Clinical Trials /

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

NCT03004183

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 therapy.

Related Conditions:
  • Breast Carcinoma
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: SBRT and Oncolytic Virus Therapy Before Pembrolizumab for Metastatic TNBC and NSCLC
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: Pro00015649
  • NCT ID: NCT03004183

Conditions

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

Interventions

DrugSynonymsArms
ADV/HSV-tkSingle arm
Valacyclovirvalacyclovir hydrochlorideSingle arm
PembrolizumabKeytrudaSingle arm

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Single armExperimentalADV/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.
  • ADV/HSV-tk
  • Valacyclovir
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          1. Willing and able to provide written informed consent/assent for the trial.

          2. Male or female aged ≥18 years on the day of informed consent signing.

          3. 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.

          4. 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.

          5. Willing to provide biopsy tissues as required by the study.

          6. Eastern Cooperative Oncology Group performance status of 0 or 1.

          7. 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

               -  Albumin >2.5 mg/dL

               -  International normalized ratio or prothrombin time (PT) ≤1.5 X ULN unless subject
                  is receiving anticoagulant therapy as long as PT or activated partial
                  thromboplastin time (aPTT) is within therapeutic range of intended use of
                  anticoagulants

               -  aPTT ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT
                  or aPTT is within therapeutic range of intended use of anticoagulants

          8. Life expectancy ≥ 6 months.

          9. ≥ 4 weeks since any major surgery, completion of radiation therapy, or completion of
             all prior systemic anticancer therapy (adequately recovered from the acute toxicities
             of any prior therapy).

         10. Female subjects of childbearing potential should have a negative serum pregnancy
             (beta-human chorionic gonadotropin) within 7 days prior to receiving the first dose of
             the trial treatment and should not be lactating.

         11. Female subjects of childbearing potential must be willing to use an adequate method of
             contraception for the course of the study through 120 days after the last dose of
             study therapy.

         12. Male subjects of childbearing potential must agree to use an adequate method of
             contraception for the course of the study through 120 days after the last dose of
             study therapy.

        Exclusion Criteria:

          1. Unwilling or unable to comply with the study protocol.

          2. Subjects for who bone metastases are the only available non-target lesions for
             abscopal effect evaluation.

          3. 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.

          4. 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.

          5. 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.

          6. Known history of active tuberculosis (Bacillus Tuberculosis).

          7. Known or suspected hypersensitivity to pembrolizumab or any of its excipients or any
             component of the proposed regimen (gene vector/valacyclovir).

          8. Known gallbladder or bile duct disease (i.e., infection or cholecystitis) or acute or
             chronic pancreatitis.

          9. Eastern Cooperative Oncology Group performance status of ≥2 or oxygen dependence
             (e.g., advanced chronic obstructive pulmonary disease).

         10. Inability to swallow food or any condition of the upper gastrointestinal tract that
             precludes administration of oral medications (valacyclovir).

         11. Congestive heart failure: New York Association class III or IV heart failure or
             unstable angina.

         12. 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.

         13. 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.

         14. History of syncope or family history of idiopathic sudden death.

         15. 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.

             - Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may
             qualify for the study.

         16. Known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
             skin that has undergone potentially curative therapy or in situ cervical cancer.

         17. Known active central nervous system metastases and/or carcinomatous meningitis.
             Subjects with previously treated brain metastases may participate provided they are
             stable (without evidence of progression by imaging for at least 4 weeks prior to the
             first dose of trial treatment and any neurologic symptoms have returned to baseline),
             have no evidence of new or enlarging brain metastases, and are not using steroids for
             at least 7 days prior to trial treatment. This exception does not include
             carcinomatous meningitis, which is excluded regardless of clinical stability.

         18. Active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment.

         19. History of (non-infectious) pneumonitis that required steroids or current pneumonitis.

         20. Active infection requiring systemic therapy.

         21. History or current evidence of any condition, therapy, or laboratory abnormality that
             might confound the results of the trial, interfere with the subject's participation
             for the full duration of the trial, or is not in the best interest of the subject to
             participate, in the opinion of the treating investigator.

         22. Known psychiatric or substance abuse disorders that would interfere with cooperation
             with the requirements of the trial.

         23. Pregnant or breastfeeding, expecting to conceive or father children within the
             projected duration of the trial, starting with the prescreening or screening visit
             through 120 days after the last dose of trial treatment, or is unwilling to practice
             an effective method of birth control. Women of childbearing potential must have a
             negative serum pregnancy test within 7 days prior to administration of trial
             treatment.

         24. Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent (TNBC cohort only).

         25. Prior treatment with immunomodulatory therapy or immunotherapy (TNBC cohort only).

         26. Prior treatment with gene vector therapy.

         27. Received prior systemic cytotoxic chemotherapy for metastatic disease (NSCLC cohort).

         28. Known history of HIV (HIV 1/2 antibodies).

         29. History of liver disease such as cirrhosis or known active hepatitis B (e.g.,
             hepatitis B surface antigen reactive) or hepatitis C (e.g., hepatitis C virus RNA
             [qualitative] is detected).

         30. History of or current alcohol misuse/abuse within the past 12 months.

         31. Major surgery within 4 weeks prior to study enrollment.

         32. Received a live vaccine within 30 days of planned start of trial therapy. Note:
             Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
             are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live
             attenuated vaccines and are not allowed.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate
Time Frame:30 days after the last dose of pembrolizumab
Safety Issue:
Description:Objective response rate of ADV/HSV-tk plus valacyclovir therapy in combination with SBRT followed by pembrolizumab

Secondary Outcome Measures

Measure:Duration of response
Time Frame:30 days after the last dose of pembrolizumab
Safety Issue:
Description:Duration of response to ADV/HSV-tk plus valacyclovir therapy in combination with SBRT followed by pembrolizumab
Measure:Overall survival rate
Time Frame:30 days after the last dose of pembrolizumab
Safety Issue:
Description:Overall survival rate in subjects receiving ADV/HSV-tk plus valacyclovir therapy in combination with SBRT followed by pembrolizumab
Measure:Progression-free survival rate
Time Frame:30 days after the last dose of pembrolizumab
Safety Issue:
Description:Progression-free survival rate in subjects receiving ADV/HSV-tk plus valacyclovir therapy in combination with SBRT followed by pembrolizumab
Measure:Number of participants with treatment-related adverse events
Time Frame:30 days after the last dose of pembrolizumab
Safety Issue:
Description:Number of participants with treatment-related adverse events as assessed by the NCI CTCAE v4.03
Measure:Antitumor activity
Time Frame:30 days after the last dose of pembrolizumab
Safety Issue:
Description:Measure the antitumor activity as assessed by RECIST 1.1. Modified immune-related response criteria will also be documented.
Measure:Clinical benefit rate
Time Frame:30 days after the last dose of pembrolizumab
Safety Issue:
Description:Clinical benefit rate of ADV/HSV-tk plus valacyclovir therapy in combination with SBRT followed by pembrolizumab

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Jenny C. Chang, MD

Last Updated

April 10, 2019