Study of Talimogene Laherparepvec In Children With Advanced Non CNS Tumors

Study Overview
=================
Brief Summary
-----------------
This is a phase 1 study to evaluate the safety of intralesional talimogene laherparepvec administration in pediatric subjects with advanced non-CNS tumors that are amenable to direct injection

Detailed Description
-----------------
This is a phase 1, multicenter, open-label study of talimogene laherparepvec in pediatric subjects with advanced non-CNS tumors that are amenable to direct injection in the clinical setting. Approximately 18 - 24 pediatric subjects are expected to be enrolled and treated with at least 1 dose of talimogene laherparepvec into 2 cohorts stratified by age. DLT will be evaluated based on at least 9 DLT-evaluable subjects in cohort A1. The DLT evaluation period is 35 days from the initial administration of talimogene laherparepvec.

Official Title
-----------------
A Phase 1, Multi-center, Open-label, Dose De-escalation Study to Evaluate the Safety and Efficacy of Talimogene Laherparepvec in Pediatric Subjects With Advanced Non Central Nervous System Tumors That Are Amenable to Direct Injection

Conditions
-----------------
Advanced Non CNS Tumors

Intervention / Treatment
-----------------
* Drug: Talimogene Laherparepvec


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Subject's legally acceptable representative has provided informed consent/assent when the subject is legally too young to provide informed consent/assent and the subject has provided written assent based on local regulations and/or guidelines prior to any study-specific activities/procedures being initiated. Should be willing to submit local HSV-1 serostatus within 28 days prior to enrollment. Subject must be a candidate for intralesional injection, defined as one or more of the following: at least 1 injectable lesion ≥ 10 mm in longest diameter multiple injectable lesions that in aggregate have a longest diameter of ≥ 10 mm Life expectancy > 4 months from the date of enrollment. Male or female subjects 2 to ≤ 21 years of age at the time of informed consent/assent. Histologically or cytologically confirmed non-CNS solid tumor that recurred after standard/frontline therapy, or for which there is no standard/frontline therapy available. Presence of measurable or non-measurable lesions as defined by irRC-RECIST Performance status as per protocol Female subject of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to dosing. Adequate organ function as defined in protocol •Exclusion Criteria Diagnosis of leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, or other hematologic malignancy. Radiotherapy to the bone marrow within 6 weeks prior to enrollment OR within 3 months prior to enrollment if prior radiotherapy to the craniospinal axis or to at least 60% of the pelvis was received; within 2 weeks prior to enrollment if local palliative radiotherapy was received. Primary ocular or mucosal melanoma. History of other malignancy within the past 5 years with the following exception: • malignancy treated with curative intent and with no known active disease present and has not received chemotherapy for > 5 years before enrolment and felt to be at low risk for recurrence by the treating physician. History or evidence of active autoimmune disease that requires systemic treatment (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Active herpetic skin lesions or prior complications of herpetic infection (eg, herpetic keratitis or encephalitis). Prior treatment with talimogene laherparepvec or any other oncolytic virus. Prior treatment with a tumor vaccine. Requires intermittent or chronic treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use. Expected to require other cancer therapy while on study with the exception of local palliative radiation treatment. Has acute or chronic active hepatitis B virus or hepatitis C virus infection or received treatment with nucleotide analogs such as those used in the treatment of hepatitis B virus (eg, lamivudine, adefovir, tenofovir, telbivudine, and entecavir), ribavirin, or interferon alpha within 12 weeks of initiation of study treatment. Known or suspected human immunodeficiency virus (HIV) infection. Received live vaccine within 28 days prior to enrollment. No antiplatelet or anticoagulation medications allowed within 7 days prior totalimogene laherparepvec injection except low-dose heparin needed to maintain venous catheter patency. 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. Note: Acceptable methods of effective contraception are defined in the informed consent/assent form. Where required by local laws and regulations, additional country-specific contraception requirements may be outlined in a country-specific protocol supplement at the end of the Appendix Section of protocol. 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 and investigator's knowledge. History or evidence of any psychiatric disorder, substance abuse or 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. 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 28 days after the last dose of talimogene laherparepvec. 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 prior to enrollment), including oral steroid doses (with the exception of maintenance physiologic replacement). Subjects who require intermittent use of steroids for inhalation or local steroid injection will not be excluded from the study less than 6 months from autologous bone marrow transplant or stem cell infusion history of allogeneic bone marrow transplant History or evidence of xeroderma pigmentosum. Sexually active subjects and their partners unwilling to use a 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. For those with latex allergies, polyurethane condoms may be used. Prior chemotherapy, treatment dose radiotherapy, or biological cancer therapy within 14 days prior to enrollment or has not recovered to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE) grade 1 or better from adverse event due to cancer therapy administered more than 14 days prior to enrollment. CNS tumor or clinically active brain metastases (patient with a history of treated brain metastases are eligible if there is radiographic evidence of improvement upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study). Currently receiving treatment in another investigational device or drug study, or less than 14 days since ending treatment on another investigational device or drug study(ies) or has not recovered to CTCAE version 4.0 grade 1 or better from adverse event due to other investigational device or drug study administered more than 14 days prior to enrollment. Other investigational procedures while participating in this study are excluded. Major surgery ≤ 14 days prior to enrollment or has not recovered to CTCAE version 4.0 grade 1 or better from adverse event due to surgery performed more than 14 days prior to enrollment.

