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Study of Temsirolimus, Erlotinib and Cisplatin in Solid Tumors

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00998036
First Posted: October 20, 2009
Last Update Posted: December 13, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
Wyeth is now a wholly owned subsidiary of Pfizer
Genentech, Inc.
Information provided by (Responsible Party):
Kevin Kalinsky, Columbia University
  Purpose
This is a Phase I research study designed to determine the maximum tolerated dose (MTD) 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 Drug: Cisplatin Drug: Erlotinib Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of Combined Temsirolimus, Erlotinib and Cisplatin in Advanced Solid Tumors

Resource links provided by NLM:


Further study details as provided by Kevin Kalinsky, Columbia University:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) of Cisplatin [ Time Frame: 6 months ]
    MTD of the drug as part of combination therapy will be determined.

  • MTD of Temsirolimus [ Time Frame: 6 months ]
    MTD of the drug as part of combination therapy will be determined.

  • MTD of Erlotinib [ Time Frame: 6 months ]
    MTD of the drug as part of combination therapy will be determined.


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

Temsirolimus will be administered intravenously weekly on days one and eight of a three week cycle. Temsirolimus will not be given on week three (usually dosed weekly) for increased tolerability given its possible plasma accumulation during week three. Temsirolimus will be given second over a 30 minute infusion during posthydration.

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

Dose Level 1: Temsirolimus 15mg

Dose Level 2: Temsirolimus 15mg

Dose Level 3: Temsirolimus 25mg

Other Name: Torisel
Drug: Cisplatin
Cisplatin at 30mg/m2 will be administered intravenously weekly on days one and eight of a three week cycle. Cisplatin will be given first over a 30 minute infusion with prehydration.
Other Name: Platinol
Drug: Erlotinib

Erlotinib will be taken by mouth daily starting at 100mg. On days of cisplatin and temsirolimus infusions, erlotinib should be taken at least two hours after the beginning of the temsirolimus infusion.

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

Dose Level 1: Erlotinib 100mg

Dose Level 2: Erlotinib 150mg

Dose Level 3: Erlotinib 150mg

Other Name: Tarceva

Detailed Description:

The stratification of breast cancer patients for treatment targeting either the estrogen receptor (ER) or human epidermal growth factor receptor 2 (HER2) receptor based upon the measurement of ER/progesterone receptor (PR) and HER2 in tumor tissue has changed 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 used to define a class of unresponsive patients, which is based upon their lack of the hormone receptors for estrogen and progesterone and the HER2 oncogene. TNBC represents a form of breast cancer for which no targeted therapy is known.

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

Available data from Phase I trials have demonstrated that 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. Therefore, as a cytotoxic DNA damaging agent, cisplatin could trigger cell death in a cell whose survival pathways are effectively inhibited by mTOR inhibition and erlotinib.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes 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: Eastern Cooperative Oncology Group (ECOG) 0-1
  • 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: absolute neutrophil count (ANC) ≥1,500/mm3, platelets ≥100,000/mm3, hemoglobin ≥9.0 g/dL, total bilirubin ≤1.5 x upper limit of normal (ULN), aspartate transaminase (AST)/alanine transaminase (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. Prothrombin time (PT)/INR ≤1.5, unless the patient is on full dose warfarin or stable dose of low-molecular-weight (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 central nervous system (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
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): 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, Inc.
Investigators
Principal Investigator: Kevin Kalinksy, MD Columbia University
  More Information

Responsible Party: Kevin Kalinsky, Assistant Professor of Medicine, Columbia University
ClinicalTrials.gov Identifier: NCT00998036     History of Changes
Other Study ID Numbers: AAAD8279
First Submitted: October 19, 2009
First Posted: October 20, 2009
Last Update Posted: December 13, 2017
Last Verified: December 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Kevin Kalinsky, Columbia University:
TNBC
Temsirolimus
Erlotinib
Cisplatin
Breast Cancer

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