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Phase I Study of Combined Temosirolimus, Erlotinib and Cisplatin in Advanced Solid Tumors

Phase 1
18 Years
Open (Enrolling)
Triple Negative Breast Cancer

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Trial Information

Phase I Study of Combined Temosirolimus, Erlotinib and Cisplatin in Advanced Solid Tumors

The stratification of breast cancer patients for treatment targeting either the estrogen
receptor (ER) or HER2 receptor based upon the measurement of ER/PR and HER2 in tumor tissue
has revolutionized the treatment of breast cancer. However, the success of this
stratification has resulted in the recognition that no effective rational treatment exists
for patients that lack these receptors. The term "triple negative breast cancer" (TNBC) has
been coined to define this class of unresponsive patients, which is based upon their lack of
the hormone receptors for estrogen and progesterone and the HER2 oncogene. TNBC thus
represents a form of breast cancer for which no targeted therapy is known.

Identifying and understanding the signaling pathways and receptors that contribute to triple
negative tumor growth is therefore of high priority in order to develop rational therapies
analogous to the ones that have already been developed for HER2 and ER.

TNBC is heterogeneous with regard to molecular alterations and prognosis and actually
encompasses diverse forms of breast cancer; hence, no single therapeutic strategy is likely
to be effective. However, subclassification of TNBC based upon the identification of
distinct sets of molecular alterations has identified a basal like form of the disease with
poor prognosis and enrichment for distinct molecular characteristics that we think is ripe
for targeted therapeutic intervention based on clinical need and improved molecular

A phase I study of the combination of erlotinib and CCI779 (temsirolimus) in glioblastoma
patients was reported at ASCO 2007. The erlotinib dose was fixed at 150 mg and the maximum
tolerated dose of temsirolimus was reported to likely be 15 mg (1 of 6 patients with grade 3
rash). Rash, diarrhea, and mucositis were the encountered dose limiting toxicities.
Pharmacokinetics and response data have yet to be reported. Therefore, the goal is to
maintain target inhibition (both mTOR and EGFR) and minimize toxicity (in this case, rash).
This toxicity may be explained in part by the interaction of erlotinib with temsirolimus
metabolism. Erlotinib has been shown to reduce the clearance of the CYP450 3A4 substrate
midazolam. Everolimus (RAD001) and temsirolimus are both CYP450 3A4 substrates. In a Phase I
trial, erlotinib increased the systemic exposure of everolimus, which was significantly
higher on day 22 (476 ± 161 ng*hr/mL) compared to day 8 (393 ± 156 ng*hr/mL; p = 0.020). A
phase I of everolimus with gefitinib has also been reported, with MTDs: everolimus 5 mg,
gefitinib 250 mg. Two patients who were treated at the 10 mg dose level of everolimus
experienced doselimiting grade 5 hypotension and grade 3 stomatitis, respectively.
Pharmacokinetics demonstrated no significant interaction between the agents. Thus, in Phase
I trials, mTOR inhibitors and EGFR inhibitors have been safely given together at doses shown
to inhibit their respective targets and Phase II studies are ongoing in advanced renal cell,
pancreatic, glioma, and breast (not specifically TNBC) cancers.

The rationale for adding cisplatin to erlotinib and an mTOR inhibitor are many. Cisplatin is
a known active cytotoxic against breast cancer. It has non overlapping toxicity with
erlotinib and TORC1 mTOR inhibitors and patients are unlikely to have been previously
treated with cisplatin. TNBC with mutant p53 are associated with an identified subset of
cisplatin sensitive cell lines and p53 mutations are also associated with PTEN loss and EGFR
overexpression. In, addition, synergistic interactions have been observed with the platinum
agent carboplatin in breast cancer cell lines. Therefore, as a cytotoxic DNA damaging agent
cisplatin could trigger apoptotic death in a cell whose PI3K survival pathways are
effectively inhibited by mTOR inhibition and erlotinib.

Inclusion Criteria:

- Confirmed pathologic diagnosis of a solid tumor that is not curable with available
therapies for which the combination of cisplatin, temsirolimus, and erlotinib is a
reasonable treatment.

