Product: Talimogene Laherparepvec Clinical Study Report: Date: 31 October 2018 Page 1

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1 Date: 31 October 2018 Page 1 2. SYNOPSIS Name of Sponsor: Amgen Inc., Thousand Oaks, CA, USA Name of Finished Product: Imlygic Name of Active Ingredient: Talimogene laherparepvec Title of Study: A Phase 2, Multicenter, Single-arm Trial to Evaluate the Biodistribution and Shedding of Talimogene Laherparepvec in Subjects with Unresected, Stage IIIB to IVM1c Melanoma Investigators and Study Centers: This study was conducted at 11 centers in the United States of America and Canada (Section ). Publications: Andtbacka RH, Mehnert J, Nemunaitis J, et al. Phase 2 Trial Evaluating Biodistribution and Shedding of Talimogene Laherparepvec in Patients With Unresectable Stage IIIB-IV Melanoma. [abstract] Mol Ther May;25(No 5S1). Abstract 16. Andtbacka RH, Mehnert J, Nemunaitis J, et al. Biodistribution and Shedding of Talimogene Laherparepvec (T-VEC) in Patients (Pts) With Unresectable Stage IIIB/IV Melanoma. [SMR Congress 2017 abstract] Pigment Cell Melanoma Res. 2018;31: Study Period: 07 April 2014 (first subject enrolled) 19 April 2018 (last subject completed follow-up) The analyses provided in this report are based on a database lock date of 22 June Development Phase: 2 Previous Reports for This Study: Primary Analysis, dated 20 October 2016; Interim report, dated 28 May 2015 Objectives and Endpoints: Objectives Primary Endpoints to estimate the proportion of subjects with detectable talimogene laherparepvec DNA in the blood and urine at any time after administration of talimogene laherparepvec within the first 3 cycles prevalence of detectable talimogene laherparepvec DNA: proportions of subjects with detectable talimogene laherparepvec DNA in the blood and urine any time after the administration of talimogene laherparepvec within the first 3 cycles

2 Date: 31 October 2018 Page 2 Objectives Secondary Endpoints to estimate the incidence of clearance of talimogene laherparepvec DNA from blood and urine overall and by baseline herpes simplex virus type 1 (HSV-1) serostatus (seronegative versus seropositive) during each of the first 3 cycles incidence of clearance of talimogene laherparepvec DNA to estimate the rate of detection and subject laherparepvec DNA and virus from exterior of occlusive dressing and surface of injected lesion viral detection on the exterior of the occlusive dressing during treatment to estimate the rate of detection and subject laherparepvec DNA and virus in oral mucosa swabs during treatment and after end of treatment viral detection from the surface of injected lesions during treatment viral detection in oral mucosa swabs during treatment viral detection in oral mucosa swabs after the end of treatment to estimate the rate of detection and subject laherparepvec DNA and virus in swabs from the anogenital area during treatment and after the end of treatment viral detection in swabs from the anogenital area during treatment viral detection in swabs from the anogenital area after the end of treatment to estimate the incidence of detection of talimogene laherparepvec DNA in lesions suspected to be herpetic in origin laherparepvec DNA detection in lesions suspected to be herpetic in origin

3 Date: 31 October 2018 Page 3 Objectives Secondary (continued) Endpoints to describe the efficacy of talimogene laherparepvec as assessed by objective response rate, best overall response rate, duration of response, and durable response rate achieved in subjects with unresected, stage IIIB to IVM1c melanoma objective response rate (ORR) (per modified World Health Organization [WHO] criteria) best overall response rate (per modified WHO criteria) duration of response time to response (TTR) durable response rate (DRR) (defined as complete response [CR] or partial response [PR] of 6 months or longer) overall survival to describe the safety profile of talimogene laherparepvec in subjects with unresected, stage IIIB to IVM1c melanoma Methodology: subject incidence of treatment-emergent and treatment-related adverse events (including all adverse events, grade 3 adverse events, serious adverse events, fatal adverse events, events of interest, adverse events requiring the discontinuation of investigational product, and clinically significant laboratory changes) This phase 2, multicenter, single-arm study was designed to investigate the biodistribution and shedding of talimogene laherparepvec in subjects with unresected, stage IIIB to IV M1c melanoma. Talimogene laherparepvec was administered by intralesional injection into injectable cutaneous, subcutaneous, and nodal lesions at an initial dose of 10 6 plaque-forming units (PFU) per ml followed by a dose of 10 8 PFU/mL 21 days after the initial dose and every 14 (± 3) days thereafter. Each injection marked the beginning of a new treatment cycle; the first cycle was 21 days in length, and subsequent cycles were 14 (± 3) days in length. Subjects were treated with talimogene laherparepvec until they achieved a complete response (CR), all injectable tumors had disappeared, clinically relevant (resulting in clinical deterioration or requiring change of therapy) disease progression per modified World Health Organization (WHO) response criteria beyond 6 months of therapy, or intolerance of study treatment, whichever occurred first. Subjects were followed for safety for up to 60 (+ 7) days at time points designated in the protocol per the schedule of assessments. Thereafter, subjects were to be followed under an ongoing separate registry protocol evaluating the long-term survival of subjects treated with talimogene laherparepvec in clinical studies (Study ). The registry protocol also monitors for late and long-term adverse events thought to be potentially related to talimogene laherparepvec and anti-cancer therapy for melanoma.

