Phase II Study of Itraconazole and Pemetrexed in Patients With Previously Treated Non-Squamous NSCLC

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00769600
• Collaborator: (none)
• Enrollment: 23
• Locations: 2
• Arms: 2
• Duration (Months): 51
• Patients Per Site: 11.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Non Small Cell Lung Cancer	Drug: Itraconazole; Drug: Pemetrexed	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II Study of Itraconazole and Pemetrexed in Patients With Previously Treated Non-Squamous Non-Small Cell Lung Cancer
• Study Start Date: Nov 1, 2008
• Actual Primary Completion Date: Jan 1, 2013
• Actual Study Completion Date: Feb 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Itraconazole with Pemetrexed Pemetrexed IV every 21 days with oral Itraconazole 200mg daily.	Drug: Itraconazole; Itraconazole 200 mg once daily; Other Names: Sporanox ; Drug: Pemetrexed; Pemetrexed every 21 days.; Other Names: Alimta
Active Comparator: Single agent pemetrexed Pemetrexed IV on day 1 of 21-day cycle.	Drug: Pemetrexed; Pemetrexed every 21 days.; Other Names: Alimta

Outcome Measures

Primary Outcome Measures

1. Overall Survival [up to 3 years]

   Median number of days alive

2. Progression Free Survival as Measured by Number of Days Without Disease Progression [1 year]

3. 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 Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 100 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland	United States	21231
2	Singapore General Hospital	Tiong Bahru Estate		Singapore	308433

Sponsors and Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Investigators

• Principal Investigator: Charles M Rudin, MD, PhD, Johns Hopkins University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT00769600
• Other Study ID Numbers: J0881JS; NA_00020074
• First Posted: Oct 9, 2008
• Last Update Posted: Feb 1, 2019
• Last Verified: Jan 1, 2019

• Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: Recurrent Non-Small Cell Lung Cancer
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Itraconazole; Pemetrexed

Study Results

Participant Flow

Arm/Group Title	Itraconazole Open Label Added to Standard of Care Pemetrexed	Single Agent Pemetrexed
Arm/Group Description	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	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
Period Title: Overall Study
STARTED	15	8
COMPLETED	15	8
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Itraconazole Open Label Added to Standard of Care Pemetrexed	Single Agent Pemetrexed	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	15	8	23
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	12 80%	5 62.5%	17 73.9%
>=65 years	3 20%	3 37.5%	6 26.1%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	60	59	59.5
Sex: Female, Male (Count of Participants)
Female	7 46.7%	5 62.5%	12 52.2%
Male	8 53.3%	3 37.5%	11 47.8%
Region of Enrollment (participants) [Number]
United States	15 100%	8 100%	23 100%

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	Median number of days alive
Time Frame	up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A	Arm B
Arm/Group Description	Itraconazole plus pemetrexed	Pemetrexed alone
Measure Participants	15	8
Median (95% Confidence Interval) [days]	971	242

2. Primary Outcome

Title	Progression Free Survival as Measured by Number of Days Without Disease Progression
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Itraconazole Open Label Added to Standard of Care Pemetrexed	Single Agent Pemetrexed
Arm/Group Description	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	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.
Measure Participants	15	8
Median (Full Range) [days]	168	84

3. Primary Outcome

Title	RECIST Response
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Itraconazole Open Label Added to Standard of Care Pemetrexed	Single Agent Pemetrexed
Arm/Group Description	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	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.
Measure Participants	15	8
PR	3 20%	0 0%
SD	8 53.3%	5 62.5%
PD	2 13.3%	2 25%
Inevaluable	2 13.3%	1 12.5%

4. Secondary Outcome

Title	Tumor Blood Flow
Description	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

Outcome Measure Data

Analysis Population Description

Data was not collected to assess this outcome measure.

Arm/Group Title	Itraconazole Open Label Added to Standard of Care Pemetrexed	Single Agent Pemetrexed
Arm/Group Description	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	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
Measure Participants	0	0

5. Secondary Outcome

Title	Tumor Metabolic Activity
Description	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

Outcome Measure Data

Analysis Population Description

Data was not collected to assess this outcome measure.

Arm/Group Title	Itraconazole Open Label Added to Standard of Care Pemetrexed	Single Agent Pemetrexed
Arm/Group Description	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	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
Measure Participants	0	0

Adverse Events

Time Frame	up to 30 days post last treatment.
Arm/Group Title	Itraconazole Open Label Added to Standard of Care Pemetrexed		Single Agent Pemetrexed
Arm/Group Description	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		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
All Cause Mortality
	Itraconazole Open Label Added to Standard of Care Pemetrexed		Single Agent Pemetrexed
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/15 (40%)		6/8 (75%)
Serious Adverse Events
	Itraconazole Open Label Added to Standard of Care Pemetrexed		Single Agent Pemetrexed
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/15 (13.3%)		2/8 (25%)
Blood and lymphatic system disorders
Neutropenia	1/15 (6.7%)		0/8 (0%)
Intratumoral Bleed	1/15 (6.7%)		0/8 (0%)
Cardiac disorders
Pulmonary Embolus	0/15 (0%)		1/8 (12.5%)
General disorders
Pain	0/15 (0%)		1/8 (12.5%)
Other (Not Including Serious) Adverse Events
	Itraconazole Open Label Added to Standard of Care Pemetrexed		Single Agent Pemetrexed
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/15 (20%)		2/8 (25%)
Blood and lymphatic system disorders
Lymphopenia	3/15 (20%)		2/8 (25%)
Leukopenia	1/15 (6.7%)		0/8 (0%)
General disorders
Vertigo	1/15 (6.7%)		0/8 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	1/15 (6.7%)		1/8 (12.5%)
Dyspnea	0/15 (0%)		1/8 (12.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.