Study of Everolimus With Paclitaxel and Carboplatin in Patients With Metastatic Melanoma
Condition: Metastatic Melanoma
MeSH terms: Melanoma
Intervention: Paclitaxel; Carboplatin; Everolimus
Intervention description: Paclitaxel, 175mg/m2 by IV infusion over 1-3 hours on day 1 of every 21 day cycle; Carboplatin, AUC 6 given by IV infusion over 20-30 minutes on day 1 of every 21 day cycle; Everolimus, 5 mg by mouth (PO) once a day, continuous dosing every 21-day cycle
Intervention MeSH terms: Paclitaxel; Carboplatin; Everolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 70.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Metastatic Melanoma; Everolimus; Paclitaxel; Carboplatin

Summary:

      Based on data demonstrating synergy between paclitaxel and mammalian target of rapamycin
      (mTOR) inhibition, the investigators propose that the addition of everolimus to paclitaxel
      with carboplatin should lead to improvements in efficacy as measured by progression-free
      survival and response rate.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Histologically confirmed metastatic melanoma.

          2. Stage III or IV disease that is not amenable to resection.

          3. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version
             1.1. If the patient has had previous radiation to the target lesion(s), there must be
             evidence of progression since the radiation.

          4. ECOG Performance Status of 0 or 1.

          5. Life expectancy ≥12 weeks.

          6. No prior cytotoxic chemotherapy or targeted therapy. Immunotherapy is allowed (i.e.,
             interleukin-2 or interferon).

          7. Adequate hematological function:

               -  absolute neutrophil count (ANC) ≥1500/µL and

               -  platelets ≥100,000/µL and

               -  hemoglobin >9 g/dL

          8. Adequate renal function: serum creatinine ≤2.0 mg/dL or calculated (measured) GFR ≥50
             mL/min.

          9. Adequate hepatic function:

               -  serum bilirubin ≤1.5 x institutional upper limit of normal (ULN);

               -  aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN,
                  or ≤5 × ULN in patients with documented liver metastases.

         10. Normal PT, INR. Patients on coumadin anticoagulation are eligible if they are on a
             stable dose, with an INR in the therapeutic range.

         11. Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5 x
             ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can be
             included after initiation of appropriate lipid lowering medication.

         12. Age ≥18 years.

         13. Ability to swallow whole pills.

         14. Patient must be accessible for treatment and follow-up.

         15. Patients must be able to understand the investigational nature of this study and give
             written informed consent prior to study entry.

        Exclusion Criteria:

          1. Previous treatment with an mTOR inhibitor (sirolimus, temsirolimus, everolimus),
             paclitaxel, or carboplatin.

          2. Treatment with any investigational agent ≤4 weeks of protocol treatment.

          3. Patients currently receiving anticancer therapies or who have received anticancer
             therapies ≤3 weeks of the start of the study drug (including radiation therapy,
             immunotherapy).

          4. Patients, who have had a major surgery or significant traumatic injury ≤4 weeks of
             start of study drug or patients who have not recovered from the side effects of any
             major surgery (defined as requiring general anesthesia).

          5. Patients receiving chronic, systemic treatment with corticosteroids (dose >10 mg daily
             of methylprednisolone or equivalent) or other immunosuppressive agents. Topical or
             inhaled steroids are allowed.

          6. Immunization with attenuated live vaccine ≤1 week of study or anytime during study
             treatment period.

          7. Patients with active brain metastases are ineligible. Patients with treated brain
             metastases are eligible if (1) radiation therapy was completed ≥4 weeks prior to study
             entry; (2) surgery was completed ≥4 weeks prior to study entry; (3) follow-up scan
             shows no disease progression; and (4) patient does not require steroids.

          8. Any severe and/or uncontrolled medical conditions or other conditions that could
             affect participation in the study such as:

               -  severely impaired lung function defined as a DLCO ≤50% of the normal predicted
                  value and/or O2 saturation ≤88% at rest on room air.

               -  symptomatic congestive heart failure of New York Heart Association Class III or
                  IV.

               -  unstable angina pectoris, symptomatic congestive heart failure, myocardial
                  infarction ≤6 months of start of study drug, serious uncontrolled cardiac
                  arrhythmia or any other clinically significant disease.

               -  uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN.

               -  active (acute or chronic) uncontrolled severe infections.

               -  liver disease such as cirrhosis, chronic active hepatitis or chronic persistent
                  hepatitis.

          9. Active, bleeding diathesis.

         10. Impairment of gastrointestinal (GI) function or GI disease that may significantly
             alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea,
             vomiting, diarrhea, malabsorption syndrome, or small bowel resection).

         11. A known history of human immunodeficiency virus (HIV) seropositivity.

         12. Known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) or
             to its excipients.

         13. Use of St. John's Wort is prohibited. Drugs or substances (e.g., grapefruits, star
             fruits, seville oranges, and their juices and products), known to be inhibitors or
             inducers of the isoenzyme CYP3A4 should be avoided. Co-administration with substrates,
             inducers, or inhibitors of P glycoprotein should also be avoided.

         14. Female patients who are pregnant or breastfeeding or adults of reproductive potential
             who are not using effective birth control methods. If barrier contraceptives are being
             used, these must be continued throughout the trial by both sexes. Hormonal
             contraceptives are not acceptable as a sole method of contraception. (Women of
             childbearing potential [WOCBP] must have a negative urine or serum pregnancy test
             within 7 days prior to administration of everolimus.) WOCBP should continue to use
             effective contraception for 8 weeks after ending everolimus treatment.

         15. Other malignancies within the past 3 years except for adequately treated carcinoma of
             the cervix or basal or squamous cell carcinomas of the skin.

         16. History of noncompliance to medical regimens. Patients unwilling to, or unable to,
             comply with the protocol.

         17. History of any other disease, physical examination finding, or clinical laboratory
             finding that gives reasonable suspicion of a disease or a condition that may render
             the patient at high risk for treatment complications using these agents.