Aflibercept for Relapsed Multiple Myeloma

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT00437034
• Collaborator: (none)
• Enrollment: 6
• Locations: 6
• Arm: 1
• Duration (Months): 51
• Patient Per Site: 1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Stage II Multiple Myeloma; Stage III Multiple Myeloma	Biological: aflibercept	Phase 2

Detailed Description

OBJECTIVES:

1. To evaluate the safety and efficacy of VEGF Trap (aflibercept) in patients with relapsed or refractory, stage II or III multiple myeloma (MM).

2. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 6 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of Aflibercept for the Treatment of Relapsed or Refractory Multiple Myeloma
• Study Start Date: Jan 1, 2007
• Actual Primary Completion Date: Oct 1, 2010
• Actual Study Completion Date: Apr 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (antiangiogenesis therapy) 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; Given IV; Other Names: vascular endothelial growth factor trap VEGF Trap Zaltrap

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate (Complete [CR] and Partial Response [PR]) [At baseline and every 4 weeks during study treatment until treatment discontinuation due to disease progression, unacceptable toxicities and/or patient withdrawal.]

   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.

Secondary Outcome Measures

1. Progression-free Survival (PFS) [Time from first treatment day until objective or symptomatic progression, assessed up to 6 months]

   Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae.

2. Overall Survival (OS) [Time from first treatment day until death, assessed up to 6 months]

   Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae.

3. Toxicities [up to 6 months]

   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.

4. Tissue Expression Patterns of VEGFR Subtypes [At baseline and post-treatment (1 week after 2nd dose and end of study)]

   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.

5. The Apoptotic State of Tumor Neovasculature [At baseline and post-treatment (1 week after 2nd dose and end of study)]

   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.

6. Proangiogenic Factors Such as VEGF [At baseline, before every course for 3 months, and then every 3 months during treatment for the first year]

   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.

7. Circulating Endothelial Progenitors [At baseline, before every course for 3 months, and then every 3 months during treatment for the first year]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Albert Einstein College of Medicine	Bronx	New York	United States	10461
2	Montefiore Medical Center	Bronx	New York	United States	10467-2490
3	North Shore University Hospital	Manhasset	New York	United States	11030
4	Mount Sinai Medical Center	New York	New York	United States	10029
5	Columbia University Medical Center	New York	New York	United States	10032
6	Weill Medical College of Cornell University	New York	New York	United States	10065

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Ruben Niesvizky-Iszaevich, Montefiore Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00437034
• Other Study ID Numbers: NCI-2009-00181; NCI-2009-00181; 0608008688; 7521; P30CA013330; N01CM62204
• First Posted: Feb 19, 2007
• Last Update Posted: Feb 8, 2021
• Last Verified: Jan 1, 2021

• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Aflibercept; Endothelial Growth Factors

Study Results

Participant Flow

Recruitment Details	A total of 6 patients were enrolled at two institutions between January 2007 and April 2010

Arm/Group Title	Treatment (Antiangiogenesis Therapy)
Arm/Group Description	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. aflibercept: Given IV
Period Title: Overall Study
STARTED	6
COMPLETED	0
NOT COMPLETED	6

Baseline Characteristics

Arm/Group Title	Treatment (Antiangiogenesis Therapy)
Arm/Group Description	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. aflibercept: Given IV
Overall Participants	6
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	59
Sex: Female, Male (Count of Participants)
Female	1 16.7%
Male	5 83.3%
Race/Ethnicity, Customized (participants) [Number]
White	4 66.7%
African American	1 16.7%
Unknown	1 16.7%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (Complete [CR] and Partial Response [PR])
Description	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.
Time Frame	At baseline and every 4 weeks during study treatment until treatment discontinuation due to disease progression, unacceptable toxicities and/or patient withdrawal.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Antiangiogenesis Therapy)
Arm/Group Description	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. aflibercept: Given IV
Measure Participants	6
Disease progression	5 83.3%
Stable disease	1 16.7%

2. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae.
Time Frame	Time from first treatment day until objective or symptomatic progression, assessed up to 6 months

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	Treatment (Antiangiogenesis Therapy)
Arm/Group Description	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. aflibercept: Given IV
Measure Participants	0

3. Secondary Outcome

Title	Overall Survival (OS)
Description	Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae.
Time Frame	Time from first treatment day until death, assessed up to 6 months

Outcome Measure Data

Analysis Population Description

Overall survival was not assessed by the Kaplan-Meier survival or calculated using the Greenwood's formulae.

