Study of Talimogene Laherparepvec With Atezolizumab for Triple Negative Breast Cancer and Colorectal Cancer With Liver Metastases

Phase 1

Completed

Conditions: Metastatic Triple Negative Breast Cancer
Metastatic Colorectal Cancer

Interventions: Biological: Talimogene Laherparepvec
Biological: Atezolizumab

Registration Number: NCT03256344

Lead Sponsor: Amgen

Brief Summary: Approximately 36 DLT-evaluable subjects will be enrolled in this study. The locations of the study will be in the United States, Australia, Europe and Switzerland.

The goal of this study is to evaluate the safety of intrahepatic injection (directly into the liver) of talimogene laherparepvec in combination with intravenously administered atezolizumab in subjects with triple negative breast cancer and colorectal cancer with liver metastases.

Detailed Description: The Screening period is 28 days prior to study enrollment. This study has 2 Cohorts. Cohort 1: Triple Negative Breast Cancer and Cohort 2: Colorectal Cancer. These cohorts will enroll in parallel. There will be a Safety Follow-up period and a Long Term Follow-up period.

Drug Administration: The participants will receive the study drugs in cycles. If the participants are found to be eligible to take part in this study, they will receive talimogene laherparepvec as an injection into the hepatic (liver) metastatic sites on Day 1 of each cycle along with receiving atezolizumab by intravenous infusion on Day 1 of each cycle. Each cycle is 21 days for 6 cycles. There is an option for an additional 6 cycles after the first 6 intra-hepatic cycles. After the first radiographic assessment at week 10, if all injectable liver lesions have been injected but the 4.0 mL maximum volume has not been used, injection of clinically assessed non-hepatic cutaneous, subcutaneous, and nodal tumor lesions with or without ultrasound guidance will be permitted. Liver lesions should be prioritized over cutaneous, subcutaneous and nodal lesions.

Treatment will continue until a participant experiences a DLT (Dose Limiting Toxicity) evaluated in the DLT period (which is 2 cycles from initial dose), has CR (Complete Response), has need for an alternative anticancer therapy or experiences a safety concern.

Study Visits: Cycle 1 to Cycle 12 - The participant will have a physical exam along with vital signs and ECOG (Eastern Cooperative Oncology Group) performance level assessment. Blood (about 2 Tablespoons) will be drawn for routine tests and to check the immune system. Adverse events and medications taken will be reviewed on each cycle.Biomarkers will be taken on cycles 1, 2, 3, 6, and safety FU. Tumor Markers (special lab tests associated with the cancer, such as particular proteins) will be completed will be take on cycles 1, 4, 7, 10, 13, every 3 cycles and SFU.

Central lab tests will be completed on cycles 1, 2, 3, and 6 and safety FU. Cycle 1 Archived (prior stored) tumor sample will be obtained. Also, a liver tumor biopsy will be completed at Cycles 1, 3 and 6.

Response Assessments will be completed at Screening and again at Cycles 4, 7, 10, 13 and every 3 cycles.

Throughout the trial a swab for Herpetic tumor will be obtained within 3 days of the event.

Cycle 1 to 12- The exposure to talimogene laherparepvec by the subject's healthcare provider and household member caregiver will be reviewed. Cycles 1, 3, 6-Liver tumor biopsy will be completed. Cycles 4, 7, 10, 13 and every 3 cycles -Response assessments will be completed by radiographic and clinical tumor assessment.

Length of Treatment:

A maximum for 12 cycles of talimogene laherparepvec are allowed during the study. The participant may continue taking the study drug for as long as the doctor thinks it is in their best interest. The participant will no longer be able to take the study drug if the disease gets worse, or if they are unable to follow study directions.

Safety Follow-up Visit:

Safety Follow-up visit will be performed about 30 days after the last dose of study treatment.

The participant will have a physical exam, have vital signs taken, assessment of ECOG status and have weight measured. Adverse events will be assessed as well as the concominant medications. Routine bloodwork and tumor markers will be taken.

