| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresected, Stage IIIB-IV Melanoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1b: To determine the safety and tolerability of talimogene laherparepvec in combination with ipilimumab as assessed by incidence of dose-limiting toxicities (DLT) in subjects with previously untreated, unresected, stages IIIB to IV melanoma.
Phase 2: To evaluate the efficacy as assessed by confirmed objective response rate (ORR) of treatment with talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in subjects with unresected, stages IIIB to IV melanoma. |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1b:
• Estimate efficacy of talimogene laherparepvec in combination with ipilimumab determined by ORR
• Assess safety of talimogene laherparepvec in combination with ipilimumab as determined by incidence of all AEs,grade ≥ 3 AEs,SAEs& events requiring discontinuation of study drug,local effects on the tumor,clinically significant laboratory changes&clinically significant changes in vital signs not defined as DLT
Phase 2:
• Evaluate efficacy of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone as determined by BOR,DCR, DRR, TTR, DOR, PFS, resection rate, OS, landmark OS by year
• Assess safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone as determined by incidence of all AEs,grade ≥ 3AEs,SAEs,and events requiring discontinuation of study drug,local effects on the tumor,clinically significant laboratory changes, and clinically significant changes in vital signs |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
4.1.1 Subject has provided informed consent
4.1.2 Histologically confirmed diagnosis of malignant melanoma
4.1.3 Stage IIIB, IIIC, IVM1a, IVM1b, or IVM1c disease that is not suitable for surgical resection
4.1.4 Phase 1b: Treatment naïve: Must not have received any prior systemic anticancer treatment consisting of chemotherapy, immunotherapy, or targeted therapy for unresected stage IIIB to IV melanoma. Note: Subjects who received prior adjuvant therapy for melanoma will not be excluded. However, if the subject received adjuvant therapy, the subject must have completed therapy at least 6 months prior to enrollment. No prior talimogene laherparepvec, ipilimumab, other CTLA-4 inhibitors , programmed death-1 (PD-1) inhibitors, or tumor vaccine is allowed, even if given in the adjuvant setting.
4.1.5 Phase 2:
• Either treatment naïve or received only one line of systemic
anticancer therapy if BRAF wild-type or up to two lines of systemic
anticancer therapy including one BRAF inhibitor-containing regimen
if BRAF mutant. Treatments given in an adjuvant setting (eg, interferon, radiotherapy, isolated limb perfusion, or investigational agents) are not considered as prior lines of therapy.
No prior talimogene laherparepvec, other oncolytic virus therapies,
or tumor vaccines are allowed, even if given in the adjuvant setting.
• Subjects treated with prior ipilimumab must have had PR, CR, or at
least 6 months of stable disease followed by disease progression
• Subjects previously treated with anti-PD1 or anti-CTLA-4 antibodies
must not have discontinued therapy due to any treatment-related
adverse events including immune-related adverse events. Prior
treatment-related adverse events should also be fully resolved and
not requiring treatment for at least 28 days prior to randomization.
4.1.6 Measurable disease defined as one or both of the following:
• at least 1 melanoma lesion that can be accurately and serially measured in at least 2 dimensions and for which the longest diameter is ≥ 10 mm and with perpendicular diameter ≥ 5 mm as measured by
contrast-enhanced or spiral computed tomography (CT) scan for visceral or nodal/soft tissue disease. Lymph nodes must measure > 15 mm in their short axis to be considered measurable by CT scan.
