Phase I Study of Docetaxel and Temsirolimus in Resistant Solid Malignancies

Study Overview
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Brief Summary
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Rationale: The Mammalian Target of Rapamycin (mTOR) is a large polypeptide serine/threonine kinase of 289 kDa; kinases have been shown to be important regulators of cancer cell cycle, proliferation, invasion, and angiogenesis, and mTOR has been shown to have a key role in the signaling of malignant cell growth, proliferation, differentiation, migration, and survival. Inhibition of mTOR would result in arrest of cell growth in the G1 phase of the cell cycle. Temsirolimus (CCI-779) is a soluble ester analogue of rapamycin (sirolimus) which has shown impressive in vitro and in vivo cytostatic activity in selectively inhibiting mTOR. In animal models, temsirolimus has demonstrated an impressive cytostatic effect on a wide variety of cancer cells. In vitro, it inhibited the growth of human T-cell leukemia, glioblastoma, melanoma, prostate, breast, renal cell, and pancreatic cells, all of which showed particular sensitivity to temsirolimus, with significant growth inhibition at concentrations of less that 0.01micrometers. In Phase I trials, temsirolimus has been investigated as a single agent on a weekly schedule as well as daily for 5 days every other week, and evidence of activity was observed over the entire dose range (15 - 220 mg/m2) in patients with both breast and renal cancer. There was no apparent relationship between exposure and clinical benefit, suggesting that the inhibition of mTOR may be achieved at doses well below dose levels that result in dose limiting toxicities. Major tumor responses were noted in Phase I trials in patients previously treated with lung, breast, renal as well as neuroendocrine tumors. Minor responses were noted in soft tissue sarcoma, endometrial, and cervical carcinoma. Docetaxel is a taxane analog which is active against many solid tumors including breast, non-small cell lung, prostate, gastric, ovarian, head and neck, and pancreatic cancers, soft tissue sarcoma, and melanoma. It has been shown in several Phase III studies to have clinically significant activity in several solid tumors. We propose treating patients with resistant solid malignancies with docetaxel and temsirolimus. In a study using human breast cancer cell lines, mTOR inhibition with rapamycin had a synergistic cytotoxic effect with paclitaxel. Given the novel mechanism of action of mTOR inhibitors and known synergistic activity of an mTOR inhibitor, rapamycin, with a taxane, paclitaxel, in vitro, we envision that this regimen would be highly active in patients with solid tumor malignancies. Objectives: Primary To define the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of temsirolimus in combination with pegylated liposomal doxorubicin in patients with resistant solid malignancies. To determine the incidence and severity of other toxicities of temsirolimus in combination with pegylated liposomal doxorubicin in patients with resistant solid malignancies. Secondary To assess the pharmacokinetic profile of temsirolimus in combination with pegylated liposomal doxorubicin. To determine any anti-tumor activity and response to the combination of temsirolimus and pegylated liposomal doxorubicin in treatment of patients with resistant solid malignancies.

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

Conditions
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Resistant Solid Malignancies

Intervention / Treatment
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* Drug: Temsirolimus
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion and Exclusion Criteria: Patients must have a histologically or cytologically proven solid malignancy which is resistant to conventional therapy or for which no effective therapy is known. 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. Patients must have recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. Neuropathy must have recovered to grade 1. No chemotherapy or radiotherapy may be given within 4 weeks prior to the start of protocol treatment. Patients must be ≥18 years old. ECOG 0-2 at study entry. Patients must have a life expectancy of greater than 8 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(SGOT)/ALT(SGPT) ≤1.5 x ULN (≤2.5 x ULN for patients with liver metastases alkaline phosphatase ≤2.5 x ULN creatinine ≤1.5 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 ≤400 mg/dL (fasting)* albumin ≥3.0 mg/dL 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 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. Patients with known hypersensitivity reactions to macrolide antibiotics (such as erythromycin, clarithromycin, and azithromycin) are not eligible for this trial. 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. Patients must not have active CNS disease. 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. 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.

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: Cohort 1<br>Temsirolimus IV 15 mg weekly Docetaxel 60 mg/m2 IV once every three weeks. | Drug: Temsirolimus<br> <br> * Other names: CCI-779;Drug: Docetaxel<br> <br> * Other names: Taxotere;|
| Experimental: Cohort 2<br>Temsirolimus IV 25 mg weekly Docetaxel IV 60 mg/m2 once every 3 weeks | Drug: Temsirolimus<br> <br> * Other names: CCI-779;Drug: Docetaxel<br> <br> * Other names: Taxotere;|
| Experimental: Cohort 1A<br>Temsirolimus IV 15 mg weekly Docetaxel IV 50 mg/m2 every 3 weeks. | Drug: Temsirolimus<br> <br> * Other names: CCI-779;Drug: Docetaxel<br> <br> * Other names: Taxotere;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To define the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of temsirolimus in combination with pegylated liposomal doxorubicin in patients with resistant solid malignancies. |  | After completion of cycle 1 by all patients | 
| To determine the incidence and severity of other toxicities of temsirolimus in combination with pegylated liposomal doxorubicin in patients with resistant solid malignancies. |  | 30 days after completion of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the pharmacokinetic profile of temsirolimus in combination with pegylated liposomal doxorubicin. | cycle 1 day 1, cycle 2 day 1 (pre-dose, 0.5 hours before end of temsirolimus infusion, 1.5 hours after start of temsirolimus infusion, 5 hours after start of temsirolimus infusion), cycle 2 day 3, cycle 2 day 5, and cycle 2 day 8 | Through cycle 2 day 8 | 
| To determine any anti-tumor activity and response to the combination of temsirolimus and pegylated liposomal doxorubicin in treatment of patients with resistant solid malignancies. |  | End of study treatment |