Phase I/II Calcitriol in Lung Cancer

Phase 1

Terminated

• Conditions: Non Small Cell Lung Cancer
• Interventions: Drug: Calcitriol

• Registration Number: NCT00794547
• Lead Sponsor: University of Michigan Rogel Cancer Center

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2008-11-19
• Study First Submitted QC: 2008-11-19
• Study First Posted: 2008-11-20
• Study Start: 2008-12
• Primary Completion: 2011-10
• Study Completion: 2013-08
• Results First Submitted: 2014-03-31
• Results First Submitted QC: 2014-03-31
• Results First Posted: 2014-05-05
• Status Verified: 2017-11
• Last Update Submitted: 2017-11-13
• Last Update Posted: 2017-12-12

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 34

Inclusion Criteria

1. Proven histological or cytological diagnosis of stage IIIB (malignant pleural effusion) IV NSCLC.
2. Age more than 18 years
3. Performance status must be ECOG 0-1.
4. No prior or concurrent malignancy, except non-melanoma skin cancer, or CIS of the cervix, unless documented disease-free for more than 2 years.
5. No prior use of chemotherapy for stage IV NSCLC; Adjuvant therapy is permitted.
6. Adequate bone marrow, hepatic, and renal function, as evidenced by the following: WBC 3.0 x 109/L, neutrophils 1.5 x 109 /L; platelet count 100 x 109/L; Hgb> 10 g/dL (may be transfused to 10g/dL); total bilirubin within the upper limit of the institutional normal range; (transaminases SGOT or SGPT) 1.5 times the upper limit of the institutional normal range. Creatinine within the upper limit of the institutional normal range; creatinine clearance >50 ml/min
7. Patients must have measurable or evaluable disease (not required for the phase I part of the study)
8. Normal cardiac function with no history of uncontrolled heart disease
9. Female patients must not be pregnant; they must be post-menopausal or practicing an accepted form of birth control. If pregnancy is a possibility, a pregnancy test will be required prior to initiation of therapy.
10. Life expectancy of at least 12 weeks.
11. Patient and investigator signed study-specific consent form, indicating the investigational nature of the study
12. Patients must be accessible for treatment and follow-up.
13. No chemotherapy or radiotherapy within 3 weeks of study entry defined here as day 1 of therapy with calcitriol plus chemotherapy (6 weeks for mitomycin C or a nitrosourea).
14. No treatment with investigational drugs within 3 weeks of study entry.
15. No other serious illness or medical condition including unstable cardiac disease requiring treatment, new onset crescendo or rest angina; history of significant neurological or psychiatric disorders including psychotic disorders, dementia, or seizures; or active infection are permitted. No evidence of grade > 2 peripheral neuropathy. No history of severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80
16. Palliative radiation is permitted (as long as marrow exposed not greater than 10%; please see Appendix IV for reference) At least 1 week since the last palliative XRT.
17. Treated brain metastasis allowed with no waiting period following gamma knife and at least 2 weeks after whole brain XRT as long as neurologically stable.

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Exclusion Criteria

1. Known hypersensitivity to Vitamin D, docetaxel, cisplatin

2. Hypercalcemia (patients with serum albumin corrected calcium* > 10.7 mg/dL)

3. History of renal/bladder stones over the past 10 years

4. History of nephrectomy.

5. Uncontrolled heart disease, unstable angina, heart failure, current digoxin therapy

6. Thiazide, Digoxin or glucocorticoid therapy (except the pre-medication Dexamethasone used in the study as prescribed)

7. Unwillingness to stop calcium supplementation

8. Concurrent use of Phenytoin, Barbiturates, Rifampin, Carbamazepine, Phenobarbital or St John's wort.

9. Treatment with any investigational drug within 3 weeks before Day 1 of protocol

10. Any unresolved toxicity (NCI CTCAE version 3.0,>2) (Please see appendix V for link)

11. Pregnancy/Lactation

12. Patients with IIIB NSCLC who are eligible for definitive chemoradiation.

    • Ca corrected = Ca (measured) + (0.8 x (4 - albumin))

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
1	Calcitriol	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.
2	Calcitriol	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.

Primary Outcome Measures

Name	Time	Method
Median Overall Survival	5 years	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.
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)	5 years	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	30 days after last dose	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	5 years	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.

Secondary Outcome Measures

Name	Time	Method
Mean AUC 1,25-D3 Concentration at 12 and 24 Hours	12 and 24 hours post dose	The mean AUC (area under the curve) concentrations of 1,25-D3 from 0-12 hours and 0-24 hours will be calculated.

Trial Locations

Locations (4)

St. Joseph Mercy Hospital; 🇺🇸 Ann Arbor, Michigan, United States

Roswell Park Cancer Institute; 🇺🇸 Buffalo, New York, United States

University of Michigan Comprehensive Cancer Center; 🇺🇸 Ann Arbor, Michigan, United States

VA Ann Arbor Healthcare System; 🇺🇸 Ann Arbor, Michigan, United States