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Induction of Sensecence Using Dexamethasone to Re-sensitize NSCLC to Anti-PD1 Therapy

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ClinicalTrials.gov Identifier: NCT04037462
Recruitment Status : Not yet recruiting
First Posted : July 30, 2019
Last Update Posted : July 31, 2019
Sponsor:
Collaborators:
Wayne State University
University of Michigan
Barbara Ann Karmanos Cancer Institute
Information provided by (Responsible Party):
VA Office of Research and Development

Brief Summary:
Lung cancer accounts for 30% of all cancers among American war Veterans and remains the leading cause of cancer related deaths. Half of all lung cancers are metastatic non-small cell lung cancer (NSCLC), with a 2-year survival rate of 10%. Immunotherapy with immune checkpoint inhibitors (ICI) has emerged as a promising therapeutic strategy that aims to harness the immune system to fight lung cancer. However, given the modest response rates of 20-25% to these immune checkpoint inhibitors, there is a greater desire to extend their benefits to more patients. Along with the desire to extend their benefits, there is a critical need for the development of novel approaches that can expand the benefit from immune checkpoint inhibitors and create more durable responses, prolonging survival from lung cancer. The investigators' studies show that extended dexamethasone (Dex) treatment induces irreversible cell cycle blockade and a senescence phenotype through chronic activation of the p27Kip1 gene in glucocorticoid receptor (GR) overexpressing lung adenocarcinoma (AC) cell populations. Further, following withdrawal of Dexamethasone, proteins associated with the senescence associated secretory phenotype (SASP) strongly attracted and expanded T-cells, NK cells and monocytes stimulated tumor cell cytolytic activity of NK cells. Therefore, dexamethasone may induce a persistent senescence phenotype in tumor cell sub-populations expressing moderate/high levels of GR and resultant chemokines produced by the senescent cells will mobilize host immune cells to reboot response to immune checkpoint inhibitors following complete Dexamethasone withdrawal.

Condition or disease Intervention/treatment Phase
Non-Small Cell Lung Cancer Immunotherapy Drug: Dexamthasone Phase 1 Phase 2

Detailed Description:

Lung cancer accounts for 30% of all cancers among American war Veterans and remains the leading cause of cancer related deaths. Half of all lung cancers are metastatic non-small cell lung cancer (NSCLC), with a 2-year survival rate of 10%. Immunotherapy with immune checkpoint inhibitors (ICI) has emerged as a promising therapeutic strategy that aims to harness the immune system to fight lung cancer. However, given the modest response rates of 20-25% to these immune checkpoint inhibitors, there is a greater desire to extend their benefits to more patients. Along with the desire to extend their benefits, there is a critical need for the development of novel approaches that can expand the benefit from immune checkpoint inhibitors and create more durable responses, prolonging survival from lung cancer.

Our studies show that extended dexamethasone (Dex) treatment induces irreversible cell cycle blockade and a senescence phenotype through chronic activation of the p27Kip1 gene in glucocorticoid receptor (GR) overexpressing lung adenocarcinoma (AC) cell populations. Further, following withdrawal of Dexamethasone, proteins associated with the senescence associated secretory phenotype (SASP), particularly CCL2, CCL4, CXCL1 and CXCL2 strongly attracted and expanded T-cells, NK cells and monocytes stimulated tumor cell cytolytic activity of NK cells.

Our overarching hypothesis is that in lung adenocarcinoma patients who are not on baseline steroids, pre-treatment with Dexamethasone will induce a persistent senescence phenotype in tumor cell sub-populations expressing moderate/high levels of GR and resultant chemokines produced by the senescent cells will mobilize host immune cells to reboot response to immune checkpoint inhibitors following complete Dexamethasone withdrawal. The investigators will test this hypothesis through the conduct of the following aims.

Specific Aim 1: Use FLT-PET imaging and blood analysis to test whether a 7-14-day pre-treatment of lung adenocarcinoma patients with Dexamethasone followed by Dexamethasone withdrawal will induce persistent senescence related cell cycle arrest in 1 lesion in 60% of patients, (based on GR expression) accompanied by release of SASP proteins and activation of T and NK cells.

Specific Aim 2: Test whether a 7-14-day pre-treatment of lung adenocarcinoma patients with Dexamethasone followed by Dexamethasone withdrawal and subsequent re-challenge with pembrolizumab will yield an overall response rate (ORR) of 33% to pembrolizumab in association with tumor GR status, SASP and immune cell activation.

These aims will be conducted through a Phase II clinical trial designed as a single-arm two-stage study in Veterans whose lung adenocarcinoma has progressed on immune checkpoint inhibitors. Based on the investigators' preliminary data, the investigators expect that Dexamethasone will induce tumor senescence in at least one lesion in 60% of patients and secondarily improve overall response to pembrolizumab by 33%. Success with these aims would inform a larger study that could potentially change the way the investigators approach patients with primary or acquired resistance to immune checkpoint inhibitors with an off the shelf medication that could re-sensitize lung adenocarcinoma to immune checkpoint inhibitors. The proposed research could substantially benefit Veterans with metastatic NSCLC, a group with the most genomically complex lung cancers and poor survival.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 39 participants
Intervention Model: Single Group Assignment
Intervention Model Description: In the first stage, three Dex escalation cohorts will be evaluated sequentially from Cohort A to Cohort C until > 2 patients exhibit FLT-PET response (i.e., 30% reduction in FLT-PET uptake in at least one target lesion); otherwise, the trial will be terminated due to futility. The secondary objective is to assess the effect of Dex on pembrolizumab in terms of overall response rate (ORR).
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Induction of Sensecence Using Dexamethasone to Re-sensitize NSCLC to Anti-PD1 Therapy
Estimated Study Start Date : October 1, 2019
Estimated Primary Completion Date : September 30, 2021
Estimated Study Completion Date : July 3, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Lead in Dexamethasone followed by immunotherapy
escalating doses of pretreatment dexamethasone in patients who have failed initial immunotherapy to 1. assess changes in FLT PET uptake 2. assess overall response rates of pretreatment dexamethasone (dose from 1) on subsequent immunotherapy re-challenge
Drug: Dexamthasone
escalating doses of pretreatment dexamethasone in patients who have failed initial immunotherapy to 1. assess changes in FLT PET uptake 2. assess overall response rates of pretreatment dexamethasone (dose from 1) on subsequent immunotherapy re-challenge




