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CURRENTLY ACTIVE CLINICAL TRIALS

Adjuvant Therapy

A Multicenter, Double-blind, Placebo-controlled, Adaptive Phase 3 Trial of POL-103A Polyvalent Melanoma Vaccine in Post-resection Melanoma Patients with a High Risk of Recurrence.

Key Eligibility Criteria:

  • Histologically confirmed AJCC Stage IIB, IIC or III melanoma, surgically excised, with no evidence of residual disease

  • Last definitive surgical resection of all clinically evident disease within 90 days of first POL-103A or placebo dosing.

COMBI-AD: A phase III randomized doubleblind study of darafenib (GSK2118436) in combInation with trametinib (GSK1120212) versus two placebos in the adjuvant treatment of high-risk BRAF V600 mutation-positive melanoma after surgical resection (opening March 2013)

Key Eligibility Criteria:

  • Histologically confirmed AJCC Stage III melanoma determined to be V600E/K mutation positive

  • Must be surgically rendered free of disease no more than 12 weeks before randomization

First- Line Therapy

A Multicenter Open-label Randomized Phase II Trial of the MEK Inhibitor Pimasertib or Dacarbazine in Previously Untreated Subjects with N-RAS Mutated Locally Advanced or Metastatic Malignant Cutaneous Melanoma

Key Eligibility Criteria:

  • Histologically confirmed unresectable melanoma that harbors the N-RAS mutation

  • No prior systemic therapy for metastatic disease

  • If patient has brain metastases, they must be treated and stable for at least 3 months

First- or Second- Line Therapy

Intralesional: A Phase 2 Study of the Efficacy and Safety of Intratumoral CAVATAKTM (Coxsackievirus A21, CVA21) in Patients with Stage IIIC and Stage IV Malignant Melanoma

Key Eligibility Criteria:

  • Histologically confirmed unresectable Stage IIIC or IV melanoma

  • At least one tumor suitable for injection

Systemic: GM-CSF and Ipilimumab as Therapy in Metastatic Melanoma, a Phase II Study.

Key Eligibility Criteria:

  • Histologically confirmed unresectable melanoma

  • If patient has brain metastases, they must be treated and stable for at least 1 month

  • No history of autoimmune disease or prior therapy with monoclonal antibodies.

 



A Multicenter, Double-blind, Placebo-controlled, Adaptive Phase 3 Trial of POL-103A Polyvalent Melanoma Vaccine in Post-resection Melanoma Patients with a High Risk of Recurrence

POL-103A is an investigational melanoma vaccine that contains multiple melanoma-associated antigens that are shed from 3 human melanoma cell lines, admixed with alum as the adjuvant.  The presence of multiple antigens is an important element in maximizing the induction of tumor-protective immune responses and reducing a tumor cell’s ability to escape the immune response.    The vaccine has been administered (in various forms) to approximately 690 subjects who were treated for up to 5 years at antigen doses of 40 µg per treatment.  These subjects were treated without significant toxicity and the results demonstrated preliminary evidence of efficacy.  In one study, a double-blind and placebo-controlled trial of a related version of the vaccine (4 melanoma cell lines plus alum) in patients with Stage III melanoma (n=38), the recurrence-free survival of the melanoma vaccine-treated subjects was over twice as long as that of placebo vaccine-treated subjects.

 

This study will be conducted in two parts.  Part A (dose evaluation, number of subjects = 99) is designed to determine the safety profile and immunogenicity of two different doses of POL-103A – 40 µg or 100 µg or vs placebo and to determine the dose to be used in Part B of the study.  The decision to proceed to Part B (clinical efficacy evaluation, number of subjects = 960) will be based on evidence of immunogenicity, safety, and tolerability.  Part B allows an evaluation of efficacy using the dose of POL-103A selected from Part A.  The objective of the efficacy evaluation is to assess whether subjects randomized to the active arm have superior recurrence-free survival or overall survival (two primary endpoints) in the active arm compared to subjects randomized to the placebo arm.  The safety of POL-103A will also be assessed.

For more information clinicaltrials.gov, NCT01546571.

Inclusion Criteria:

  1. Histologically confirmed AJCC Stage IIB, IIC, or III melanoma

  2. Last definitive surgical resection of all clinically evident disease within 90 days of first POL-103A or placebo dosing. Subjects with positive margins of resection should have re-excision prior to randomization.

  3. Subjects with positive sentinel nodes must have a complete lymphadenectomy.

  4. Male or female subjects ≥ 18 and ≤ 75 years of age.

  5. Female subjects of childbearing potential must have a negative pregnancy test within 2 weeks of study randomization, must agree to use adequate contraception throughout the treatment duration and for 3 months after the last POL-103A or placebo dosing, and must not be breastfeeding.

