Cisplatin and Everolimus in Treating Patients With Advanced Solid Tumors

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier:
NCT00423865
First received: January 16, 2007
Last updated: September 19, 2012
Last verified: September 2012
  Purpose

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 Intervention 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

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Memorial Sloan-Kettering Cancer Center:

Primary Outcome Measures:
  • Recommended phase II dose of everolimus [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Pharmacokinetic profile of cisplatin and everolimus [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • Pharmacodynamic profile of cisplatin and everolimus [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Enrollment: 30
Study Start Date: November 2006
Study Completion Date: September 2011
Primary Completion Date: September 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00423865

Locations
United States, New York
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
Sponsors and Collaborators
Memorial Sloan-Kettering Cancer Center
Investigators
Principal Investigator: Matthew G. Fury, MD, PhD Memorial Sloan-Kettering Cancer Center
Principal Investigator: David G. Pfister, MD Memorial Sloan-Kettering Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT00423865     History of Changes
Obsolete Identifiers: NCT00406666
Other Study ID Numbers: MSKCC 06-129, MSKCC-06129
Study First Received: January 16, 2007
Last Updated: September 19, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Memorial Sloan-Kettering Cancer Center:
unspecified adult solid tumor, protocol specific
CISPLATIN
RAD001 (EVEROLIMUS)
06-129

Additional relevant MeSH terms:
Neoplasms
Cisplatin
Sirolimus
Everolimus
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Radiation-Sensitizing Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents

ClinicalTrials.gov processed this record on July 31, 2014