Phase II Window of Opportunity Trial of Stereotactic Body Radiation Therapy and In Situ Oncolytic Virus Therapy in Metastatic Triple Negative Breast Cancer and Metastatic Non-Small Cell Lung Cancer Followed by Pembrolizumab
Overview
- Phase
- Phase 2
- Intervention
- ADV/HSV-tk
- Conditions
- Metastatic Non-small Cell Lung Cancer
- Sponsor
- The Methodist Hospital Research Institute
- Enrollment
- 57
- Locations
- 1
- Primary Endpoint
- Objective Response Rate
- Status
- Completed
- Last Updated
- last year
Overview
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.
Detailed Description
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. Male and female patients aged ≥ 18 years with histologically confirmed locally advanced or metastatic TNBC that has relapsed on or is refractory to 1 or more lines of 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 are eligible to participate in the study. ADV/HSV-tk (5 x 1011 viral particles) in a 2-mL total volume will be injected intratumorally on Day 0 of the study. Valacyclovir will be orally administered at a dose of 2 g three times daily for 14 days. Valacyclovir treatment will be administered 24 hours after the gene vector injection from Day 1 to Day 15 of the study. SBRT of 30 gray (Gy; 6 Gy X 5 fractions) will be administered over 2 weeks from Day 2 to Day 16 of the study. Pembrolizumab (200 mg) will be administered intravenously over 30 minutes every 3 weeks starting on Day 17 of the study and continuing until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. The primary endpoint will be the objective response rate of ADV/HSV-tk + valacyclovir therapy in combination with SBRT used as a window of opportunity treatment before pembrolizumab in patients with metastatic TNBC and metastatic NSCLC. RECIST 1.1 will be used to assess treatment response. Secondary endpoints will include a) clinical benefit rate; b) duration of response; c) overall survival and progression-free survival rates; d) toxicity (toxicity will be defined as any treatment-related death or any ≥ grade 3 toxicity excluding alopecia and constitutional symptoms as assessed by the NCI CTCAE v4.03); and e) antitumor activity of ADV/HSV-tk plus valacyclovir therapy in combination with SBRT used as a window of opportunity treatment before pembrolizumab.
Investigators
Jenny C. Chang, MD
Director of the Houston Methodist Cancer Center
The Methodist Hospital Research Institute
Eligibility Criteria
Inclusion Criteria
- •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
- •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)
Exclusion Criteria
- •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).
Arms & Interventions
Single arm
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.
Intervention: ADV/HSV-tk
Single arm
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.
Intervention: Valacyclovir
Single arm
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.
Intervention: SBRT
Single arm
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.
Intervention: Pembrolizumab
Outcomes
Primary Outcomes
Objective Response Rate
Time Frame: 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).
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.
Secondary Outcomes
- 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).)
- Progression-free Survival in Months(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.)