  6. ECOG Performance Status 0 or 1.

  7. White blood cell (WBC) count ≥ 4,000/mm3.

  8. Absolute neutrophil count ≥ 1,500/mm3.

  9. Hemoglobin ≥ 11 g/dL.

  10. Platelet count ≥ 100,000/mm3.

  11. Creatinine ≤ 2.0 mg/dL.

  12. Bilirubin ≤ 1.5 times the upper limit of normal (ULN).

  13. Albumin ≥ 3.5 mg/dL.

  14. Asparate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.0 times ULN.

  15. Subjects must have known BRAF mutation tumor status or have tumor tissue (fresh or archived sample) available for testing of BRAF mutation status (note: as long as it is confirmed that tumor tissue is available for testing, the subject may be considered eligible for the study; testing of BRAF mutation status on that tissue may be conducted at a later time during the study).

  16. Competent to comprehend, sign, and date an IEC/IRB-approved informed consent.

Exclusion Criteria: 

  1. Any prior melanoma treatment other than surgery or regional irradiation, including adjuvant or neoadjuvant treatment.

  2. Subjects who have a history of another malignancy within the past 5 years with the exception of adequately treated in situ squamous cell carcinoma, basal cell carcinoma, or carcinoma in situ of the cervix. See treatment exclusions noted within the other exclusion criteria.

  3. Diagnosis of non-cutaneous melanoma or melanoma with unknown primary.

  4. Use of interferon or other biologic response modifiers (e.g., interleukin-2, colony-stimulating factors, other cytokines, BCG) within 60 days of first POL-103A or placebo dosing.

  5. Any evidence of loco-regional or metastatic melanoma after definitive surgical resection, based on any of the following screening studies:

    a. Histological review of resected tumor,
    b. Physical examination findings,
    c. CT/PET scans of chest and abdomen, plus CT/PET scans of the pelvis for subjects with loco-regional disease below the waist, and CT/PET scans of the neck for subjects with disease in the head and neck region, d. Brain MRI or CT scan.

  6. Chronic use of systemic corticosteroids or other immunosuppressants.

  7. Known allergy to alum.

  8. Prior use of any investigational agents within 30 days of first POL-103A or placebo dosing.

  9. History of any chronic medical or psychiatric condition or laboratory abnormality that, in the judgment of the principal investigator, may contraindicate study participation or study drug administration or may interfere with the interpretation of study results.

  10. Any kind of disorder that compromises the ability of the subject to give written informed consent and/or comply with the study procedures.

  11. Prior splenectomy.

  12. Known positivity for human immunodeficiency virus (HIV).

  13. Positive for antinuclear antibodies (ANA) at screening.

  14. Female subjects of childbearing potential not consenting to use adequate contraceptive precautions throughout the treatment duration and for 3 months after the last POL-103A or placebo dosing.

  15. Female subjects who are pregnant or lactating.

Treatment Regiment

  • Subjects will be offered a Consent Form to allow screening and participation in the study.  Subjects who meet all inclusion and exclusion criteria following screening will be randomized to receive either the vaccine or placebo on a 2:1 treatment allocation schedule.  If the subject meets eligibility criteria s/he will be given treatment with the vaccine or placebo by intradermal injection.  The study treatments will be administered 5 times at 2-week intervals, then 4 times at monthly intervals, then every 3 months until they have been treated for 2 years.  Each subject will be treated with POL-103A or placebo unless one of the following occurs: development of recurrent disease that does not meet the criteria for continued dosing, death, subject withdrawal, or study termination, whichever comes first.  Subjects will be monitored for disease progression and survival for up to 12 years after treatment is completed or discontinued.

 



GM-CSF and Ipilimumab as Therapy in Metastatic Melanoma, a Phase II Study

In March, 2011, the anti-CTLA-4 monoclonal antibody ipilimumab (Yervoy) was approved for the treatment of unresectable or metastatic melanoma. This is the first agent ever proven to improve survival in patients with advanced melanoma. The results showed a best overall response rate (BORR) of 10.9% as measured by the modified WHO (mWHO) criteria, a disease control rate of 28.5 %, and a median overall survival of 10.1 months. The 1-year and 2-year survival rates were 45.6% and 23.5%, respectively. While these results are promising, it is likely that efficacy can be improved by combination therapy of the antibody with other agents. Combination therapy of cancer is well accepted and in many instances has been shown to be superior to monotherapy. GM-CSF (Leukine) activates and stimulates the growth of antigen presenting cells, most importantly macrophages and dendritic cells. Since Yervoy has been approved for therapy of melanoma, patients can receive it from their oncologists. However, participation in this clinical trial offers the following potential advantages over receiving Yervoy as approved by the FDA: • The dose of Yervoy used in this trial is higher (10 mg/kg, rather than 3 mg/kg as approved by the FDA). • The Yervoy is given in ongoing dosing for up to 2 years rather than being limited to 4 doses, as approved by the FDA. The ongoing dosing is continued if the patient is tolerating it well and the disease is not progressing. • The Yervoy is given in combination with GM-CSF, which may add to the clinical benefit seen with Yervoy monotherapy.  For more information clinicaltrials.gov, NCT01363206.

