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Intratumoral Administration of CCL21-gene Modified Dendritic Cell With Intravenous Pembrolizumab for Advanced NSCLC

NCT03546361

Description:

This is a phase 1 trial of intratumoral administration of CCL21-gene modified dendritic cells combined with intravenous pembrolizumab for advanced non-small cell lung cancer. Up to 12 patients will participate in the dose escalation phase and during dose expansion, 12 patients will be evaluated. Before the first injection of dendritic cells, blood will be collected from the patient and leukapheresis will be performed. Dendritic cells obtained from this blood draw will be cultured and induced with Ad-CCL21 gene. Then, the patient's lung tumor will be injected with these modified dendritic cells. This injection will be followed by treatment with 200 mg intravenous pembrolizumab. Patients will receive an injection of Ad-CCL21 DC followed by treatment with pembrolizumab on Days 0, 21, and 42. After these three injections, patients will receive pembrolizumab 200 mg every three weeks for up to one year. From enrollment of the first patient to the last dose administered to the last subject, this study is anticipated to take approximately 5 years to complete.

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

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Intratumoral Administration of CCL21-gene Modified Dendritic Cell With Intravenous Pembrolizumab for Advanced NSCLC
  • Official Title: A Phase I Trial of Intratumoral Administration of CCL21-gene Modified Dendritic Cell (DC) Combined With Intravenous Pembrolizumab for Advanced NSCLC

Clinical Trial IDs

  • ORG STUDY ID: 17-000174
  • SECONDARY ID: HEMONC CIRM IST Lung
  • NCT ID: NCT03546361

Conditions

  • Carcinoma, Non-Small-Cell Lung

Interventions

DrugSynonymsArms
PembrolizumabDose Expansion

Purpose

This is a phase 1 trial of intratumoral administration of CCL21-gene modified dendritic cells combined with intravenous pembrolizumab for advanced non-small cell lung cancer. Up to 12 patients will participate in the dose escalation phase and during dose expansion, 12 patients will be evaluated. Before the first injection of dendritic cells, blood will be collected from the patient and leukapheresis will be performed. Dendritic cells obtained from this blood draw will be cultured and induced with Ad-CCL21 gene. Then, the patient's lung tumor will be injected with these modified dendritic cells. This injection will be followed by treatment with 200 mg intravenous pembrolizumab. Patients will receive an injection of Ad-CCL21 DC followed by treatment with pembrolizumab on Days 0, 21, and 42. After these three injections, patients will receive pembrolizumab 200 mg every three weeks for up to one year. From enrollment of the first patient to the last dose administered to the last subject, this study is anticipated to take approximately 5 years to complete.

Detailed Description

      A phase I, non-randomized, dose escalating, multi-cohort trial followed by dose expansion at
      the dose established during dose escalation (ExD) will be conducted. During dose escalation,
      a modified 3+3 design will be used. Three patients will be assigned to each cohort. Patients
      enrolled into a given cohort will receive the same Ad-CCL21-DC dose by CT-guided or
      bronchoscopic intratumoral injection followed by intravenous pembrolizumab 200mg one hour
      after DC injection on days 0, 21, and 42, and intravenous pembrolizumab 200mg every three
      weeks thereafter for up to a year. The Ad-CCL21-DC dose is 1 x 107 cells/injection in the
      first cohort (1), and will be increased to 3 x 107 cells/injection (2) pending tolerability
      in earlier cohort. Dose escalation may proceed only if all 3 patients enrolled in the lower
      dose cohort experience no DLT or 1 of 6 patients in a cohort has a DLT. If a patient dies
      within 30 days of receiving investigational treatment and the death is considered to be at
      least possibly related, further study enrolment will be held until further evaluation by the
      UCLA DSCMB. If the dose regimen in cohort 1 (Ad-CCL21-DC 1 x 107 cells/injection) is not well
      tolerated, de-escalation to Ad-CCL21-DC 0.5 x 107 cells/injection will be allowed (-1). If
      the dose regimen specified for Cohort 2 (Ad-CCL21-DC 3 x 107 cells/injection) is not the
      maximum tolerated dose (MTD), no further dose escalation will be conducted, and this dose
      level will be defined as maximum administered dose (MAD).

