Phase I/II Calcitriol in Lung Cancer

• To conduct a phase I study to determine the MTD and the DLT 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: 3-6 months ] [ Designated as safety issue: Yes ]
• To conduct phase II study using MTD of calcitriol determined from phase I study in combination with fixed dose cisplatin (75mg/m2) and docetaxel (75 mg/m2) administered q 3 weeks in patients with advanced NSCLC; toxicity and response of combination. [ Time Frame: 3-6 months ] [ Designated as safety issue: Yes ]

• 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 ]

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 dihydroxycholcalciferol) 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.

• Drug: Calcitriol
  Escalating dose of Calcitriol will be infused IV over 1 hour every 21 days.
• 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

• 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.
  Intervention: Drug: Calcitriol
• 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.
  Intervention: Drug: Calcitriol

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))