Everolimus, Carboplatin, and Etoposide in Treating Patients With Small Cell Lung Cancer or Other Advanced Solid Tumors

Sponsor

University of California, Davis (Other)

Overall Status

Terminated

CT.gov ID

NCT00807755

Collaborator

Novartis (Industry)

Enrollment

Location

Arm

Actual Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Drugs used in chemotherapy, such as carboplatin and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) together with everolimus may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of everolimus, carboplatin, and etoposide in treating patients with small cell lung cancer or other advanced solid tumors.

Condition or Disease	Intervention/Treatment	Phase
Lung Cancer Unspecified Adult Solid Tumor, Protocol Specific	Drug: Carboplatin Drug: Etoposide Drug: RAD001	Phase 1

Detailed Description

OBJECTIVES:

Primary

Determine the safety and feasibility of everolimus combined with carboplatin and etoposide in patients with advanced solid tumors, with emphasis on small cell lung cancer (SCLC).

Secondary

Determine the maximum-tolerated dose of this regimen in these patients.
Describe the dose-limiting toxicities and toxicity profile associated with this regimen in these patients.
Determine, preliminarily, the efficacy of this regimen in an expanded cohort of patients with SCLC.
Assess the pharmacokinetic parameters of everolimus in this combination.

OUTLINE: This is a dose-escalation study.

Patients receive oral everolimus on days 1-21, carboplatin IV over 15-30 minutes on day 1, and etoposide IV over 30 minutes on days 1-3. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Patients in the expanded cohort undergo blood collection on days 1, 15, and 22 for pharmacokinetic studies by liquid chromatography-tandem mass spectrometry.

After completion of study therapy, patients are followed for 30 days.

Study Design

Study Type:

Interventional

Actual Enrollment :

5 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I Trial of Carboplatin and Etoposide in Combination With Everolimus (RAD001) in Advanced Solid Tumors, With Emphasis on Small Cell Lung Cancer (SCLC)

Actual Study Start Date :

Mar 1, 2009

Actual Primary Completion Date :

Aug 1, 2010

Actual Study Completion Date :

Dec 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase I Dose-Escalation This is a phase I dose escalation study of RAD001 and carboplatin/etoposide. Patients will be accrued in a standard 3 + 3 design based on toxicities experienced during the first cycle. Ten additional chemotherapy naive extensive stage small cell lung cancer (ES-SCLC) patients will be accrued at the Maximum Tolerated Dose (MTD) for further toxicity and response assessment.	Drug: Carboplatin Intravenous (IV) on Day 1 of each 21-day cycle, as per dose escalation schedule (dose levels 1 and 2: dose levels 3 and 4). Number of cycles: 6 maximum. Other Names: Paraplatin Drug: Etoposide 80mg/m2, Intravenous on Days 1, 2, 3 of a 21-day cycle (all dose levels). Number of cycles: 6 maximum. Other Names: Eposin Etopophos Vepesid VP-16 Drug: RAD001 Orally on Days 1-21 of a 21-day cycle, as per dose escalation schedule (dose level 1: 2.5 mg, dose level 2: 5 mg, dose level 3: 5.0 mg, and dose level 4: 10.0 mg). Number of cycles: unlimited (drug taken from Day 1 until progression of disease or unacceptable toxicity). Other Names: Everolimus Afinitor

Arm

Intervention/Treatment

Experimental: Phase I Dose-Escalation

This is a phase I dose escalation study of RAD001 and carboplatin/etoposide. Patients will be accrued in a standard 3 + 3 design based on toxicities experienced during the first cycle. Ten additional chemotherapy naive extensive stage small cell lung cancer (ES-SCLC) patients will be accrued at the Maximum Tolerated Dose (MTD) for further toxicity and response assessment.

Drug: Carboplatin

Intravenous (IV) on Day 1 of each 21-day cycle, as per dose escalation schedule (dose levels 1 and 2: dose levels 3 and 4). Number of cycles: 6 maximum.

