Investigational New Drugs

, Volume 28, Issue 3, pp 334–342

Phase I, pharmacokinetic study of temsirolimus administered orally to patients with advanced cancer

Authors

    • Mayo Clinic
  • Bahram Forouzesh
    • Institute for Drug DevelopmentCancer Therapy and Research Center
    • The University of Texas Health Science Center
    • Audi Murphy Veterans Affairs Hospital
    • Liverpool Oncology, Liverpool Hospital
  • Charles Erlichman
    • Mayo Clinic
  • Manuel Hidalgo
    • Institute for Drug DevelopmentCancer Therapy and Research Center
    • The University of Texas Health Science Center
    • The Sydney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • Joseph P. Boni
    • Wyeth Research
  • Gary Dukart
    • Wyeth Research
  • Anna Berkenblit
    • Wyeth Research
  • Eric K. Rowinsky
    • Institute for Drug DevelopmentCancer Therapy and Research Center
    • The University of Texas Health Science Center
    • ImClone Systems Incorporated
PHASE I STUDIES

DOI: 10.1007/s10637-009-9257-1

Cite this article as:
Buckner, J.C., Forouzesh, B., Erlichman, C. et al. Invest New Drugs (2010) 28: 334. doi:10.1007/s10637-009-9257-1

Summary

An oral formulation of temsirolimus (Torisel®), an inhibitor of the mammalian target of rapamycin, was evaluated on an intermittent schedule (once daily for 5 days every 2 weeks) in patients with advanced cancer. The maximum tolerated dose was determined to be 75 mg after dose-limiting toxicities of grade 3 elevated aminotransferases (1 patient) and grade 3 rash (1 patient) occurred with a 100-mg dose. The most common temsirolimus-related adverse events were mucositis, rash/maculopapular rash, and asthenia. Six of 12 patients who received the 75-mg dose required dose reductions due to temsirolimus-related adverse events. Two patients who received 75-mg temsirolimus and did not have dose reductions had minor tumor responses. Relative exposure from contributions of both temsirolimus and sirolimus, the principal metabolite, was 17.9% of the 75-mg dose. Thus, oral temsirolimus, 75 mg administered once daily for 5 days every 2 weeks, was further evaluated in patients with metastatic breast cancer.

Keywords

mTORTargeted chemotherapyPharmacokineticsPhase I

Introduction

Temsirolimus is a specific inhibitor of the mammalian target of rapamycin (mTOR) kinase, a central component of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway that mediates cell growth and proliferation [1, 2] and angiogenesis [3, 4]. Temsirolimus binds with high affinity to the immunophilin FK506/rapamycin binding protein and the complex binds to mTOR and inhibits its kinase activity [5]. Thus, mTOR-mediated phosphorylation of the p70 S6 kinase and the eukaryotic translation initiation factor 4E binding protein-1 is down regulated and translation of key proteins involved in cell cycle progression [6, 7] and angiogenesis [3, 810] is inhibited.

Temsirolimus has been shown to inhibit proliferation of cells in culture by arresting cells in the G1 phase of the cell cycle [3, 6, 11, 12]. In tumor xenograft models, the predominant anticancer activity of temsirolimus was manifested as tumor growth inhibition; overt tumor regression was not observed [6, 7, 911, 13, 14].

Clinical studies have indicated that temsirolimus has antitumor activity when administered intravenously to patients with different tumor types. For patients with advanced refractory renal cell carcinoma (RCC), in a phase II study, single-agent temsirolimus was administered on a weekly intravenous (IV) schedule at several different doses, and partial responses were observed [15]. In a phase III study, patients with poor-prognosis, advanced RCC and no prior systemic treatment for their disease received IV temsirolimus 25 mg weekly and had significantly longer overall survival than those treated with interferon-α, a standard therapy [16]. For patients with relapsed mantle cell lymphoma (MCL), in two phase II studies, single-agent temsirolimus was administered on a weekly IV schedule at a low or high dose and complete and partial responses were observed [17, 18]. In a phase III study, patients with relapsed or refractory MCL received IV temsirolimus 175 mg weekly for 3 weeks followed by 75 mg weekly and had significantly longer progression-free survival than those treated with investigator’s choice therapy [19]. Partial tumor responses after treatment with IV temsirolimus also were observed for patients with relapsed or refractory non-Hodgkin’s lymphoma subtypes [20], recurrent or metastatic endometrial cancer [21], metastatic breast cancer [22, 23], relapsed or refractory multiple myeloma [24], and non-small cell lung cancer [25].

