Melanoma
Conditions
Keywords
Melanoma, Stage IIIb, IIIc and IV Disease, oncolytic, OncoVex, OncoVEX^GM-CSF
Brief summary
The purpose of this study is to learn about the safety and the risks of using talimogene laherparepvec in patients who already received treatment with talimogene laherparepvec in study 005/05 (NCT00769704), and to see if extended treatment with talimogene laherparepvec can destroy melanoma tumors.
Interventions
BIOLOGICALTalimogene Laherparepvec
Up to 4 mL of 10⁸ pfu/mL/per intratumoral injection
125 µg/m² subcutaneous injection
Sponsors
BioVex Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Previously participated in protocol 005/05 (NCT00769704) and: 1. received the maximum number of talimogene laherparepvec treatment injections or cycles of GM-CSF allowable for that patient on study 005/05, or 2. new injectable lesion(s) appeared after previous resolution of all injectable disease while on study 005/05. New injectable lesions must have appeared within ≤ 12 months from the End of Treatment visit on the 005/05 study. 2. In the opinion of the investigator and the sponsor's medical monitor further treatment is warranted \[e.g., those patients who do not have clinically relevant progressive disease (PDr)\]. 3. Performance status (Eastern Cooperative Oncology Group, ECOG) 0 or 1. 4. For patients randomized to talimogene laherparepvec only: 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. There is no minimum size for injection.
Exclusion criteria
1. Prior Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or 4 toxicity related to talimogene laherparepvec of any organ system (with the exception of injection site reactions, fever and vomiting). 2. History of Grade 3 fatigue lasting \> 1 week while on talimogene laherparepvec treatment. 3. History of Grade 3 arthralgia/myalgias while on talimogene laherparepvec treatment. 4. History of ≥ Grade 2 autoimmune reactions, allergic reactions or urticaria or other talimogene laherparepvec related non-hematological toxicities while on talimogene laherparepvec treatment that required a dose delay or discontinuation of talimogene laherparepvec therapy. 5. PDr while participating in study 005/05 6. Patient requested to be withdrawn from study 005/05 or was unable to comply with the demands of the 005/05 trial. 7. At the discretion of the investigator, patient was withdrawn from the 005/05 trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (AEs) | From first administration of study drug in the extension period until 30 days after last dose. Median duration of treatment was 50 weeks in the GM-CSF group and 36 weeks in the talimogene laherparepvec group. | AEs were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 based on the following guideline: Grade 1: Mild AE; Grade 2: Moderate AE; Grade 3: Severe AE; Grade 4: Life-threatening or disabling AE; Grade 5: Death related to AE. Treatment-related AE refers to AEs that have possible or probable relation to study treatment as determined by the investigator. A serious AE is one that meets one or more of the following criteria/outcomes: * Results in death. * Is life-threatening. * Requires inpatient hospitalization or prolongation of existing hospitalization. * Results in persistent or significant disability/incapacity. * Is a congenital anomaly/birth defect. * Is an important medical event. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | From randomization in study 005/05 until the data-cut-off date for the extension period of 08 August 2014; median treatment duration for 005/05 and 005/05-E studies combined was 88 weeks for talimogene laherparepvec and 100 weeks for GM-CSF. | Objective response rate was defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) assessed by the investigator. Best overall response for a patient is the best overall response observed across all time points and is cumulative (ie, includes responses during the parent study 005/05 and during Study 005/05-E). Disease assessments were performed at the beginning of each treatment cycle and assessed in accordance with modified World Health Organization criteria. CR: Disappearance of all clinical evidence of tumor (both measurable and non-measurable but evaluable disease); PR: ≥ 50% reduction in the sum of the products of the perpendicular diameters of all measurable tumors at the time of assessment as compared to baseline. |
| Durable Response Rate | From randomization in study 005/05 until the data-cut-off date for the extension period of 08 August 2014; median treatment duration for 005/05 and 005/05-E studies combined was 88 weeks for talimogene laherparepvec and 100 weeks for GM-CSF. | Durable response rate is defined as the percentage of participants with a complete response (CR) or partial response (PR) assessed by the investigator, initiating at any time while receiving talimogene laherparepvec or GM-CSF therapy on the 005/05 or the 005/05-E study and maintained continuously for at least 6 months from response initiation. This reflects all new sites of disease as well as disease sites identified at baseline. Disease assessments were performed at the beginning of each treatment cycle in accordance with modified World Health Organization criteria. CR: Disappearance of all clinical evidence of tumor (both measurable and non-measurable but evaluable disease); PR: ≥ 50% reduction in the sum of the products of the perpendicular diameters of all measurable tumors at the time of assessment as compared to baseline. |
Countries
United Kingdom, United States
Participant flow
Recruitment details
This extension was available to patients who participated in study 005/05 (NCT00769704), received the maximum allowable number of treatments or developed new lesion(s) within ≤ 12 months from the end of treatment visit after previous resolution of all disease while on study 005/05, and warranted further treatment per the investigator.