• at least 1 superficial cutaneous or subcutaneous melanoma lesion that can be accurately and serially measured in at least 2 dimensions
and for which the short axis is ≥ 5 mm as measured by calipers
4.1.7 Injectable disease (ie, suitable for direct injection or through the use of ultrasound [US] guidance) defined as follows:
• at least 1 injectable cutaneous, subcutaneous, or nodal melanoma
lesion ≥ 5 mm in longest diameter
4.1.8 Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
4.1.9 Male or female, age ≥ 18 years
4.1.10 Adequate hematologic, hepatic, renal, and coagulation functions as described in the protocol Section 4.1 |
|
| E.4 | Principal exclusion criteria |
4.2.1 Primary uveal or mucosal melanoma
4.2.2 History/evidence of melanoma associated with immunodeficiency states (eg, hereditary immune deficiency, organ transplant, or leukemia)
4.2.3 Phase 1b:History/evidence of central nervous system (CNS) metastases
4.2.4 Phase 2: Clinically active cerebral melanoma metastases.Subjects with up to 3 cerebral metastases,&neurological performance status
of 0 may be enrolled, provided that all lesions have been adequately treated with stereotactic radiation therapy,craniotomy,or Gamma knife therapy, with no evidence of progression, and have not required steroids,for at least 2 months prior to enrollment.
4.2.5 History of other malignancy within the past 3yrs with exceptions (details in protocol)
4.2.6 History or evidence of symptomatic autoimmune disease (such as pneumonitis, glomerulonephritis, vasculitis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, scleroderma, or other), or history of autoimmune disease that required systemic treatment (ie, use of corticosteroids, immunosuppressive drugs or biological agents used for treatment of autoimmune diseases) in past 2 months prior to enrollment. Replacement therapy (eg, thyroxine for hypothyroidism, insulin for diabetes mellitus) is not considered a form of systemic treatment for autoimmune disease.
4.2.7 Evidence of clinically significant immunosuppression for any reason (see details in protocol)
4.2.8 Active herpetic skin lesions or prior complications of HSV-1 infection (eg, herpetic keratitis or encephalitis)
4.2.9 Requires intermittent or chronic systemic (intravenous or oral) treatment with antiherpetic drug(eg,acyclovir),other than intermittent topical use 4.2.11 Known HIV disease (if clinically suspected HIV infection,subject requires negative test)
4.2.12 Known acute or chronic hepatitis B or C infection (if clinically suspected hepatitis B or C infection,subject requires negative test. However,if positive results are not indicative of true active/chronic infection,subject may be enrolled/randomized after approval is obtained from Amgen medical monitor).
4.2.13 Female subject is pregnant/breast-feeding/planning to become pregnant during study treatment and through 3mo after last dose of treatment 4.2.14 Female subject of childbearing potential who is unwilling to use acceptable methods of effective contraception during study treatment and through 3mo after last dose of talimogene laherparepvec/ipilimumab,whichever is later.
4.2.15 Male subject who is unwilling to use acceptable method of effective contraception during ipilimumab treatment&through 3 months after the last dose of ipilimumab
4.2.16 Phase 1b: Prior talimogene laherparepvec, ipilimumab,other CTLA-4 inhibitors,PD-1 inhibitors,or tumor vaccine
4.2.17 Phase 2: Prior talimogene laherparepvec,other oncolytic virus therapies,or tumor vaccines
4.2.18 Currently receiving or less than 28days since ending systemic anticancer treatment consisting of chemotherapy,immunotherapy,or targeted therapy for unresected stage IIIB-IV melanoma
4.2.19 Currently receiving treatment in another investigational device or drug study,or less than 30days since ending treatment on another investigational device or drug study(s)
4.2.20 Other investigational procedures while participating in this study are excluded
4.2.21 Has known sensitivity to any of the products or components to be administered during dosing
4.2.22 Previously has entered this study
4.2.23 Subject likely to not be available to complete all protocol-required study visits or procedures and/or to comply with all required study
procedures to the best of the subject and investigator's knowledge
4.2.24 History or evidence of any other clinically significant disorder, condition,or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician,if consulted,would pose a risk to subject safety or interfere with the study evaluation, procedures or completion
4.2.25 Sexually active subject who is unwilling to use a barrier method (preferably latex condom) to avoid potential viral transmission during sexual contact during and within 30 days after treatment with talimogene laherparepvec
4.2.26 Subject who is unwilling to minimize exposure with his/her blood or other body fluids to individuals who are at higher risks for HSV-1 induced complications (immunosuppressed individuals, HIV-positive individuals, pregnant women, or children under the age of 1 year) during talimogene laherparepvec treatment and through 30 days after the last dose of talimogene laherparepvec |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1b: The primary endpoint is the incidence of AEs and clinical laboratory abnormalities defined as dose limiting toxicity (DLT).