An oral formulation of temsirolimus was developed because it was felt that this would be a convenient method of administration of the drug. In this study, the oral formulation of temsirolimus was administered to patients with advanced cancer to determine the maximum tolerated dose (MTD), assess safety, characterize its pharmacokinetic profile, and evaluate its preliminary antitumor activity. Similar to a schedule that was used previously for IV temsirolimus to achieve antitumor activity and minimize immunosuppressive effects [25], an intermittent schedule of administration, once daily for 5 days every 2 weeks, was used.

Patients and methods

Patient selection

Patients with histologically confirmed advanced cancer (solid tumors or lymphomas) that was refractory to standard therapy or for which standard therapy was not appropriate were included in this study. Eligible patients were ≥18 years of age and had an Eastern Cooperative Oncology Group performance status of ≤2; life-expectancy of ≥12 weeks; measurable or evaluable disease; adequate hematopoietic, hepatic, and renal function (hemoglobin level ≥8.5 g/dL, absolute neutrophil count ≥1500/μL, platelet count ≥100,000/μL, bilirubin level ≤1.5 mg/dL, aspartate aminotransferase [AST] and alanine aminotransferase [ALT] levels ≤3 times the institutional upper limit of normal or ≤5 times that limit if liver metastases were present, and serum creatinine <2 mg/dL); and serum levels of cholesterol and triglycerides ≤350 mg/dL and ≤400 mg/dL, respectively.

Patients were excluded if they could not swallow temsirolimus tablets or had prior chemotherapy, hormonal therapy, immunotherapy, or radiotherapy within 3 weeks of study entry; treatment with immunosuppressive agents, except for corticosteroids used as antiemetics, within 3 weeks of study entry; symptomatic central nervous system metastases or peritumoral edema; active infection or serious intercurrent illness; unstable angina or myocardial infarction within 6 months of study entry; any other major illness; or known hypersensitivity to diphenhydramine or any of the components in the temsirolimus infusion or tablet. Women who were pregnant, nursing, or of childbearing potential and not using an effective contraceptive method or men with partners of childbearing potential who were not using an effective contraceptive method also were excluded.

The study protocol was approved by the institutional review boards of the participating institutions and all patients gave written informed consent before treatment. The study was conducted according to the Declaration of Helsinki and its amendments.

Drug administration

Cohorts of three to six patients were treated with temsirolimus both in a bioavailability phase and a treatment phase of the study. To determine absolute bioavailability, patients received a single dose of oral or IV temsirolimus, followed by a washout period of approximately 1 week. This was followed by a single dose of temsirolimus administered by the other route of administration, followed by a second washout period of approximately 1 week. The order in which patients received oral or IV temsirolimus was randomly assigned. Based on animal studies, bioavailability of the oral formulation was expected to be 10% to 25%. A starting IV temsirolimus dose of 5 mg was selected based on the phase I study that utilized IV temsirolimus administered daily for 5 days every 2 weeks [25]. The comparable starting oral dose was selected to be 25 mg. Thus, the first cohort of three patients received a 25-mg oral temsirolimus dose and a 5-mg IV dose.

After the second washout period, patients began the treatment phase of the study and received the same oral temsirolimus dose as in the bioavailability determination, daily for 5 days of an approximate 14-day cycle. The decision to escalate to higher doses of temsirolimus for subsequent cohorts of patients was based on toxicities observed during the first cycle. The temsirolimus dose was doubled until a drug-related toxicity of at least grade 2 (National Cancer Institute Common Toxicity Criteria, version 2.0) occurred in cycle 1 for a patient. Then, escalation was to proceed using a modified Fibonacci scheme with steps of 67%, 50%, 40%, and 33% (rounded based on tablet sizes of 5 mg or 10 mg). Patients could continue treatment as long as it was tolerated and there was no evidence of disease progression. Dose escalation for an individual patient was not permitted.

