Cisplatin and Everolimus in Treating Patients With Advanced Solid Tumors

Sponsor

Memorial Sloan Kettering Cancer Center (Other)

Overall Status

Completed

CT.gov ID

NCT00423865

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arm

Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Everolimus may also help cisplatin work better by making tumor cells more sensitive to the drug. Giving cisplatin together with everolimus may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of everolimus when given together with cisplatin in treating patients with advanced solid tumors or recurrent or metastatic solid tumors.

Condition or Disease	Intervention/Treatment	Phase
Unspecified Adult Solid Tumor, Protocol Specific	Drug: cisplatin Drug: everolimus Genetic: gene expression analysis Other: immunohistochemistry staining method Other: laboratory biomarker analysis Other: pharmacological study Procedure: biopsy	Phase 1

Detailed Description

OBJECTIVES:

Primary

Determine the recommended phase II dose of everolimus when administered with low-dose cisplatin in patients with advanced solid tumors.

Secondary

Determine the safety and tolerability of this regimen in these patients.
Describe the pharmacokinetics of this regimen in patients with advanced solid tumors.
Assess the effects of this regimen on p53 and p21 immunohistochemistry assays of pre- and post-treatment tumor biopsies from patients with recurrent or metastatic solid tumors.

OUTLINE: This is a dose-escalation study of everolimus (part A) followed by a biological marker study (part B).

Part A (closed to accrual as of 1/2009): Patients receive cisplatin* IV over 30 minutes on days 1, 8, and 15 and oral everolimus* once daily on days 1-21. Treatment repeats every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of everolimus until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose proceeding that at which 2 of 6 patients experience dose-limiting toxicity (DLT) during course 1. The recommended phase II dose is defined as the dose at which 1 of 6 patients experience DLT during course 1.

Blood is drawn periodically on days 1 and 8 of course 1 for pharmacokinetic studies.

NOTE: *Patients who have completed 5 courses of treatment and maintain stable disease or better may continue treatment with everolimus alone or in combination with cisplatin
Part B: Patients undergo biopsy of the primary tumor, metastatic deposit, or involved lymph node. No more than 14 days later, patients receive everolimus at the recommended phase II dose and cisplatin as in part A.

Patients undergo another tumor biopsy on day 15 of course 1, before receiving chemotherapy. The pre- and post-therapy tissue is examined by immunochemistry and analyzed for p53 and p21 expression.

PROJECTED ACCRUAL: A total of 30 people will be accrued for this study.

Study Design

Study Type:

Interventional

Actual Enrollment :

30 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I Study of Weekly Low-Dose Cisplatin Plus Escalating Doses of Oral RAD001(Everolimus) for Patients With Advanced Solid Tumors

Study Start Date :

Nov 1, 2006

Actual Primary Completion Date :

Sep 1, 2011

Actual Study Completion Date :

Sep 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: cisplatin & RAD001 This will be a single institution phase I study of low dose weekly cisplatin (20 mg/m2 intravenously on Days 1, 8, and 15) plus escalating doses of daily RAD001 tablets (per oral or via percutaneous gastrostomy tube, Days 1 -21 of a 28-Day Cycle) for patients with advanced solid tumors	Drug: cisplatin cisplatin (20 mg/m2 intravenously on Days 1, 8, and 15) Drug: everolimus escalating doses of daily RAD001 tablets (per oral or via percutaneous gastrostomy tube, Days 1 -21 of a 28-Day Cycle) Genetic: gene expression analysis Each biopsy specimen will be formalin-fixed and paraffin-embedded for IHC, and analysis of p53 and p21 will follow methods previous reported by our group. The avidin-biotin immunoperoxidase technique will be employed. Other: immunohistochemistry staining method After the phase 2 recommended dose is established in the phase I portion of the study (Part A), we plan to enroll an additional 6 patients for pharmacodynamic studies (Part B). Entry into Part B requires the patient have tumor tissue which is easily accessible for research biopsy. The patients will be asked to provide written informed consent for the research biopsies. Patients also will be asked to provide written informed consent to allow the use of their tissue for future research studies. The research biopsies are not mandatory for any patient. Patients who do not consent to the research biopsies or who withdraw consent for the research biopsies may still receive RAD001 + cisplatin in the study Other: laboratory biomarker analysis Laboratory data (complete blood count, comprehensive metabolic panel including magnesium) regarding adverse events will be collected on each cisplatin treatment day. Additional adverse event data will be collected at regularly scheduled clinic visits at which history and physical are performed by the investigator (Cycle 1 - Days 1, 8, 15, and 21. Cycle 2 - Days 1 and 15. Cycle 3 and beyond - Day 1) Other: pharmacological study For patients in Part A, research bloods for pharmacokinetics are drawn on Day 1 and Day 8. Procedure: biopsy "Pre-treatment Research Biopsy:" Within 14 days prior to treatment, research biopsy (of primary tumor, metastatic deposit, or involved lymph node) will be performed. Baseline labs should be drawn within 14 days of the research biopsy. The biopsy sample will be formalin-fixed and paraffin-embedded for immunohistochemistry. Post-treatment Research Biopsy:" Research biopsy (of primary tumor, metastatic deposit, or involved lymph node) will be requested again for Day 15 of Cycle 1, prior to administration of RAD001 and cisplatin on that day.