4 Date: 31 October 2018 Page 4 Samples (blood, urine, swabs from oral mucosa, swabs from the anogenital area [added as of Protocol Amendment 1 (Section of this report)], swabs from the exterior of the occlusive dressing and the surface of injected lesions, and swabs of lesions suspected to be of herpetic origin) were collected to evaluate the biodistribution and shedding of talimogene laherparepvec during the treatment period and safety follow-up at time points designated in the protocol per the schedule of assessments. Number of Subjects Planned: Approximately 50 to 60 Diagnosis and Main Criteria for Eligibility: Eligible subjects were men and women 18 years of age with a histologically confirmed diagnosis of unresected stage IIIB, IIIC, IV M1a, IV M1b, or IV M1c melanoma, regardless of prior line of therapy. Subjects were required to be candidates for intralesional therapy administration into cutaneous, subcutaneous, or nodal disease and were also required to have measurable disease, serum lactate dehydrogenase 1.5 x upper limit of normal, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate hematologic, hepatic, and renal organ function. Subjects must not have had > 3 visceral metastases (not including lung metastases or any nodal metastases associated with visceral organs) or any bone metastases, primary ocular or mucosal melanoma, history or evidence of symptomatic autoimmune pneumonitis, glomerulonephritis, vasculitis, or symptomatic autoimmune disease, or evidence of immunosuppression for any reason. Investigational Products, Dose and Mode of Administration, Manufacturing Batch Number: Talimogene laherparepvec was supplied as a sterile frozen liquid in single-use vials containing a minimum of 1.0 ml talimogene laherparepvec at concentrations of either 10 6 PFU/mL or 10 8 PFU/mL. Talimogene laherparepvec was administered by intralesional injection into injectable cutaneous, subcutaneous, and nodal lesions with or without image ultrasound guidance. The initial dose of talimogene laherparepvec was up to 4.0 ml of 10 6 PFU/mL. Subsequent doses of talimogene laherparepvec were up to 4.0 ml of 10 8 PFU/mL. The second dose was to be administered 21 (+ 5) days after the initial dose, and subsequent doses were to be given every 14 (± 3) days. Manufacturing batch numbers are provided in Section Duration of Treatment: The duration of treatment varied for each subject (see Methodology). Statistical Methods: This study was completed, and this report describes the final analysis of the study (ie, conducted after all enrolled subjects had a chance to complete their 60-day safety follow-up visit) as prespecified in the statistical analysis plan. The primary endpoint, the proportion of subjects with detectable talimogene laherparepvec DNA in blood and urine after investigational product administration during the first 3 cycles, was analyzed using the blood/urine evaluable analysis set. The point-wise exact 95% confidence intervals (CI) for the binomial proportion were provided using F-distributions. The number and proportion of subjects with clearance of talimogene laherparepvec DNA per quantitative polymerase chain reaction (qpcr) analysis at cycles 1, 2, and 3 after