Dose limiting toxicity (DLT) was defined as a temsirolimus-related grade 3 or 4 nonhematologic toxicity (excluding nausea or vomiting in patients on suboptimal antiemetic therapy or serum triglycerides <1500 mg/dL, if recovery occurred in the next cycle), neutropenic fever, grade 4 thrombocytopenia or neutropenia lasting more than 5 days, or toxicity of any grade that resulted in a treatment delay of more than 2 weeks. If one of three patients in a dose cohort had a DLT during cycle 1, three additional patients were entered in the cohort. If two or more patients of the six developed a DLT, the MTD was exceeded and additional patients were treated at a lower dose. The MTD was the highest dose for which fewer than two of six patients had a DLT during cycle 1. A patient who had a DLT could continue treatment with temsirolimus after a dose reduction by one level.

Dose reductions were made if DLTs occurred, including grade 1 or 2 toxicities which delayed treatment in the subsequent cycle for more than 2 weeks. Patients were allowed a maximum of two dose reductions. If further dose reductions were required, the patient discontinued treatment.

Patients were to take the temsirolimus tablets within 20 min of completing a moderate fat meal at the same time each day. For the bioavailability determination, IV temsirolimus was administered as a 30-minute infusion following premedication with IV diphenhydramine, 25 to 50 mg, over 30 min. If a patient developed a hypersensitivity reaction, a histamine H2-receptor antagonist could be administered.

Evaluation of patients

Safety was assessed with adverse event monitoring by physical examinations including vital signs, complete blood count with differential, serum electrolytes, serum chemistry for renal and hepatic function, coagulation studies, urinalysis, and electrocardiograms. All patients who received at least one dose of temsirolimus were included in the safety evaluation.

Imaging studies were performed to assess tumor status. Tumor assessments were made approximately every 2 months. Patients who completed at least two cycles of temsirolimus treatment and had a tumor assessment following initiation of the study or who discontinued because of disease progression were evaluable for tumor response. Response was defined using World Health Organization guidelines. A complete response was reported if there was disappearance of all active disease. A partial response was reported if there was at least a 50% reduction in total baseline tumor size (the sum of the product of the perpendicular diameters of all measurable lesions). A minor response was reported if there was at least a 25% decrease but less than a 50% decrease in total baseline tumor size. Progressive disease was reported if there was at least a 25% increase in total baseline tumor size or the appearance of any new lesion. Stable disease was reported if complete, partial, or minor responses or progressive disease did not occur.

Duration of tumor response was measured from the first time a response was reported until the date of progressive disease. Time to tumor progression was defined as the interval from the date of first dose of temsirolimus to the first date of documented progressive disease. Results for time to tumor progression were analyzed by Kaplan-Meier estimates.

Pharmacokinetic analysis

Whole blood and plasma were collected for analysis of concentrations of temsirolimus and sirolimus, its principal metabolite. For determination of bioavailability, whole blood was collected at 0, 0.25 (IV only), 0.5, 1, 2, 3 (oral only), 4 h, 6 h, 8 h, 24 h, 48 h, 72 h, and 120 h. Plasma was collected after both routes of administration at 0.5 h, 2 h, 4 h, 6 h, 8 h, and 24 h. During the treatment phase of the study, whole blood was collected during cycle 1 on days 1 and 5 at 0 hour; on day 5 at 1, 3, 8, 24, and 96 (±24) hours; and before the day-1 dose of cycle 2. Plasma was collected during cycle 1 on day 5 at 1 h, 8 h, and 24 h and before the day-1 dose of cycle 2. If a patient received 3 cycles of treatment, whole blood was collected during cycle 3 at the same times as for cycle 1.