• The dose of Yervoy used in this trial is higher (10 mg/kg, rather than 3 mg/kg as approved by the FDA).

• The Yervoy is given in ongoing dosing for up to 2 years rather than being limited to 4 doses, as approved by the FDA. The ongoing dosing is continued if the patient is tolerating it well and the disease is not progressing.

• The Yervoy is given in combination with GM-CSF, which may add to the clinical benefit seen with Yervoy monotherapy.

Inclusion Criteria (conditions the patient must meet):

  1. Histologically confirmed, (surgically incurable or unresectable) stage III or IV metastatic malignant melanoma.

  2. Prior systemic therapy for metastatic disease is permitted but not required

  3. A minimum of 1 measurable lesion according to irRC criteria.

  4. ECOG performance status of 0-2.

  5. Men and women, age ≥ 18 years.

  6. Adequate hematologic, renal and liver function as defined by laboratory values performed within 14 days prior to initiation of dosing.
  7. WBC ³ 2000/mL

  8. Absolute neutrophil count (ANC) ³ 1000/mL

  9. Platelet count ³ 50,000/mL

  10. Hemoglobin ³ 8.0 g/dL

  11. Serum creatinine ≤ 3.0 x upper limit of normal

  12. Total serum bilirubin £ 3.0 x upper limit of normal (except patients with Gilbert’s Syndrome, who must have a total bilirubin less than 3.0 mg/dL

  13. LDH ≤ 4 times upper limit of laboratory normal

  14. Serum aspartate transaminase (ASAT/SGOT) or serum alanine transaminase (ALAT/SGPT) £ 2.5 times upper limit of laboratory normal for patients without liver metastases

  15. Alkaline phosphatase ≤ 2.5 times upper limit of normal, unless bone metastasis is present in the absence of liver metastases

  16. No active or chronic infection with HIV, Hepatitis B, or Hepatitis C

  17. Patients must have recovered from effects of major surgery.

  18. Women of childbearing potential (WOCBP) must be using an adequate method contraception to avoid pregnancy throughout the study and for up to 8 weeks after the study in such a manner that the risk of pregnancy is minimized. Men must agree to use and utilize an adequate method of contraception throughout treatment and for at least 8 weeks after study drug is stopped.

  19. Must have recovered from all prior treatment-related toxicities to NCI CTCAE (v 4.0) Grade of 0 or 1, except for alopecia.

  20. Willing and able to give written informed consent.  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: 

  1. Patients who exhibit any of the following conditions at screening will not be eligible for admission into the study:
  1. Brain metastases that are not treated and not stable for at least 1 month.
  2. History of or known spinal cord compression, or carcinomatous meningitis, or evidence of symptomatic brain or leptomeningeal disease on screening CT or MRI scan.

  3. Any other malignancy from which the patient has been disease-free for less than 5 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix.

  4. Autoimmune disease: Patients with a history of inflammatory bowel disease are excluded from this study as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis (e.g., Wegener’s Granulomatosis), motor neuropathy considered of autoimmune origin (e.g. Guillain-Barré Syndrome).

  5. Any underlying medical condition, which in the opinion of the Investigator, will make the administration of study drug hazardous or obscure the interpretation of AEs, such as a condition associated with frequent diarrhea.

  6. 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.

  7. Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to one month prior to or after any dose of ipilimumab.

  8. A history of prior treatment with ipilimumab, CD137 agonist, CTLA-4 inhibitor or agonist; GM-CSF, or monoclonal antibody.

  9. Concomitant therapy with any of the following: IL-2, interferon or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids.

  10. Women of child-bearing potential (WOCBP) who:

    1. are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 8 weeks after cessation of study drug, or

    2. have a positive pregnancy test at baseline, or

    3. are pregnant or breastfeeding

  11. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness

  12. Persons of reproductive potential must agree to use and utilize an adequate method of contraception throughout treatment and for at least 8 weeks after study drug is stopped

Treatment Regiment

  • Subjects will be offered a Consent Form to allow screening and participation in the study. Subjects who meet all inclusion and exclusion criteria following screening will be treated with 4 courses of GM-CSF and ipilimumab, 10 mg/kg administered intravenously every 3 weeks. GM-CSF will be administered subcutaneously daily for 14 days in a dose of 125 µg/m2 beginning on Day 1 of each 21-day cycle. Patients will be instructed in self-administration of GM-CSF and, after they have demonstrated competency with the procedure, they will self-administer the treatment at home. After the initial 3 months of treatment (4 doses; weeks 0, 3, 6, 9), GM-CSF administration will continue on the same schedule and dose without ipilimumab for 14 days every 21 days until month 6. Maintenance therapy will begin at month 6 and will consist of ipilimumab in the same dose as originally administered combined with 14 days of GM-CSF. Administration of this combination will be repeated every 3 months for up to 2 years or until disease progression or unacceptable toxicity. GM-CSF will only be administered in conjunction with ipilimumab and will not be administered in the intervening time period.

 

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