Metastatic Malignant Melanoma
Conditions
Keywords
Metastatic malignant melanoma, First-line therapy
Brief summary
The study is an open-label, single arm multicenter Phase II study to evaluate the safety and efficacy of the combination of Abraxane and Avastin as first-line therapy for patients with unresectable metastatic malignant melanoma. The patient sample will be approximately 50 individuals, males and females 18 years of age or older with measurable metastatic melanoma. Patients will be treated with Abraxane administered weekly for 3 weeks via a 30-minute IV infusion at150 mg/m2 followed by 1 week rest (28-day cycle). Avastin will be administered in a dose of 10 mg/kg every 2 weeks (without rest period). Patients will be evaluated for disease progression every 2 months and those who do not have disease progression or unacceptable toxicity will be offered ongoing therapy until they have progressive disease or unacceptable toxicity.
Detailed description
It has been suggested that chemotherapy administration may be synergistic with the effects of an antiangiogenic agent such as Avastin. A Proof of Principal of the concept of the synergistic effects of chemotherapy and antiangiogenic therapy has been shown in the favorable results reported with temozolomide administered in combination with thalidomide in melanoma, the favorable results reported for the use of FOLFOX4 in combination with Avastin in previously treated patients with advanced or metastatic colorectal cancer, and the approval of the combination of Avastin with 5-fluorouracil-based chemotherapy in the treatment of patients with metastatic carcinoma of the colon or rectum. A number of lines of evidence suggest that the combination of Abraxane and Avastin may be effective as first-line therapy for melanoma: * Taxanes are active agents in melanoma: 1. In a clinical trial in patients who had failed combination chemotherapy (the Dartmouth regimen, there was a 24% response rate in patients treated with paclitaxel (in combination with tamoxifen). 2. Paclitaxel is being used in a Phase III trial with carboplatin and Sorafenib in patients with metastatic melanoma who have failed no more than one previous systemic chemotherapeutic treatment. 3. In a phase II trial of docetaxel in patients with metastatic melanoma, objective responses lasting more than 2 years were observed. * Abraxane is a taxane that has efficacy superior to that of Taxol for the treatment of metastatic breast cancer. Abraxane was evaluated as first- and second-line therapy for patients with metastatic melanoma. Results were encouraging. In this study, Abraxane will be combined with Avastin in an effort to improve the clinical benefit and prolong the time to disease progression. The primary end-point of the study is progression-free survival (PFS) at 4 months. Secondary end-points include progression-free survival, overall survival (OS), objective Response Rate (RR) in patients with measurable lesions, time to objective response, duration of objective response in patients with measurable lesions, and safety and tolerability of this combination.
Interventions
DRUGAvastin
Avastin 10 mg/kg IV every 2 weeks (without rest period).
DRUGAbraxane
Abraxane 150 mg/m2 IV weekly for 3 weeks of a 28-day cycle.
Sponsors
Celgene Corporation
Genentech, Inc.
Lynn E. Spitler, MD
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed, (surgically incurable or unresectable) stage III or IV metastatic malignant melanoma.. * Must be chemo naïve. Surgical adjuvant therapy with interferon, vaccines, or cytokines is permitted. Prior adjuvant therapy with chemotherapeutic agents is not allowed. Prior therapy for metastatic disease that is not chemotherapy is allowed. Must have discontinued prior allowable therapy at least 4 weeks prior to initiation of dosing. * A minimum of 1 measurable lesion according to RECIST criteria. * ECOG performance status of 0-1. * Age ≥ 18 years. * Adequate hematologic, renal and liver function as defined by laboratory values performed within 14 days prior to initiation of dosing. * Patients must have recovered from effects of major surgery. * Women of childbearing potential should be using an effective method of contraception. Women of childbearing potential must have a negative urine or serum pregnancy test up to 28 days prior to commencement of dosing and be practicing medically approved contraceptive precautions for at least 6 months after completion of treatment as directed by their physician. * Men should use an effective method of contraception during treatment and for at least 6 months after completion of treatment as directed by their physician. * Must have recovered from all prior treatment-related toxicities to NCI CTCAE (v 3.0) Grade of 0 or 1, except for toxicities not considered a safety risk such as alopecia. * Before study entry, written informed consent must be obtained. Written informed consent must be obtained from the patient prior to performing any study-related procedures.