Temsirolimus and sirolimus concentrations in whole blood were measured using a validated liquid chromatography-tandem mass spectrometry procedure with internal standard (Taylor Technology, Inc., Princeton, NJ) as described [22]. The lower limit of detection for both temsirolimus and sirolimus was 0.25 ng/mL. Both temsirolimus and sirolimus concentration data were analyzed by noncompartmental methods based on actual blood collection times [26]. Peak concentration (Cmax) for each weekly dose and the time to Cmax (tmax) were taken from observed data. The terminal half-life (t1/2) was taken as the quotient of 0.693 and λz, the slope of the terminal phase of concentrations read on a logarithmic scale. The area under the concentration-time curve through the last measurable time point (AUCT) was estimated by using the log-linear trapezoidal rule. The AUC0-24 was determined by calculating the partial AUC through the 24-hour time point. Area under the curve extrapolated to infinity (AUC) was determined from the sum of AUCT and the quotient of the last measurable concentration and λz. The clearance (CL) was determined from the quotient of dose and AUC. The steady-state volume of distribution (Vdss) was determined from the product of CL and mean residence time (MRT), in which MRT = (AUMC/AUC) + (T/2). In this equation, AUMC is the area under the first moment curve and T is the duration of drug infusion. Absolute bioavailability (F) was determined by taking the dose-normalized ratio of AUCs following oral to IV treatments during the bioavailability phase of the study. The whole blood-to-plasma ratio (B/P) of temsirolimus and sirolimus was determined by taking the ratio of the concentrations measured in simultaneously collected specimens. The ratio of AUCsirolimus to AUCtemsirolimus (AUCratio) and the sum of the AUCs of temsirolimus and sirolimus (AUCsum) were calculated unadjusted for differences in molecular weight (~ 13%). The relative exposure was determined from the dose-normalized quotient of AUCsum (oral) and AUCsum (IV). Dose proportionality for Cmax, AUC, and AUCsum and analysis of variance were analyzed as previously described [25].

Results

Patient characteristics

A total of 24 patients were enrolled over a 17-month period. The predominant primary cancer types, as depicted in Table 1, were renal (8 patients) and colorectal, leiomyosarcoma, and non-small cell lung (2 each). All patients had prior surgical therapy, 88% had prior chemotherapy, and 50% had prior radiation therapy. Patients started temsirolimus treatment a median of 38 months (range, 8 to 145) from their primary cancer diagnosis and a median of 15 months (range, 5 to 65) from metastasis.
Table 1

Patient characteristics

Characteristic

No.

No. of patients enrolled

24

Sex, n

 Men

13

 Women

11

Age, years

 Median

54

 Range

25–83

ECOG performance status, n

 0

11

 1

10

 2

3

Prior therapy, n

 Surgical therapy

24

 Chemotherapy

21

 Radiotherapy

12

 Chemotherapy and radiotherapy

10

Primary cancer diagnosis, n

 Renal cancer

8

 Colorectal cancer

2

 Leiomyosarcoma

2

 Non-small cell lung cancer

2

 Othera

10

ECOG Eastern Cooperative Oncology Group

aOne each of carcinoma of unknown primary site, chondrosarcoma, melanoma, mesothelioma, neuroblastoma, osteosarcoma; and bladder, pancreatic, salivary gland, and small cell lung cancer

Dose escalation

Three patients were treated with 25 mg temsirolimus daily for 5 days and, at the end of 14 days, no DLT was observed. Then, 3 patients were treated with 50 mg temsirolimus and no DLT was observed. Of 3 patients in the 100-mg dose cohort, one had DLTs of grade 3 elevations in AST and ALT. Thus, three additional patients were enrolled in this cohort and one had a DLT of grade 3 rash. Based on these DLTs, dose escalation was stopped. Three patients were treated with the intermediate dose of 75 mg temsirolimus daily for 5 days and, at the end of 14 days, no DLT was observed. Thus, the 75-mg temsirolimus dose was determined to be the MTD and nine additional patients were treated at this dose to further assess safety.

The median number of cycles for all patients on study was 5 (range, 1 to 49). At the MTD, patients were on study for a median of 4 cycles (range, 2 to 44).

