rendering them more sensitive to chemotherapy. The investigators therefore propose to do an initial pilot study 1) to explore the safety of the combination of G-CSF and bortezomib-, carfilzomib-, or IMID-based treatment regimens in patients with bortezomib-, carfilzomib-, or IMID-refractory myeloma and 2) to generate correlative data for a subsequent larger study looking at the combination.

Study Overview

• Status: Terminated
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Filgrastim; Drug: Cyclophosphamide; Drug: Carfilzomib; Drug: Lenalidomide; Drug: Dexamethasone; Drug: Pomalidomide; Drug: Thalidomide; Drug: Bortezomib

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Washington 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:

• Patient must have a confirmed diagnosis of multiple myeloma. The patient may be any stage of multiple myeloma. The patient may have received one or more lines of prior therapy (there is no limit to number of prior lines of therapy permissible).
• Patient must be ≥18 years of age

• Patient must be in active treatment with one of the following:

  • twice-weekly bortezomib (on Days 1, 4, 8, and 11 of a 21-day cycle) with or without dexamethasone
  • carfilzomib (on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle) with or without dexamethasone
  • an IMID with or without dexamethasone daily on Days 1 to 21.
  • Patients being treated with bortezomib or carfilzomb may also be receiving an IMID or PO cyclophosphamide with the regimen.
• Patient must have shown stable or progressive disease on the current bortezomib-, carfilzomib-, or IMID-containing regimen with a measurable monoclonal protein component in the serum (at least 0.5 g/dl on electrophoresis or 0.05 g/dl [50mg/dl] on serum-free-light-chain). Patients who had an initial response on the current bortezomib-, carfilzomib-, or IMID-containing regimen but now have stable (plateaued) disease are eligible.
• Patient must have an ECOG performance status of 0 - 2
• Patient must be receiving concurrent treatment with bisphosphonates, with one dose occurring within 30 days prior to first day (Day -3) of protocol treatment

• Patient must have acceptable hematologic parameters, defined as:

  • Absolute neutrophil count > 1000 cells/mm3
  • Platelets ≥ 50,000 cells/mm3
  • Hemoglobin ≥ 8 g/dl

• Patient must have adequate liver function, defined as:

  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 x upper limit of normal
  • Total bilirubin < 2 x upper limit of normal
• Patient must be able to understand and willing to sign a written informed consent document

Exclusion Criteria:

• Patient must not be receiving any agents with known or suspected anti-myeloma activity (other than bortezomib, carfilzomib, dexamethasone, an IMID or PO cyclophosphamide, and bisphosphonates with the current regimen)
• Patient must not be actively using myeloid growth factors
• Patient must not have had any prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in-situ cervical cancer, or other cancer from which the subject has been disease-free for at least 2 years
• Patient must not have any uncontrolled medical problems such as diabetes mellitus, coronary artery disease, hypertension, unstable angina, arrhythmias, pulmonary disease, and symptomatic heart failure
• Patient must not have neuropathy ≥ grade 3 or painful neuropathy ≥ grade 2 (NCI CTCAE v 4.0)
• Patient must not have any known active infections requiring IV antibiotic, antiviral, or antifungal therapy
• Patient must not be pregnant or breastfeeding

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: Arm 1; Filgrastim 5 ug/kg from Day -3 to Day 10 of a single cycle. Bortezomib will be given at the patient's current dose on Days 1, 4, 8, and 11 OR Carfilzomib will be given at the patient's current dose on Days 1, 2, 8, 9, 15, and 16 OR IMID will be given at the patient's current dose once daily on Days 1-21. Patients receiving an IMID (thalidomide, lenalidomide, or pomalidomide) as part of a bortezomib or carfilzomb regimen should continue the same scheduled as the current regimen. Dexamethasone should be continued at the same dose and schedule as the patient's current regimen. PO cyclophosphamide should be continued at the same dose and schedule as the patient's current regimen.

Drug: Filgrastim; Other Names: G-CSF; Granulocyte Colony-Stimulating Factor; Neupogen®; Drug: Cyclophosphamide; Other Names: Cytoxan; Drug: Carfilzomib; Other Names: Kyprolis®; Drug: Lenalidomide; Other Names: Revlimid; Drug: Dexamethasone; Drug: Pomalidomide; Other Names: Pomalyst; Drug: Thalidomide; Other Names: Thalomid; Drug: Bortezomib; Other Names: Velcade®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of the combination of G-CSF and bortezomib-, carfilzomib-, or IMID-based treatment regimens in patients with refractory multiple myeloma.	Number and grade of adverse events based on NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	Up to 30 days after last treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effects of G-CSF on bone marrow and bone marrow cytokine and chemokine levels. Including: Quantification of marrow osteoblasts and CAR cells, measurement of SDF-1 (CXCL12), IL-6, BAFF, assessment of myeloma cell proliferation and survival in bone marrow		14 days after last drug treatment
Response rate as defined by the International Myeloma Working Group (IMWG) criteria		14 days after last drug treatment
Overall survival duration of patients treated on study	Defined as the date of first dose of study drug to the date of death from any cause.	1 year
Progression-free survival of patients treated on study	Defined as the interval from the date of first treatment to date of first documentation of disease progression.	1 year
Duration of response of patients treated on study	Defined as the interval from the date of first documentation of response to the first documentation of disease progression.	1 year

Collaborators and Investigators

• Sponsor: Washington University School of Medicine

Publications and helpful links

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start: June 1, 2012
• Primary Completion (Actual): February 1, 2014
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: February 15, 2012
• First Submitted That Met QC Criteria: February 17, 2012
• First Posted (Estimate): February 23, 2012

Study Record Updates

• Last Update Posted (Estimate): January 26, 2015
• Last Update Submitted That Met QC Criteria: January 21, 2015
• Last Verified: January 1, 2015

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; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Adjuvants, Immunologic; Dexamethasone; Cyclophosphamide; Thalidomide; Pomalidomide; Lenalidomide; Lenograstim; Bortezomib
• Other Study ID Numbers: 201204086