Phase I/II Calcitriol in Lung Cancer
According to the Cancer Atlas, lung cancer remains the major cancer among the 10.9 million new cases of cancer diagnosed annually worldwide. The mortality from lung cancer is greater than the combined mortality for breast, colon and prostate cancer combined. Most patients with metastatic non-small-cell lung cancer (NSCLC) are treated with platinum-based chemotherapy regimens. The drug combination of cisplatin and docetaxel is one of the commonly used regimens in metastatic NSCLC. Although both drugs are powerful disruptors of cell growth, positive therapeutic response rates to this therapy remain low for NSCLC patients, from 25% to 30%. While adding new biologics such as bevacizumab to the current treatment standard can improve treatment response, median survival for advanced NSCLC patients receiving this type of treatment remains low at under 12 months. Research studies have demonstrated that Vitamin D, and it's signaling pathways are important biological targets in cancer therapeutics. In vitro and in vivo calcitriol (1, 25 dihydroxycholecalciferol) is antiproliferative and potentiates the antitumor effects of cytotoxic agents (e.g. taxanes, platinum analogues). We have shown that administration of high doses of calcitriol and cisplatin is feasible and associated with complete tumor regressions in dogs with spontaneous cancers. Calcitriol has also shown to be synergistic with docetaxel both in preclinical as well as in a recent phase II clinical trial in prostate cancer. Based on these results and other supporting data from studies indicating that calcitriol functions as a potent and well tolerated anti-tumor agent when used in combination with drugs likes cisplatin and docetaxel, we hypothesize that introducing calcitriol into treatment regimes for NSCLC patients has the potential to demonstrably improve treatment response for these patients. The overall goals for conducting this phase I/II clinical study will be (1) to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of calcitriol in combination with cisplatin/docetaxel in patients with advanced NSCLC, (2) to assess the response rates of patients with advanced NSCLC to the combination of calcitriol with cisplatin/docetaxel, (3) to evaluate the pharmacokinetics (PK) of administering calcitriol intravenously at the MTD, and (4) to evaluate correlations between calcitriol PK and changes on specific coding regions of the gene associated with calcitriol breakdown.
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I/II Clinical Trial of Intravenous (IV) Calcitriol With Fixed Dose of Cisplatin and Docetaxel in Advanced Non-Small Cell Lung Cancer|
- MTD of Intravenous Calcitriol When Administered Prior to Fixed Dose Cisplatin 75mg/m2 and Docetaxel 75 mg/m2, Every 3 Weeks in Patients With Advanced Non-small Cell Lung Cancer (NSCLC) [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]The primary objective was to determine the Maximum Tolerated Dose (MTD) of intravenous calcitriol when administered prior to fixed dose cisplatin 75mg/m2 and docetaxel 75 mg/m2, every 3 weeks in patients with advanced non-small cell lung cancer (NSCLC). Accrual duration for the study is 5 years.
- Number of Participants That Experience Grade 3 or Greater Neutropenia [ Time Frame: 30 days after last dose ] [ Designated as safety issue: Yes ]The second primary objective was to characterize the toxicity and response of patients treated with a combination of calcitriol, cisplatin and docetaxel. Toxicity was assessed, in part, by noting the number of participants that experience grade 3 or greater neutropenia in each phase of the trial. Toxicities were recorded using NCI CTCAE (Common Terminology Criteria for Adverse Events) version 3.0 and were followed for 30 days after the date of withdrawal from study drug.
- Median Time to Progression [ Time Frame: 5 years ] [ Designated as safety issue: No ]The second primary objective was to characterize the toxicity and response of patients treated with a combination of calcitriol, cisplatin and docetaxel. To assess the response, median time to progression was determined. Progression was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions.
- Median Overall Survival [ Time Frame: 5 years ] [ Designated as safety issue: No ]The second primary objective was to characterize the toxicity and response of patients treated with a combination of calcitriol, cisplatin and docetaxel. To assess the response, overall survival was determined.
- To Assess Pharmacokinetics (PK) of Intravenous (IV) Calcitriol in Combination With Cisplatin and Docetaxel During Cycle 1 of the Phase II Part of the Study Using a Validated Limited Sampling Technique. [ Time Frame: 3-6 months ] [ Designated as safety issue: Yes ]
- To Correlate the Pharmacokinetic Parameters of Systemic Calcitriol Exposure (AUC) With SNPs of the 24-hydroxylase (CYP24), the Major Vitamin D3 Inactivating Enzyme. [ Time Frame: 3-6 months ] [ Designated as safety issue: Yes ]
|Study Start Date:||December 2008|
|Study Completion Date:||August 2013|
|Primary Completion Date:||October 2011 (Final data collection date for primary outcome measure)|
In the Phase I part of the study, we will test the safety of calcitriol along with standard chemotherapy. In addition, the goal is to see what effects (good and bad) it has on you and your type of Non-Small Cell Lung Cancer. This study is ongoing. In this portion of the study, we are testing increasing doses of calcitriol in combination with standard chemotherapy. If 2/3 patients at any dose level experience side effects that are limiting, we will call the dose level below that dose the maximum tolerated dose.
Escalating dose of Calcitriol will be infused IV over 1 hour every 21 days.
In the Phase II part of the study, we will find out the response of subjects' cancer has to the combination of a fixed dose of calcitriol (determined in the phase I study) with standard chemotherapy.
In this portion of the study, all patients will get the same dose of calcitriol (determined from the Phase I study) along with the standard chemotherapy
Please refer to this study by its ClinicalTrials.gov identifier: NCT00794547
|United States, Michigan|
|University of Michigan Comprehensive Cancer Center|
|Ann Arbor, Michigan, United States, 48109|
|VA Ann Arbor Healthcare System|
|Ann Arbor, Michigan, United States, 48105|
|St. Joseph Mercy Hospital|
|Ann Arbor, Michigan, United States, 48106|
|United States, New York|
|Roswell Park Cancer Institute|
|Buffalo, New York, United States, 14263|
|Principal Investigator:||Nithya Ramnath, MD||University of Michigan Cancer Center|