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Recurrent MelanomaPhase 2Mel47NCT00397982

Temsirolimus and Bevacizumab in Treating Patients With Stage III or Stage IV Malignant Melanoma

A Phase 2 study testing Bevacizumab, Laboratory Biomarker Analysis and Temsirolimus in people with Recurrent Melanoma and Stage IIIB Skin Melanoma, run by National Cancer Institute (NCI) at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

This phase II trial is studying how well giving temsirolimus together with bevacizumab works in treating patients with stage III or stage IV malignant melanoma. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for their growth. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Bevacizumab, Laboratory Biomarker Analysis and Temsirolimus
Could I receive a placebo?
No, everyone receives an active treatment
How many people
17 participants
Where
2 sitesUnited States
Study dates
Jan 2008to Jul 2013
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Histologically or cytologically confirmed melanoma
  • Stage III or IV disease
  • Recurrent disease allowed
  • Measurable disease defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension as ≥ 20 mm with conventional techniques OR ≥ 10 mm with spiral CT scan
  • Tumor lesions in previously irradiated areas are not considered measurable disease
  • Prior brain metastases allowed provided all of the following criteria are met:
Show all 83Show fewer
  • No more than a total of 5 brain metastases
  • All metastases are no more than 2.5 cm
  • Surgically resected or have been treated with gamma-knife or stereotactic radiosurgery
  • More than 30 days since prior disease progression
  • More than 30 days since prior steroids for managing brain metastases
  • Concurrent steroids for other reasons allowed provided the dose is < that required for managing brain metastases
  • Disease accessible for core needle biopsy, incisional biopsy, and/or surgical resection and meets one of the following criteria:
  • One large tumor deposit ≥ 5 cm³ from which biopsies can be harvested multiple times
  • Multiple deposits that can be biopsied or excised individually on different dates, measured as follows:
  • One lesion ≥ 5 cm^3
  • Two lesions ≥ 3 cm^3
  • Three lesions ≥ 2 cm^3
  • ECOG performance status 0-1
  • Weight ≥ 110 pounds (without clothes)
  • WBC ≥ 3,000 mm³
  • Absolute neutrophil count ≥ 1,500/mm³
  • Platelet count ≥ 100,000/mm³
  • Bilirubin normal
  • AST and ALT ≤ 2.5 times upper limit of normal
  • Creatinine normal OR creatinine clearance ≥ 60 mL/min
  • Urine protein: creatinine ratio < 1.0 OR 24-hour urine protein < 1,000 mg
  • Fasting cholesterol < 350 mg/dL (cholesterol medications are allowed)
  • Fasting triglycerides < 400 mg/dL
  • PT INR ≤ 1.5 (unless on full-dose anticoagulants)
  • Hematocrit < 41% (for males) or < 38% (for females)
  • None of the following within the past 4 weeks:
  • Uncontrolled intercurrent illness
  • Ongoing or active acute (CTCAE v.3 grade 3 or 4) infection
  • Abdominal fistula
  • Gastrointestinal perforation
  • Intra-abdominal abscess
  • Serious or nonhealing wound, ulcer, or bone fracture
  • No psychiatric illness or social situations that would preclude study compliance
  • No clinically significant cardiovascular disease, including the following:
  • Cerebrovascular accident within the past 6 months
  • Transient ischemic attack within the past 6 months
  • Myocardial ischemia within the past 6 months
  • Myocardial infarction within the past 6 months
  • Other thromboembolic event within the past 6 months
  • Unstable angina within the past 6 months
  • Uncontrolled hypertension (i.e., hypertension despite maximal therapy)
  • New York Heart Association class II-IV heart disease
  • Congestive heart failure
  • Serious cardiac arrhythmia requiring medication
  • Clinically significant peripheral vascular disease
  • History of stroke
  • Artificial valve, pacemaker, or similar device
  • No uncontrolled diabetes
  • Hemoglobin A1c < 7%
  • No significant traumatic injury within the past 28 days
  • No history of allergic reactions to compounds of similar chemical or biological composition to temsirolimus or bevacizumab
  • No hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies (e.g., infliximab)
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception during and for ≥ 6 months after completion of study treatment
  • HIV negative
  • Hepatitis C negative
  • See Disease Characteristics
  • More than 4 weeks since any of the following prior treatments and recovered:
  • Chemotherapy (6 weeks for nitrosoureas or mitomycin C)
  • Radiotherapy to nontarget lesions or lesions that are not to be biopsied
  • Immunotherapy
  • Cytokine therapy
  • Enzyme-inducing antiepileptic drugs (EIAEDs) or other CYP3A4 inducers
  • Investigational agents
  • More than 4 weeks since prior major surgery or open biopsy and recovered
  • No prior temsirolimus, rapamycin, bevacizumab, or systemic therapies targeted primarily to vascular endothelial growth factor (VEGF), VEGF receptors, or to mTOR inhibition
  • Concurrent full-dose anticoagulants (e.g., warfarin/low molecular weight heparin) with PT INR > 1.5 are allowed provided the following criteria are met:
  • In-range INR (usually between 2 and 3.5) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin
  • No active, clinically significant bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
  • Minimal tumor bleeding of the skin allowed at the clinician's discretion
  • No concurrent medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of the following:
  • Temsirolimus
  • Bevacizumab
  • CYP450 isoenzymes
  • No concurrent nonstudy-related surgical procedures
  • No other concurrent anticancer agents or therapies

