Study of Talimogene Laherparepvec In Children With Advanced Non CNS Tumors

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

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02756845

Enrollment

Registered

2016-04-29

Start date

2017-08-16

Completion date

2022-11-29

Last updated

2024-02-20

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Advanced Non CNS Tumors

Keywords

Non CNS Tumor

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.

Interventions

DRUGTalimogene Laherparepvec

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.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Intervention 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).

Eligibility

Sex/Gender

ALL

Age

2 Years to 21 Years

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants Who Experienced a Dose-limiting Toxicity (DLT)	Day 1 to Day 35	All toxicities were graded using the Common Terminology Criteria for Adverse Events version 4.0: * Grade 1: Mild * Grade 2: Moderate * Grade 3: Severe/medically significant but not immediately life-threatening * Grade 4: Life-threatening * Grade 5: Death related to adverse event The occurrence of any of the below was considered a DLT, if judged to be related to talimogene laherparepvec: * Grade 4 non-hematologic toxicity * Grade 3 non-hematologic toxicity that lasted \> 3 days despite optimal supportive care * Any ≥ grade 3 non-hematologic laboratory value if medical intervention was required, the abnormality led to hospitalization or the abnormality persisted for \> 1 week unless deemed not clinically important per both investigator & sponsor * Febrile neutropenia grade 3/4 * Thrombocytopenia \< 25 x 10\^9/L associated with bleeding event that required intervention * Serious herpetic event * Grade 5 toxicity * Any intolerable toxicity that led to permanent discontinuation of talimogene laherparepvec

Secondary

Measure	Time frame	Description
Duration of Response (DOR)	Every 12 weeks until the end of follow-up; maximum duration of follow-up was 54.51 months	DOR was defined as the time from the date of an initial response of CR or PR to the earlier of PD/death.
Time to Response (TTR)	Every 12 weeks until the end of follow-up; maximum duration of follow-up was 54.51 months	TTR was defined as the number of days from the first dose of talimogene laherparepvec to the first objective assessment of response as per modified irRC-RECIST.
Overall Response Rate (ORR)	Every 12 weeks until the end of follow-up; maximum duration of follow-up was 54.51 months	ORR was defined as the percentage of participants who experienced either complete response (CR) or partial response (PR) per modified immune-related response criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) response criteria. CR was defined as the disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment no less than 4 weeks (28 days) from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR was defined as the decrease in tumor burdena ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks (28 days) after first documentation.
Progression Free Survival (PFS)	Every 12 weeks until the end of follow-up; maximum duration of follow-up was 54.51 months	PFS was defined as the time from the first dose to the earlier of disease progression per modified irRC-RECIST or death from any cause. PFS was estimated using the Kaplan-Meier method.
Overall Survival (OS)	Every 12 weeks until the end of follow-up; maximum duration of follow-up was 54.51 months	OS was defined as as the time from first dose to the event of death from any cause. OS was estimated using the Kaplan-Meier method.
Time to Progression (TTP)	Every 12 weeks until the end of follow-up; maximum duration of follow-up was 54.51 months	TTP was defined as the time from the first dose of talimogene laherparepvec until objective tumor progression per irRC-RECIST. TTP was estimated using the Kaplan-Meier method.

Countries

Belgium, Canada, France, Italy, Spain, Switzerland, United States

Participant flow

Recruitment details

A total of 15 participants were enrolled across 11 centers in Belgium, Canada, France, Spain, Switzerland and the United States from August 2017 to November 2022.