Other Names:

Paraplatin

Drug: Etoposide

80mg/m2, Intravenous on Days 1, 2, 3 of a 21-day cycle (all dose levels). Number of cycles: 6 maximum.

Other Names:

Eposin

Etopophos

Vepesid

VP-16

Drug: RAD001

Orally on Days 1-21 of a 21-day cycle, as per dose escalation schedule (dose level 1: 2.5 mg, dose level 2: 5 mg, dose level 3: 5.0 mg, and dose level 4: 10.0 mg). Number of cycles: unlimited (drug taken from Day 1 until progression of disease or unacceptable toxicity).

Other Names:

Everolimus

Afinitor

Outcome Measures

Primary Outcome Measures

Safety and feasibility of combining RAD001 with carboplatin and etoposide in advanced solid tumors, with emphasis on SCLC. [Up to 1 year from start of treatment]

Secondary Outcome Measures

Maximum-tolerated dose as assessed by NCI CTCAE, Version 3.0 [April 2011]
Dose-limiting toxicities and toxicity profile as assessed by NCI CTCAE, Version 3.0 [Up to one year.]
Preliminary efficacy of this regimen in patients with small cell lung cancer [Up to one year]
Pharmacokinetic parameters [Up to one year]
Exploratory biomarker analysis [Up to one year]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically or cytologically confirmed advanced solid tumors for which curative standard treatments are not available
Ten additional patients with extensive stage small cell lung cancer are accrued to the expanded cohort once a maximum tolerate dose (or a dose for further exploration) is determined
Must be chemotherapy naive
Measurable or evaluable disease
Prior irradiated disease sites are considered measurable if there is clear disease progression following radiation therapy
No uncontrolled brain or leptomeningeal metastases (including those requiring glucocorticoids)

PATIENT CHARACTERISTICS:

Zubrod performance status 0-2
Life expectancy > 3 months
Granulocyte count ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3
Creatinine ≤ 1.3 mg/dL OR creatinine clearance > 40 mL/min
Serum bilirubin ≤ 1.5 mg/dL (regardless of liver involvement)
SGOT ≤ 3 times upper limit of normal (ULN)
INR ≤ 1.3 (≤ 3 if on anticoagulation)
Fasting serum cholesterol ≤ 300 mg/dL*
Fasting triglycerides ≤ 2.5 times ULN*
No severe and/or uncontrolled medical co-morbidities or other conditions that could affect participation in the study including, but not limited to, the following:
Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤ 6 months prior to first study treatment
Serious uncontrolled cardiac arrhythmia
Severely impaired lung function
Active (acute or chronic) or uncontrolled infection
Non-malignant medical illness that is uncontrolled or that the control may be jeopardized by the study therapy
Liver disease (i.e., cirrhosis, chronic active hepatitis, chronic persistent hepatitis)
No uncontrolled diabetes mellitus (i.e., fasting serum glucose > 1.5 times ULN)
No HIV seropositivity
Not pregnant or nursing
Fertile patients must use effective contraception
No oral, implantable, or injectable contraceptives
No impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
No active, bleeding diathesis
No known hypersensitivity to everolimus or other rapamycins (e.g., sirolimus, temsirolimus) or to its excipients
Must be able to take and retain oral medication
No peripheral neuropathy > grade 1 as per NCI CTCAE vs. 3 NOTE: *In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid-lowering medication.

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
Recovered from prior therapy
More than 3 weeks since prior and no concurrent investigational drugs
At least 3 weeks since prior chemotherapy
At least 2 weeks since prior major surgery or completion of radiotherapy
No immunization with attenuated live vaccines within the past week or during study therapy
No prior treatment with an mTOR inhibitor (e.g., sirolimus, temsirolimus, or everolimus)
No chronic treatment with systemic steroids or other immunosuppressive agents
No concurrent oral anti-vitamin K medication (except low dose coumadin)
No concurrent medications interfering with everolimus
No other concurrent anticancer agents