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Approximately 18 to 24 treated pediatric subjects are expected to be enrolled into 2 cohorts stratified by age (permissible based on the incidence of DLTs, a minimum of 6 subjects/cohort and a minimum of 18 subjects total). Cohort A1 (12 to ≤ 21 years of age) Cohort B1 (2 to < 12 years of age) Initially, 3 subjects 12 to ≤ 21 years of age are to be enrolled and treated at 100% of the recommended adult dose regimen of talimogene laherparepvec (cohort A1). The dose level review team (DLRT) will review the safety data of the first 3 subjects in the older age cohort A1 to decide if the younger age cohort B1 can be opened for enrollment. If a DLT occurs in the first 3 DLT-evaluable subjects in the older age cohort (A1 or A2), the younger age cohort will not open until a DLT rate < 33% is observed with at least 6 DLT-evaluable subjects in the older age cohort (A1 or A2).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Talimogene Laherparepvec (TVEC)<br>The first dose of talimogene laherparepvec will be administered at a dose of up to 4.0 mL of 10ᶺ6 PFU/mL followed by a dose of up to 4.0 mL of 10ᶺ8 PFU/mL 21 days (+3 days) later. Subsequent doses of up to 4.0 mL of 10ᶺ8 PFU/mL will be administered every 14 days (± 3 days) thereafter. Cohorts will be assigned as follows: Cohort A1 (age 12 to ≤ 21 years). Cohort B1 (age 2 to < 12 years). The DLRT will review the safety data of the first 3 subjects in the older age cohort A1 to decide if the younger age cohort B1 can be opened for enrollment. If dose de-escalation is needed and if permissible based on the incidence of DLTs, additional DLT-evaluable subjects will be enrolled and treated at a lower dose level of talimogene laherparepvec. Dose de-escalation cohorts will be assigned as follows and the same DLT rules will be applied: Cohort A2 (age 12 to ≤ 21 years), Cohort B2 (age 2 to < 12 years). | Drug: Talimogene Laherparepvec<br>* Talimogene laherparepvec will be administered by intralesional injection only into injectable cutaneous, subcutaneous, nodal tumors, and other non-visceral tumors with or without image ultrasound guidance. The first dose of talimogene laherparepvec will be up to 4.0 mL of 10^6 PFU/mL administered on day 1. The second injection, up to 4.0 mL of 10^8 PFU/mL (or up to 4.0 mL of 10^6 PFU/mL for a dose de-escalated cohort), will be administered 21 (+3) days after the initial injection. All subsequent injections, up to 4.0 mL of 10^8 PFU/mL (or up to 4.0 mL of 10^6 PFU/mL for a dose de-escalated cohort), will be administered every 14 (± 3) days. The treatment cycle interval may be increased due to toxicity.<br>* Other names: TVEC;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subject incidence of DLT | To evaluate the safety of talimogene laherparepvec, as assessed by incidence of dose-limiting toxicities (DLT). | At least 35 days from administration of talimogene laherpaprevec. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subject incidence of adverse events. |  | Start of treatment through 30 (+7) days after end of treatment. | 
| Subject incidence of laboratory abnormalities |  | Start of treatment through 30 (+7) days after end of treatment. | 
| Overall Response Rate (ORR) | Response evaluation by Investigator using irRC-RECIST. | Up to 24 months of treatment. | 
| Duration of Response (DOR) | Response evaluation by Investigator using irRC-RECIST. | Up to 24 months of treatment | 
| Time to Response (TTR) | Response evaluation by Investigator using irRC-RECIST. | Up to 24 months of treatment | 
| Time to Progression (TTP) | Response evaluation by Investigator using irRC-RECIST. | Up to 24 months of treatment | 
| Progression-free Survival (PFS) | Response evaluation by Investigator using irRC-RECIST. | Up to 24 months of treatment | 
| Overall Survival (OS) |  | Up to 24 months of treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Non CNS Tumor