| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresected stage IIIB to IVM1c 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 |
| To explore the correlation between a baseline immunoprofile (ie, intratumoral CD8+ cell density) and objective response rate (ORR) in subjects with unresected stage IIIB to IVM1c melanoma treated with talimogene laherparepvec. |
|
| E.2.2 | Secondary objectives of the trial |
- to explore the correlation between a baseline immunoprofile (ie, intratumoral CD8+ cell density) and durable response rate (DRR), duration of response (DOR), and changes in tumor burden
- to explore the correlation between changes in an immunoprofile intratumoral CD8+ cell density during treatment and ORR, DRR, DOR, and changes in tumor burden
- to evaluate ORR, DOR, time to treatment failure (TTF), DRR, OS, and change in tumor burden during treatment
- to evaluate the safety and tolerability of talimogene laherparepvec |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Subject has provided informed consent prior to initiation of any study-specific activities/procedures
- Male or female age ≥ 18 years at the time of informed consent
- Histologically confirmed diagnosis of melanoma
- Subject with unresected stage IIIB to IVM1c melanoma for whom surgery is not recommended
- Subject who is treatment naïve or had received prior treatment for
melanoma. Any systemic treatment for melanoma must have been
completed at least 28 days prior to enrollment
- Candidate for intralesional therapy (ie, disease is appropriate for direct injection or through the use of ultrasound guidance) defined as one of the following:
-at least 1 injectable cutaneous, subcutaneous, or nodal melanoma lesion ≥ 10 mm in longest diameter, or
- multiple injectable melanoma lesions that in aggregate have a longest diameter of ≥ 10 mm
- Measurable disease defined as one or more of the following:
- 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, magnetic resonance imaging (MRI), or ultrasound for nodal/soft tissue disease (including lymph nodes)
- at least 1 ≥ 10 mm superficial cutaneous or subcutaneous melanoma lesion as measured by calipers
- multiple superficial melanoma lesions which in aggregate have a total diameter of ≥ 10 mm
- Serum lactate dehydrogenase (LDH) levels ≤ 1.5 X upper limit of normal (ULN) within 28 days prior to enrollment
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (see Appendix E)
- Adequate organ function determined within 28 days prior to enrollment, defined as follows:
- absolute neutrophil count ≥ 1500/mm3
- platelet count ≥ 75,000/mm3
- hemoglobin ≥ 8 g/dL without need for hematopoietic growth factor or transfusion support
- serum creatinine ≤ 1.5 x ULN
- 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 ≥ 2.5 g/dL
- prothrombin time (PT) ≤ 1.5 x ULN (or international normalization ratio [INR] ≤ 1.3)*
- partial thromboplastin time (PTT) ≤ 1.5 x ULN
|
|
| E.4 | Principal exclusion criteria |
- Clinically active cerebral metastases. Subjects with up to 3 cerebral
metastases may be enrolled, provided that all lesions have been
adequately treated with stereotactic radiation therapy (including Gamma
Knife) or resecttion, with no evidence of progression and have not
required steroids for at least two months prior to enrollment.
- Greater than 3 visceral metastases (this does not include lung
metastases or nodal metastases associated with visceral organs). For
subjects with 3 visceral metastases, no lesion > 3 cm and liver lesions
must be stable for at least 1 month prior to enrollment.
- Bone metastases
- Primary ocular or mucosal melanoma
- History or evidence of symptomatic autoimmune disease in the past 2
months prior to enrollment
- Evidence of clinically significant immunosuppression such as the
following:
- primary immunodeficiency state such as Severe Combined
Immunodeficiency Disease
- concurrent opportunistic infection
- receiving systemic immunosuppressive therapy (> 2 weeks),
including oral steroid doses > 10 mg/day of prednisone or equivalent
during the 2 months prior to enrollment
- Active herpetic skin lesions or prior complications of HSV-1 infection
(eg, herpetic keratitis or encephalitis)
- Requires intermittent or chronic systemic (intravenous or oral)
treatment with an antiherpetic drug (eg, acyclovir), other than
intermittent topical use
- Previous treatment with talimogene laherparepvec
- Currently receiving treatment with another investigational device or
drug study, or less than 28 days since ending treatment with another
investigational device or drug study(s)
- Other investigational procedures while participating in this study are
excluded
- Known to have acute or chronic active hepatitis B infection
- Known to have acute or chronic active hepatitis C infection
- Known to have human immunodeficiency virus infection
- History of other malignancy within the past 3 years with the following
exceptions:
- malignancy treated with curative intent and with no known active
disease present for ≥ 3 years before enrollment and felt to be at low risk
for recurrence by the treating physician
- adequately treated non-melanoma skin cancer without evidence of
disease
- adequately treated cervical carcinoma in situ without evidence of
disease
- adequately treated breast ductal carcinoma in situ without evidence
of disease
-prostatic intraepithelial neoplasia without evidence of prostate cancer
- adequately treated urothelial papillary noninvasive carcinoma or
carcinoma in situ
- Subject has known sensitivity to any of the products or components to
be administered during dosing
- 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's and investigator's knowledge
- 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 medical monitor, if consulted,
would pose a risk to subject safety or interfere with the study
evaluation, procedures, or completion
- Subject previously has entered this study
- Female subject is pregnant or breast-feeding, or planning to become
pregnant during study treatment and through 3 months after the last
dose of talimogene laherparepvec
- Female subject of childbearing potential who is unwilling to use
acceptable method(s) of effective contraception during study treatment
and through 3 months after the last dose of talimogene laherparepvec
-Sexually active subjects and their partners unwilling to use male or
female latex condom to avoid potential viral transmission during sexual
contact while on treatment and within 30 days after treatment with
talimogene laherparepvec |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of the study is the correlation between baseline intratumoral CD8+ cell density and objective response rate (ORR). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The timing of the primary analysis will be when all subjects have had the opportunity to complete 12 months of treatment of talimogene laherparepvec. |
|
| E.5.2 | Secondary end point(s) |
Multiple biomarkers will be examined to assess the correlation between their baseline value and DRR, DOR, and changes in tumor burden as well as the changes in their value during treatment with ORR, DRR, DOR, changes in tumor burden.
Subject incidence rates of treatment-emergent adverse events (including all adverse events, grade ≥ 3 adverse events, serious adverse events, adverse events of interest and events requiring the discontinuation of study drug,and local effects on the tumor [ie, pain, inflammation and ulceration]) will be summarized.
Clinically significant laboratory changes and clinically significant changes in vital signs will be summarized with descriptive statistics. Summary statistics will also be provided for concomitant medications, dose delay, study drug discontinuation, overall exposure, and changes in ECOG performance status. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The timing of the primary analysis will be when all subjects have had the opportunity to complete 12 months of treatment of talimogene laherparepvec. |
|
| 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 | No |
| E.6.5 | Efficacy | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 47 |
| 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 |
| Russian Federation |
| United States |
|
| 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 end of study will occur when the last subject discontinues talimogene laherparepvec and has had the opportunity to complete the safety follow-up visit or the last long term follow-up visit, whichever occurs later |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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