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Phase I Study of DOXIL and Temsirolimus in Resistant Solid Malignancies

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

 No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

 Interventional
Eligible Ages 18 Years and Over
Gender All
More Inclusion & Exclusion 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.

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

 NCT00703170
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

 Phase 1
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

 Washington University School of Medicine
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

 Joel Picus, M.D.
Principal Investigator Affiliation Washington University School of Medicine
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

 Other
Overall Status Completed
Countries United States
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

 Resistant Solid Malignancies
Study Website: View Trial Website
Arms & Interventions

Arms

Experimental: Dose Level 1 (original)

Temsirolimus IV 20 mg weekly Pegylated liposomal doxorubicin IV 30 mg/m2 once every 4 weeks

Experimental: Dose Level 1 (revised)

Temsirolimus IV 20 mg weekly Pegylated liposomal doxorubicin IV 25 mg/m2 once every 4 weeks

Experimental: Dose Level 2

Temsirolimus IV 25 mg weekly Pegylated liposomal doxorubicin IV 25 mg/m2 once every 4 weeks

Interventions

Drug: - Temsirolimus

Drug: - Pegylated liposomal doxorubicin

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

Washington University School of Medicine, St. Louis, Missouri

Status

Address

Washington University School of Medicine

St. Louis, Missouri, 63110

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