Phase I Study of DOXIL and Temsirolimus in Resistant Solid Malignancies

Study Overview
=================
Brief Summary
-----------------
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 0.01micrometer. 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. Pegylated liposomal doxorubicin has been FDA approved for use in refractory metastatic ovarian cancer and AIDS-related Kaposi's Sarcoma. It has also been shown to be effective in previously treated metastatic breast cancer. Combination studies in preclinical models suggest that rapamycin and its analogues are at least additive in effect with standard chemotherapy and radiation. In addition, studies in breast cancer cell lines suggest that the mTOR inhibitors may reverse resistance to anti-estrogen agents. Thus, we are proposing that the combination of temsirolimus and liposomal doxorubicin will be highly effective in metastatic 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
-----------------
Phase I Study of Pegylated Liposomal Doxorubicin and Temsirolimus in Resistant Solid Malignancies

Conditions
-----------------
Resistant Solid Malignancies

Intervention / Treatment
-----------------
* Drug: Temsirolimus
* Drug: Pegylated liposomal doxorubicin


Participation Criteria
=================
Eligibility Criteria
-----------------
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. 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 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. Patients with known hypersensitivity reactions to macrolide antibiotics (such as erythromycin, clarithromycin, and azithromycin) are not eligible for this trial. Patients must have a normal left ventricular ejection fraction (LVEF ≥50%) by MUGA scan. 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 receiving anti-retroviral therapy (HAART) for HIV infection are excluded from the study because of possible pharmacokinetic interactions. 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
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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 1 (original)<br>Temsirolimus IV 20 mg weekly Pegylated liposomal doxorubicin IV 30 mg/m2 once every 4 weeks | Drug: Temsirolimus<br> <br> * Other names: CCI-779;Drug: Pegylated liposomal doxorubicin<br> <br> * Other names: DOXIL;|
| Experimental: Dose Level 1 (revised)<br>Temsirolimus IV 20 mg weekly Pegylated liposomal doxorubicin IV 25 mg/m2 once every 4 weeks | Drug: Temsirolimus<br> <br> * Other names: CCI-779;Drug: Pegylated liposomal doxorubicin<br> <br> * Other names: DOXIL;|
| Experimental: Dose Level 2<br>Temsirolimus IV 25 mg weekly Pegylated liposomal doxorubicin IV 25 mg/m2 once every 4 weeks | Drug: Temsirolimus<br> <br> * Other names: CCI-779;Drug: Pegylated liposomal doxorubicin<br> <br> * Other names: DOXIL;|

What is the study measuring?
-----------------
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. |  | 2 years | 
| 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. |  | Completion of study treatment |