Arm/Group Title	Treatment (Antiangiogenesis Therapy)
Arm/Group Description	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. aflibercept: Given IV
Measure Participants	0

4. Secondary Outcome

Title	Toxicities
Description	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.
Time Frame	up to 6 months

Outcome Measure Data

Analysis Population Description

Participants with grade 1 and 2 adverse events

Arm/Group Title	Treatment (Antiangiogenesis Therapy)
Arm/Group Description	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. aflibercept: Given IV
Measure Participants	6
Count of Participants [Participants]	6 100%

5. Secondary Outcome

Title	Tissue Expression Patterns of VEGFR Subtypes
Description	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.
Time Frame	At baseline and post-treatment (1 week after 2nd dose and end of study)

Outcome Measure Data

Analysis Population Description

data not collected

Arm/Group Title	Treatment (Antiangiogenesis Therapy)
Arm/Group Description	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. aflibercept: Given IV
Measure Participants	0

6. Secondary Outcome

Title	The Apoptotic State of Tumor Neovasculature
Description	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.
Time Frame	At baseline and post-treatment (1 week after 2nd dose and end of study)

Outcome Measure Data

Analysis Population Description

data not collected

Arm/Group Title	Treatment (Antiangiogenesis Therapy)
Arm/Group Description	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. aflibercept: Given IV
Measure Participants	0

7. Secondary Outcome

Title	Proangiogenic Factors Such as VEGF
Description	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.
Time Frame	At baseline, before every course for 3 months, and then every 3 months during treatment for the first year

Outcome Measure Data

Analysis Population Description

data not collected

Arm/Group Title	Treatment (Antiangiogenesis Therapy)
Arm/Group Description	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. aflibercept: Given IV
Measure Participants	0

8. Secondary Outcome

Title	Circulating Endothelial Progenitors
Description	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.
Time Frame	At baseline, before every course for 3 months, and then every 3 months during treatment for the first year

Outcome Measure Data

Analysis Population Description

data not collected

Arm/Group Title	Treatment (Antiangiogenesis Therapy)
Arm/Group Description	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. aflibercept: Given IV
Measure Participants	0

Adverse Events

Arm/Group Title	Treatment (Antiangiogenesis Therapy)
Arm/Group Description	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. aflibercept: Given IV
All Cause Mortality
	Treatment (Antiangiogenesis Therapy)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Antiangiogenesis Therapy)
	Affected / at Risk (%)	# Events
Total	0/6 (0%)
Other (Not Including Serious) Adverse Events
	Treatment (Antiangiogenesis Therapy)
	Affected / at Risk (%)	# Events
Total	6/6 (100%)
Blood and lymphatic system disorders
Anemia	4/6 (66.7%)	4
Gastrointestinal disorders
ODYNOPHAGIA (PAINFUL SWALLOWING)	1/6 (16.7%)	1
Diarrhea	1/6 (16.7%)	1
Anorexia	1/6 (16.7%)	1
General disorders
Fatigue	3/6 (50%)	3
Investigations
Leukocytes decreased	1/6 (16.7%)	1
Alkaline phosphatase increased	1/6 (16.7%)	1
Neutrophil count decreased	2/6 (33.3%)	2
Platelet count decreased	1/6 (16.7%)	1
Creatinine increased	1/6 (16.7%)	1
Metabolism and nutrition disorders
Hypocalcemia	1/6 (16.7%)	1
Musculoskeletal and connective tissue disorders
Pain: Muscle	1/6 (16.7%)	1
Muscle weakness	1/6 (16.7%)	1
Nervous system disorders
Dizziness	1/6 (16.7%)	1
Ataxia	1/6 (16.7%)	1
Headache	2/6 (33.3%)	2
Psychiatric disorders
Insomnia	1/6 (16.7%)	1
Depression	1/6 (16.7%)	1
Respiratory, thoracic and mediastinal disorders
Cough	2/6 (33.3%)	2
Voice changes	2/6 (33.3%)	2
Dyspnea	1/6 (16.7%)	1
Nasal cavity/paranasal sinus reactions	1/6 (16.7%)	1
Skin and subcutaneous tissue disorders
Rash: desquamation	1/6 (16.7%)	1
Vascular disorders
Hypertension	6/6 (100%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.