Melanoma
Conditions
Keywords
gene transfer, gene therapy, oncolytic virus, GM-CSF, melanoma
Brief summary
The primary objective of the study was to assess the clinical efficacy of talimogene laherparepvec in terms of tumor response rates.
Interventions
DRUGTalimogene Laherparepvec
Up to 4 mL of 10⁸ pfu/mL/per intratumoral injection
Sponsors
Symbion Research International
BioVex Limited
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients with histologically proven stage IIIc (including two or more palpable lymph nodes, extracapsular or in-transit metastases) or stage IV melanoma that is not eligible for curative surgery and who have one or more tumors that are accessible for direct injection. 2. Tumors 0.5 to 10 cm in the longest diameter that are suitable for injection (i.e. not bleeding or weeping). 3. Serum lactate dehydrogenase (LDH) levels ≤ 2.0 times the upper limit of normal. 4. Aged 18 years or more. 5. Eastern Cooperative Oncology Group (ECOG) Performance status 0 or 1. 6. Clinically immunocompetent. 7. Recovered from prior therapy with at least 4 weeks since the last exposure to chemotherapy or radiotherapy. 8. Total white cell count ≥ 3.0 x 10\^9/L, platelet count ≥ 80 x 10\^9/L. 9. Serum creatinine ≤ 0.2 mmol/L. 10. Bilirubin ≤ 1.5 times the upper limit of the normal range, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) equal to or less than twice the upper limit of the normal range and alkaline phosphatase equal to or less than twice the upper limit of the normal range.
Exclusion criteria
1. Participation in any previous melanoma immunotherapy trial within one month prior to entry to this trial or any trial of any other investigational agent within the last month prior to entry to this trial. 2. Tumors to be injected lying in mucosal regions or close to an airway, major blood vessel or spinal cord that, in the opinion of the Investigators, could cause occlusion or compression in the case of tumor swelling or erosion into a major vessel in the case of necrosis. 3. Pregnancy, lactation or lack of effective contraception in women of child-bearing potential; lack of effective contraception in men if the partner is of child-bearing potential; women must have been practising an effective contraceptive method for at least three months prior to entry in to the trial (hormonal contraception or intrauterine device in conjunction with a barrier method OR surgically sterilised). Men must use a condom or be surgically sterilised. 4. Major surgery within the 14 days prior to entry to the trial. 5. Intercurrent serious infections within the 28 days prior to entry to the trial. 6. Life-threatening illness unrelated to cancer. 7. Treatment with antiviral agents within the 14 days prior to entry to the trial. 8. Uncontrolled congestive cardiac failure. 9. Clinically active autoimmune disease. 10. Dermatoses involving or near to the tumors to be injected. Limb tumors may not be injected if active dermatoses are present on the same limb. Trunk and head and neck tumors must not be injected if dermatoses are present within 50 cm of the tumor. 11. Known to test positive for human immunodeficiency virus (HIV), hepatitis B or C or syphilis. 12. Patient only has injectable tumors that are not potentially resectable in the case of tumor necrosis or swelling. 13. Previous history of malignancies of other types that have occurred or recurred within the previous 5 years with the exception of cone biopsied carcinoma of the cervix. 14. Corticosteroid use.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Tumor Response Rate | From enrollment until the data cut-off date of 29 November 2008; Median duration of follow-up was 253 days | Objective response rate is defined as the percentage of participants with an overall best response of complete response or partial response. The objective response to treatment was assessed by computed tomography (CT) scanning or other clinical measurement using modified Response Evaluation Criteria In Solid Tumors (RECIST). Responses must have been confirmed on two visits not less than 4 weeks apart. Tumor burden for a visit was calculated as the sum of the longest diameters of all tumors identified and measured up to that visit. Tumor response at each visit was derived from tumor burden, as follows: * Complete response (CR): zero tumor burden * Partial response (PR): a 30% or greater decrease in tumor burden * Progressive disease (PD): a 20% or greater increase in tumor burden * Stable disease (SD): none of the above (a \< 30% decrease and \< 20% increase in tumor burden) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From enrollment until the data cut-off date of 29 November 2008; Median duration of follow-up was 253 days | Overall survival (OS) was calculated from the date of the first talimogene laherparepvec dose to the date of death. Median OS was estimated using the Kaplan-Meier method. |
