Non Small Cell Lung Cancer
Conditions
Keywords
lung cancer; nsclc
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.
Interventions
DRUGCalcitriol
Escalating dose of Calcitriol will be infused IV over 1 hour every 21 days.
Sponsors
University of Michigan Rogel Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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))
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Other
| Measure | Time frame |
|---|---|
| To Correlate the Pharmacokinetic Parameters of Systemic Calcitriol Exposure (AUC) With SNPs of the 24-hydroxylase (CYP24), the Major Vitamin D3 Inactivating Enzyme. | 3-6 months |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Calcitriol + Cisplatin + Docetaxel Calcitriol, administered IV at 30, 45, 60, 80, or 100 mcg/m\^2 (every 21 days), along with Cisplatin, 75 mg/m\^2 (every three weeks), and Docetaxel, 75 mg/m\^2 (every three weeks). | 34 |
| Total | 34 |
Baseline characteristics
| Characteristic | Calcitriol + Cisplatin + Docetaxel |
|---|---|
| Age, Continuous | 54 years |
| Histology Adenocarcinoma | 21 participants |
| Histology NSCLC NOS | 1 participants |
| Histology Squamous carcinoma | 12 participants |
| Performance Status Performance Status 0 | 16 participants |
| Performance Status Performance Status 1 | 18 participants |
| Region of Enrollment United States | 34 participants |
| Sex: Female, Male Female | 22 Participants |
| Sex: Female, Male Male | 12 Participants |
| Smoking Status Ever Smoker | 29 participants |
| Smoking Status Never Smoker | 2 participants |
| Smoking Status Unknown | 3 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 34 / 34 |
| serious Total, serious adverse events | 20 / 34 |
Outcome results
Primary
Median Overall Survival
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.
Time frame: 5 years
Population: 22 patients were treated at the Maximum Tolerated Dose, including 6 phase I patients who received the MTD during the phase 1 component. 1 of 6 phase 1 patients was not evaluable due to toxicity. 1 patient (of 16) in the phase 2 study went to another therapy prior to the 30 day window and was excluded from analysis. 20 patients were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Calcitriol + Cisplatin + Docetaxel | Median Overall Survival | 8.7 months |
Primary
Median Time to Progression
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.
Time frame: 5 years
Population: 22 patients were treated at the Maximum Tolerated Dose, including 6 phase I patients who received the MTD during the phase 1 component. 1 of 6 phase 1 patients was not evaluable due to toxicity. 1 patient (of 16) in the phase 2 study went to another therapy prior to the 30 day window and was excluded from analysis. 20 patients were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Calcitriol + Cisplatin + Docetaxel | Median Time to Progression | 5.8 months |
Primary
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)
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.
Time frame: 5 years
Population: Eighteen patients were enrolled, and 16 were evaluable for toxicity assessments. Two patients were not evaluable as they progressed prior to completion of cycle 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Calcitriol + Cisplatin + Docetaxel | 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) | 60 mcg/m^2 |
Primary
Number of Participants That Experience Grade 3 or Greater Neutropenia
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.
Time frame: 30 days after last dose
Population: Thirty-four patients were enrolled (18 in phase I and 16 in phase II). 16 of 18 patients enrolled in the Phase 1 portion of the study were evaluable for toxicity. One patient in the phase II study went to another therapy prior to the 30 day window for a confirmatory scan and was thus excluded from analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Calcitriol + Cisplatin + Docetaxel | Number of Participants That Experience Grade 3 or Greater Neutropenia | # of Phase 1 Participants w/ Grade 3+ Neutropenia | 8 participants |
| Calcitriol + Cisplatin + Docetaxel | Number of Participants That Experience Grade 3 or Greater Neutropenia | # of Phase 2 Participants w/ Grade 3+ Neutropenia | 9 participants |
Secondary
Mean AUC 1,25-D3 Concentration at 12 and 24 Hours
The mean AUC (area under the curve) concentrations of 1,25-D3 from 0-12 hours and 0-24 hours will be calculated.
Time frame: 12 and 24 hours post dose
Population: Patients from the phase II portion of the study were included in the pharmacokinetics analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Calcitriol + Cisplatin + Docetaxel | Mean AUC 1,25-D3 Concentration at 12 and 24 Hours | AUC 0-12 Hours | 15.95 h*ng/mL | Standard Error 0.92 |
| Calcitriol + Cisplatin + Docetaxel | Mean AUC 1,25-D3 Concentration at 12 and 24 Hours | AUC 0-24 Hours | 31.74 h*ng/mL | Standard Error 1.92 |
Other Pre-specified
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