Archive for the ‘Melanoma’ Category

Melanoma Study at CORT Testing Targeted Therapeutic Agents

December 17, 2008

Metastatic melanoma remains one of the most difficult to treat malignancies for oncologists.  This cancer of the pigmented cells in the skin, mucous membranes, or retina may eventually spread to other sites such as lymph nodes, other skin sites, lung, bone, liver, or brain.  The disease is rarely curable at such advanced stage, and treatment with chemotherapy has limited benefits in producing response or remissions.  Radiotherapy and surgery may have a limited role in palliation of patients with limited metastatic disease.  The most commonly employed chemotherapy agent is dacarbazine (DTIC), which may produce response in up to 20% of patients, with responses lasting between 3 and 6 months.  Addition of other chemotherapy drugs to DTIC have not significant improved survival outcomes.  While immunotherapy with interferon-alpha (IFN) or interleukin-2 (IL-2) may rarely produce a longer lasting remission, the general response rate is not greater than 10-15%, and toxicities are substantial. 

Important advances in the understanding of melanoma cell biology have been made.  Certain genetic alterations within melanoma cells may trigger or sustain the growth of the cells.  The intracellular signaling proteins b-raf and N-ras are activated in about 60% of melanomas, which promotes cell growth.  Tumors with these mutations (compared to those without) have a shortened clinical course (worsened prognosis).  Research has shown that mutation of either b-raf or N-ras appears to be mutually exclusive in an individual melanoma.   Ras protein localizes to the cell membrane by farnesylation of the protein by the enzyme farnesyl transferase.  This is an important step in the activation sequence of ras protein. 

Loss of function of PTEN (phosphatase and tensin homologue on chromosome 10) is also seen in melanoma.   This leads to activation of the Akt and mTor.  This alteration may be present in 30-60% of melanoma. 

New drugs have been developed that inhibit these intracellular signaling proteins.  Sorafenib (Nexavar), an oral agent already approved for treatment of renal cancer, inhibits b-raf.  CCI-779 (temsirolimus, Torisel), is an IV agent that has already gained approval for treatment of renal cancer.  It inhibits mTor.  R115777 (tipifarnib) is an oral agent that blocks farnesyl transferase. 

The SWOG S0438 Study open at CORT tests two combinations of these drugs in patients with metastatic melanoma that has not been previously treated.  The first combination will be sorafenib and temsirolimus.  The second combination tests sorafenib and tipifarnib.  Patients will be randomly assigned between the two therapies.  Patients must have measurable disease, no brain metastases, and a history of mucosal or cutaneous primary melanoma.  Occular melanoma is not eligible for this study.  

For more information about this study, contact a CORT Research Coordinator at 972-566-5588, or visit our website at www.CORTPA.com.

Adjuvant Therapy of Melanoma: BMS CA184-029/EORTC 18071 Study at CORT

November 12, 2008

Melanoma, malignant cancer of the pigmented cells (melanocytes), has increased in incidence.  This cancer is the most serious form of skin cancer, with a higher likelihood of recurrence or metastatic spread than other forms of skin cancer.  Other less common sites for origination of melanoma include the pigmented layer of the retina, or mucosal areas such as the rectum.  Principle treatment is surgical, with wide excision.  The extent of local disease is defined by the T stage (tumor depth of invasion), and the N stage (presence of nodal involvement).  TNM staging for melanoma may be found at http://en.wikipedia.org/wiki/Melanoma.  Nodal staging is important in defining overall stage, so resection of lymph nodes to determine involvement has become a standard practice, in patients other than the shallowest depths of invasion (with more significant chances of nodal involvement).  The risk of lymph node sampling may include lymphedema, so sampling of nodes by selective means (sentinel lymph node dissection) is often employed first, with full regional lymphadenectomy reserved for cases with initially positive sentinel lymph nodes.  Patients with positive lymph nodes and no other evidence of metastatic disease spread are Stage III in overall stage.  The 5-year survival for Stage III disease ranges from 25-60%, depending on the extent of involvement. 

