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Phase I, Pharmacokinetic and Pharmacodynamic Study of BAY 43-9006 (Sorafenib) in Combination With CCI-779 (Temsirolimus) in Advanced Solid Malignancies

Phase 1
18 Years
Open (Enrolling)
Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

Phase I, Pharmacokinetic and Pharmacodynamic Study of BAY 43-9006 (Sorafenib) in Combination With CCI-779 (Temsirolimus) in Advanced Solid Malignancies


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.


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.

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

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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

Outcome Time Frame:

4 weeks

Safety Issue:


Principal Investigator

Muralidhar Beeram

Investigator Role:

Principal Investigator

Investigator Affiliation:

Cancer Therapy and Research Center at The UT Health Science Center at San Antonio


United States: Food and Drug Administration

Study ID:




Start Date:

October 2005

Completion Date:

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific



Cancer Therapy and Research Center at The UT Health Science Center at San Antonio San Antonio, Texas  78229