Erlotinib and Temsirolimus for Solid Tumors

Study Overview
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Brief Summary
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Define the maximum tolerated dose and dose limiting side-effects of temsirolimus in combination wtih erlotinib in patients with resistant solid tumors

Official Title
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Phase I Study of Erlotinib and Temsirolimus in Resistant Solid Malignancies

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: Erlotinib
* Drug: Temsirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic Diagnosis: Patients must have a histologically or cytologically proven solid malignancy which is resistant to conventional therapy or for which no effective therapy is known. Dose Expansion Phase ONLY: Patients must have archived tumor tissue available (paraffin blocks, unstained tissue sections, tissue cores). Tumor Mutational Status (Dose Expansion Phase ONLY): Patients must have tumor harboring PTEN loss, PIK3CA mutation, , and/or EGFR mutation. Patients cannot have KRAS or BRAF mutations. Patients must have mutational status determined by Genomic and Pathology Services at Washington University (GPS@WU) or other CLIA-certified laboratories. Dose Expansion Phase ONLY: Patients with squamous carcinoma histology, papillary thyroid carcinoma, and adenoid cystic carcinoma are eligible for the expansion cohort regardless of genetic alterations.. Measurable or Non-Measurable Disease: Patients with measurable or non-measurable disease are eligible for entry to this study. In addition, patients without measurable or non-measurable disease are also eligible. Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥20 mm with conventional techniques (PET, CT, MRI, x-ray) or as ≥10 mm with spiral CT scan. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). Tumor markers may be considered non-measurable disease. A positive bone scan, osteoblastic metastases, and pleural or peritoneal effusions are not considered measurable or non-measurable. Patients with only these lesions are eligible for entry to the study. Dose Expansion Phase ONLY: Patients must have a tumor that is easily accessible for biopsy determined by the treating physician or the study PI. Patients must agree to a mandatory biopsy at the end of cycle 1 treatment. Recovery from Prior Therapy: 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. No prior therapy with erlotinib or temsirolimus allowed. Age: Patients must be ≥18 years old. Because no dosing or toxicity data are currently available on the use of temsirolimus in combination with erlotinib in patients <18 years of age, children are excluded from this study, but will be eligible for the pediatric phase I single-agent trials, when available. Performance Status: ECOG 0-1 at study entry. Life Expectancy: Patients must have a life expectancy of greater than 12 weeks. Required Laboratory Values: absolute neutrophil count ≥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 creatinine clearance ≥60 mL/min/1.732 for patients with creatinine levels above 2.0 mg/dl serum cholesterol ≤350 mg/dL /9.0 mmol/L (fasting) triglycerides ≤300 mg/dL (fasting)* 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. Temsirolimus is primarily metabolized by CYP3A4. Patients cannot be receiving enzyme-inducing antiepileptic drugs (EIAEDs; e.g., phenytoin, carbamazepine, phenobarbital) nor any other CYP3A4 inducer such as rifampin or St. John's wort, as these may decrease temsirolimus levels. A partial list of agents which interact with cytochrome P450 (CYP3A) is found in Appendix AB. Use of agents that potently inhibit CYP3A (and hence may raise temsirolimus levels), such as ketoconazole, is discouraged, but not specifically prohibited. Temsirolimus can inhibit CYP2D6, and may decrease metabolism (and increase drug levels) of drugs that are substrates for CYP2D6, such as codeine. The appropriateness of use of such agents is left to physician discretion. A list of drugs that may have potential interactions with CYP2D6 is found in Appendix A. If there is any doubt about eligibility based on concomitant medication, the Principal Investigator, Dr. Andrea Wang-Gillam, should be contacted. All concomitant medications must be recorded. Known Allergies: Patients with known hypersensitivity reactions to macrolide antibiotics (such as erythromycin, clarithromycin, and azithromycin) are not eligible for this trial. 