SBRT and Oncolytic Virus Therapy Before Pembrolizumab for Metastatic TNBC and NSCLC

NCT03004183 | Completed Phase 2 Results FDA Drug

• 1 other identifier: Pro00015649
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase II trial to determine the efficacy and safety of stereotactic body radiation therapy (SBRT) and in situ oncolytic virus therapy used as a window of opportunity treatment before pembrolizumab in patients with metastatic triple negative breast cancer (TNBC) and metastatic non-small cell lung cancer (NSCLC). In situ oncolytic virus therapy will consist of adenovirus-mediated expression of herpes simplex virus thymidine kinase (ADV/HSV-tk) plus valacyclovir therapy.

Conditions

Metastatic Non-small Cell Lung Cancer; Metastatic Triple-negative Breast Cancer

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate

  The objective response rate (ORR) of ADV/HSV-tk plus (+) valacyclovir therapy in combination with SBRT used as a window of opportunity treatment before pembrolizumab in patients with metastatic TNBC and metastatic NSCLC. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 will be used to assess treatment response. Modified immune-related response criteria (irRC; derived from RECIST 1.1) will also be documented.

  30 days after the last dose of pembrolizumab until disease progression, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-up. Median duration of follow-up was 8.3 months (95% CI 3.0-10.1 months).

Secondary Outcomes (6)

• Duration of Response

  30 days after the last dose of pembrolizumab until disease progression, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-up. Median duration of follow-up was 8.3 months (95% CI 3.0-10.1 months).

• Overall Survival Rate

  After confirmed disease progression or starts a new therapy, the subject moves into the Survival Follow-up to be contacted every 12 weeks to assess for survival status until death, withdrawal, or end of study. Median duration of follow-up was 8.3 months.

• Number of Participants With Treatment-related Adverse Events

  Adverse Events (AEs) and Serious Adverse Events (SAEs) will be captured from the time of informed consent signing up to 30 days after the final dose of pembrolizumab, (up to 24 months of treatment for patients without disease progression).

• Antitumor Activity

  30 days after the last dose of pembrolizumab

• Clinical Benefit Rate

  30 days after the last dose of pembrolizumab until disease progression, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-up. Median duration of follow-up was 8.3 months (95% CI 3.0-10.1 months).

Other Outcomes (2)

• Computed Tomography-based Response of a Non-target Lesion

  baseline and 30 days after the last dose of pembrolizumab

• Change in Immunohistochemical Expression of Tumor-infiltrating Lymphocytes in Tumor Biopsy Tissues

  baseline and 30 days after the last dose of pembrolizumab

Study Arms (1)

Single arm

EXPERIMENTAL

ADV/HSV-tk (5 x 1011 virus particles) in a 2-mL total volume will be injected intratumorally on Day 0. Valacyclovir will be orally administered at a dose of 2 g three times daily for 14 days from Day 1 to Day 15. SBRT of 30 Gy (6 Gy X 5 fractions) will be administered over 2 weeks from Day 2 to Day 16. Pembrolizumab (200 mg) will be administered intravenously over 30 minutes every 3 weeks starting on Day 17 and continuing until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Biological: ADV/HSV-tk; Drug: Valacyclovir; Radiation: SBRT; Drug: Pembrolizumab