Exclusion criteria
* Prior systemic therapy for metastatic disease with chemotherapy. * Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before trial entry. * Major surgery or radiation therapy within 4 weeks of starting the study treatment. * Known CNS disease. * Previous Grade 2 or higher sensory neuropathy * NCI CTCAE (V 3.0) grade 3 hemorrhage within 4 weeks of starting the study treatment. * History of or known spinal cord compression, or carcinomatous meningitis, or evidence of symptomatic brain or leptomeningeal disease on screening CT or MRI scan. * Any of the following within the 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, or pulmonary embolism. * Ongoing cardiac dysrhythmias of NCI CTCAE Version 3.0 grade ≥ 2. * Inadequately controlled hypertension (defined as systolic blood pressure \> 150 and/or diastolic blood pressure \> 100 mmHg on antihypertensive medications) * Any prior history of hypertensive crisis or hypertensive encephalopathy * Concurrent treatment on another clinical trial. Supportive care trials or non-treatment trials, e.g. QOL, are allowed. * Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the subject inappropriate for entry into this study. * Previous cancer (unless a DRS interval of at least 5 years) or concurrent malignancies at other sites with the exception of surgically cured carcinoma in-situ of the cervix and basal or squamous cell carcinoma of the skin. * Known clinically uncontrolled infectious disease including HIV positivity or AIDS-related illness. * Pregnant or nursing. Use of effective means of contraception (men and women) in subjects of child-bearing potential. * New York Heart Association (NYHA) Grade II or greater congestive heart failure. * Symptomatic peripheral vascular disease. * Significant vascular disease (e.g. aortic aneurysm, aortic dissection). * Evidence of bleeding diathesis or coagulopathy. * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, anticipation of need for major surgical procedure during the course of the study * Minor surgical procedures such as fine needle aspirations or core biopsies within 7 days prior to Day 0 * Proteinuria at screening as demonstrated by 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). * History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 0 * Serious, non-healing wound, ulcer, or bone fracture * Inability to comply with study and/or follow-up procedures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) at 4 Months | 4 months. | Progression-free survival at 4 months from first treatment as determined by RECIST 1.0 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | From start of treatment to disease progressin; median duration of follow-up for surviving patients was 41.6 months. | Median time of progression-free survival from first treatment according to RECIST 1.0 |
| Overall Survival (OS) | April 2007 through December 2010 | The duration of overall survival was defined as the number of months between the start date of protocol treatment and the date of death (irrespective of cause), and was right-censored at the date of last contact for patients who were alive as of the data cutoff. |
| Objective Response Rate (RR) in Patients With Measurable Lesions Time to Objective Response | The median duration of follow-up for surviving patients was 41.6 months. | The objective response rate is defined as the percentage of patients showing complete or partial response. |
| Safety and Tolerability of This Combination | April 2007 through December 2010 | See adverse events Table |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Single Arm, Open Label Single Arm, Open Label trial of Abraxane and Avastin
Abraxane and Avastin : Abraxane 150 mg/m2 IV weekly for 3 weeks of a 28-day cycle; Avastin 10 mg/kg IV every 2 weeks (without rest period). | 50 |
| Total | 50 |
Baseline characteristics
| Characteristic | Single Arm, Open Label |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 21 Participants |
| Age, Categorical Between 18 and 65 years | 29 Participants |
| Age, Continuous | 62 years |
| Region of Enrollment United States | 50 participants |
| Sex: Female, Male Female | 18 Participants |
| Sex: Female, Male Male | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 11 / 50 |
| serious Total, serious adverse events | 13 / 50 |
Outcome results
Primary
Progression-free Survival (PFS) at 4 Months
Progression-free survival at 4 months from first treatment as determined by RECIST 1.0
Time frame: 4 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Arm, Open Label | Progression-free Survival (PFS) at 4 Months | 75 percentage of patients |
Secondary
Objective Response Rate (RR) in Patients With Measurable Lesions Time to Objective Response
The objective response rate is defined as the percentage of patients showing complete or partial response.
Time frame: The median duration of follow-up for surviving patients was 41.6 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Arm, Open Label | Objective Response Rate (RR) in Patients With Measurable Lesions Time to Objective Response | 36 Percentage of participants |
Secondary
Overall Survival (OS)
The duration of overall survival was defined as the number of months between the start date of protocol treatment and the date of death (irrespective of cause), and was right-censored at the date of last contact for patients who were alive as of the data cutoff.
Time frame: April 2007 through December 2010
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single Arm, Open Label | Overall Survival (OS) | 16.8 months |
Secondary
Progression-free Survival
Median time of progression-free survival from first treatment according to RECIST 1.0
Time frame: From start of treatment to disease progressin; median duration of follow-up for surviving patients was 41.6 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single Arm, Open Label | Progression-free Survival | 7.63 Months |
Secondary
Safety and Tolerability of This Combination
See adverse events Table
Time frame: April 2007 through December 2010