Response of Bony Metastasis to Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancers With Actionable Driver Mutations.

Response of Bony Metastasis to Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancers With Actionable Driver Mutations

The purpose of this study is to assess percentage reduction in the of urine NTX and serum CTX , in patients with NSCLC and bone metastases 1) with actionable driver oncogene on standard of care (SOC) TKI at 3 months post treatment and 2) without actionable mutations on standard of care therapy (chemotherapy/immunotherapy) treated with zoledronic acid or denosumab at the same time period.

Study Overview

• Status: Recruiting
• Conditions: Carcinoma, Non-Small-Cell Lung
• Intervention / Treatment: Biological: Tyrosine Kinase Inhibitor; Drug: Zoledronic Acid 4 MG/100 ML Intravenous Solution [ZOMETA]; Drug: Denosumab 120 MG/1.7 ML Subcutaneous Solution [XGEVA]

Detailed Description

This is an observational study involving two arms of NSCLC with metastatic bony disease at the time of enrollment in the study. One group will have an actionable driver oncogene and initiate treatment in any line with a TKI as standard of care and concurrent to participation to this study; expected to have an objective response rate in ≥40% who have not previously seen anti-bone resorptive therapy. The other group will not have actionable mutations and initiate treatment with chemotherapy/immunotherapy along with new onset therapy with IV zoledronic acid 4mg Q4 weeks or subcutaneous denosumab 120 mg Q12 weeks for bone disease, which is standard of care and would be concurrent to participation in this study.

Baseline and on-treatment imaging and serum total alkaline phosphatase will be performed per SOC.

Additional non-SOC bone turnover markers including , urine N-telopeptide (NTX) and serum C-terminal telopeptide (CTX), will be checked at baseline and then at 1, 3, 6, and 12 months.

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

• Study Contact: Name: Vincent Johnson; Phone Number: 13037249805; Email: vincent.p.johnson@cuanschutz.edu

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • University of Colorado Hospital
      • Principal Investigator: Tejas Patil, MD
      • Contact: Vincent Johnson; Phone Number: 303-724-9805; Email: vincent.p.johnson@cuanschutz.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

About 30-40% of patients w/ lung cancer develop bone metastases during their disease; the median survival time of patients w/ this secondary lesion is 7 months. In a retrospective study of 259 non-small cell lung cancer (NSCLC) patients, the most common site of skeletal metastases was the spine in 50% of patients, followed by the ribs (27.1%), ilium (10%), sacrum (7.1%), femur (5.7%) &humerus, scapula & sternum (2.9%). At our institution, it is standard practice not to use anti-bone resorptive therapy in driver mutation-addicted NSCLC w/ bony metastasis, while anti-bone resorptive therapies are commonly used in NSCLC w/ bony metastases w/o any actionable driver mutation. This study relates to exploring the potential differential need for anti-resorptive bone medications (bisphosphonates or RANK-L inhibitors) in patients w/ advanced non-small cell lung cancer & bone metastases w/ & w/o actionable driver mutations.

Description

Inclusion Criteria:

1. Provision to sign and date the consent form
2. Stated willingness to comply with all study procedures and be available for the duration of the study
3. Be a male or female aged 18-100 years
4. Pathologically confirmed non-small cell lung cancer
5. Molecular testing through a CLIA-validated NGS assay. This can be done using either tissue based samples or blood-based samples (ctDNA)
6. ECOG PS 0-2
7. Decision to be on a particular standard of care TKI or chemotherapy +/- immunotherapy (clinical decision that would occur prior to study enrollment)
8. Patients who will be treated with an osteoclast inhibitor must receive dental clearance prior to starting treatment
9. Bone metastases must be detected through radiographic imaging prior to enrollment on this study.