Arm

Intervention/Treatment

Experimental: cisplatin & RAD001

This will be a single institution phase I study of low dose weekly cisplatin (20 mg/m2 intravenously on Days 1, 8, and 15) plus escalating doses of daily RAD001 tablets (per oral or via percutaneous gastrostomy tube, Days 1 -21 of a 28-Day Cycle) for patients with advanced solid tumors

Drug: cisplatin

cisplatin (20 mg/m2 intravenously on Days 1, 8, and 15)

Drug: everolimus

escalating doses of daily RAD001 tablets (per oral or via percutaneous gastrostomy tube, Days 1 -21 of a 28-Day Cycle)

Genetic: gene expression analysis

Each biopsy specimen will be formalin-fixed and paraffin-embedded for IHC, and analysis of p53 and p21 will follow methods previous reported by our group. The avidin-biotin immunoperoxidase technique will be employed.

Other: immunohistochemistry staining method

After the phase 2 recommended dose is established in the phase I portion of the study (Part A), we plan to enroll an additional 6 patients for pharmacodynamic studies (Part B). Entry into Part B requires the patient have tumor tissue which is easily accessible for research biopsy. The patients will be asked to provide written informed consent for the research biopsies. Patients also will be asked to provide written informed consent to allow the use of their tissue for future research studies. The research biopsies are not mandatory for any patient. Patients who do not consent to the research biopsies or who withdraw consent for the research biopsies may still receive RAD001 + cisplatin in the study

Other: laboratory biomarker analysis

Laboratory data (complete blood count, comprehensive metabolic panel including magnesium) regarding adverse events will be collected on each cisplatin treatment day. Additional adverse event data will be collected at regularly scheduled clinic visits at which history and physical are performed by the investigator (Cycle 1 - Days 1, 8, 15, and 21. Cycle 2 - Days 1 and 15. Cycle 3 and beyond - Day 1)

Other: pharmacological study

For patients in Part A, research bloods for pharmacokinetics are drawn on Day 1 and Day 8.

Procedure: biopsy

"Pre-treatment Research Biopsy:" Within 14 days prior to treatment, research biopsy (of primary tumor, metastatic deposit, or involved lymph node) will be performed. Baseline labs should be drawn within 14 days of the research biopsy. The biopsy sample will be formalin-fixed and paraffin-embedded for immunohistochemistry. Post-treatment Research Biopsy:" Research biopsy (of primary tumor, metastatic deposit, or involved lymph node) will be requested again for Day 15 of Cycle 1, prior to administration of RAD001 and cisplatin on that day.

Outcome Measures

Primary Outcome Measures

Recommended phase II dose of everolimus [1 year]

Secondary Outcome Measures

Pharmacokinetic profile of cisplatin and everolimus [1 year]
Pharmacodynamic profile of cisplatin and everolimus [1 year]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically confirmed diagnosis of 1 of the following:
Advanced solid tumor (part A)
Confirmation by core biopsy or fine-needle aspiration allowed
Solid tumor (part B)
Recurrent or metastatic disease
Easily accessible for biopsy
Measurable disease
No uncontrolled brain or leptomeningeal metastases
No requirement for glucocorticoids

PATIENT CHARACTERISTICS:

Karnofsky performance status 70-100%
Absolute neutrophil count ≥ 1,500/mm³
Platelet count ≥ 100,000/mm³
Hemoglobin > 10 g/dL
Bilirubin ≤ 1.5 times upper limit of normal (ULN)
AST and ALT ≤ 2.5 times ULN (< 5 times ULN if liver metastases are present)
Creatinine normal OR creatinine clearance ≥ 55 mL/min
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for at least 3 months after completion of study therapy
No HIV positivity
No peripheral neuropathy ≥ grade 2
No hypertriglyceridemia ≥ grade 2
No impaired gastrointestinal function or gastrointestinal disease that may alter the absorption of everolimus, including any of the following:
Ulcerative disease
Uncontrolled nausea
Vomiting
Diarrhea
Malabsorption syndrome
Small bowel resection
No other concurrent severe and/or uncontrolled medical disease that would compromise study participation, including any of the following:
Uncontrolled diabetes
Unstable angina
New York Heart Association class III or IV congestive heart failure

PRIOR CONCURRENT THERAPY:

No more than 3 prior cytotoxic chemotherapy regimens for recurrent or metastatic disease
At least 4 weeks since prior major surgery and recovered
At least 4 weeks since prior radiation therapy and recovered
At least 4 weeks since prior systemic anticancer therapy and recovered
At least 4 weeks since prior and no other concurrent investigational drugs
No prior everolimus or other agents specifically targeting mTOR
No prior radiation therapy to > 25% of the bone marrow
No prior radiation therapy to the whole pelvis and/or brain
No concurrent chronic steroid treatment (> 5 mg/day of prednisone)
Concurrent low-dose steroid replacement regimens (≤ 5 mg/day of prednisone) allowed
No concurrent immunosuppressive agents
No other concurrent anticancer agents
No concurrent agents known to be strong inhibitors or inducers of isoenzyme CYP3A

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065

Sponsors and Collaborators

Memorial Sloan Kettering Cancer Center
National Cancer Institute (NCI)

Investigators

Principal Investigator: Matthew G. Fury, MD, PhD, Memorial Sloan Kettering Cancer Center
Principal Investigator: David G. Pfister, MD, Memorial Sloan Kettering Cancer Center