Patient case: 54-year-old female with Breast cancer. Genetic variant: PTEN Loss. Other conditions: Congestive Heart Failure.

Clinical trial: Study of Temsirolimus, Erlotinib and Cisplatin in Solid Tumors

Summary: This is a Phase I research study designed to determine the maximum tolerated doses of cisplatin, temsirolimus, and erlotinib in combination for treatment in triple negative breast cancer (TNBC) patients.

Detailed description: 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 understanding.
  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.

Eligibility: 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.

Relevance to patient case: not relevant