Pre-assignment details
Participants received the same treatment as randomized under the 005/05 study.
Participants by arm
| Arm | Count |
|---|---|
| GM-CSF GM-CSF was administered at a dose of 125 μg/m²/day subcutaneously for 14 consecutive days followed by 14 days of rest, in 28-day treatment cycles for up to 12 months or until a complete response, occurrence of an unacceptable toxicity, death or another criterion for withdrawal from treatment was met. Participants who demonstrated a partial response after being on treatment for 12 months could continue to be treated until disease progression or another treatment discontinuation criterion was met. | 3 |
| Talimogene Laherparepvec Talimogene laherparepvec was administered at a concentration of 10⁸ PFU/mL injected into 1 or more skin or subcutaneous tumors on Days 1 and 15 of each 28-day cycle for up to 12 months or until a complete response, occurrence of an unacceptable toxicity, death or another criterion for withdrawal from treatment was met. Participants who demonstrated a partial response after being on treatment for 12 months could continue to be treated until disease progression or another treatment discontinuation criterion was met. | 28 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 10 |
Baseline characteristics
| Characteristic | GM-CSF | Talimogene Laherparepvec | Total |
|---|---|---|---|
| Age, Continuous | 54.7 years STANDARD_DEVIATION 25 | 64.2 years STANDARD_DEVIATION 13.2 | 63.3 years STANDARD_DEVIATION 14.4 |
| Disease Stage Stage IIIB | 0 participants | 1 participants | 1 participants |
| Disease Stage Stage IIIC | 0 participants | 6 participants | 6 participants |
| Disease Stage Stage IV M1a | 1 participants | 9 participants | 10 participants |
| Disease Stage Stage IV M1b | 1 participants | 8 participants | 9 participants |
| Disease Stage Stage IV M1c | 1 participants | 4 participants | 5 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 | 3 participants | 20 participants | 23 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 | 0 participants | 8 participants | 8 participants |
| Race/Ethnicity, Customized White | 3 participants | 28 participants | 31 participants |
| Sex: Female, Male Female | 2 Participants | 14 Participants | 16 Participants |
| Sex: Female, Male Male | 1 Participants | 14 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 21 / 28 |
| serious Total, serious adverse events | 0 / 3 | 9 / 28 |
Outcome results
Primary
Number of Participants With Treatment-emergent Adverse Events (AEs)
AEs were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 based on the following guideline: Grade 1: Mild AE; Grade 2: Moderate AE; Grade 3: Severe AE; Grade 4: Life-threatening or disabling AE; Grade 5: Death related to AE. Treatment-related AE refers to AEs that have possible or probable relation to study treatment as determined by the investigator. A serious AE is one that meets one or more of the following criteria/outcomes: * Results in death. * Is life-threatening. * Requires inpatient hospitalization or prolongation of existing hospitalization. * Results in persistent or significant disability/incapacity. * Is a congenital anomaly/birth defect. * Is an important medical event.
Time frame: From first administration of study drug in the extension period until 30 days after last dose. Median duration of treatment was 50 weeks in the GM-CSF group and 36 weeks in the talimogene laherparepvec group.