Safety

All patients were evaluable for safety and had at least one temsirolimus-related adverse event (Table 2). The most frequently occurring grade 1 to 3 temsirolimus-related adverse events that occurred in all cycles were mucositis (58% patients), rash/maculopapular rash (58%), and asthenia (46%). No grade 4 related adverse events occurred. Ten patients (42%) had at least one grade 3 related adverse event (Table 2). Three patients had grade 3 rash/maculopapular rash and two each had grade 3 anemia, leukopenia, or hyperglycemia.
Table 2

Number of patients with temsirolimus-related adverse events reported in >10% of the total population, all cycles

Adverse Event

Total n = 24

25 mg n = 3

50 mg n = 3

75 mg n = 12

100 mg n = 6

Gradea

Gradea

Gradea

Gradea

Gradea

All

3

All

3

All

3

All

3

All

3

At least one

24

10b

3

1

3

1

12

4b

6

4

Mucositisc

14

-

-

-

3

-

6

-

5

-

Rashd

14

3

1

-

2

1

6

-

5

2

Asthenia

11

-

-

-

3

-

4

-

4

-

Anorexia

8

-

-

-

2

-

4

-

2

-

Diarrhea

7

-

-

-

1

-

3

-

3

-

Anemia

7

2

1

1

1

-

3

-

2

1

Thrombocytopenia

7

-

-

-

-

-

6

-

1

-

Nausea

6

-

-

-

1

-

3

-

2

-

Vomiting

5

-

-

-

1

-

3

-

1

-

Epistaxis

5

-

-

-

-

-

2

-

3

-

Acnee

5

-

-

-

-

-

1

-

4

-

Nail disorder

5

-

-

-

-

-

3

-

2

-

Hypertriglyceridemia

5

-

1

-

1

-

2

-

1

-

Headache

4

-

-

-

-

-

1

-

3

-

Leukopenia

4

2

-

-

-

-

3

1

1

1

Peripheral edema

4

-

1

-

-

-

2

-

1

-

Dry skin

4

-

-

-

2

-

1

-

1

-

Taste perversion

3

-

1

-

-

-

-

-

2

-

Creatinine increased

3

-

-

-

2

-

1

-

-

-

Hypercholesteremia

3

1

-

-

-

-

1

1

2

-

AST increased

3

1

-

--

-

-

2

-

1

1

aBased on National Cancer Institute Common Toxicity Criteria, version 2.0

bCertain grade 3 related adverse events are not listed because that adverse event did not occur in >10% of the total patient population. Grade 3 hyperglycemia occurred in 2 patients; grade 3 hypokalemia, hypophosphatemia, elevated ALT level, elevated fibrinogen level, and urticaria each occurred in 1 patient

cIncludes aphthous stomatitis, mouth ulceration, mucositis, stomatitis, and ulcerative stomatitis

dIncludes rash and maculopapular rash

eIncludes acne and pustular rash

Eleven (46%) patients required dose reductions because of temsirolimus-related adverse events; 9 had dose reductions because of grade 1 or 2 adverse events which resulted in treatment delays of more than 2 weeks. Six of 12 patients in the 75-mg cohort and five of six in the 100-mg cohort had one or more dose reductions. The most frequent drug-related adverse events that led to dose reductions were mucositis, rash, and thrombocytopenia. Two patients, one initially treated with 75 mg and one initially treated with 100 mg, had dose reductions because of stomatitis. The patient treated initially with 75 mg temsirolimus developed grade 2 stomatitis on study day 2 (the second day in the treatment phase), which led to a dose reduction to 50 mg beginning in cycle 2. The second patient treated initially with 100 mg had 2 dose reductions, one for grade 1 pruritus on day 8, which led to a dose reduction to 50 mg beginning in cycle 2, and then one for grade 2 stomatitis on day 64, which led to a dose reduction to 25 mg beginning in cycle 6. One patient treated initially with 100 mg temsirolimus had a dose reduction because of several temsirolimus-related adverse events, grade 1 mouth ulceration on day 1, grade 1 acne on day 10, and grade 3 rash on day 15, which led to a dose reduction to 50 mg beginning with cycle 2. One patient treated initially with 100 mg had grade 2 rash on day 85, which led to a dose reduction to 50 mg beginning in cycle 5. Two patients required dose reductions because of thrombocytopenia; both were treated initially with 75 mg temsirolimus and had grade 1 and 2 thrombocytopenia on days 10 and 8, respectively, which led to a dose reduction to 50 mg beginning in cycle 2.