Exposure to talimogene laherparepvec by the healthcare providers of the participant and/or close contacts will be assessed.

Long-Term Follow-up Visits: Participants will be followed for survival every 12 weeks from the date of the safety follow-up visit until approximately 24 months after the last subject is enrolled. Subsequent cancer treatments will be collected as part of the long-term follow-up survival assessment. This is an investigational study. The study doctor can explain how the study drugs are designed to work.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 36

Inclusion Criteria

Criteria1, Participant provided informed consent prior to any study-specific activities/procedures.
Criteria 2, Confirmation of triple negative breast cancer or colorectal cancer with liver metastases by laboratory testing.
Criteria 3, Subjects with triple negative breast cancer with liver metastases, or subjects with colorectal cancer with liver metastases are eligible if they have had disease progression during or after one or more prior standard of care systemic anti-cancer therapy (eg,chemotherapy, targeted therapy) for metastatic disease or if they progress during or within 6 months of receiving adjuvant therapy. If subjects, in the opinion of the investigator, are deemed not appropriate candidates for systemic anti-cancer therapy for metastatic disease or if they refuse systemic anti-cancer therapy for metastatic disease, they may be eligible after investigator discussion with Sponsor medical monitor for approval.
Criteria 4, Participants have measurable disease which is equal to one or more metastatic liver lesions that can be accurately and serially measured that are greater than or equal to 1 cm dimension and for which the longest diameter is greater or equal to 1 cm as measured by CT (Computed Tomography) scan or magnetic resonance imaging. The metastatic liver lesion(s) must not be in an area that received prior localized therapies.
Criteria 5, Metastatic liver lesions for injection must be without necrosis (dead tissue )and must be be located where any tumor swelling will not lead to gall bladder tract obstruction or lead to bleeding risk.
Criteria 6, Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1.
Criteria 7, Life expectancy greater than or equal to 5 months.
Criteria 8, Adequate organ function within 4 weeks prior to enrollment. This includes hematology, renal, hepatic and blood-clotting functions as defined by protocol.
Criteria 9, Female subjects of childbearing potential should have a negative serum pregnancy test within 1 week prior to enrollment.
Criteria 10, Other Inclusion Criteria May Apply.

Exclusion criteria:

Criteria 1, Participant is a candidate for hepatic surgery or local regional therapy of liver metastases with curative intent.
Criteria 2, More than one third of the liver is estimated to be involved with metastases.
Criteria 3, There is invasion by cancer into the main blood vessels such as the portal vein, hepatic vein or the vena cava.
Criteria 4, Participant is currently receiving or has received liver metastatic-directed therapy ( eg: radiation, ablation, embolization) less than 4 wks prior to enrollment or hepatic surgery.
Criteria 5, History of other malignancy within the past 5 years prior to enrollment with some exceptions, as outlined in the protocol.
Criteria 6, Active or untreated central nervous system (CNS) metastases per CT or magnetic resonance imagine (MRI) evaluation during screening.
Participants with a history of CNS metastases are eligible provided they are stable and meet the criteria details in the protocol.
Criteria 7, Other Medical Conditions as noted in the protocol.
Criteria 8, Other Exclusion Criteria May Apply.

