A Phase II Trial of Temozolomide Plus Bevacizumab in Patients With Metastatic Melanoma Involving the Central Nervous System
Temozolomide Plus Bevacizumab in Patients With Metastatic Melanoma Involving the Central Nervous System
Sponsors
Source
Mt. Sinai Medical Center, Miami
Oversight Info
Has Dmc
No
Brief Summary
This research is being done because melanoma in the brain is very difficult to treat because
it does not respond to radiation or to chemotherapy, such as temozolomide. One of the reasons
for this is that the melanoma can make chemicals that signal the brain to provide new blood
vessels for the tumor. The main signal is called VEGF. Bevacizumab is an antibody that blocks
VEGF. The investigators want to see if the combination of bevacizumab and temozolomide will
stop the melanoma from growing.
Detailed Description
This study proposes the use of a combination of temozolomide and bevacizumab in a carefully
selected group of patients with metastatic melanoma to the brain. This combination has been
tested in primary brain tumors and in melanoma not involving the brain. The 6-week on, 2-week
off low-dose schedule proposed in this trial capitalizes on preclinical data demonstrating
that temozolomide inhibits angiogenesis at low, non-toxic doses that correspond to the plasma
concentrations achieved by an oral administration, a so-called 'metronomic' scheduling. The
precise mechanism of its antiangiogenic action remains to be elucidated. This potential
synergistic mechanism, together with the bulk of evidence for activity presented above
suggests that the combination will be well-tolerated, safe and possibly more effective.
Overall Status
Completed
Start Date
2009-11-01
Completion Date
2011-09-01
Primary Completion Date
2011-09-01
Phase
Phase 2
Study Type
Interventional
Primary Outcome
Measure |
Time Frame |
Primary Outcome Measures: one-year survival rate |
one year |
Secondary Outcome
Measure |
Time Frame |
Secondary Outcome Measures: response rate and safety profile |
one year |
Enrollment
34
Condition
Intervention
Intervention Type
Drug
Intervention Name
Description
Temozolomide 75mg/m2 for six continuous weeks
Arm Group Label
Temozolomide/Bevacizumab
Intervention Type
Drug
Intervention Name
Description
Bevacizumab 10mg/kg every 2 weeks without interruption
Arm Group Label
Temozolomide/Bevacizumab
Eligibility
Criteria
Inclusion Criteria:
1. Patients must have histologically or cytologically confirmed malignant melanoma and
clinical evidence of metastatic disease to the brain. Mucosal and ocular melanomas are
included.
2. Untreated asymptomatic brain metastases ≤ 2 cm in maximal diameter, with mild or
minimal edema, without associated hemorrhage or midline shift.
3. Progressing brain metastases of any size, not amenable to surgical resection and/or
progressing through radiation therapy but without evidence of active associated
hemorrhage. Treatment with bevacizumab may not be initiated until 4 weeks after
surgical resection or radiation therapy completion.
4. Hemorrhagic metastases that have resolved after previous resection or radiation
therapy do not exclude patients with new non-hemorrhagic metastases meeting the
criteria described above from participating.
5. Patients must have measurable metastases to the brain, defined as at least one lesion
that can be accurately measured in at least one dimension (longest diameter to be
recorded) as >10 mm in the brain MRI with gadolinium. For disease outside the brain,
tumors must be > 20 mm with conventional techniques or > 10 mm with spiral CT scan.
Measurable disease outside the brain is NOT required.
6. Patients with any number of previous systemic therapies are eligible. Previous
temozolomide treatment given on a different schedule is allowed, as long as it had not
been given in combination with VEGF-targeting drugs.
7. Age > 18 years. Because no dosing or adverse event data are currently available on the
use of bevacizumab in patients <18 years of age, children are excluded from this
study.
8. Life expectancy of 8 weeks or greater.
9. ECOG performance status < 2 (Karnofsky > 60%).
10. Patients must have normal organ and marrow function as defined below:
- Leukocytes > 3,000/µl
- Absolute neutrophil count > 1,500/µl
- Platelets > 100,000/µl
- Total Bilirubin ** Within institutional upper limit of normal
- AST(SGOT)/ALT(SGPT) < 2.5 X institutional upper limit of normal
- Creatinine* Within institutional upper limit of normal*
- If creatinine > upper limit of normal, a creatinine clearance >/= 60 ml/m2
is required
- Except for patients with known Gilbert's syndrome
11. The effects of bevacizumab on the developing human fetus at the recommended
therapeutic dose are unknown. For this reason and because the anti-angiogenic agent
used in this trial may be teratogenic, women of child-bearing potential and men must
agree to use adequate contraception (hormonal or barrier method of birth control)
prior to study entry and for the duration of study participation. Should a woman
become pregnant or suspect she is pregnant while participating in this study, she
should inform her treating physician immediately.
12. Concomitant use of steroids to treat cerebral edema is allowed.
13. Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria:
- Disease-Specific Exclusions Patients with metastatic disease to the brain not fitting
the inclusion criteria. Patients with leptomeningeal disease are not excluded.