5 Date: 31 October 2018 Page 5 positive qpcr testing in each cycle were summarized. Exact 95% CIs were calculated using the F-distribution. Summary statistics were calculated for the incidence (overall and by time point) of talimogene laherparepvec DNA detection (and viral detection by the 50% tissue culture infective dose [TCID 50] assay) in swabs collected from oral mucosa, the anogenital area, exterior of the occlusive dressing, and surface of injected lesions. Subject incidence was defined as the proportion of subjects having detectable talimogene laherparepvec DNA or detectable talimogene laherparepvec virus among subjects who provided samples. Rate of detection was defined as the proportion of samples exhibiting detection of talimogene laherparepvec DNA or detection of talimogene laherparepvec virus. The laherparepvec DNA detection in lesions suspected to be herpetic in origin was also summarized. Exact 95% CIs were calculated using the F-distribution. Subject incidence rates of treatment-emergent adverse events after the initiation of therapy through the 30-day safety follow-up visit were summarized. In addition, subject incidence rates of serious adverse events from the 30-day safety follow-up visit to the 60-day safety follow-up visit were summarized. Clinically significant laboratory changes and clinically significant changes in vital signs were summarized using descriptive statistics. Potential or known unintended exposure to talimogene laherparepvec, related suspected signs or symptoms, and detection of talimogene laherparepvec DNA in a subject s household member, caregiver, or healthcare provider were summarized. Summary of Results: Subject Disposition: A total of 61 subjects were enrolled at 11 centers in the United States and Canada. Sixty subjects received at least 1 dose of investigational product and were included in the safety analysis set. Baseline Demographics: Sex: men (55.0%); women (45.0%) Age: mean (standard deviation [SD]; range): 63.3 (16.7, 19 to 93) years Race: white (100.0%)Ethnicity: not Hispanic or Latino (100.0%) Disease Stage at Baseline: IIIB (16.7%); IIIC (53.3%); IVM1a (18.3%); IVM1b (5.0%); IVM1c (6.7%) ECOG Performance Status at Baseline: 0 (75.0%); 1 (25.0%) BRAF Mutation: mutation (33.3%); wild type (63.3%); other 1 (1.7%); missing 1 (1.7%) Efficacy Results: The ORR was 35.0%, including 9 subjects (15.0%) with a CR and 12 subjects (20.0%) with a PR. Median actual follow-up time was 28.9 weeks (range: 4 to 151 weeks). The median TTR (95% CI) among all subjects in the safety analysis set was 8.7 (5.3, not estimable) months. Among responders (N = 21), the median TTR was 3.1 (2.6, 5.3) months. All 21 responders were in response as of their last assessment during the study, with a median duration of response that was not reached (95% CI: not estimable not estimable), including 3 subjects (5.0%) who met the criteria for a durable response.

6 Date: 31 October 2018 Page 6 Overall survival was 100% during the study reporting period; however, there was no long-term follow-up in this study. Talimogene Laherparepvec Biodistribution and Shedding Results: As noted in the table below, the incidence of subjects and samples with detectable talimogene laherparepvec DNA (as assayed by qpcr) varied by the type of sample that was taken. Talimogene laherparepvec DNA was detected in blood in 98.3% of subjects and in urine in 31.7% of subjects. Subjects With Detectable Talimogene Laherparepvec DNA Any Time During the Study a Baseline HSV-1 Seronegativ e (N=17) b n/m (%) c Blood 17/17 (100.0) Urine 5/17 (29.4) Injected lesions Exterior of occlusive dressing Oral mucosa Anogenita l Area 17/17 (100.0) 13/17 (76.5) 4/17 (23.5) 0/7 (0.0) Baseline HSV-1 Seropositiv e (N=40) b n/m (%) c 39/40 (97.5) 14/40 (35.0) 40/40 (100.0) 33/40 (82.5) 3/40 (7.5) 5/17 (29.4) Overall (N=60) b n/m (%) c 59/60 (98.3) 19/60 (31.7) 60/60 (100.0) 48/60 (80.0) 8/60 (13.3) 5/26 (19.2) Samples With Detectable Talimogene Laherparepvec DNA Any Time During the Study a Baseline HSV-1 Seronegative n/m (%) d 136/311 (43.7) 9/308 (2.9) 168/399 (42.1) 51/289 (17.6) 8/302 (2.6) 0/123 (0.0) Baseline HSV-1 Seropositive n/m (%) d 234/728 (32.1) 22/725 (3.0) 519/1045 (49.7) 145/741 (19.6) 3/599 (0.5) 7/244 (2.9) Overall n/m (%) d 383/1094 (35.0) 31/1088 (2.8) 741/1520 (48.8) 212/108 5 (19.5) 12/964 (1.2) HSV = herpes simplex virus; qpcr = quantitative polymerase chain reaction a For oral mucosa and the anogenital area, values represent any time during treatment. b N = number of subjects in the analysis set. c n = number of subjects with positive qpcr testing result; m = number of subjects with samples collected. d n = number of samples with positive qpcr testing result; m = number of samples collected. Source: Table , Table , Table , Table , Table , Table , Table , Table , Table , Table , Table , Table /448 (1.6) The proportion of samples with detectable talimogene laherparepvec DNA in blood and urine was highest during the second cycle of treatment and was 0 at the safety follow-up visit (30 days after the end of treatment). No samples from the oral mucosa or anogenital region had detectable talimogene laherparepvec DNA after the end of treatment (at all timepoints: safety follow-up day 30, between day 30 and 60, and day 60). While talimogene laherparepvec DNA was detected in the injected lesions of all subjects at some point during the study, no samples from injected lesions were positive for talimogene laherparepvec DNA 60 (+ 7) days after the end of treatment. Overall, during the study, 3 of 19 subjects had samples from lesions of suspected herpetic origin that had detectable talimogene laherparepvec DNA. These 4 lesions