Efforts to improve the outcome of Stage III melanoma patients have focused on immunotherapy, because adjuvant radiation or chemotherapy have not improved outcome.  High dose Interferon-alpha-2b (Intron-A) has been studied in large, randomized placebo-controlled adjuvant Phase III studies (ECOG 1684, ECOG 1690).  Lower doses have also been studied in other randomized clinical trials.  An overview of the results of those randomized studies has been published (http://jco.ascopubs.org/cgi/content/full/20/7/1818).  The ECOG studies reported improvement in disease free survival (DFS), and the ECOG 1684 study reported an overall survival (OS) improvement that was not confirmed in other studies.  Interferon therapy has potentially serious toxicities, including abnormal liver functions, rash, fatigue, anemia, thrombocytopenia, leukopenia, abnormal thyroid function, and exacerbation of autoimmune phenomena.  Many patients are unable to complete interferon therapy at high dose, and the value of low dose therapy is not as certain.  In the ECOG interferon protocol, continuation of lower dose interferon continues for up to one year, and many patients are unable to complete the duration of therapy.  Studies utlizing a newer form of interferon (pegylated interferon alpha, the EORTC Trial 18991) have been reported more recently (ASCO 2007 Annual Meeting, Abstract 8504).  That study demonstrated reduced relapse, but again, survival was not improved.  Overall, the conclusion can be reached that Stage III melanoma patients should be offered interferon therapy, or a clinical trial of new treatment. 

Ipilimumab (MDX-010, Anti-CTLA4) is an antibody therapy that activate the immune response against melanoma.  Ipilimumab has been studied in patients with metastatic melanoma, and responses have been seen in 13% of patients treated, some of which were fairly durable.  The response rate appears to be somewhat higher than that of interferon in metastatic patients. 

Therefore, ipilimumab has entered testing for adjuvant therapy of Stage III melanoma.  This study is the BMS CA184-029/EORTC 18071 study http://clinicaltrials.gov/ct2/show/NCT00636168 Patients with completely resected melanoma, with adequate lymph node dissection staging, good performance status, and absence of autoimmune disease are potential candidates.  Patients may not have received other adjuvant therapy for disease, and they must enter the study and be randomized within 12 weeks of surgery.  Other inclusion and exclusion criteria do apply.  The study is placebo controlled.  CORT has been selected as a participating site in this trial.  For more information on the study, visit the CORT website (www.CORTPA.com), or contact a Research Coordinator at 972-566-5588.  

Adjuvant Immunotherapy Study for Stage III Melanoma Open at CORT

September 13, 2008

CORT has opened a study of adjuvant non-interferon-based immunotherapy for patients with lymph-node positive cutaneous melanoma.  The study is enrolling patients who have had curative surgery and lymphadenectomy.  Patients who meet other clinical and lab eligibility criteria are potentially eligible.  This is a multicenter, multinational Phase III study of an anti-CTLA-4 therapy versus placebo for adjuvant therapy.   For further information about the study, contact one of our Study Coordinators at: 972-566-5588, or visit our website at www.CORTPA.com.

Thoracic Melanoma Metastasis Becomes Resectable After Investigational Therapy

August 21, 2008

A patient at CORT presented with isolated right hilar metastasis of melanoma.  The patient’s original truncal melanoma was removed completely from the right posterior thorax in 2001.  After his recurrence in the right hilum, he had received high-dose IL-2, with progression.  His staging studies included PET/CT demonstrating intense uptake in the hilar mass, but no other metastases.  Brain MRI scan and conventional CT scans were also negative, except for the hilar mass. The disease was not felt to be resectable because of the large size and proximity to the hilar structures.  

The patient received an investigational treatment at CORT from 1/2/08 through 7/9/08.  His disease in the right hilum decreased from 3 cm to 12-15 mm, and the regression was enough for surgical intervention to be reconsidered.  Re-staging prior to surgery continued to show no other metastatic disease.  The PET SUV of the hilar mass had substantially decreased, to 1.8 at follow-up.

The patient had thoracic exploration and surgical excision of the hilar disease in early 8/08.  He had a necrotic, regional with inflammatory cells but no tumor.  An area adjacent to this contained a node measuring 1.2 cm, which contained residual viable metastatic melanoma. The disease was completely resected, and the patient had an uneventful postoperative course and was discharged from the hospital after 3 days. 

The investigational drug in this case cannot be mentioned in this time, because of confidentiality of the ongoing study.   However, this case is an illustration of the importance of ongoing research efforts in melanoma therapy.  Patients with this disease have limited treatment options, and new therapies may hold substantial promise for improving survival.

Melanoma Study at CORT: BMS-663513, agonist of CD137 Immune Stimulatory Molecule

June 6, 2008

CORT continues Dallas-Fort Worth leadership in clinical trials for patients with advanced and metastatic melanoma with its ongoing study BMS CA-185006 of the BMS-663513 drug, an agonist of the CD137 immune cell regulatory protein.  CD137 stimulates cell-mediated anti-melanoma tumor immunity.  Studies have demonstrated that stimulation of CD137 may enhance anti-tumor immune responses against melanoma.  BMS-663513 is a stimulator of CD137. 

