Phase I Study of Docetaxel and Temsirolimus in Resistant Solid Malignancies

NCT00703625 | Completed Phase 1 DMC

• 1 other identifier: 07-0444
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

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 0.01micrometers. 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.

Conditions

Resistant Solid Malignancies

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (2)

• To assess the pharmacokinetic profile of temsirolimus in combination with pegylated liposomal doxorubicin.

  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

Study Arms (3)

Cohort 1

EXPERIMENTAL

Temsirolimus IV 15 mg weekly Docetaxel 60 mg/m2 IV once every three weeks.

Drug: Temsirolimus; Drug: Docetaxel

Cohort 2

EXPERIMENTAL

Temsirolimus IV 25 mg weekly Docetaxel IV 60 mg/m2 once every 3 weeks

Drug: Temsirolimus; Drug: Docetaxel

Cohort 1A

EXPERIMENTAL

Temsirolimus IV 15 mg weekly Docetaxel IV 50 mg/m2 every 3 weeks.

Drug: Temsirolimus; Drug: Docetaxel

Interventions

Temsirolimus DRUG

Also known as: Torisel, CCI-779

Cohort 1; Cohort 1A; Cohort 2

Docetaxel DRUG

Also known as: Taxotere

Cohort 1; Cohort 1A; Cohort 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• 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

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Publications (33)

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Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Interventions

temsirolimus; Docetaxel

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Study Officials

• Joel Picus, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 20, 2008
• First Posted: June 23, 2008
• Study Start: March 8, 2008
• Primary Completion: May 1, 2011
• Study Completion: June 1, 2011
• Last Updated: March 7, 2017

Record last verified: 2017-03

Locations

US (1)