Who cannot join

  • Participants who have received these medications or treatments at any time ≤ 4 weeks of registration:
  • Chemotherapy
  • Radiotherapy to non-target lesions and lesions that are not to be biopsied. Prior radiotherapy to target lesions or lesions to be biopsied/resected is not permitted
  • Immunotherapy
  • Cytokine therapy
  • Investigational reagents
Show all 37Show fewer
  • Invasive procedures defined as follows:
  • Major surgical procedure, open biopsy or significant traumatic injury
  • Anticipation of need for non-study related surgical procedures from registration until Cycle 26 (One year).
  • Enzyme-inducing antiepileptic drugs (EIAEDs) or any other CYP3A4 inducer (Appendix C).
  • OR Participants who have not recovered from adverse events resulting from the administration of these agents/procedures > 4 weeks prior to registration.
  • Participants who have received nitrosureas or mitomycin C ≤ 6 weeks of registration.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to CCI-779 or bevacizumab, or with known hypersensitivity to Chinese hamster ovary cell products (t-PA) or other recombinant human antibodies (e.g., Remicade®).
  • Participants who have previously received CCI-779, rapamycin, bevacizumab, or systemic therapies targeted primarily to VEGF, VEGF receptors, or to mTOR inhibition.
  • Participants who have experienced any of the following ≤ 4 weeks prior to registration:
  • Uncontrolled intercurrent illness
  • Infection, CTCAE3 grade 3 or 4 (either ongoing, chronic, or active infection)
  • Abdominal fistula
  • Gastrointestinal perforation
  • Intra-abdominal abscess
  • Serious or non-healing wound
  • Serious or non-healing ulcer
  • Serious or non-healing bone fracture.
  • Potential subjects with clinically significant cardiovascular disease
  • Recent history (defined as ≤ 6 months of registration) of thromboembolic events including cerebrovascular accident (CVA), transient ischemic attack (TIA), myocardial ischemia, myocardial infarction (MI)
  • Uncontrolled hypertension (hypertension despite maximal therapy)
  • Unstable angina ≤ 6 months of registration
  • New York Heart Association Classification of ≥ class II heart disease
  • Congestive heart failure
  • Serious cardiac arrhythmia requiring medication
  • Clinically significant peripheral vascular disease
  • Have a history of stroke
  • Have an artificial valve, pace-maker, or similar device
  • Psychiatric illness/social situations that would limit compliance with study requirements.
  • Pregnant (positive pregnancy test) or nursing women. Both fertile men and women must agree to use adequate contraceptive measures during study therapy and for at least 6 months after the completion of their participation in the study therapy.
  • PT INR > 1.5, (unless the potential subject is on full dose anticoagulants and meet criteria described in Section 3.1.8).
  • Participants with uncontrolled diabetes, defined as having a HGBA1C ≥ 7%.

