Recurrent Non Small Cell Lung Cancer
Conditions
Keywords
Recurrent Non-Small Cell Lung Cancer
Brief summary
Primary Objective To evaluate the 3-month event-free survival of the combination of the combination of itraconazole and pemetrexed in patients with recurrent/refractory non-small cell lung cancer. Secondary Objectives To determine the objective response rate of the combination of itraconazole and pemetrexed in patients with recurrent/refractory non-small cell lung cancer.
Detailed description
Primary Objective To evaluate the 3-month event-free survival of the combination of the combination of itraconazole and pemetrexed in patients with recurrent/refractory non-small cell lung cancer. 3-month event-free survival (EFS) is defined as the proportion of patients who are alive and without event after 3 months (evaluated in a window of +/- 1 week) of treatment. Events are defined as disease progression or death from any cause. All patients treated on protocol will be included in the determination of EFS, regardless of treatment modification or discontinuation. Secondary Objectives To determine the objective response rate of the combination of itraconazole and pemetrexed in patients with recurrent/refractory non-small cell lung cancer. The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.
Interventions
DRUGItraconazole
Itraconazole 200 mg once daily
DRUGPemetrexed
Pemetrexed every 21 days.
Sponsors
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Patients must have histologically or cytologically confirmed NSCLC. * Patient must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \>20 mm with conventional techniques or as \>10 mm with spiral CT scan. See Section 11 for the evaluation of measurable and non-measurable disease. * Patients must have received at least one previous chemotherapy regimen and have recurrent or refractory disease. * Age \>18 years. Because no dosing or adverse event data are currently available on the use of itraconazole in combination with pemetrexed in patients \< 18 years of age, such patients are excluded from this study but will be eligible for future pediatric phase 2 combination trials. * Life expectancy of greater than 12 weeks. * ECOG performance status \< 2 (Karnofsky \> 60%; see Appendix A). * Patients must have normal organ and marrow function as defined below: * leukocyte \> 3,000/mcL * absolute neutrophil count \> 1,500/mcL * platelets \> 100,000/mcL * total bilirubin within normal institutional limits * AST(SGOT)/ALT(SGPT)\< 2.5 X institutional upper limit of normal * creatinine within normal institutional limits * creatinine clearance \> 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal * Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. * Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
* Patients who have had chemotherapy or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier. * Patients may not be receiving any other investigational agents. * Patients who have received prior pemetrexed chemotherapy. * Patients with uncontrolled brain metastases. Patients with brain metastases must have stable neurologic status following local therapy (surgery or radiation) for at least 2 weeks, and must be without neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to itraconazole and pemetrexed or other agents used in the study. * Itraconazole is a strong CYP3A4 inhibitor and may increase plasma concentrations of drugs metabolized by this pathway. Coadministration of cisapride, midazolam, pimozide, quinidine, lovastatin, simvastatin, triazolam, dofetilide, or levacetylmethadol (levomethadyl) with itraconazole is contraindicated. Patients who take any of these medications and who are not able to change to an alternative medication will be excluded. Lists including medications and substances known or with the potential to interact with the CYP3A4 isoenzymes are provided in Section 7.1. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Pregnant women are excluded from this study because itraconazole and pemetrexed are Class C and D agents, respectively, with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with itraconazole and pemetrexed, breastfeeding should be discontinued if the mother is treated with itraconazole or pemetrexed. These potential risks may also apply to other agents used in this study. * HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with itraconazole or pemetrexed. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | up to 3 years | Median number of days alive |
| Progression Free Survival as Measured by Number of Days Without Disease Progression | 1 year | — |
| RECIST Response | Up to 3 years | Number of participants with partial response (PR), stable disease (SD) and progressive disease (PD) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Blood Flow | 3 years | Tumor blood flow activity in patients with previously treated non-squamous non-small cell lung cancer receiving pemetrexed alone or pemetrexed plus itraconazole. |
| Tumor Metabolic Activity | 3 years | Tumor metabolic activity in patients with previously treated non-squamous non-small cell lung cancer receiving pemetrexed alone or pemetrexed plus itraconazole. |
Countries
Singapore, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Itraconazole Open Label Added to Standard of Care Pemetrexed Subjects will receive standard dose pemetrexed day 1 of each 21-day cycle, IV. Participants will be randomized at the beginning of the study to receive either oral itraconazole 200 mg once daily during the period of chemotherapy (days 1-21).
Itraconazole: Itraconazole 200 mg once daily | 15 |
| Single Agent Pemetrexed Subjects will receive standard dose pemetrexed day 1 of each 21-day cycle, IV. Participants will be randomized at the beginning of the study to receive pemetrexed alone.
Pemetrexed | 8 |
| Total | 23 |
Baseline characteristics
| Characteristic | Single Agent Pemetrexed | Itraconazole Open Label Added to Standard of Care Pemetrexed | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 3 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 12 Participants | 17 Participants |
| Age, Continuous | 59 years | 60 years | 59.5 years |
| Region of Enrollment United States | 8 participants | 15 participants | 23 participants |
| Sex: Female, Male Female | 5 Participants | 7 Participants | 12 Participants |
| Sex: Female, Male Male | 3 Participants | 8 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 15 | 6 / 8 |
| other Total, other adverse events | 3 / 15 | 2 / 8 |
| serious Total, serious adverse events | 2 / 15 | 2 / 8 |
Outcome results
Primary
Overall Survival
Median number of days alive
Time frame: up to 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A | Overall Survival | 971 days |
| Arm B | Overall Survival | 242 days |
Primary
Progression Free Survival as Measured by Number of Days Without Disease Progression
Time frame: 1 year
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A | Progression Free Survival as Measured by Number of Days Without Disease Progression | 168 days |
| Arm B | Progression Free Survival as Measured by Number of Days Without Disease Progression | 84 days |
Primary
RECIST Response
Number of participants with partial response (PR), stable disease (SD) and progressive disease (PD) as defined by Response Evaluation Criteria in Solid Tumors (RECIST)
Time frame: Up to 3 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | RECIST Response | PR | 3 Participants |
| Arm A | RECIST Response | SD | 8 Participants |
| Arm A | RECIST Response | PD | 2 Participants |
| Arm A | RECIST Response | Inevaluable | 2 Participants |
| Arm B | RECIST Response | Inevaluable | 1 Participants |
| Arm B | RECIST Response | PR | 0 Participants |
| Arm B | RECIST Response | PD | 2 Participants |
| Arm B | RECIST Response | SD | 5 Participants |
Secondary
Tumor Blood Flow
Tumor blood flow activity in patients with previously treated non-squamous non-small cell lung cancer receiving pemetrexed alone or pemetrexed plus itraconazole.
Time frame: 3 years
Population: Data was not collected to assess this outcome measure.
Secondary
Tumor Metabolic Activity
Tumor metabolic activity in patients with previously treated non-squamous non-small cell lung cancer receiving pemetrexed alone or pemetrexed plus itraconazole.
Time frame: 3 years
Population: Data was not collected to assess this outcome measure.