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

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ClinicalTrials.gov Identifier: NCT03546361
Recruitment Status : Recruiting
First Posted : June 5, 2018
Last Update Posted : February 28, 2019
Sponsor:
Collaborators:
California Institute for Regenerative Medicine (CIRM)
Merck Sharp & Dohme Corp.
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Jonsson Comprehensive Cancer Center

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Carcinoma, Non-Small-Cell Lung Genetic: Ad-CCL21-DC 1 x 07 Genetic: Ad-CCL21-DC 3 x 07 Genetic: Ad-CCL21-DC .05 x 07 Drug: Pembrolizumab Genetic: Ad-CCL21-DC ExD Phase 1

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


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Trial of Intratumoral Administration of CCL21-gene Modified Dendritic Cell (DC) Combined With Intravenous Pembrolizumab for Advanced NSCLC
Actual Study Start Date : December 5, 2018
Estimated Primary Completion Date : November 1, 2022
Estimated Study Completion Date : November 1, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 1 Dose Escalation
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 1 x 107 cells/injection in the first cohort.
Genetic: Ad-CCL21-DC 1 x 07
Ad-CCL21-DC dose is 1 x 107

Experimental: 2 Dose Escalation
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 (2) The Ad-CCL21-DC dose is 3 x 107 cells/injection in the second cohort.
Genetic: Ad-CCL21-DC 3 x 07
Ad-CCL21-DC dose is 3 x 107

Experimental: -1 Dose Escalation
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). 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.
Genetic: Ad-CCL21-DC .05 x 07
Ad-CCL21-DC dose is .05 x 107

Experimental: Dose Expansion

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 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)

Drug: Pembrolizumab
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.

Genetic: Ad-CCL21-DC ExD
Ad-CCL21-DC dose at determined maximum tolerated dose (MTD) or maximum administered dose (MAD)




Primary Outcome Measures :
  1. Dose Escalation [ Time Frame: up to 2 years ]
    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.

  2. Dose Expansion [ Time Frame: up to 2 years ]
    To evaluate the objective response rate (ORR) in subjects treated with the dose established during dose escalation (ExD) of intratumoral injection of Ad-CCL21-DC when administered with intravenous pembrolizumab in patients with previously untreated, advanced NSCLC whose tumors express PD-L1 in less than 50% of tumor cells.


Secondary Outcome Measures :
  1. Adverse Event Profile [ Time Frame: up to 5 years ]
    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.

  2. Drug Target Activity [ Time Frame: up to 5 years ]
    For PD-L1 expression, percentage of tumor cells with positive staining by the 22c3 antibody will be evaluated.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03546361


Contacts
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Contact: Lia Etheridge 310-825-7174 letheridge@mednet.ucla.edu
Contact: Krikor Bornazyan 310-825-7174 KBornazyan@mednet.ucla.edu

Locations
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United States, California
University of California at Los Angeles Recruiting
Los Angeles, California, United States, 90095
Contact: Lia Etheridge    310-825-7174    letheridge@mednet.ucla.edu   
Contact: Krikor Bornazyan    310-825-7174    KBornazyan@mednet.ucla.edu   
Sponsors and Collaborators
Jonsson Comprehensive Cancer Center
California Institute for Regenerative Medicine (CIRM)
Merck Sharp & Dohme Corp.
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Edward Garon, M.D. University of California, Los Angeles

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Responsible Party: Jonsson Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT03546361     History of Changes
Other Study ID Numbers: 17-000174
HEMONC CIRM IST Lung ( Other Identifier: Jonsson CCC )
First Posted: June 5, 2018    Key Record Dates
Last Update Posted: February 28, 2019
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Carcinoma, Non-Small-Cell Lung
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents