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

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

A Phase 1b Study of Talimogene Laherparepvec in Combination With Atezolizumab in Subjects With Triple Negative Breast Cancer and Colorectal Cancer With Liver Metastases

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.

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.

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.

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.

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.

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.

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

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.

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

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

DRR was defined as the percentage of participants with an objective response with a DOR of at least 6 months.

DCR was defined as the percentage of participants that have a best overall response in one of the following categories: CR/PR/SD.

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.

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.

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.

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request

Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.

Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors. If not approved, a Data Sharing Independent Review Panel will arbitrate and make the final decision. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the URL below.