7 Date: 31 October 2018 Page 7 (located on the breast, right arm/axilla, and oral cavity) had not been injected during the study. Samples that were positive for talimogene laherparepvec DNA from the surface of injected lesions, the exterior of occlusive dressings, the oral mucosa, and lesions of suspected herpetic origin were tested for viral infectivity using the TCID 50 method. No samples from the exterior of occlusive dressings, oral mucosa, or lesions of suspected herpetic origin had detectable talimogene laherparepvec viral activity by TCID 50 assay. For injected lesions, 8 of 740 samples (1.1%) from 7 of 60 subjects (11.7%) were positive for viral activity by a TCID 50 assay. Seven of the positive samples were from cycle 1 (4 positive samples from cycle 1 day 3 and 3 positive samples from cycle 1 day 8), and 1 positive sample was from cycle 2 (day 3); no samples tested positive for viral activity by TCID 50 assay after cycle 2. Among subjects who had detectable talimogene laherparepvec DNA in the blood or urine during cycle 1, most were clear before the next dose (38 of 41 subjects [92.7%] blood; 3 of 3 [100.0%] urine). Similarly, most subjects with detectable talimogene laherparepvec DNA in the blood or urine during cycle 2 were clear before the third dose (49 of 57 subjects [86.0%] blood; 13 of 14 [92.9%] urine). Three subjects had detectable DNA in the blood during cycle 3, and 1 of these (33.3%) cleared talimogene laherparepvec DNA before the next dose. Two subjects had detectable DNA in the urine during cycle 3, and both subjects (100.0%) cleared talimogene laherparepvec DNA before the fourth dose. No subjects had detectable talimogene laherparepvec DNA in the blood or urine at the 30-day safety follow-up visit. During cycles 1 and 2, the subject incidence for talimogene laherparepvec DNA blood clearance was higher among subjects who were HSV-1 seropositive at baseline versus those who were seronegative at baseline (100% vs 78.6%, respectively, in cycle 1 and 94.7% vs 64.7% in cycle 2). Few subjects had detectable talimogene laherparepvec in urine samples; as a result, comparisons of clearance between subjects who were seropositive versus seronegative at baseline are not meaningful. Safety Results: A total of 60 subjects were treated for a mean (standard deviation [SD]) of 14.5 (11.5) visits (median [minimum, maximum]: 12 [2, 71] visits) over (23.71) weeks (median [minimum, maximum]: 23.1 [3.1, 141.1] weeks). The mean (SD) volume for the first injection was 2.62 (1.30) ml of 10 6 PFU/mL talimogene laherparepvec. For all other doses, the mean (SD) volume of injection was 2.50 (1.23) ml of 10 8 PFU/mL. Overall, 60 subjects (100%) had 1 treatment-emergent adverse event during the study, and most subjects (57 subjects [95.0%]) had 1 adverse event that was related to investigational product. The most common adverse events ( 25%) were chills (65.0%), fatigue (56.7%), headache (45.0%), nausea (45.0%), pyrexia (40.0%), injection site pain, pain, and vomiting (each in 25.0%). Of the adverse events that were grade 3 or higher in severity, the events of upper abdominal pain, delirium, and fatigue (2 subjects [3.3%] each) were reported in > 1 subject. One subject had an event of lymphopenia that was grade 4 in severity. None of the subjects had fatal adverse events. Thirteen subjects (21.7%) had 1 serious adverse events. Serious adverse events reported in > 1 subject were delirium and pyrexia (2 subjects, 3.3% each).