- General Medical Exclusions
Subjects meeting any of the following criteria are ineligible for study entry:
1. Inability to comply with study and/or follow-up procedures.
2. Life expectancy of less than 8 weeks
3. Current, recent (within 4 weeks of the first infusion of this study), or planned
participation in an experimental drug study other than this study.
4. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to bevacizumab or temozolomide.
5. Patients must not exhibit any clinical evidence of coagulopathy. The INR must be < 1.5
and the values for PTT must be within normal limits. Anticoagulation is not allowed.
6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, untreated
cardiac arrhythmia, or psychiatric illness/social situations that would limit
compliance with study requirements.
7. Pregnant women are excluded from this study because bevacizumab is an agent with the
potential for teratogenic or abortifacient effects. Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with bevacizumab, breastfeeding should be discontinued if the mother is treated
with bevacizumab. These potential risks may also apply to other agents used in this
study.
8. Otherwise well HIV-positive patients will be permitted to enroll on this trial.
Bevacizumab-Specific Exclusions
1. Previous treatment with bevacizumab.
2. Inadequately controlled hypertension (defined as systolic blood pressure 150 and/or
diastolic blood pressure > 100 mmHg on antihypertensive medications)
3. Any prior history of hypertensive crisis or hypertensive encephalopathy
4. New York Heart Association (NYHA) Grade II or greater congestive heart failure (see
Appendix E)
5. History of myocardial infarction or unstable angina within 6 months prior to study
enrollment
6. History of stroke or transient ischemic attack within 6 months prior to study
enrollment
7. Significant vascular disease (e.g., aortic aneurysm, aortic dissection)
8. Symptomatic peripheral vascular disease
9. Evidence of bleeding diathesis or coagulopathy
10. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to study enrollment or anticipation of need for major surgical procedure during
the course of the study
11. Core biopsy or other minor surgical procedure, excluding placement of a vascular
access device, within 7 days prior to study enrollment
12. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
within 6 months prior to study enrollment
13. Serious, non-healing wound, ulcer, or bone fracture
14. Proteinuria at screening as demonstrated by either
- Urine protein:creatinine (UPC) ratio 1.0 at screening OR
- Urine dipstick for proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria
on dipstick urinalysis at baseline should undergo a 24 hour urine collection and
must demonstrate ≤ 1g of protein in 24 hours to be eligible).
Gender
All
Minimum Age
18 Years
Maximum Age
90 Years
Healthy Volunteers
No
Overall Official
Last Name |
Role |
Affiliation |
Jose Lutzky, MD |
Principal Investigator |
Mt Sinai Medical Center |
Location
Facility |
Saint Mary's Medical Center, 6th Floor San Francisco California 94117 United States |
The Angeles Clinic and Research Institute Santa Monica California 90404 United States |
Mount Sinai Medical Center Miami Beach Florida 33140 United States |
Location Countries
Country
United States
Verification Date
2012-04-01
Lastchanged Date
N/A
Firstreceived Date
N/A
Responsible Party
Responsible Party Type
Principal Investigator
Investigator Affiliation
Mt. Sinai Medical Center, Miami
Investigator Full Name
Jose Lutzky
Investigator Title
Principal Investigator Jose Lutzky, M.D.
Keywords
Has Expanded Access
No
Condition Browse
Number Of Arms
1
Intervention Browse
Mesh Term
Bevacizumab
Temozolomide
Arm Group
Arm Group Label
Temozolomide/Bevacizumab
Arm Group Type
Other
Description
Patients will be treated with a combination of temozolomide at 75 mg/m2/day for six continuous weeks, followed by a two-week rest period and bevacizumab 10 mg/kg every 2 weeks without interruption. Cycles will be repeated every 8 weeks. Patients will be restaged every 8 weeks.
Firstreceived Results Date
N/A
Acronym
MEL0107
Firstreceived Results Disposition Date
N/A
Study Design Info
Allocation
Non-Randomized
Intervention Model
Single Group Assignment
Primary Purpose
Treatment
Masking
None (Open Label)
Study First Submitted
January 12, 2010
Study First Submitted Qc
January 12, 2010
Study First Posted
January 13, 2010
Last Update Submitted
April 18, 2012
Last Update Submitted Qc
April 18, 2012
Last Update Posted
April 19, 2012
Pending Results
Submitted
May 8, 2014
Returned
June 9, 2014
ClinicalTrials.gov processed this data on December 12, 2019
Conditions
Conditions usually refer to a disease, disorder, syndrome, illness, or injury. In ClinicalTrials.gov,
conditions include any health issue worth studying, such as lifespan, quality of life, health risks, etc.
Interventions
Interventions refer to the drug, vaccine, procedure, device, or other potential treatment being studied.
Interventions can also include less intrusive possibilities such as surveys, education, and interviews.
Study Phase
Most clinical trials are designated as phase 1, 2, 3, or 4, based on the type of questions
that study is seeking to answer:
In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.
In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.