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. Pregnant and nursing women are not eligible. HIV-Positive Patients: Patients receiving anti-retroviral therapy (HAART) for HIV infection are excluded from the study because of possible pharmacokinetic interactions. Appropriate studies will be undertaken in patients receiving HAART therapy, when indicated. Neurologic Status: Patients must not have active CNS disease. Recovery from Intercurrent Illness: 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. Informed Consent: Patients must have signed a Washington University Human Research Protection Office (HRPO) approved informed consent. The patient should not have any serious medical or psychiatric illness that would prevent either the giving of informed consent or the receipt of treatment. Inclusion of Women and Minorities: Entry to this study is open to both men and women and to all racial and ethnic subgroups.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level 1A<br>Erlotinib 100 mg administered orally on a once daily schedule for 35 days for the first cycle. Erlotinib 100 mg administered orally on a once daily schedule for 28 days for subsequent cycles. Temsirolimus 10 mg IV on days 8, 15, 22, and 29 during the first cycle. Temsirolimus 10 mg IV on days 8, 15, and 22 during subsequent cycles. | Drug: Erlotinib<br> <br> * Other names: Tarceva®;Drug: Temsirolimus<br> <br> * Other names: Torisel™;|
| Experimental: Dose Level 1<br>Erlotinib 100 mg administered orally on a once daily schedule for 35 days for the first cycle. Erlotinib 100 mg administered orally on a once daily schedule for 28 days for subsequent cycles. Temsirolimus 15 mg IV on days 8, 15, 22, and 29 during the first cycle. Temsirolimus 15 mg IV on days 8, 15, and 22 during subsequent cycles. | Drug: Erlotinib<br> <br> * Other names: Tarceva®;Drug: Temsirolimus<br> <br> * Other names: Torisel™;|
| Experimental: Dose Level 2<br>Erlotinib 100 mg administered orally on a once daily schedule for 35 days for the first cycle. Erlotinib 100 mg administered orally on a once daily schedule for 28 days for subsequent cycles. Temsirolimus 20 mg IV on days 8, 15, 22, and 29 during the first cycle. Temsirolimus 20 mg IV on days 8, 15, and 22 during subsequent cycles. | Drug: Erlotinib<br> <br> * Other names: Tarceva®;Drug: Temsirolimus<br> <br> * Other names: Torisel™;|
| Experimental: Dose Level 3<br>Erlotinib 100 mg administered orally on a once daily schedule for 35 days for the first cycle. Erlotinib 100 mg administered orally on a once daily schedule for 28 days for subsequent cycles. Temsirolimus 25 mg IV on days 8, 15, 22, and 29 during the first cycle. Temsirolimus 25 mg IV on days 8, 15, and 22 during subsequent cycles. | Drug: Erlotinib<br> <br> * Other names: Tarceva®;Drug: Temsirolimus<br> <br> * Other names: Torisel™;|
| Experimental: Dose Expansion Phase<br>Erlotinib 100 mg administered orally on a once daily schedule for 35 days for the first cycle. Erlotinib 100 mg administered orally on a once daily schedule for 28 days for subsequent cycles. Temsirolimus 25 mg IV on days 8, 15, 22, and 29 during the first cycle. Temsirolimus 25 mg IV on days 8, 15, and 22 during subsequent cycles. | Drug: Erlotinib<br> <br> * Other names: Tarceva®;Drug: Temsirolimus<br> <br> * Other names: Torisel™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To define the maximum tolerated dose and dose-limiting toxicities of temsirolimus in combination with erlotinib in patients with resistant solid malignancies. |  | 3 years for MTD to be determined, DLT occurs in 1st cycle only | 
| To determine the incidence and severity of other toxicities of temsirolimus in combination with erlotinib in patients with resistant solid malignancies. |  | 30 days after end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the pharmacodynamic profile of temsirolimus in combination with erlotinib. |  | Prior to each cycle | 
| To determine any anti-tumor activity and response to the combination of temsirolimus and erlotinib in treatment of patients with resistant solid malignancies. |  | End of treatment | 
| To evaluate the relation between pS6K1 and p-Akt to clinical response to temsirolimus. |  | End of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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any solid tumors