Participants by arm

Arm	Count
Cohort A1: Talimogene Laherparepvec (TVEC) - Aged 12 to ≤ 21 Years Participants aged 12 to ≤ 21 years were administered an initial dose of talimogene laherparepvec 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) later. All subsequent injections, up to 4.0 mL of 10\^8 PFU/mL were administered every 14 (± 3) days for up to approximately 9 months. Talimogene laherparepvec was administered by intralesional injection only into injectable cutaneous, subcutaneous, nodal tumors, and other non-visceral tumors with or without image ultrasound guidance.	13
Cohort B1: Talimogene Laherparepvec (TVEC) - Aged 2 to < 12 Years Participants aged 2 to \< 12 years were administered an initial dose of talimogene laherparepvec 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) later. All subsequent injections, up to 4.0 mL of 10\^8 PFU/mL were administered every 14 (± 3) days for up to approximately 9 months. Talimogene laherparepvec was administered by intralesional injection only into injectable cutaneous, subcutaneous, nodal tumors, and other non-visceral tumors with or without image ultrasound guidance.	2
Total	15

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Death	12	2
Overall Study	Withdrawal by Subject	1	0

Baseline characteristics

Characteristic	Cohort B1: Talimogene Laherparepvec (TVEC) - Aged 2 to < 12 Years	Total	Cohort A1: Talimogene Laherparepvec (TVEC) - Aged 12 to ≤ 21 Years
Age, Continuous	9.0 years STANDARD_DEVIATION 2.8	14.3 years STANDARD_DEVIATION 3.5	15.2 years STANDARD_DEVIATION 2.8
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants	3 Participants	2 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	1 Participants	11 Participants	10 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized Other	0 Participants	3 Participants	3 Participants
Race/Ethnicity, Customized White	2 Participants	11 Participants	9 Participants
Sex: Female, Male Female	0 Participants	5 Participants	5 Participants
Sex: Female, Male Male	2 Participants	10 Participants	8 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	12 / 13	2 / 2
other Total, other adverse events	13 / 13	2 / 2
serious Total, serious adverse events	5 / 13	1 / 2

Outcome results

Primary

Percentage of Participants Who Experienced a Dose-limiting Toxicity (DLT)

All toxicities were graded using the Common Terminology Criteria for Adverse Events version 4.0: * Grade 1: Mild * Grade 2: Moderate * Grade 3: Severe/medically significant but not immediately life-threatening * Grade 4: Life-threatening * Grade 5: Death related to adverse event The occurrence of any of the below was considered a DLT, if judged to be related to talimogene laherparepvec: * Grade 4 non-hematologic toxicity * Grade 3 non-hematologic toxicity that lasted \> 3 days despite optimal supportive care * Any ≥ grade 3 non-hematologic laboratory value if medical intervention was required, the abnormality led to hospitalization or the abnormality persisted for \> 1 week unless deemed not clinically important per both investigator & sponsor * Febrile neutropenia grade 3/4 * Thrombocytopenia \< 25 x 10\^9/L associated with bleeding event that required intervention * Serious herpetic event * Grade 5 toxicity * Any intolerable toxicity that led to permanent discontinuation of talimogene laherparepvec

Time frame: Day 1 to Day 35

Population: DLT Analysis Set: all DLT evaluable participants defined as participants who had the opportunity to be followed for at least 35 days from the initial dosing of talimogene laherparepvec and received at least two treatments of talimogene laherparepvec (except participants who had a DLT after the first dose).

Arm	Measure	Group	Value (NUMBER)
Cohort A1: Talimogene Laherparepvec (TVEC) - Aged 12 to ≤ 21 Years	Percentage of Participants Who Experienced a Dose-limiting Toxicity (DLT)	Experienced a DLT	0.0 Percent of participants
Cohort A1: Talimogene Laherparepvec (TVEC) - Aged 12 to ≤ 21 Years	Percentage of Participants Who Experienced a Dose-limiting Toxicity (DLT)	Did Not Experience a DLT	100.0 Percent of participants
Cohort B1: Talimogene Laherparepvec (TVEC) - Aged 2 to < 12 Years	Percentage of Participants Who Experienced a Dose-limiting Toxicity (DLT)	Experienced a DLT	0.0 Percent of participants
Cohort B1: Talimogene Laherparepvec (TVEC) - Aged 2 to < 12 Years	Percentage of Participants Who Experienced a Dose-limiting Toxicity (DLT)	Did Not Experience a DLT	100.0 Percent of participants

Secondary

Duration of Response (DOR)

DOR was defined as the time from the date of an initial response of CR or PR to the earlier of PD/death.