      After completion of the dose-escalation phase, all safety and tolerability data will be
      reviewed and the ExD will be determined. A dose expansion cohort of 24 patients (D) will be
      enrolled and treated at ExD for up to a year. All enrolled patients will continue to be
      followed by a physician, and undergo a history and physical examination every 3 months until
      progressive disease (PD) or withdrawal from the study. Eligible patients will be assigned to
      a cohort and will receive intratumoral injections of autologous Ad-CCL21-DC and intravenous
      pembrolizumab in conjunction with tumor sampling and patient monitoring
    

Trial Arms

NameTypeDescriptionInterventions
1 Dose EscalationExperimentalthree patients will be assigned to the cohort. All three will receive the same Ad-CCL21-DC dose by CT-guided or bronchoscopic intratumoral injection followed by intravenous pembrolizumab 200mg one hour after DC injection on days 0, 21, and 42, and intravenous pembrolizumab 200mg every three weeks thereafter for up to a year. for cohort (1) The Ad-CCL21-DC dose is 1 x 107 cells/injection in the first cohort.
    2 Dose EscalationExperimentalthree patients will be assigned to the cohort. All three will receive the same Ad-CCL21-DC dose by CT-guided or bronchoscopic intratumoral injection followed by intravenous pembrolizumab 200mg one hour after DC injection on days 0, 21, and 42, and intravenous pembrolizumab 200mg every three weeks thereafter for up to a year. for cohort (2) The Ad-CCL21-DC dose is 3 x 107 cells/injection in the second cohort.
      -1 Dose EscalationExperimentalIf the dose regimen in cohort 1 (Ad-CCL21-DC 1 x 107 cells/injection) is not well tolerated, de-escalation to Ad-CCL21-DC 0.5 x 107 cells/injection will be allowed (-1). three patients will be assigned to the cohort. All three will receive the same Ad-CCL21-DC dose by CT-guided or bronchoscopic intratumoral injection followed by intravenous pembrolizumab 200mg one hour after DC injection on days 0, 21, and 42, and intravenous pembrolizumab 200mg every three weeks thereafter for up to a year. for cohort (-1) The Ad-CCL21-DC dose is 0.5 x 107 cells/injection in the third cohort.
        Dose ExpansionExperimentalAfter completion of the dose-escalation phase, all safety and tolerability data will be reviewed and the ExD will be determined. A dose expansion cohort of 24 patients will be enrolled and treated at ExD for up to a year (note: only intravenous pembrolizumab is given after day 42). Ad-CCL21-DC dose at determined maximum tolerated dose (MTD) or maximum administered dose (MAD)
        • Pembrolizumab

        Eligibility Criteria

                Inclusion Criteria:
        
                  1. Adults over the age of 18 capable of giving informed consent.
        
                  2. Stage IV pathologically proven NSCLC.
        
                  3. Staining for PD-L1 in less than half of the tumor cells using the CC23 antibody (0%
                     staining is acceptable)
        
                  4. Measurable disease by RECIST Guidelines (see Appendix B).
        
                  5. ECOG performance status of 0, 1(see Appendix A).
        
                  6. Must be naïve to systemic treatment for NSCLC. Patients who received adjuvant or
                     neo-adjuvant chemotherapy
        
                  7. Adequate renal function (defined as BUN≤40 or serum creatinine≤2).
        
                  8. Adequate liver function (defined as serum total bilirubin≤2X the upper limits of
                     normal (ULN), or serum transaminases≤3X ULN).
        
                  9. Adequate coagulation parameters (defined as PT and/or PTT≤1.5X ULN or
                     platelets≥100,000).
        
                 10. Adequate neutrophils (defined as absolute neutrophil count≥1,500/mm3).
        
                 11. In woman who have not experienced menopause, negative pregnancy test prior to
                     initiation of treatment and adequate contraception throughout treatment.
        
                 12. All subjects must demonstrate adequate respiratory function (defined as SaO2 >90% on
                     room air; PCO2 <45mmHg; or FEV1 >1.0 liter).
        