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Talimogene Laherparepvec with Atezolizumab: Triple Negative Breast Cancer (TNBC)	Talimogene Laherparepvec	Participants with TNBC with liver metastases administered intrahepatic injection of talimogene laherparepvec into liver metastases via guided injection (either ultrasound or computerized tomography) on Day 1 of each cycle for a maximum of 12 cycles, where each cycle is 21 days. Participants administered 10\^6 plaque-forming units/milliliter (PFU/mL) on Day 1 of Cycle 1 and 10\^8 PFU/mL on Day 1 of each cycle thereafter. Participants also administered 1200 mg atezolizumab via intravenous injection on Day 1 of each cycle.
Talimogene Laherparepvec with Atezolizumab: Colorectal Cancer (CRC)	Talimogene Laherparepvec	Participants with CRC with liver metastases administered intrahepatic injection of talimogene laherparepvec into liver metastases via guided injection (either ultrasound or computerized tomography) on Day 1 of each cycle for a maximum of 12 cycles, where each cycle is 21 days. Participants administered 10\^6 PFU/mL on Day 1 of Cycle 1 and 10\^8 PFU/mL on Day 1 of each cycle thereafter. Participants also administered 1200 mg atezolizumab via intravenous injection on Day 1 of each cycle.
Talimogene Laherparepvec with Atezolizumab: Triple Negative Breast Cancer (TNBC)	Atezolizumab	Participants with TNBC with liver metastases administered intrahepatic injection of talimogene laherparepvec into liver metastases via guided injection (either ultrasound or computerized tomography) on Day 1 of each cycle for a maximum of 12 cycles, where each cycle is 21 days. Participants administered 10\^6 plaque-forming units/milliliter (PFU/mL) on Day 1 of Cycle 1 and 10\^8 PFU/mL on Day 1 of each cycle thereafter. Participants also administered 1200 mg atezolizumab via intravenous injection on Day 1 of each cycle.
Talimogene Laherparepvec with Atezolizumab: Colorectal Cancer (CRC)	Atezolizumab	Participants with CRC with liver metastases administered intrahepatic injection of talimogene laherparepvec into liver metastases via guided injection (either ultrasound or computerized tomography) on Day 1 of each cycle for a maximum of 12 cycles, where each cycle is 21 days. Participants administered 10\^6 PFU/mL on Day 1 of Cycle 1 and 10\^8 PFU/mL on Day 1 of each cycle thereafter. Participants also administered 1200 mg atezolizumab via intravenous injection on Day 1 of each cycle.

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Experienced a Dose-Limiting Toxicity (DLT)	From Day 1 up to the start of Cycle 3 (each cycle is 21 days)	Toxicities were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. A DLT was considered as any of the below, if judged by the investigator to be related to either treatment: * Grade ≥ 4 neutropenia (absolute neutrophil count \[ANC\] \< 500/μl) lasting ≥ 7 days * Grade ≥ 3 febrile neutropenia * Grade ≥ 4 thrombocytopenia * Grade ≥ 4 anemia * Grade ≥ 4 rash * Serious herpetic events * Grade ≥ 3 symptomatic hepatic toxicities that do not resolve to Grade ≤ 2 within 48 hours or Grade ≥ 3 asymptomatic hepatic toxicities that do not resolve to Grade ≤ 1 within 3 weeks of onset * Grade ≥ 3 non-hematologic, non-hepatic organ toxicity * Grade 5 toxicity (ie, death) * Any other intolerable toxicity leading to permanent discontinuation of treatment DLTs were to occur within the DLT evaluation period, defined as the period between the initial 10\^6 PFU/mL dose and 3 weeks following the initial 10\^8 PFU/mL dose or the start of Cycle 3, whichever occurred first.