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • University of Virginia Cancer Center

    Charlottesville, Virginia, 22908

  • Fox Chase Cancer Center

    Philadelphia, Pennsylvania, 19111

Other trials in United States

About this study

Official title: A Phase II Study of CCI-779 in Combination With Bevacizumab in Stage III or IV Melanoma

This phase II trial is studying how well giving temsirolimus together with bevacizumab works in treating patients with stage III or stage IV malignant melanoma. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for their growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of malignant melanoma by blocking blood flow to the tumor. Giving temsirolimus together with bevacizumab may kill more tumor cells.

Read the detailed description

PRIMARY OBJECTIVES:

  1. Determine the objective tumor response rate (complete response and partial response) in patients with stage III or IV melanoma treated with temsirolimus and bevacizumab.

SECONDARY OBJECTIVES:

  1. Describe the adverse event profile of this regimen in these patients. II. Determine the efficacy of this regimen, in terms of progression-free survival, in these patients.

III. Compare pre- vs post-treatment measurements of biomarkers and vascular system/immune system parameters in patients treated with this regimen.

IV. Correlate tumor and blood biomarkers with clinical response in these patients.

OUTLINE: This is a multicenter study.

Patients receive temsirolimus intravenously (IV) over 30 minutes on days 1 and 8 and bevacizumab IV over 30-90 minutes on day 8. Treatment repeats every 14 days for a maximum of 26 courses in the absence of disease progression or unacceptable toxicity. Patients undergo tumor resection on day 9 of course 2.Blood samples are collected during courses 1 and 2. Samples are examined by flow cytometry to evaluate peripheral blood mononuclear cells for molecular effects of study agents. Patients also undergo normal and tumor tissue biopsy (by core needle biopsy, incisional biopsy, or surgical resection) during courses 1 and 2. Samples are examined by immunohistochemistry, western blotting, protein array technology, gene expression analyses, DNA mutation analyses, and genomic analyses for pre-and post-treatment measurements of target molecules (epidermal growth factor receptor, B-Raf, MEK, MAPK), downstream pathway components (PI-3 kinase, AKT, mTOR), markers of angiogenesis, proliferation and apoptosis, markers that may modulate cell signaling or the response to investigational agents, and vascular and immune system parameters.

After completion of study treatment, patients are followed at 1 month, every 3 months for up to 2 years, and then periodically for up to 5 years.

Being tested
Bevacizumab, Laboratory Biomarker Analysis, Temsirolimus, Therapeutic Conventional Surgery
Medical subject headings
Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BevacizumabBiological

    Also called Anti-VEGF, Anti-VEGF Humanized Monoclonal Antibody, Anti-VEGF rhuMAb, Avastin

    Given IV

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • TemsirolimusDrug

    Also called CCI-779, CCI-779 Rapamycin Analog, Cell Cycle Inhibitor 779, Rapamycin Analog

    Given IV

  • Therapeutic Conventional SurgeryProcedure or surgery

    Undergo tumor resection

Study groups in NCT00397982
Study groupRoleWhat they receive
Treatment (enzyme inhibitor, monoclonal antibody)ExperimentalPatients receive temsirolimus IV over 30 minutes on days 1 and 8 and bevacizumab IV over 30-90 minutes on day 8. Treatment repeats every 14 days for a maximum of 26 courses in the absence of disease progression or unacceptable toxicity. Patients undergo tumor resection on day 9 of course 2.
Receives: Biological: Bevacizumab; Other: Laboratory Biomarker Analysis; Drug: Temsirolimus; Procedure: Therapeutic Conventional Surgery

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Objective Tumor Response (Complete Response and Partial Response) and Progression in Participants With Stage III or IV Melanoma Following Treatment With Temsirolimus and Bevacizumab

    Evaluated using Response Evaluation Criteria In Solid Tumor (RECIST) criteria. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI and/or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progression of Disease (POD); POD, 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Complete Response (CR), Disappearance of all target lesions.

