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

• ClinicalTrials.gov Identifier: NCT03958565
• Recruitment Status: Recruiting
• First Posted: May 22, 2019
• Last Update Posted: November 8, 2021
• Sponsor: University of Colorado, Denver
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): University of Colorado, Denver

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment
Carcinoma, Non-Small-Cell Lung	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 Design

• Study Type: Observational
• Estimated Enrollment: 100 participants
• Observational Model: Other
• Time Perspective: Prospective
• Official Title: Response of Bony Metastasis to Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancers With Actionable Driver Mutations
• Actual Study Start Date: April 15, 2019
• Estimated Primary Completion Date: March 5, 2022
• Estimated Study Completion Date: March 5, 2023

Groups and Cohorts

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

Outcome Measures

Primary Outcome Measures :

1. Percentage reduction of urine NTX and serum CTX [ Time Frame: 3 months post-treatment ]
   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).

Secondary Outcome Measures :

1. Skeletal-related events (SREs) [ Time Frame: 1, 3, 6, and 12 months post-treatment ]
   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.
2. Progression Free Survival (PFS) [ Time Frame: at 1 year ]
   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.
3. Objective Response Rate (ORR) [ Time Frame: at 1 year ]
   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.
4. Percentage reduction in the bone turnover markers including urine N-telopeptide (NTX) and serum C-terminal telopeptide (CTX) [ Time Frame: From Baseline at 1, 6, and 12 months post-treatment ]
   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.
5. Percentage normalization of blood total alkaline phosphatase [ Time Frame: From baseline at 1, 3, 6, and 12 months ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 100 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Probability Sample

Study Population

About 30-40% of patients with lung cancer develop bone metastases during the course of their disease; the median survival time of patients with 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%) and humerus, scapula and sternum (2.9%). At our institution it is a standard practice not to use anti-bone resorptive therapy in driver mutation addicted NSCLC with bony metastasis, while anti-bone resorptive therapies are commonly used in NSCLC with bony metastases without 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 with advanced non-small cell lung cancer and bone metastases with and without actionable driver mutations.

Criteria

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 with bone metastasis and with or without driver actionable oncogene
5. ECOG PS 0-2
6. Decision to be on a particular standard of care TKI or chemotherapy/immunotherapy (clinical decision that would occur prior to study enrollment)

Exclusion Criteria:

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

Contacts and Locations

Contacts

Contact: Paula Fisk; 720-848-0671; Paula.fisk@ucdenver.edu

Contact: Joshua Saginaw; 720-848-9281; Joshua.saginaw@ucdenver.edu

Locations

United States, Colorado

University of Colorado Hospital; Recruiting

Aurora, Colorado, United States, 80045

Contact: Paula Fisk 720-848-0671 Paula.fisk@ucdenver.edu

Principal Investigator: Tejas Patil, MD

Sponsors and Collaborators

University of Colorado, Denver

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Tejas Patil, MD; Colorado Research Center

More Information

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT03958565
• Other Study ID Numbers: 19-0392.cc; P30CA046934 ( U.S. NIH Grant/Contract )
• First Posted: May 22, 2019
• Last Update Posted: November 8, 2021
• Last Verified: November 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

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.

• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• Time Frame: immediately following publication. no end date.
• Access Criteria: Anyone who wishes to access the data. any purpose. Data are available indefinitely.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

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; Zoledronic Acid; Denosumab; Pharmaceutical Solutions; Bone Density Conservation Agents; Physiological Effects of Drugs