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Sorafenib and Temsirolimus in Treating Patients With Unresectable or Metastatic Solid Tumors

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ClinicalTrials.gov Identifier: NCT00255658
Recruitment Status : Completed
First Posted : November 21, 2005
Last Update Posted : April 15, 2015
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE November 18, 2005
First Posted Date  ICMJE November 21, 2005
Last Update Posted Date April 15, 2015
Study Start Date  ICMJE September 2005
Actual Primary Completion Date April 2007   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 29, 2013)
Maximum tolerable dose (MTD) and recommended dose for phase II determined by dose-limiting toxicities (DLT) graded according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 [ Time Frame: 4 weeks ]
Original Primary Outcome Measures  ICMJE Not Provided
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Sorafenib and Temsirolimus in Treating Patients With Unresectable or Metastatic Solid Tumors
Official Title  ICMJE Phase I, Pharmacokinetic and Pharmacodynamic Study of BAY 43-9006 (Sorafenib) in Combination With CCI-779 (Temsirolimus) in Advanced Solid Malignancies
Brief Summary This phase I trial is studying the side effects and best dose of temsirolimus when given together with sorafenib in treating patients with unresectable or metastatic solid tumors. Sorafenib and temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Sorafenib may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving sorafenib together with temsirolimus may kill more tumor cells.
Detailed Description

PRIMARY OBJECTIVES:

I. To characterize the safety and the toxicities of BAY 43-9006 (sorafenib) administered continuously twice daily by oral route in combination with CCI-779 (temsirolimus) administered intravenously once weekly in advanced solid malignancies.

II. To determine the maximum-tolerated dose (MTD) and recommended dose for the phase II study (RD) of this regimen.

III. To describe the pharmacokinetic behavior of BAY 43-9006 (sorafenib) and CCI-779 (temsirolimus) when combined.

SECONDARY OBJECTIVES:

I. To evaluate the relationship between pharmacokinetic (PK) parameters of exposure and drug effect on biological surrogates of proliferation, cell survival, differentiation and angiogenesis in peripheral blood mononuclear cells (PBMCs) and tumor tissue where the tumor is accessible for biopsy.

II. To analyze the biologic effects of BAY 43-9006 and CCI-779 on downstream targets of the P13K/Akt/mTOR and Raf signaling pathways.

III. To evaluate preliminary antitumor activity of the combination.

OUTLINE: This is an open-label, dose-escalation study of temsirolimus.

Patients receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. They also receive oral sorafenib* twice daily starting on day 8 of course 1. Treatment repeats every 4 weeks in the absence of disease progression or unacceptable toxicity.

NOTE: *On the days of the temsirolimus infusion, temsirolimus should be taken concurrently with the morning dose of sorafenib.

Cohorts of 3-6 patients receive escalating doses of temsirolimus until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Up to 12 patients are treated at the MTD.

After completion of study treatment, patients are followed for 4 weeks.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Unspecified Adult Solid Tumor, Protocol Specific
Intervention  ICMJE
  • Drug: sorafenib tosylate
    Given orally
    Other Names:
    • BAY 43-9006
    • BAY 43-9006 Tosylate Salt
    • BAY 54-9085
    • Nexavar
    • SFN
  • Drug: temsirolimus
    Given IV
    Other Names:
    • CCI-779
    • cell cycle inhibitor 779
    • Torisel
  • Other: laboratory biomarker analysis
    Correlative studies
Study Arms  ICMJE Experimental: Treatment (sorafenib tosylate, temsirolimus)

Patients receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. They also receive oral sorafenib* twice daily starting on day 8 of course 1. Treatment repeats every 4 weeks in the absence of disease progression or unacceptable toxicity.

NOTE: *On the days of the temsirolimus infusion, temsirolimus should be taken concurrently with the morning dose of sorafenib.

Cohorts of 3-6 patients receive escalating doses of temsirolimus until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Up to 12 patients are treated at the MTD.

Interventions:
  • Drug: sorafenib tosylate
  • Drug: temsirolimus
  • Other: laboratory biomarker analysis
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 29, 2013)
40
Original Enrollment  ICMJE Not Provided
Actual Study Completion Date  ICMJE April 2007
Actual Primary Completion Date April 2007   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients must have histologically confirmed solid malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective
  • ECOG performance status =< (Karnofsky >= 60%)
  • Predicted life expectancy of greater than 12 weeks
  • Leukocytes >= 3,000 mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Hemoglobin >= 9.0 g/dL
  • Platelets >= 100,000/mcL
  • Fasting serum cholesterol =< 350 mg/dL (9.0 mmol/L)
  • Total bilirubin within normal institutional limits
  • AST (SGOT)/ALT (SGPT) =< 2.5 x institutional upper limit of normal (ULN)
  • Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Patients on prophylactic anticoagulation therapy (e.g., low-dose warfarin) are eligible provided their coagulation parameter levels are as follows: INR (International Normalized Ratio of prothrombin time) < 1.1 x ULN
  • Patients on full-dose anticoagulants (e.g., warfarin) with PT INR > 1.5 are eligible provided that both of the following criteria are met:

    • The patient has an in-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin
    • The patient has no active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
  • Eligibility of patients receiving any other medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of BAY 43-9006 or CCI-779 will be determined following review of individual cases by the Principal Investigator; patients cannot be receiving enzyme-inducing antiepileptic drugs (EIAEDs) such as phenytoin, phenobarbital, carbamazepine, rifampin, or St. John's wort; patients must avoid grapefruit and grapefruit juice
  • 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
  • Complete supportive and palliative care will continue to be provided to ameliorate signs and symptoms that were pre-existing or may arise while on study and which do not interfere with the objectives of the study; the use of erythropoietin and bisphosphonates is permitted
  • Patients with CNS metastases are eligible for enrollment if they have received prior treatment (including radiation therapy, stereotactic radiosurgery, surgical resection) to site(s) of CNS metastatic disease, have no requirement for glucocorticoids, are not taking anticonvulsants, and have no overt evidence of neurological deficit; in addition, radiologic scans performed within < 14 days of study entry should not show evidence of disease progression or peritumoral edema

Exclusion Criteria:

  • Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events to =< grade 1 due to agents administered more than 4 weeks earlier, excluding alopecia
  • Patients who have received any investigational compound within the past 28 days; patients may not be receiving any other investigational agents while participating in the study
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to BAY 43-9006 or CCI-779
  • Hypertension with systolic blood pressure of > 140 mmHg or diastolic pressure > 90 mmHg; however, patients with well-controlled hypertension are eligible
  • Patients must not have any evidence of bleeding diathesis or coagulopathy; patients with PT INR > 1.5 are excluded, unless the patient is on full dose warfarin
  • Patients with any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow pills are excluded
  • Uncontrolled intercurrent illness including, but not limited to, uncontrolled hypertension, 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; breastfeeding should be discontinued if the mother is treated with either of these agents
  • HIV-positive patients on combination antiretroviral therapy are ineligible
  • Patients undergoing major surgery or sustaining a significant traumatic injury within 21 days prior to treatment are ineligible
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00255658
Other Study ID Numbers  ICMJE NCI-2012-03164
NCI-2012-03164 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NCI-7146
U01CA069853 ( U.S. NIH Grant/Contract )
CTRC-IDD-0512
CDR0000446567
IDD#05-12 ( Other Identifier: Cancer Therapy and Research Center at The UT Health Science Center at San Antonio )
7146 ( Other Identifier: CTEP )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Muralidhar Beeram Cancer Therapy and Research Center at The UT Health Science Center at San Antonio
PRS Account National Cancer Institute (NCI)
Verification Date December 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP