Study of Temsirolimus, Erlotinib and Cisplatin in Solid Tumors

This study has been completed.
Sponsor:
Collaborators:
Wyeth is now a wholly owned subsidiary of Pfizer
Genentech
Information provided by (Responsible Party):
Matthew A. Maurer, Columbia University
ClinicalTrials.gov Identifier:
NCT00998036
First received: October 19, 2009
Last updated: July 29, 2013
Last verified: July 2013
  Purpose

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.


Condition Intervention Phase
Triple Negative Breast Cancer
Drug: Temsirolimus, cisplatin, erlotinib
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Study of Combined Temosirolimus, Erlotinib and Cisplatin in Advanced Solid Tumors

Resource links provided by NLM:


Further study details as provided by Columbia University:

Primary Outcome Measures:
  • Maximum tolerated doses of cisplatin, temsirolimus, and erlotinib [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]

Enrollment: 9
Study Start Date: September 2009
Study Completion Date: October 2012
Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Temsirolimus, cisplatin, erlotinib

Cisplatin and temsirolimus will be administered weekly on days one and eight of a three week cycle.

Erlotinib will be taken by mouth daily

Drug: Temsirolimus, cisplatin, erlotinib

Cisplatin at 30mg/m2 and temosirolimus will be administered intravenously weekly on days one and eight of a three week cycle. Temosirolimus will not be given on week three (usually dosed weekly) for increased tolerability given its possible plasma accumulation during week three. Cisplatin will be given first over a 30 minute infusion with prehydration and temsirolimus will be given second over a 30 minute infusion during posthydration. Erlotinib will be taken by mouth daily starting at 100mg. On days of cisplatin and temosirolimus infusions, erlotinib should be taken at least two hours after the beginning of the temosirolimus infusion.

Dose escalation will follow the standard 3 by 3 design with three set dosing levels.

Dose Level 1: Temosirolimus 15mg, Erlotinib 100mg

Dose Level 2: Temosirolimus 15mg, Erlotinib 150mg

Dose Level 3: Temosirolimus 25mg, Erlotinib 150mg

Other Names:
  • Platinol
  • Torisell
  • Tarceva

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00998036

Locations
United States, New York
Columbia University Medical Center
New York, New York, United States, 10032
Sponsors and Collaborators
Columbia University
Wyeth is now a wholly owned subsidiary of Pfizer
Genentech
Investigators
Principal Investigator: Matthew Maurer, MD Columbia University
  More Information

No publications provided

Responsible Party: Matthew A. Maurer, Assistant Professor of Medicine, Columbia University
ClinicalTrials.gov Identifier: NCT00998036     History of Changes
Other Study ID Numbers: AAAD8279
Study First Received: October 19, 2009
Last Updated: July 29, 2013
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Columbia University:
TNBC

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Cisplatin
Sirolimus
Everolimus
Erlotinib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Radiation-Sensitizing Agents
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Antifungal Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Anti-Bacterial Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 28, 2014