Population: Safety population (randomized participants who received at least one dose of extension treatment).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GM-CSF | Number of Participants With Treatment-emergent Adverse Events (AEs) | All adverse events | 3 participants |
| GM-CSF | Number of Participants With Treatment-emergent Adverse Events (AEs) | Worst grade of 3 | 0 participants |
| GM-CSF | Number of Participants With Treatment-emergent Adverse Events (AEs) | Worst grade of 4 | 0 participants |
| GM-CSF | Number of Participants With Treatment-emergent Adverse Events (AEs) | Worst grade of 5 | 0 participants |
| GM-CSF | Number of Participants With Treatment-emergent Adverse Events (AEs) | Serious adverse events | 0 participants |
| GM-CSF | Number of Participants With Treatment-emergent Adverse Events (AEs) | Treatment-related adverse events | 3 participants |
| GM-CSF | Number of Participants With Treatment-emergent Adverse Events (AEs) | Treatment-related serious adverse events | 0 participants |
| GM-CSF | Number of Participants With Treatment-emergent Adverse Events (AEs) | Leading to discontinuation of study treatment | 0 participants |
| GM-CSF | Number of Participants With Treatment-emergent Adverse Events (AEs) | Leading to study treatment delay | 0 participants |
| GM-CSF | Number of Participants With Treatment-emergent Adverse Events (AEs) | Fatal adverse events on-study | 0 participants |
| Talimogene Laherparepvec | Number of Participants With Treatment-emergent Adverse Events (AEs) | Leading to discontinuation of study treatment | 4 participants |
| Talimogene Laherparepvec | Number of Participants With Treatment-emergent Adverse Events (AEs) | All adverse events | 26 participants |
| Talimogene Laherparepvec | Number of Participants With Treatment-emergent Adverse Events (AEs) | Treatment-related adverse events | 20 participants |
| Talimogene Laherparepvec | Number of Participants With Treatment-emergent Adverse Events (AEs) | Worst grade of 3 | 5 participants |
| Talimogene Laherparepvec | Number of Participants With Treatment-emergent Adverse Events (AEs) | Fatal adverse events on-study | 2 participants |
| Talimogene Laherparepvec | Number of Participants With Treatment-emergent Adverse Events (AEs) | Worst grade of 4 | 1 participants |
| Talimogene Laherparepvec | Number of Participants With Treatment-emergent Adverse Events (AEs) | Treatment-related serious adverse events | 1 participants |
| Talimogene Laherparepvec | Number of Participants With Treatment-emergent Adverse Events (AEs) | Worst grade of 5 | 2 participants |
| Talimogene Laherparepvec | Number of Participants With Treatment-emergent Adverse Events (AEs) | Leading to study treatment delay | 4 participants |
| Talimogene Laherparepvec | Number of Participants With Treatment-emergent Adverse Events (AEs) | Serious adverse events | 9 participants |
Secondary
Durable Response Rate
Durable response rate is defined as the percentage of participants with a complete response (CR) or partial response (PR) assessed by the investigator, initiating at any time while receiving talimogene laherparepvec or GM-CSF therapy on the 005/05 or the 005/05-E study and maintained continuously for at least 6 months from response initiation. This reflects all new sites of disease as well as disease sites identified at baseline. Disease assessments were performed at the beginning of each treatment cycle in accordance with modified World Health Organization criteria. CR: Disappearance of all clinical evidence of tumor (both measurable and non-measurable but evaluable disease); PR: ≥ 50% reduction in the sum of the products of the perpendicular diameters of all measurable tumors at the time of assessment as compared to baseline.
Time frame: From randomization in study 005/05 until the data-cut-off date for the extension period of 08 August 2014; median treatment duration for 005/05 and 005/05-E studies combined was 88 weeks for talimogene laherparepvec and 100 weeks for GM-CSF.
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GM-CSF | Durable Response Rate | 33.3 percentage of participants |
| Talimogene Laherparepvec | Durable Response Rate | 32.1 percentage of participants |
p-value: 195% CI: [-57.3, 54.9]Fisher Exact
Secondary
Objective Response Rate
Objective response rate was defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) assessed by the investigator. Best overall response for a patient is the best overall response observed across all time points and is cumulative (ie, includes responses during the parent study 005/05 and during Study 005/05-E). Disease assessments were performed at the beginning of each treatment cycle and assessed in accordance with modified World Health Organization criteria. CR: Disappearance of all clinical evidence of tumor (both measurable and non-measurable but evaluable disease); PR: ≥ 50% reduction in the sum of the products of the perpendicular diameters of all measurable tumors at the time of assessment as compared to baseline.
Time frame: From randomization in study 005/05 until the data-cut-off date for the extension period of 08 August 2014; median treatment duration for 005/05 and 005/05-E studies combined was 88 weeks for talimogene laherparepvec and 100 weeks for GM-CSF.
Population: The full analysis set for the extension study is defined as all participants who received at least one dose of extension treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GM-CSF | Objective Response Rate | 100.0 percentage of participants |
| Talimogene Laherparepvec | Objective Response Rate | 57.1 percentage of participants |
p-value: 0.2645Fisher Exact