Patients who have failed first-line therapy for advanced unresectable or metastatic melanoma are eligible, if they meet other criteria.  Patients who have not yet had first-line therapy for their disease are eligible for other melanoma studies at CORT.  For more information about this important study, call 972-566-5588 (Dallas) or 972-981-4012 (Plano), and ask to speak with a Research Coordinator.  Further information about CORT and CORT studies is available at www.CORTPA.com.

 

DTIC (Dacarbazine) and IMCL-1121B for First-Line Treatment of Metastatic Melanoma

September 29, 2007

DTIC (Dacarbazine) chemotherapy is the most active approved chemotherapy agent for treatment of metastatic melanoma. Responses are infrequent, and generally of short duration. The risks of Dacarbazine are hair loss, nausea, vomiting, and low blood counts.

Anti-angiogenic drugs that block tumor blood vessel formation have shown promise in treatment of melanoma. IMCL-1121B is a fully-human monoclonal antibody that blocks the vascular endothelial growth factor receptor (VEGF-R2). The risks of IMCL-1121B are similar to other, approved anti-VEGF treatments: infusion reaction, proteinuria (protein in the urine), delayed wound healing, bleeding, thrombosis, hypertension, and rare bowel perforation.

CORT is conducting a phase II study of Dacarbazine and IMCL-1121B in the first-line treatment of metastatic melanoma. All patients who participate will receive both drugs.  The study will determine if the addition of IMCL-1121B to Dacarbazine therapy improves the response rate and delays progression of the disease.

For more information on these studies, visit www.CORTPA.com, or speak with a Study Coordinator at 972-566-5588.

MDX-010 (Ipilimumab), a CTLA-4 Inhibitor: Second-Line Treatment of Metastatic Melanoma

September 29, 2007

Immunotherapies that enhance anti-cancer immune responses against melanoma have shown infrequent, but occasionally durable (long-lasting) remissions of metastatic melanoma. Treatment with high-dose interleukin-2 (IL-2) is an example of such therapy. Treatment toxicities of high-dose IL-2 are very high, and potentially fatal. Patients who are older, with renal, pulmonary, or cardiac disease cannot usually be treated with such therapy.

Other immune therapies are in testing for the treatment of metastatic melanoma. MDX-010 (Ipilimumab) is an inhibitor of CTLA-4. CTLA-4 suppresses T-cell lymphocyte function, inhibiting anti-tumor immunity. By blocking CTLA-4, ipilimumab enhances T-cell anti-tumor immunity. Phase I and II studies have demonstrated that ipilimumab has activity in metastatic melanoma. Some responses have been durable. These studies have demonstrated that response to ipilimumab is related to HLA-A2 status (a protein marker on human lymphocyte white blood cells).

CORT is participating in a multicenter study of ipilimumab for the second-line treatment of metastatic melanoma. Patients who qualify and who are HLA-A2 positive are randomly assigned to one of three dose levels of ipilimumab treatment.

The risks of ipilimumab are fever, rash, diarrhea, bowel inflammation (which may be severe), infusion reaction, loss of pituitary hormone function, and hypothyroidism.

For more information on these studies, visit www.CORTPA.com, or speak with a Study Coordinator at 972-566-5588.

Chemotherapy and Sorafenib (Nexavar) for First-Line Treatment of Metastatic Melanoma

September 29, 2007

The combination of carboplatin (Paraplatin) and paclitaxel (Taxol) is active in metastatic melanoma. This combination of drugs is not approved for melanoma treatment, but is approved and commonly utilized in treatment of lung and other cancers. Treatment with Paraplatin and Taxol has manageable risks, which include fatigue, hair loss, nausea, vomiting, low blood counts, fever, infection, sensory neuropathy, and allergic reactions.

Sorafenib (Nexavar) is an oral drug that targets several specific growth promoting proteins in cancer cells. It inhibits b-raf (increased in melanoma cells) and it blocks angiogenesis (blood vessel formation). It is FDA-approved in the treatment of metastatic renal (kidney) cancer. The risks of Nexavar include fatigue, nausea, vomiting, diarrhea, rash, proteinuria (protein in the urine), increased blood pressure, low thyroid function, low blood counts, delayed wound healing, bleeding and thrombosis.

CORT is testing the combination of Paraplatin and Taxol with or without Nexavar in the first-line treatment of metastatic melanoma.

For more information on these studies, visit www.CORTPA.com, or speak with a Study Coordinator at 972-566-5588.