Exclusion Criteria:

1. Actionable driver mutation NSCLC patient who has been on anti-bone resorptive therapy

   a. Excluded anti-bone resorptive therapy includes: zolendronic acid, pamidronate, alendronate, denosumab or any medication that acts as an osteoclast inhibitor

2. Have any condition or illness that, in the opinion of the investigator, would compromise participant safety or interfere with evaluation while on standard of care treatments for the NSCLC.
3. Patients with actionable driver mutation who received TKI in past or currently on TKI prior to screening
4. Bone metastases that have received prior radiotherapy unless unequivocal progression has occurred since radiation therapy

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Actionable driver oncogene; One group will have an actionable driver oncogene and initiate treatment in any line with a TKI as standard of care and concurrent to participation to this study; expected to have an objective response rate in ≥40% who have not previously seen anti-bone resorptive therapy.	Biological: Tyrosine Kinase Inhibitor; Targeted therapy given as standard of care.
No Actionable Mutations; The other group will not have actionable mutations and initiate treatment with chemotherapy/immunotherapy along with new onset therapy with IV zoledronic acid 4mg Q4 weeks or subcutaneous denosumab 120 mg Q12 weeks for bone disease, which is standard of care and would be concurrent to participation in this study.	Drug: Zoledronic Acid 4 MG/100 ML Intravenous Solution [ZOMETA]; Given Q4 weeks as standard of care; Drug: Denosumab 120 MG/1.7 ML Subcutaneous Solution [XGEVA]; Given Q12 weeks for bone disease as standard of care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage reduction of urine NTX and serum CTX	The percentage reduction in the bone turnover markers including urine N-telopeptide (NTX) and serum C-terminal telopeptide (CTX) from baseline at 3 months from starting TKI (oncogene arm) or anti-resorptive therapy as part of standard systemic therapy (non-oncogene arm).	3 months post-treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Skeletal-related events (SREs)	Skeletal-related events (SREs) defined as the adverse events associated with bone metastases. SREs would include pathologic fractures, the requirement for surgery or radiotherapy, spinal cord compression.	1, 3, 6, and 12 months post-treatment
Progression Free Survival (PFS)	Progression Free Survival (PFS) would be defined as progression of disease or death from any cause from time of randomization until the end of study.	at 1 year
Objective Response Rate (ORR)	Objective Response Rate (ORR) defined as proportion of patients with reduction in bony metastases as evaluated by using both the MD Anderson (MDA) criteria for patients who receive CT or bone scans and Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) for patients who undergo FDG PET/CT. These criteria allow for categorization of disease response from complete response to progressive disease.	at 1 year
Percentage reduction in the bone turnover markers including urine N-telopeptide (NTX) and serum C-terminal telopeptide (CTX)	Percentage reduction in the bone turnover markers including urine N-telopeptide (NTX) and serum C-terminal telopeptide (CTX) from baseline at 1, 6 and 12 months.	From Baseline at 1, 6, and 12 months post-treatment
Percentage normalization of blood total alkaline phosphatase	Percentage normalization of blood total alkaline phosphatase from baseline at 1, 3, 6, and 12 months. Normal level of blood total alkaline phosphatase would be defined as equal or less than 147 IU/L.	From baseline at 1, 3, 6, and 12 months

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Investigators: Principal Investigator: Tejas Patil, MD, Colorado Research Center

Study record dates

Study Major Dates

• Study Start (Actual): April 28, 2020
• Primary Completion (Estimated): March 5, 2025
• Study Completion (Estimated): March 5, 2026

Study Registration Dates

• First Submitted: May 14, 2019
• First Submitted That Met QC Criteria: May 20, 2019
• First Posted (Actual): May 22, 2019

Study Record Updates

• Last Update Posted (Actual): March 20, 2024
• Last Update Submitted That Met QC Criteria: March 19, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Bone Density Conservation Agents; Pharmaceutical Solutions; Zoledronic Acid; Denosumab; Tyrosine Kinase Inhibitors
• Other Study ID Numbers: 19-0392.cc

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and clinical laboratory data will be entered into REDCap; the data system includes password protection and internal quality checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the source documents.Data will be tracked using REDCap. Data collected for this study will be analyzed and stored at the University of Colorado Cancer Center.

When the study is completed, access to study data will be provided through the UCCC Oncology Clinical Research Support Team.

• IPD Sharing Time Frame: immediately following publication. no end date.
• IPD Sharing Access Criteria: Anyone who wishes to access the data. any purpose. Data are available indefinitely.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No