- Patients with measurable or non-measurable disease are eligible for entry to this
study. Tumor markers may be considered non-measurable disease.

- Patients must have recovered from the acute toxic effects of all prior chemotherapy,
immunotherapy, or radiotherapy prior to entering this study. No chemotherapy or
radiotherapy may be given within 3 weeks prior to the start of protocol treatment.

- Patients must be ≥18 years old.

- Performance Status: ECOG 0-1 (as defined in section 10.4).

- Life expectancy of greater than 12 weeks.

- Patients must have recovered from uncontrolled intercurrent illness including, but
not limited to, ongoing or active infection, symptomatic congestive heart failure,
unstable angina pectoris or cardiac arrhythmia.

- Required Laboratory Values: ANC ≥1,500/mm3, platelets ≥100,000/mm3, hemoglobin ≥9.0
g/dL, total bilirubin ≤1.5 x ULN, AST/ALT ≤3.0 x ULN, alkaline phosphatase ≤2.5 x
ULN, creatinine ≤2.0 x ULN OR Patients must have either a normal serum creatinine (<=
IULN) OR estimated creatinine clearance 60 ml/min (Cockcroft-Gault formula) within
28 days prior to registration. PT/INR ≤1.5, unless the patient is on full dose
warfarin or stable dose of LMW heparin with a therapeutic INR of >1.5 - ≤3. Patients
with triglyceride levels >400 mg/dL can be started on lipid lowering agents and
reevaluated within 1 week. If levels go to ≤400 mg/dL, they can be considered for the
trial and continue the lipid lowering agents.

- Concomitant Medications: Temsirolimus and Erlotinib are primarily metabolized by
CYP3A4. Patients CANNOT be receiving enzyme-inducing or enzyme inhibiting agents
listed here: Inhibitors: Amiodarone, Amprenavir, Atazanavir, Chloramphenicol,
Clarithromycin, Conivaptan, Cyclosporine, Darunavir, Dasatinib, Delavirdine,
Diltiazem, Erythromycin, Fluconazole, Fluoxetine, Fluvoxamine, Fosamprenavir,
Imatinib, Indinavir, Isoniazid, Itraconazole, Ketoconazole, Lapatinib, Miconazole,
Nefazodone, Nelfinavir, Posaconazole, Ritonavir, Quinupristin, Saquinavir, Tamoxifen,
Telithromycin, Troleandomycin, Verapamil, Voriconazole. Inducers: Aminoglutethimide,
Bexarotene, Bosentan, Carbamazepine, Efavirenz, Fosphenytoin, Griseofulvin,
Modafinil, Nafcillin, Nevirapine, Oxcarbazepine, Phenobarbital, Phenytoin, Primidone,
Rifabutin, Rifampin, Rifapentine, St. John's wort, Sulfadimidine, Sulfinpyrazone,
Troglitazone, Troleandomycin. All concomitant medications must be recorded. Patients
also must agree to refrain from drinking grapefruit juice while on study.

- Sexually Active Patients: For all sexually active patients, the use of adequate
contraception (hormonal or barrier method of birth control) will be required prior to
study entry and for the duration of study participation. Non-pregnant status will be
determined in all women of childbearing potential.

- Patients must have signed an approved informed consent.

Exclusion Criteria:

- More than 3 prior chemotherapy treatments for metastatic disease.

- Patients receiving anti-retroviral therapy (HAART) for HIV infection because of
possible pharmacokinetic interactions.

- Active CNS disease

- Any serious medical or psychiatric illness that would prevent either the giving of
informed consent or the receipt of treatment.

- Patients pregnant or nursing.

- Patients who have used tobacco or nicotine products containing medications within the
last three months given their significant effect on erlotinib drug levels.

Type of Study:


Study Design:

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

Outcome Measure:

Maximum tolerated doses of cisplatin, temsirolimus, and erlotinib

Outcome Time Frame:

6 months

Safety Issue:


Principal Investigator

Matthew Maurer, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Columbia University


United States: Food and Drug Administration

Study ID:




Start Date:

September 2009

Completion Date:

September 2014

Related Keywords:

  • Triple Negative Breast Cancer
  • TNBC
  • Breast Neoplasms



Columbia University Medical Center New York, New York  10032