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.
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
Drug | Synonyms | Arms |
---|
Dexamthasone | | Lead 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
Name | Type | Description | Interventions |
---|
Lead in Dexamethasone followed by immunotherapy | Experimental | 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 | |
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: | Recruiting |
Lead Sponsor: | VA Office of Research and Development |
Last Updated
February 5, 2021