8 Date: 31 October 2018 Page 8 Events of interest were reported for 59 subjects (98.3%). The most common events of interest ( 20% identified by the narrow search strategy) were in the categories of flu-like symptoms (57 subjects [95.0%]), impaired wound healing (28 subjects [46.7%]), injection site reactions (28 subjects [46.7%]), rash (22 subjects [36.7%]), and hypersensitivity (19 subjects [31.7%]). Most subjects had events that were grade 1 (24 subjects [40.0%]) or grade 2 (28 subjects [46.7%]) in severity. Events of interest reported as serious included pyrexia, delirium (2 subjects each), body temperature increased, influenza-like illness, posterior reversible encephalopathy syndrome, cellulitis, congestive cardiac failure, and deep vein thrombosis (1 subject each). Conclusions: Talimogene laherparepvec biodistribution and shedding data from this final analysis were comparable with those reported previously for the primary analysis. Talimogene laherparepvec DNA was detected with the lowest frequency in samples from the oral mucosa (12 of 964 samples [1.2%] and 8 of 60 subjects [13.3%]), from the anogenital area (7 of 448 samples [1.6%] and 5 of 26 subjects [19.2%]), and in urine (31 of 1088 samples [2.8%] and 19 of 60subjects [31.7%]). In contrast, and consistent with the method of administration, talimogene laherparepvec DNA was detected with the greatest frequency in swabs of injected lesions (741 of 1520 samples [48.8%] and 60 of 60 subjects [100.0%]) and in the blood (383 of 1094 samples [35.0%] and 59 of 60 subjects [98.3%]). Most of the samples with detectable talimogene laherparepvec DNA were obtained during cycle 2 when talimogene laherparepvec was administered in concentration of 10 8 PFU/mL for the first time. Overall, 3 of 19 subjects had detectable talimogene laherparepvec DNA by qpcr testing from swabs of lesions of suspected herpetic origin; these lesions had not been injected during the study. The clearance rate of talimogene laherparepvec DNA from the blood was 92.7% before cycle 2 and 86.0% before cycle 3. The subjects who were HSV-1 seropositive at baseline had a numerically higher clearance of talimogene laherparepvec DNA from the blood during cycles 1 and 2 (100% and 94.7%, respectively), compared with subjects who were seronegative at baseline (78.6% and 64.7%, respectively). Among the swab samples collected, the incidence of viral infectivity by TCID 50 assay was low (8 of 740 samples [1.1%] and 7 of 60 subjects [11.7%]) with all positive samples obtained from injected lesions. Seven of these samples were from cycle 1, and 1 positive sample was from cycle 2; no swabs had detectable talimogene laherparepvec viral activity by TCID 50 testing after cycle 2. The ORR was 35.0%, including 9 subjects (15.0%) with a CR and 12 subjects (20.0%) with a PR. All 21 responders were continuing to respond as of their last assessment during the study, including 3 subjects (5.0%) who met the criteria for a durable response.

9 Date: 31 October 2018 Page 9 Safety data from this final analysis were comparable with those reported previously for the primary analysis including the type, frequency, and severity of adverse events, serious adverse events, and adverse events leading to discontinuation of investigational product. The most common adverse events ( 25%) were chills (65.0%), fatigue (56.7%), headache (45.0%), nausea (45.0%), pyrexia (40.0%), injection site pain, pain, and vomiting (each in 25.0%). Thirteen subjects had serious adverse events and no subjects died during the study. Serious adverse events of delirium and pyrexia were reported in 2 subjects (3.3%) each; all other serious adverse events occurred in a single subject each. The serious events were consistent with the viral nature of talimogene laherparepvec, subjects existing medical history, and/or prior therapies received.

Summary of the risk management plan (RMP) for Imlygic (talimogene laherparepvec)

EMA/713818/2015 Summary of the risk management plan (RMP) for Imlygic ( laherparepvec) This is a summary of the risk management plan (RMP) for Imlygic, which details the measures to be taken in order to