| Time to Progression | From enrollment until the data cut-off date of 29 November 2008; Median duration of follow-up was 253 days. | Time to progression was calculated from the date of the first talimogene laherparepvec dose to the first date of documented progressive disease (via clinical symptom or tumor burden assessment) that was not followed by a later response of CR, PR, or stable disease. Median time to progression was calculated using the Kaplan-Meier method. |
| Time to Longest Continuous Response | From enrollment until the data cut-off date of 29 November 2008; Median duration of follow-up was 253 days. | Time to response was calculated from the date of the first talimogene laherparepvec dose to the initial date of the participant's last response interval. |
| Duration of Response | From enrollment until the data cut-off date of 29 November 2008; Median duration of follow-up was 253 days. | Duration of response was calculated from the initial date of response (CR or PR) until the date of progressive disease (or until last follow up that was CR or PR). Participants could have multiple response periods; in this situation, the last response interval was used for the calculation of duration of response. |
| Number of Participants With Adverse Events | From first dose of talimogene laherparepvec until 30 days after the last dose; the median (minimum, maximum) duration of treatment was 82 (1, 346) days. | The severity of an adverse event (AE) was graded according to Common Toxicity Criteria for Adverse Events (CTCAE) Version 3 (1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death). Serious adverse events include death, life-threatening events, events requiring or prolonging hospitalization, result in persistent or significant disability/incapacity, or a congenital anomaly/birth defect, or otherwise important medical events that may jeopardise the patient or require intervention to prevent one of the above outcomes. |
Countries
United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Talimogene Laherparepvec Participants received talimogene laherparepvec at an initial dose of 10⁶ plaque forming units (PFU)/mL injected into 1 or more tumors with maximum total volume of 4 mL (up to 2 mL per tumor). Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks for up to 15 weeks. After the initial 8 doses, if indications of biological activity were observed, treatment could continue for up to 16 additional doses. | 50 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Death | 2 |
| Overall Study | Disease Progression | 29 |
| Overall Study | Other | 1 |
| Overall Study | Unrelated Medical Condition or Accident | 2 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Talimogene Laherparepvec |
|---|---|
| Age, Continuous | 63 years STANDARD_DEVIATION 15.2 |
| Eastern Cooperative Oncology Group (ECOG) Performance 0 (Fully active) | 31 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance 1 (Restrictive but ambulatory) | 19 participants |
| Race/Ethnicity, Customized Asian | 1 participants |
| Race/Ethnicity, Customized Hispanic | 1 participants |
| Race/Ethnicity, Customized White | 48 participants |
| Sex: Female, Male Female | 28 Participants |
| Sex: Female, Male Male | 22 Participants |
| Tumor, Node, Metastasis (TNM) Disease Stage Stage IIIC | 13 participants |
| Tumor, Node, Metastasis (TNM) Disease Stage Stage IVM1a | 13 participants |
| Tumor, Node, Metastasis (TNM) Disease Stage Stage IVM1b | 5 participants |
| Tumor, Node, Metastasis (TNM) Disease Stage Stage IVM1c | 19 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 48 / 50 |
| serious Total, serious adverse events | 17 / 50 |
Outcome results
Primary
Objective Tumor Response Rate
Objective response rate is defined as the percentage of participants with an overall best response of complete response or partial response. The objective response to treatment was assessed by computed tomography (CT) scanning or other clinical measurement using modified Response Evaluation Criteria In Solid Tumors (RECIST). Responses must have been confirmed on two visits not less than 4 weeks apart. Tumor burden for a visit was calculated as the sum of the longest diameters of all tumors identified and measured up to that visit. Tumor response at each visit was derived from tumor burden, as follows: * Complete response (CR): zero tumor burden * Partial response (PR): a 30% or greater decrease in tumor burden * Progressive disease (PD): a 20% or greater increase in tumor burden * Stable disease (SD): none of the above (a \< 30% decrease and \< 20% increase in tumor burden)
Time frame: From enrollment until the data cut-off date of 29 November 2008; Median duration of follow-up was 253 days
Population: Intent-to-treat (ITT) population (all participants who received at least 1 dose of talimogene laherparepvec)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Talimogene Laherparepvec | Objective Tumor Response Rate | 28 percentage of participants |
Secondary
Duration of Response
Duration of response was calculated from the initial date of response (CR or PR) until the date of progressive disease (or until last follow up that was CR or PR). Participants could have multiple response periods; in this situation, the last response interval was used for the calculation of duration of response.