    Measured: Up to 18 weeks after registration.

Secondary outcomes (5)

  1. Adverse Events in Participants With Stage III or IV Melanoma Treated With Temsirolimus and Bevacizumab

    Defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome, or disease which either occurs during the study (having been absent at baseline) or if present at baseline, appears to worsen. Graded using scales found in the revised National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Tabulated by type and severity: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE.

    Measured: On days 1 and 8 of each cycle, and up to 2 years after registration.

  2. Association Between Expression or Activation of One Biomarker With Another, With Biochemical and Clinical Responses, With Alterations in Cell Proliferation and Apoptotic Markers, and With Time to Progression

    Changes in the ratio of phospho-S6Kinase (pS6K) S240/244 to total S6, in the tumor, from day 1 to day 23. These were assessed by reverse-phase protein array. A linear model was fit with PROC MIXED in SAS 9.3 using the log base 10 of expression as the outcome measure. This measure type is not listed in the data table form; so the number of patients who had decreases in that ratio is listed.

    Measured: Day 1 of course 1 and day 8 of course 2

  3. Comparison of Biomarkers to Antitumor Activity/Patient Outcomes

    Assessed in both tumor tissue pretreatment. Mutations in BRAF were assessed in all 16 of the patients and were assessed for any association with clinical response

    Measured: Day 1 of course 1 and day 8 of course 2

  4. Comparison of Pre- vs Post-treatment Measurements of Biomarkers and Vascular System/Immune System Parameters

    Biomarker expression in tumor and normal skin will be assessed by immunohistochemistry (IHC) or Western blotting, using marker-specific antibodies.

    Measured: Day 1 of course 1 and day 8 of course 2

  5. Progression-free Survival

    Defined as the duration of time from start of treatment to time of progression, death or date of last follow-up.

    Measured: Day 11 of courses 4, 8, 12, 16, 20, and 24, and then annually for up to 5 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted10 Nov 2006 (estimated)
  2. Study startJan 2008
  3. Primary completionJul 2013
  4. Study completionJul 2013

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
17 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00397982
Sponsor's protocol ID
NCI-2009-00133
Other IDs
NCI-2009-00133, NCI-7190, CDR0000512836, UVACC-MEL-47, MEL47, 7190, P30CA044579, R21CA128367
Acronym
Mel47
Status last verified
May 2017
First submitted
9 Nov 2006
Last updated
9 Jun 2017
Data monitoring committee
No
Individual data sharing
No

Publications

  • Slingluff CL Jr, Petroni GR, Molhoek KR, Brautigan DL, Chianese-Bullock KA, Shada AL, Smolkin ME, Olson WC, Gaucher A, Chase CM, Grosh WW, Weiss GR, Wagenseller AG, Olszanski AJ, Martin L, Shea SM, Erdag G, Ram P, Gershenwald JE, Weber MJ. Clinical activity and safety of combination therapy with temsirolimus and bevacizumab for advanced melanoma: a phase II trial (CTEP 7190/Mel47). Clin Cancer Res. 2013 Jul 1;19(13):3611-20. doi: 10.1158/1078-0432.CCR-12-3919. Epub 2013 Apr 25.

    PubMed 23620404

  • Wagenseller AG, Shada A, D'Auria KM, Murphy C, Sun D, Molhoek KR, Papin JA, Dutta A, Slingluff CL Jr. MicroRNAs induced in melanoma treated with combination targeted therapy of Temsirolimus and Bevacizumab. J Transl Med. 2013 Sep 18;11:218. doi: 10.1186/1479-5876-11-218.

    PubMed 24047116

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Bevacizumab, Laboratory Biomarker Analysis and Temsirolimus in people with Recurrent Melanoma and Stage IIIB Skin Melanoma, run by National Cancer Institute (NCI) at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 83 inclusion and 37 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 9 Jun 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 9 Jun 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Objective Tumor Response (Complete Response and Partial Response) and Progression in Participants With Stage III or IV Melanoma Following Treatment With Temsirolimus and Bevacizumab (time frame: Up to 18 weeks after registration.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00397982, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Jun 2017.

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