Fifteen (63%) patients who received doses of 50 mg or higher of temsirolimus required dose delays. The most frequent drug-related adverse events that led to dose delays were thrombocytopenia (6 patients) and rash/maculopapular rash (3).

Two patients discontinued treatment because of adverse events. One patient treated with 25 mg temsirolimus had grade 2 pain and arthralgia, which occurred on study day 1 and was unrelated to drug treatment. The second patient treated with 50 mg temsirolimus had grade 3 rash beginning on day 109, which was considered related to drug treatment. She was treated with prednisone and topical therapies. One patient each treated with 25-mg, 50-mg, or 75-mg doses of temsirolimus withdrew consent and discontinued treatment. Nineteen patients discontinued treatment because of disease progression. Two patients died of causes unrelated to temsirolimus treatment: one died 38 days after the last dose of temsirolimus due to disease-related causes and the other died 80 days after the last dose due to cardiopulmonary arrest.

Pharmacokinetics

Whole blood and plasma samples were available from all 24 patients. After administration of a single, oral 75-mg dose of temsirolimus, absorption was moderately rapid (tmax of 2.2 h, Table 3) followed by a decrease in temsirolimus concentration with time in a monoexponential manner (Fig. 1a). Mean temsirolimus Cmax was 24.9 ng/mL, apparent CL was 424 L/h, apparent Vdss was 7277 L, and t1/2 was 12.6 h (Table 3). The sirolimus metabolite exhibited a similar rapid onset of peak exposure as observed for temsirolimus but was followed by a slower rate of decrease in concentration with time (Fig. 1b). For sirolimus, mean Cmax was 160 ng/mL and was higher than that observed for temsirolimus (24.9 ng/mL); t1/2 was 53.1 h (Table 4).
Table 3

Pharmacokinetic parameters of temsirolimus in blood in patients after a single oral or intravenous dose, mean ± SD (no. patients)

Dose, mg

Cmaxng/mL

tmaxhr

t1/2hr

AUC ng·h/mL

CLaL/h

VdssaL

F %

B/P Ratio

Oral administration

 25

13.7 ± 3.0 (3)

3.3 ± 2.3 (3)

10.0 ± 4.2 (3)

116 ± 29 (3)

222 ± 48 (3)

3338 ± 1933 (3)

2.0 ± 1.8 (3)

16.4 ± 4.5 (3)

 50

15.0 ± 2.6 (3)

1.7 ± 0.6 (3)

11.2 ± 0.8 (3)

120 ± 42 (3)

447 ± 131 (3)

7161 ± 1741 (3)

2.2 ± 0.8 (3)

9.7 ± 3.3 (3)

 75

24.9 ± 7.4 (12)

2.2 ± 1.4 (12)

12.6 ± 2.9 (12)

217 ± 108 (12)

424 ± 209 (12)

7277 ± 2822 (12)

2.5 ± 1.2 (12)

13.0 ± 6.3 (12)

 100

19.1 ± 5.9 (6)

1.4 ± 0.9 (6)

18.5 ± 4.6 (5)

149 ± 81 (6)

933 ± 707 (6)

16890 ± 5733 (5)

1.5 ± 0.7 (6)

13.6 ± 8.7 (6)

Intravenous administration

 5

217 ± 13 (2)

0.5 ± 0 (2)

23.9 ± 0.7 (2)

835 ± 11 (2)

6.0 ± 0.1 (2)

207 ± 9 (2)

-

8.0 ± 0.3 (2)

 10

378 ± 34 (2)

0.6 ± 0.4 (2)

18.1 ± 3.7 (3)

1190 ± 510 (3)

10.0 ± 5.6 (3)

245 ± 92 (3)

-

14.1 ± 10.7 (3)

 15

516 ± 108 (12)

0.4 ± 0.1 (12)

19.1 ± 4.3 (12)

1759 ± 385 (12)

8.8 ± 1.6 (12)

244 ± 71 (12)

-

17.9 ± 7.9 (12)

 20

551 ± 83 (6)

0.4 ± 0.1 (6)

18.7 ± 3.0 (6)

1964 ± 407 (6)

10.5 ± 1.9 (6)