Secondary Outcome Measures

Name	Time	Method
Lesion Level Response in Injected Tumor Lesions	Every 12 weeks (± 28 days) up to approximately 3.5 years.	Responses for individual tumor lesions for hepatic and non-hepatic tumors injected wtih treatment were assessed for the following responses: * Lesion complete response rate (L-CRR): Disappearance of lesion * Lesion partial response rate (L-PRR): Decrease in tumor burden 30% or more relative to baseline * Lesion objective response rate (L-ORR): Either a L-CRR or L-PRR based on modified irRC-RECIST criteria
Objective Response Rate (ORR)	Every 12 weeks (± 28 days) up to approximately 3.5 years.	ORR was defined as the incidence rate of either a complete response (CR) or partial response (PR) based on modified immune-related response criteria simulating Response Evaluation Criteria in Solid Tumors(irRC-RECIST) criteria. A CR was a complete disappearance of all lesions and a PR was a decrease in tumor burden 30% or more relative to baseline.
Best Overall Response (BOR)	Every 12 weeks (± 28 days) up to approximately 3.5 years.	BOR was defined as the best visit response based on modified irRC-RECIST criteria: * CR: a complete disappearance of all lesions * PR: a decrease in tumor burden 30% or more relative to baseline * Stable disease (SD): neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for progressive disease (PD) * PD: an increase in tumor burden of 20% or more and at least 5 mm absolute increase relative to nadir (minimum recorded tumor burden) * Unevaluable (UE): any lesion present at baseline which was not assessed or was unable to be evaluated leading to an inability to determine the status of that particular tumor
Duration of Response (DOR)	Every 12 weeks (± 28 days) up to approximately 3.5 years.	DOR was defined as the time from the date of an initial response that is subsequently confirmed to the earlier of PD per modified irRC RECIST or death. Participants who have not ended their response at the time of analysis were censored at the last evaluable tumor assessment.
Lesion Level Response in Uninjected Tumor Lesions	Every 12 weeks (± 28 days) up to approximately 3.5 years.	Responses for individual tumor lesions for hepatic and non-hepatic tumors that were not injected with treatment were assessed for the following responses: * L-CRR: Disappearance of lesion * L-PRR: Decrease in tumor burden 30% or more relative to baseline * L-ORR: Either a L-CRR or L-PRR based on modified irRC-RECIST criteria
Overall Survival (OS)	Every 12 weeks (± 28 days) up to approximately 3.5 years.	OS was defined as the time from the date of first dose to the date of death from any cause. Results were estimated using the Kaplan-Meier method.
Durable Response Rate (DRR)	Every 12 weeks (± 28 days) up to approximately 3.5 years.	DRR was defined as the percentage of participants with an objective response with a DOR of at least 6 months.
Disease Control Rate (DCR)	Every 12 weeks (± 28 days) up to approximately 3.5 years.	DCR was defined as the percentage of participants that have a best overall response in one of the following categories: CR/PR/SD.
Progression-free Survival (PFS)	Every 12 weeks (± 28 days) up to approximately 3.5 years.	PFS was defined as time from first dose to the date of first of confirmed disease progression per modified irRC-RECIST criteria, or death (whichever occurred first). Results were estimated using the Kaplan-Meier method.

Trial Locations

Locations (17): Columbia University Medical Center
🇺🇸
New York, New York, United States
University of California Los Angeles
🇺🇸
Los Angeles, California, United States
Liverpool Hospital
🇦🇺
Liverpool, New South Wales, Australia
Stony Brook University
🇺🇸
Stony Brook, New York, United States
UniversitÃ¤tsklinikum Bonn
🇩🇪
Bonn, Germany
Charite UniversitÃ¤tsmedizin Berlin, CharitÃ© Campus Virchow-Klinikum
🇩🇪
Berlin, Germany
UniversitÃ¤tsklinik TÃ¼bingen
🇩🇪
TÃ¼bingen, Germany
Hospital del Mar
🇪🇸
Barcelona, CataluÃ±a, Spain
Hospital General Universitario Gregorio MaraÃ±on
🇪🇸
Madrid, Spain
Hospital Universitario Ramon y Cajal
🇪🇸
Madrid, Spain
Fiona Stanley Hospital
🇦🇺
Murdoch, Western Australia, Australia
Breast Cancer Research Centre - WA
🇦🇺
Nedlands, Western Australia, Australia
Universitair Ziekenhuis Gent
🇧🇪
Gent, Belgium
Monash Medical Centre
🇦🇺
Clayton, Victoria, Australia
Hopitaux Universitaires de Geneve
🇨🇭
Geneva 14, Switzerland
Universite Catholique de Louvain Cliniques Universitaires Saint Luc
🇧🇪
Bruxelles, Belgium
Inselspital Bern
🇨🇭
Bern, Switzerland