Clinical Trials /

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

NCT04037462

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. 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.

Related Conditions:
  • Lung Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Induction of Sensecence Using Dexamethasone to Re-sensitize NSCLC to Anti-PD1 Therapy
  • Official Title: Induction of Sensecence Using Dexamethasone to Re-sensitize NSCLC to Anti-PD1 Therapy

Clinical Trial IDs

  • ORG STUDY ID: CSDR-002-18F
  • NCT ID: NCT04037462

Conditions

  • Non-Small Cell Lung Cancer
  • Immunotherapy

Interventions

DrugSynonymsArms
DexamthasoneLead in Dexamethasone followed by immunotherapy

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Lead in Dexamethasone followed by immunotherapyExperimentalescalating 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
  • Dexamthasone

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Reduction in FLT-PET signal
Time Frame:12 months
Safety Issue:
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.

Secondary Outcome Measures

Measure:Response rate
Time Frame:24 months
Safety Issue:
Description: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%).

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:VA Office of Research and Development

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