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Phase I/II Calcitriol in Lung Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00794547
Recruitment Status : Terminated
First Posted : November 20, 2008
Results First Posted : May 5, 2014
Last Update Posted : December 12, 2017
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Non Small Cell Lung Cancer Drug: Calcitriol Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 34 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (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
Study Start Date : December 2008
Actual Primary Completion Date : October 2011
Actual Study Completion Date : August 2013

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer
Drug Information available for: Calcitriol

Arm Intervention/treatment
Experimental: 1
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.
Drug: Calcitriol
Escalating dose of Calcitriol will be infused IV over 1 hour every 21 days.

Experimental: 2
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.
Drug: Calcitriol
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

Primary Outcome Measures :
  1. 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 ]
    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.

  2. Number of Participants That Experience Grade 3 or Greater Neutropenia [ Time Frame: 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.

  3. Median Time to Progression [ Time Frame: 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.

  4. Median Overall Survival [ Time Frame: 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.

Secondary Outcome Measures :
  1. Mean AUC 1,25-D3 Concentration at 12 and 24 Hours [ Time Frame: 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.

Other Outcome Measures:
  1. 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 ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

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))

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00794547

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United States, Michigan
VA Ann Arbor Healthcare System
Ann Arbor, Michigan, United States, 48105
St. Joseph Mercy Hospital
Ann Arbor, Michigan, United States, 48106
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, United States, 48109
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
Sponsors and Collaborators
University of Michigan Rogel Cancer Center
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Principal Investigator: Nithya Ramnath, MD University of Michigan Rogel Cancer Center

Publications of Results:
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Responsible Party: University of Michigan Rogel Cancer Center Identifier: NCT00794547    
Obsolete Identifiers: NCT00470431
Other Study ID Numbers: UMCC 2008.042
HUM 21242 ( Other Identifier: University of Michigan Medical IRB )
First Posted: November 20, 2008    Key Record Dates
Results First Posted: May 5, 2014
Last Update Posted: December 12, 2017
Last Verified: November 2017
Keywords provided by University of Michigan Rogel Cancer Center:
lung cancer; nsclc
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Calcium-Regulating Hormones and Agents
Physiological Effects of Drugs
Calcium Channel Agonists
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Vasoconstrictor Agents
Growth Substances
Bone Density Conservation Agents