A Randomized Phase 3 Clinical Trial to Evaluate the Efficacy and Safety of Treatment with OncoVEX GM-CSF Compared to Subcutaneously Administered GM-CSF in Patients with Untreated or with Previously Treated Unresectable Stage IIIc and IV Melanoma

The concept of using viruses in the treatment of cancer dates back to the beginning of the 20th century.  Although tumor regression without toxicity was observed in more than half of the patients, subsequent disease progression was observed in all patients.  The absence of durable anti-tumor activity and advances in the development of chemotherapy, led investigators to abandon this mode of therapy.  However, advances in tumor biology, genetics, and virology in the intervening years have provided us with the tools to develop oncolytic viruses into potentially more effective cancer therapies than was previously the case. 

OncoVEX^GM-CSF is a product that consists of herpes simplex virus-1 (HSV-1) modified through genetic engineering to increase it’s efficacy in therapy of melanoma.  HSV-1 is a highly lytic virus which can infect and rapidly kill most human tumor cell types by lytic virus replication.  This replication is rendered tumor selective through deletion of a gene.  Moreover, the HSV-1 is engineered to express GM-CSF, which has the potential of enhancing the systemic immune responses to the tumor-associated antigens being released by the lytic process, thus carrying the potential to control disease in uninjected sites through immunologic mechanisms.  Results of a Phase II trial of OncoVEX^GM-CSF in patients with melanoma were encouraging and led to the design of this Phase III trial.

Inclusion Criteria (conditions the patient must meet)

1. Males or females age ≥ 18 years.
2. Histologically confirmed diagnosis of malignant melanoma.
3. Stage IIIb, IIIc or stage IV disease that is not surgically resectable.
4. Measurable disease defined as:
   • at least 1 melanoma lesion that can be accurately and serially measured in at least 2 dimensions and for which the greatest diameter is ≥ 10 mm as measured by contrast-enhanced or spiral computed tomography (CT) scan for visceral or nodal/soft tissue disease (including lymph nodes) and/or;
   • at least 1 ≥ 10 mm superficial cutaneous melanoma lesion as measured by calipers and/or;
   • at least 1 ≥ 10 mm subcutaneous melanoma lesion and/or;
   • multiple superficial melanoma lesions which in aggregate have a total diameter of ≥ 10 mm.
5. Injectable disease (i.e. suitable for direct injection or through the use of ultrasound guidance) defined as:
   • at least 1 injectable cutaneous, subcutaneous or nodal melanoma lesion ≥ 10 mm in longest diameter or,
   • multiple injectable melanoma lesions which in aggregate have a longest diameter of ≥ 10 mm.
6. Serum LDH levels ≤ 1.5 x ULN.
7. ECOG Performance Status of 0 or 1.
8. Life expectancy >4 months from the date of randomization.
9. Able to provide written informed consent in accordance with all applicable regulations and follow the study procedures. Patients must be capable of understanding the investigational nature, potential risks and benefits of the study.
10. Adequate organ function determined within 4 weeks prior to randomization, defined as:
    • Absolute neutrophil count (ANC) ≥ 1500/mm³
    • Platelet count ≥ 100,000/mm³
    • Hemoglobin ≥ 8 g/dL without need for hematopoietic growth factor or transfusion support
    • Serum creatinine ≤ 1.5 x ULN, or 24-hour creatinine clearance ≤ 50 cc/min. (Note: Creatinine clearance need not be determined if the baseline serum creatinine is within normal limits.)
    • Serum bilirubin ≤ 1.5 x ULN
    • Aspartate amino transferase (AST) ≤ 2.5 x ULN
    • Alanine amino transferase (ALT) <2.5 x ULN
    • Alkaline phosphatase ≤ 2.5 x ULN
    • Serum albumin must be ≥ 2.5 g/dL.
    • Prothrombin time (PT) ≤ 1.5 x ULN (or INR ≤ 1.3)
    • Partial thromboplastin time (PTT) ≤ 1.5 x ULN.

Exclusion Criteria
Patients who exhibit any of the following conditions at screening will not be eligible for admission into the study: 

1. Clinically active cerebral or any bone metastases. Patients with up to 3 asymptomatic (neurological performance status of 0) cerebral metastases may be enrolled, provided that all lesions have been adequately treated with stereotactic radiation therapy or gammaknife therapy, with no evidence of progression, and have not required steroids or anticonvulsant therapy, for at least two months prior to randomization.
2. Greater than 3 visceral metastases (this does not include lung metastases or nodal metastases associated with visceral organs). For patients with ≤ 3 visceral metastases, no lesion >3 cm, and liver lesions must meet RECIST criteria for SD for at least 1 month prior to randomization.
3. Any underlying medical condition, which in the opinion of the investigator, would make administration of the study drugs hazardous or make it difficult to monitor adverse effects.
4. History of second cancer, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient had been disease-free for ≥ 5 years.
5.  Primary ocular or mucosal melanoma.
6.  Evidence of immunosuppression for any reason:
   • known HIV disease
   • acute or chronic active hepatitis B or hepatitis C infection
   • chronic oral or systemic steroid medication use
   • other signs or symptoms of clinical immune system suppression
7. Baseline prolongation of QT/QTc interval (QTc interval >470 msec).
8. Open herpetic skin lesions.
9. Pregnant or breast-feeding female. Confirmation that the patient is not pregnant must be established by a negative serum or urine β-human chorionic gonadotropin (β-hCG) pregnancy test result obtained during the screening period.
10. Fertile males and females who are unwilling to employ adequate means of contraception (e.g., condom with spermacide, diaphragm with spermacide, birth control pills, injections, patches, or intrauterine device) during study treatment and through 30 days after the last dose of study treatment.
11. Previous treatment with OncoVEX^GM-CSF or treatment with GM-CSF for active disease (prior adjuvant therapy with GM-CSF is permitted).
12. Currently enrolled in another clinical research study or received an investigational agent for any reason within 4 weeks prior to randomization.
13. Require intermittent or chronic treatment with an anti-herpetic drug (e.g., acyclovir), other than intermittent topical use.

Treatment Regimen
This is multinational, open label, randomized, Phase III trial to evaluate the efficacy and safety of treatment with OncoVEX^GM-CSF monotherapy compared to control therapy in previously treated melanoma patients with unresectable Stage IIIb, IIIc and Stage IV disease.  Approximately 430 patients will be enrolled to provide 360 evaluable patients (240 OncoVEX^GM-CSF, 120 GM-CSF). Eligible patients are males and females 18 years of age or older with at least one cutaneous, subcutaneous, or nodal mass ≥ 10 mm in longest diameter (or masses which in aggregate are ≥ 10 mm in longest diameter) who meet other eligibility criteria described above.

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