Phase 2: Objective Response Rate (ORR): Incidence rate of subjects with confirmed response (CR or PR) (response evaluation by an investigator using modified irRC). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1b
The primary analysis will occur when the last subject enrolled in the
phase 1b has had the opportunity to be on treatment for at least 6 weeks
from the initial dosing of ipilimumab.
Phase 2
The primary analysis of ORR will be conducted on both the ITT Analysis
Set approximately 6 months after the date the last subject is randomized
in the phase 2. |
|
| E.5.2 | Secondary end point(s) |
Efficacy Endpoints: For the phase 1b part, objective response rate. For the phase 2 part, best overall response, disease control rate, durable response rate, time to response, duration of response, progression-free survival, resection rate, overall survival (OS), landmark OS by year.
• Best overall response (BOR): The best overall response in descending order a subject can achieve is CR, PR, SD and PD per the modified irRC, where the SD must be no earlier than 77 days after the date of enrollment/randomization.
• Disease control rate (DCR): A confirmed CR/PR or a SD, per the modified irRC, is considered disease control.
• Durable response rate (DRR): The incidence rate of subjects with a duration of response of at least 6 months
• Time to response (TTR): Time from randomization date to the date of the first confirmed objective response (CR/PR) per the modified irRC
• Duration of response (DOR): (calculated only for those subjects with an objective response) time from first confirmed objective response to confirmed disease progression per the modified irRC or death, whichever occurs earlier.
• Progression-free survival (PFS): Time from randomization to the date of first of confirmed disease progression per modified irRC criteria,or
death, whichever occurs earlier.
• Resection rate: Incidence rate of surgical procedures for melanoma that resulted in partial reduction or complete eradication of all previously unresectable cutaneous or visceral metastatic disease. Subjects who received surgical procedures for melanoma with palliative intent (eg, for pain control) in the presence of disease progression will be excluded from the denominator.
• Overall Survival (OS): time from randomization date to the date of death from any cause.
• Landmark OS by year: The Kaplan-Meier (K-M) estimate for OS of the proportion of subjects alive at yearly intervals.
Safety Endpoints:
• For phase 2: Incidence of all AEs, grade ≥ 3 AEs, SAEs, and events requiring the discontinuation of study drug, local effects on the tumor
(ie, pain, inflammation and ulceration), clinically significant laboratory
changes and clinically significant changes in vital signs.
• For phase 1b: The same safety endpoints will be evaluated as phase 2 but not including AEs and clinical laboratory abnormalities defined as DLT. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
BOR of CR, PR, SD, PD and UE, per modified irRC, will be tabulated by treatment group. A BOR of SD, not due to unconfirmed CR or PR, will require a minimum duration of 77 days from the date of enrollment/randomization. If, at the primary analysis of ORR, the null hypothesis of no treatment effect in comparing ORR between the 2 treatment arms is rejected, OS will be compared with an un-stratified log-rank test at the study's Final Analysis (2 sided 0.05). Interim analyses of OS will be performed at the time of the ORR primary analysis and at 2 years after the last subject has been randomized. Both interim analyses will be descriptive. Analyses of time-to-event endpoints such as TTR, PFS and DOR will follow the ones described for OS, except that all
p-values will be descriptive. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The time when the last subject is assessed or receives an intervention for evaluation in the study. The end of study will occur when the last subject discontinues the study treatment and has had the opportunity to complete the safety follow-up visit or the long-term survival follow-up, whichever is later. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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