                 13. Patients with a major endobronchial lesion in the segmental, lobar, or mainstem
                     bronchus with complete obstruction of the airway may be eligible for bronchoscopic
                     injection if there is no evidence of respiratory failure (defined as SaO2 >90% on room
                     air; PCO2 <45mmHg; or FEV1 >1.0 liter).
        
                 14. Patients with an endobronchial lesion in the segmental bronchus with variable stenosis
                     (not completely obstructed) and not amenable to standard palliative airway treatments
                     (i.e. laser and stenting) may be eligible for bronchoscopic injection if there is no
                     evidence of respiratory failure (defined as SaO2 >90% on room air; PCO2 <45mmHg; or
                     FEV1 >1.0 liter).
        
                 15. Subjects with bullous disease may undergo CT-guided transthoracic injection if the
                     targeted tumor has an intended needle path without crossing bullae.
        
                Exclusion Criteria:
        
                  1. Previous systemic therapy for Stage IV NSCLC, including chemotherapy, radiation
                     therapy or non-cytotoxic investigational agents.
        
                  2. Comorbid disease or a medical condition that would impair the ability of the patient
                     to receive or comply with the study protocol.
        
                  3. Any use of systemic corticosteriods within 10 days of treatment or during treatment.
        
                  4. Renal insufficiency (defined as BUN>40 or serum creatinine>2).
        
                  5. Liver insufficiency (defined as serum total bilirubin > 2x ULN, or serum transaminases
                     > 3X ULN). Note: Transaminases can be up to 5X ULN in the setting of liver metastases
        
                  6. Coagulopathy (defined as PT and/or PTT > 1.5X ULN or platelets < 100,000).
        
                  7. Neutropenia (defined as absolute neutrophil count < 1,500/mm3).
        
                  8. Respiratory failure (defined as SaO2 <90% on room air; PCO2 >44mmHg; or FEV1 <1.0
                     liter)
        
                  9. Acute viral, bacterial, or fungal infection, which requires specific therapy. Acute
                     therapy must have been completed within 14 days prior to study treatment.
        
                 10. HIV infected patients.
        
                 11. Hypersensitivity to any reagents used in the study.
        
                 12. Pregnancy or inadequate contraception.
        
                 13. Lactating females.
        
                 14. Active CNS metastasis, which has not been treated with radiation therapy
        
                 15. Subjects with organ allografts.
        
                 16. Subjects with bullous disease may not undergo CT-guided transthoracic injection if the
                     targeted tumor has an intended needle path that requires crossing the bullae.
        
                 17. Previous or concurrent evidence of autoimmune disease requiring systemic steroids.
        
                 18. Patients with a major endobronchial lesion in the lobar or mainstem bronchus amenable
                     to standard palliative airway treatments or with >50% stenosis (not completely
                     obstructed airway) will be excluded from bronchoscopic injection.
        
                Sample
              
        Maximum Eligible Age:N/A
        Minimum Eligible Age:18 Years
        Eligible Gender:All
        Healthy Volunteers:No

        Primary Outcome Measures

        Measure:Dose Escalation
        Time Frame:up to 2 years
        Safety Issue:
        Description:To determine the safety and maximum tolerated dose (MTD) of intratumoral injection of CCL21 gene-modified DC (Ad-CCL21-DC) when combined with intravenous pembrolizumab in patients with previously untreated, advanced non-small cell lung cancer (NSCLC), whose tumors express PD-L1 in less than 50% of tumor cells.

        Secondary Outcome Measures

        Measure:Adverse Event Profile
        Time Frame:up to 5 years
        Safety Issue:
        Description:To define the adverse event (AE) profile of intratumoral injection of Ad-CCL21-DC (determined during dose escalation) when administered with intravenous pembrolizumab in patients with previously untreated, advanced NSCLC whose tumors express PD-L1 in less than 50% of tumor cells, and to determine relationship of AEs to study treatment.
        Measure:Drug Target Activity
        Time Frame:up to 5 years
        Safety Issue:
        Description:For PD-L1 expression, percentage of tumor cells with positive staining by the 22c3 antibody will be evaluated.

        Details

        Phase:Phase 1
        Primary Purpose:Interventional
        Overall Status:Recruiting
        Lead Sponsor:Jonsson Comprehensive Cancer Center

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