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

NCT04037462 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: CSDR-002-18F
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

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.

Conditions

Non-Small Cell Lung Cancer; Immunotherapy

Outcome Measures

Primary Outcomes (1)

• Change in Fluoro-3' Deoxythymidine Positron Emission Tomography (FLT-PET) Signal

  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 SUVmax will be measured at baseline and after Dex run-in and wash out period. For example, in Cohort A, patients will get an FLT- PET at baseline, then receive Dexamethasone 4mg PO BID given for 7 days, followed by taper over 2-4 days and 3 day wash out and then the post-Dex FLT-PET.

  Baseline and Post DEX (14 days)

Secondary Outcomes (1)

• Response Rate

  3 months

Study Arms (1)

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

Drug: Dexamthasone

Interventions

Dexamthasone DRUG

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

Lead in Dexamethasone followed by immunotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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).

Sponsors & Collaborators

• VA Office of Research and Development: lead
• Wayne State University: collaborator
• University of Michigan: collaborator
• Barbara Ann Karmanos Cancer Institute: collaborator

Study Sites (1)

VA Ann Arbor Healthcare System, Ann Arbor, MI

Ann Arbor, Michigan, 48105-2303, United States

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Limitations and Caveats

We consented 3 participants and had one subject rescind consent leaving us with 2 enrolled participants. of the 2 participants only was was evaluable. Therefore, we do not have sufficient data to prove outcomes measures

Results Point of Contact

• Title: Dr. Nithya Ramnath
• Organization: VA Ann Arbor Healthcare System

Nithya.Ramnath@va.gov

(734) 845-5800

Study Officials

• Nithya Ramnath, MD

  VA Ann Arbor Healthcare System, Ann Arbor, MI

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: FED
• Responsible Party: SPONSOR

Model Details: 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).

Study Record Dates

• First Submitted: July 26, 2019
• First Posted: July 30, 2019
• Study Start: July 7, 2021
• Primary Completion: February 23, 2022
• Study Completion: February 23, 2023
• Last Updated: June 14, 2024
• Results First Posted: June 14, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)