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A Phase I Pharmacokinetic and Pharmacodynamic Study of Temsirolimus (CCI-779) in Patients With Advanced Malignancies and Normal and Impaired Liver Function: An NCI Organ Dysfunction Working Group Study

Phase 1
18 Years
Not Enrolling
Hepatic Complications, Lymphoma, Unspecified Adult Solid Tumor, Protocol Specific

Thank you

Trial Information

A Phase I Pharmacokinetic and Pharmacodynamic Study of Temsirolimus (CCI-779) in Patients With Advanced Malignancies and Normal and Impaired Liver Function: An NCI Organ Dysfunction Working Group Study


I. To evaluate the safety, tolerability, and to establish the maximum tolerated recommended
dose (RD) CCI-779 (temsirolimus) in cohorts of patients with varying degrees of hepatic
dysfunction (mild, moderate, and severe) in order to provide appropriate dosing
recommendations for CCI-779 (temsirolimus) in this population.


I. To characterize the pharmacokinetic (PK) profile of CCI-779 (temsirolimus) in patients
with varying degrees of hepatic function.

II. To determine if the pharmacodynamic (PD) profile of CCI-779 (temsirolimus) as measured
by drug effects on p70s6 kinase and p4EBP1 phosphorylation and other markers of mTOR
inhibition in peripheral blood mononuclear cells (PBMC) is altered in patients with varying
degrees of hepatic function.

III. To document the non-dose limiting toxicities and any anti-tumor efficacy associated
with administration of CCI-779 (temsirolimus) in this patient population.

IV. To compare the NCI ODWG criteria and the Child-Pugh classification of hepatic
dysfunction in terms of their predictive value in reducing interpatient variability in the
PK and PD of CCI-779 (temsirolimus).

OUTLINE: This is a dose-escalation, multicenter study. Patients are stratified according to
hepatic function (normal vs mild dysfunction vs moderate dysfunction vs severe dysfunction
vs liver transplant).

Patients receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Courses repeat
every 28 days in the absence of disease progression or unacceptable toxicity.

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 periodically for 30 days.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed solid tumor or lymphoma
that is metastatic or unresectable and for which standard curative or palliative
measures do not exist or are no longer effective; all solid and lymphoma tumor types
are eligible; patients with a liver mass (radiologically evident), elevated
alpha-fetoprotein level (>= 500 ng/mL), and positive serology for viral hepatitis or
history of alcoholic cirrhosis consistent with a diagnosis of hepatocellular
carcinoma will be eligible without the need for pathologic confirmation of the

- Life expectancy of >= 2 months

- ECOG performance status =< 2 (KPS >= 50)

- Absolute neutrophil count >= 1,000/mcl, and

- Platelets >= 100,000/mcl, and

- Serum creatinine =< 1.5 x ULN OR calculated creatinine clearance >= 60 mL/min/1.73

- Patients with abnormal liver function will be eligible and will be grouped according
to total bilirubin and AST (SGOT); no distinction will be made between liver
dysfunction due to metastases and liver dysfunction due to other causes; for patient
stratification, liver function tests should be repeated within 72 hours of starting
initial therapy

- Patients with biliary obstruction for which a shunt has been placed are eligible,
provided the liver function tests have stabilized (two measurements at least tow days
apart that put the patient in the same hepatic dysfunction stratum will be accepted
as evidence of stable hepatic function); there must be no evidence of biliary sepsis
and at least 2 weeks must have elapsed after the placement of a biliary shunt

- Patients receiving medications or substances with the potential to affect the
activity the activity or pharmacokinetics of CCI-779 (temsirolimus), such as CYP3A4
substrates, inducers, or inhibitors may be enrolled at the discretion of the
investigator; however, consideration should be given to stopping or switching to
non-interfering agents if clinically feasible; in all cases, the use of these agents
should be listed on the concomitant medication record

- The effects of CCI-779 (temsirolimus) on the developing human fetus and newborn are
unknown; for this reason and because CCI-779 (temsirolimus) may be teratogenic,
patients must not be pregnant or nursing; men or women of childbearing potential must
have agreed to use an effective contraceptive method prior to study entry and for the
duration of study participation; since interaction with CCI-779 (temsirolimus) and
oral contraceptives is possible, a barrier method should be used and oral
contraceptives are not permitted; a negative pregnancy test is required prior to
starting therapy for women of childbearing age; 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
in accordance with institutional and federal guidelines; all patients must be
informed of the investigational nature of this study

- Patients must agree to undergo PK sampling and sample submission as outlined by the

Exclusion Criteria:

- Patients who have had chemotherapy, radiotherapy, or immunotherapy within 4 weeks (6
weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have
not recovered from serious adverse events due to agents administered more than 4
weeks earlier

- Patients with a history of major surgery within 21 days prior to treatment

- Patients may not be receiving any other investigational agents

- Patients must not be planning to receive concurrent radiation, other chemotherapy, or
immuno therapy for malignancy while receiving protocol treatment; hormonal treatment
for prostate carcinoma may be continued and bisphosphonate treatment for bone disease
is permitted

- Patients with unstable or untreated (non-irradiated) brain metastases should be
excluded from this clinical trial because of their poor prognosis and because they
often develop progressive neurological dysfunction that would confound the evaluation
of neurological and other adverse events; subjects with a prior history of CNS
metastases will be eligible if the metastases have been treated with either RT or
surgical resection ONLY and subjects are asymptomatic, with stable disease and no
longer requiring steroids for at least 2 weeks; a screening magnetic resonance
imaging (MRI)/CT (with contrast) is required

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to rapamycin or CCI-779 (temsirolimus)

- Uncontrolled serious intercurrent medical illness or psychiatric illness/social
situations that would limit compliance with study requirements

- Pregnant women are excluded from this study because CCI-779 (temsirolimus) is an
agent with the potential for teratogenic or abortifacient effects; nursing women are
also excluded, as there is an unknown but potential risk for adverse events in
nursing infants secondary to treatment of the mother with CCI-779 (temsirolimus);
breastfeeding should be discontinued if the mother is treated with CCI-779

- HIV-positive patients receiving anti-retroviral therapy are excluded from the study
due to the possibility of pharmacokinetic interactions with CCI-779 (temsirolimus);
however, patients will not routinely be screened for HIV

- Patients who are currently receiving Rapamycin (RAP, Rapamune, Sirolimus) therapy are
excluded from the study due to the possibility of overdosing, as CCI-779 is
metabolized into sirolimus

Type of Study:


Study Design:

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

Outcome Measure:

RD, defined as the highest dose level at which less than 33% of at least six patients experience DLT

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

John Sarantopoulos

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:

December 2005

Completion Date:

Related Keywords:

  • Hepatic Complications
  • Lymphoma
  • Unspecified Adult Solid Tumor, Protocol Specific
  • Lymphoma



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