Interventions

ADV/HSV-tk BIOLOGICAL

Replication-defective recombinant adenovirus vector

Single arm

Valacyclovir DRUG

Prodrug of the antiviral drug acyclovir

Also known as: valacyclovir hydrochloride

Single arm

SBRT RADIATION

Low-dose SBRT

Single arm

Pembrolizumab DRUG

Humanized immunoglobulin G4 anti-programmed death-1 (PD-1) monoclonal antibody

Also known as: Keytruda

Single arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing and able to provide written informed consent/assent for the trial.
• Male or female aged ≥18 years on the day of informed consent signing.
• Histologically confirmed locally advanced or metastatic TNBC that has relapsed on or is refractory to standard of care therapy OR histologically or cytologically confirmed metastatic NSCLC that is immunotherapy and chemotherapy naïve or previously treated with 1 cycle of platinum-containing chemotherapy. Epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) mutation-negative NSCLC patients and NSCLC patients with EGFR or ALK genomic tumor aberrations that have failed FDA-approved targeted therapy for these aberrations will be eligible for enrollment in the study.
• Measurable disease based on RECIST 1.1, a target lesion of suitable diameter (at least 1 cm) for SBRT, and a non-target lesion (visceral metastatic lesion) at least 1 cm in diameter for abscopal effect evaluation.
• Willing to provide biopsy tissues as required by the study.
• Eastern Cooperative Oncology Group performance status of 0 or 1.
• Adequate organ function as defined by the following laboratory values:
• Absolute neutrophil count ≥1,500/µL (without granulocyte colony stimulating factor support within 14 days of assessment)
• Platelets ≥100,000/µL
• Hemoglobin ≥8 g/dL or ≥5.6 mmol/L without transfusion or erythropoietin dependency (within 7 days of assessment)
• White blood cell count \>2,500/µL and \<15,000/µL
• Lymphocyte count ≥500/µL
• Serum creatinine \<2 X upper limit of normal (ULN)
• Serum total bilirubin ≤1.0 X ULN (Subjects with known Gilbert's disease who have serum bilirubin level ≤3 X ULN may be enrolled)
• Asparate transaminase and alanine transaminase ≤2.5 X ULN with normal alkaline phosphatase (≤5 X ULN for subjects with liver metastases) OR ≤1.5 X ULN in conjunction with alkaline phosphatase \>2.5 X ULN

You may not qualify if:

• Unwilling or unable to comply with the study protocol.
• Subjects for who bone metastases are the only available non-target lesions for abscopal effect evaluation.
• Subjects with tumors for which SBRT is not considered appropriate standard therapy. This includes subjects with target lesions less than 1 cm in diameter and those with large central lung lesions.
• Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of trial treatment.
• Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
• Known history of active tuberculosis (Bacillus Tuberculosis).
• Known or suspected hypersensitivity to pembrolizumab or any of its excipients or any component of the proposed regimen (gene vector/valacyclovir).
• Known gallbladder or bile duct disease (i.e., infection or cholecystitis) or acute or chronic pancreatitis.
• Eastern Cooperative Oncology Group performance status of ≥2 or oxygen dependence (e.g., advanced chronic obstructive pulmonary disease).
• Inability to swallow food or any condition of the upper gastrointestinal tract that precludes administration of oral medications (valacyclovir).
• Congestive heart failure: New York Association class III or IV heart failure or unstable angina.
• Sustained or clinically significant cardiac arrhythmias including sustained ventricular tachycardia, ventricular fibrillation, clinically significant bradycardia, advanced heart block (Mobitz II or higher atrioventricular nodal block), prolonged corrected QT interval (longer than 470 milliseconds), or history of acute myocardial infarction.
• Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused by diabetes or Parkinson's disease), human immunodeficiency virus (HIV), cirrhosis, uncontrolled hypothyroidism, or cardiac failure.
• History of syncope or family history of idiopathic sudden death.
• Targeted small molecule therapy or monoclonal antibody or radiation therapy within 3 weeks prior to study Day 0 or has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.

Sponsors & Collaborators

• The Methodist Hospital Research Institute: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

Houston Methodist Cancer Center

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Triple Negative Breast Neoplasms

Interventions

Valacyclovir; pembrolizumab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Breast Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Acyclovir; Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Jenny C Chang, MD
• Organization: Houston Methodist Cancer Center

ccresearch@houstonmethodist.org

713-441-0629

Study Officials

• Jenny Chang, MD

  Houston Methodist Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of the Houston Methodist Cancer Center

Study Record Dates

• First Submitted: December 20, 2016
• First Posted: December 28, 2016
• Study Start: July 1, 2017
• Primary Completion: July 22, 2022
• Study Completion: January 9, 2024
• Last Updated: October 15, 2024
• Results First Posted: January 25, 2023

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: During and/or after result submission.
• Access Criteria: The study protocol will be included on clinicaltrials.gov

Locations

US (1)