Time frame: From enrollment until the data cut-off date of 29 November 2008; Median duration of follow-up was 253 days.
Population: ITT population with an objective response (PR or CR)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Talimogene Laherparepvec | Duration of Response | 223 days |
Secondary
Number of Participants With Adverse Events
The severity of an adverse event (AE) was graded according to Common Toxicity Criteria for Adverse Events (CTCAE) Version 3 (1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death). Serious adverse events include death, life-threatening events, events requiring or prolonging hospitalization, result in persistent or significant disability/incapacity, or a congenital anomaly/birth defect, or otherwise important medical events that may jeopardise the patient or require intervention to prevent one of the above outcomes.
Time frame: From first dose of talimogene laherparepvec until 30 days after the last dose; the median (minimum, maximum) duration of treatment was 82 (1, 346) days.
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Talimogene Laherparepvec | Number of Participants With Adverse Events | Any adverse event | 48 participants |
| Talimogene Laherparepvec | Number of Participants With Adverse Events | Treatment-related adverse event | 39 participants |
| Talimogene Laherparepvec | Number of Participants With Adverse Events | Adverse event ≥ grade 3 | 23 participants |
| Talimogene Laherparepvec | Number of Participants With Adverse Events | Fatal adverse events | 5 participants |
| Talimogene Laherparepvec | Number of Participants With Adverse Events | Serious adverse events | 17 participants |
| Talimogene Laherparepvec | Number of Participants With Adverse Events | Discontinued study treatment due to adverse event | 2 participants |
| Talimogene Laherparepvec | Number of Participants With Adverse Events | Injection site reactions | 27 participants |
| Talimogene Laherparepvec | Number of Participants With Adverse Events | Flu-like symptoms | 42 participants |
Secondary
Overall Survival
Overall survival (OS) was calculated from the date of the first talimogene laherparepvec dose to the date of death. Median OS was estimated using the Kaplan-Meier method.
Time frame: From enrollment until the data cut-off date of 29 November 2008; Median duration of follow-up was 253 days
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Talimogene Laherparepvec | Overall Survival | 448.0 days |
Secondary
Time to Longest Continuous Response
Time to response was calculated from the date of the first talimogene laherparepvec dose to the initial date of the participant's last response interval.
Time frame: From enrollment until the data cut-off date of 29 November 2008; Median duration of follow-up was 253 days.
Population: ITT population with an objective response (PR or CR)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Talimogene Laherparepvec | Time to Longest Continuous Response | 100 days |
Secondary
Time to Progression
Time to progression was calculated from the date of the first talimogene laherparepvec dose to the first date of documented progressive disease (via clinical symptom or tumor burden assessment) that was not followed by a later response of CR, PR, or stable disease. Median time to progression was calculated using the Kaplan-Meier method.
Time frame: From enrollment until the data cut-off date of 29 November 2008; Median duration of follow-up was 253 days.
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Talimogene Laherparepvec | Time to Progression | 146.0 days |