Primary Outcome Measures :
  1. Reduction in FLT-PET signal [ Time Frame: 12 months ]
    In the first stage, three Dex escalation cohorts will be evaluated sequentially from Cohort A to Cohort C until > 2 patients exhibit FLT-PET response (i.e., 30% reduction in FLT-PET uptake in at least one target lesion); otherwise, the trial will be terminated due to futility.


Secondary Outcome Measures :
  1. Response rate [ Time Frame: 24 months ]
    The primary objective in SA 2 is to assess the effect of Dex on pembrolizumab in terms of overall response rate (ORR). Based on pre-clinical and clinical studies, the investigators hypothesize that the true ORR of Dex followed by pembrolizumab will be at least 33% (i.e., p1 = 0.33) vs. the historical control whose ORR is at most 7% (i.e., p0 = 0.07). The ORR will be statistically evaluated when the FLT-PET response trial enters the third stage, where the number of patients with the selected optimal Dex duration will be 21. Otherwise, ORR will be summarized descriptively. The null hypothesis (p0 = 7%) will be rejected if five or more responses are observed in 21 patients, which yields a 1-sided type I error rate of 5% and power of 87% when the true ORR is 33% (i.e. p1 = 33%).



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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:

  • Be willing and able to provide written informed consent/assent for the trial.
  • Be 18 years of age on day of signing informed consent.
  • Have a life expectancy of at least 6 months.
  • Have a histologically confirmed diagnosis of stage IV NSCLC (includes patients who have progressed on durvalumab for Stage III NSCLC) and have at least one measurable lesion based on RECIST v1.1.
  • Have a performance status of 0, 1 or 2 on the ECOG Performance Scale (Appendix 15.1).
  • Demonstrate adequate organ function all screening labs should be performed within 14 days of enrollment.
  • Female subject of childbearing potential should have a serum pregnancy within 14 days of enrollment and 72 hours prior to receiving the first dose of study medications.
  • Female subjects of childbearing potential must be willing to use a highly effective method of contraception as outlined in Section 6.3.3 for the course of the study through 180 days after the last dose of study medications.

    • Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
  • Male subjects of childbearing potential must agree to use an adequate method of contraception starting with the first dose of study therapy through 180 days after the last dose of study therapy.

    • Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
  • Adequate tissue sample for correlative studies. A new sample is not necessary if archival specimen is available and has adequate amount of tumor content (at least 30%). This needs to be determined by a pathologist.

Exclusion Criteria:

  • Received palliative radiation within 7 days of enrollment.
  • Has a known history of prior malignancy except if the patient has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy.

    • Note: the time requirement for no evidence of disease for 5 years does not apply to the NSCLC tumor for which a subject is enrolled in the study. The time requirement also does not apply to subjects who underwent successful definitive resection of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in situ cervical cancer, or other in situ cancers.
  • Has known active central nervous system (CNS) 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 four weeks prior to enrollment 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 enrollment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
  • Has active autoimmune disease that has required systemic treatment within the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs).

    • Note: 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.
  • Subjects requiring daily corticosteroids >10mg of prednisone (or its equivalent) would be excluded from the study.

    • Note: Subjects with asthma that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would NOT be excluded from the study.
  • Has evidence of interstitial lung disease or a history of non-infectious pneumonitis that required oral or intravenous glucocorticoids to assist with management.

    • Note: Lymphangitic spread of the NSCLC is not exclusionary.
  • Has an active infection requiring systemic therapy.
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  • Subjects with cognitive functioning/impairment based on medical record review ad physician decision.
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with informed consent through 180 days after the last dose of trial treatment.
  • Has a diagnosis of immunodeficiency (including Human Immunodeficiency Virus (HIV) or acquired immunodeficiency (AIDS)-related illness) or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to enrollment.
  • Has a known history of active TB (Bacillus Tuberculosis).
  • Has known active Hepatitis B or Hepatitis C.
  • Has received a live vaccine within 30 days of enrollment.

    • 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.
  • BASELINE CORTICOSTEROID AT STUDY ENTRY - subjects may not be on any steroids (dexamethasone, prednisone, etc) at the time of consent/study start.

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): NCT04037462


Contacts
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Contact: Brittany M Pannecouk, BS (734) 845-3966 brittany.pannecouk@va.gov

Locations
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United States, Michigan
VA Ann Arbor Healthcare System, Ann Arbor, MI Not yet recruiting
Ann Arbor, Michigan, United States, 48105
Contact: Brittany M Pannecouk, BS    734-845-3966    brittany.pannecouk@va.gov   
Principal Investigator: Nithya Ramnath, MD         
Sponsors and Collaborators
VA Office of Research and Development
Wayne State University
University of Michigan
Barbara Ann Karmanos Cancer Institute
Investigators
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Principal Investigator: Nithya Ramnath, MD VA Ann Arbor Healthcare System, Ann Arbor, MI

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Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT04037462     History of Changes
Other Study ID Numbers: CSDR-002-18F
First Posted: July 30, 2019    Key Record Dates
Last Update Posted: July 31, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: 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
Dexamethasone
Dexamethasone acetate
BB 1101
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action