280 ± 54 (6)

-

27.0 ± 8.0 (6)

aFor oral administration, CL and Vdss are designated as CL/F and Vdss/F, respectively, to account for the effect of bioavailability (F)

https://static-content.springer.com/image/art%3A10.1007%2Fs10637-009-9257-1/MediaObjects/10637_2009_9257_Fig1_HTML.gif
Fig. 1

Mean concentrations of temsirolimus a and sirolimus b versus time in blood of patients after administration of a single oral dose of temsirolimus

Table 4

Pharmacokinetic parameters of sirolimus in blood in patients after a single oral or intravenous dose of temsirolimus, mean ± SD (no. patients)

 

Sirolimus

Composite

Dose, mg

Cmaxng/mL

tmaxhr

t1/2hr

AUC ng·h/mL

B/P Ratio

AUCratio

AUCsumng·h/mL

Relative Exposure, %

Oral administration

 25

61 ± 34 (3)

3.7 ± 2.1 (3)

39.8 ± 14.9 (3)

1695 ± 667 (3)

26.7 ± 11.8 (3)

14.5 ± 4.7 (3)

1812 ± 687 (3)

8.8 ± 8.1 (3)

 50

177 ± 104 (3)

2.0 ± 0 (3)

59.9 ± 31.9 (3)

4080 ± 2850 (3)

31.8 ± 17.0 (3)

31.7 ± 11.3 (3)

4200 ± 2890 (3)

26.5 ± 11.9 (3)

 75

160 ± 50 (12)

2.9 ± 1.4 (12)

53.1 ± 24.2 (12)

4687 ± 2238 (12)

28.0 ± 16.3 (12)

25.7 ± 13.3 (12)

4905 ± 2213 (12)

17.9 ± 5.2 (12)

 100

211 ± 73 (6)

2.0 ± 0.6 (6)

52.4 ± 10.6 (6)

5751 ± 970 (6)

30.7 ± 12.6 (6)

54.2 ± 43.9 (6)

5901 ± 992 (6)

19.7 ± 5.6 (6)

Intravenous administration

 5

22.7 ± 6.4 (2)

4.0 ± 0 (2)

88.7 ± 33.7 (2)

1735 ± 277 (2)

18.7 ± 14.1 (2)

2.1 ± 0.3 (2)

2571 ± 288 (2)

-

 10

29.1 ± 1.6 (3)

1.8 ± 0.8 (3)

45.0 ± 19.6 (3)

2225 ± 1690 (3)

40.3 ± 31.4 (3)

1.7 ± 0.8 (3)

3416 ± 2128 (3)

-

 15

62.1 ± 21.7 (12)

1.6 ± 0.6 (12)

57.1 ± 24.5 (12)

3815 ± 2084 (12)

35.7 ± 20.4 (12)

2.2 ± 1.2 (12)

5575 ± 2179 (12)

-

 20

70.1 ± 27.2 (6)

1.3 ± 0.5 (6)

59.5 ± 17.3 (6)

4343 ± 1734 (6)

47.4 ± 20.4 (6)

2.3 ± 1.1 (6)

6307 ± 1690 (6)

-

After a single oral dose, temsirolimus exposure increased in a less than proportional manner with dose (Table 3), while sirolimus exposure increased in a dose proportional manner (Table 4). Sirolimus exposure was much greater than temsirolimus exposure. For the oral 25- and 100-mg temsirolimus doses, the AUCratio of sirolimus to temsirolimus was 14.5 and 54.2, respectively (Table 4). In contrast, for the comparable IV doses of 5 mg and 20 mg, the AUCratio was 2.1 and 2.3, respectively. Thus, mean F of temsirolimus ranged from 1.5% ± 0.7% to 2.5% ± 1.2% (Table 3), but mean relative exposure, based on contributions by both temsirolimus and sirolimus, ranged from 8.8% ± 8.1% to 26.5% ± 11.9% (Table 4).

After a single oral dose of temsirolimus, mean apparent CL and Vdss of temsirolimus in blood was extensive and increased with dose (Table 3). Temsirolimus and sirolimus were preferentially partitioned into formed elements of the blood; for 75 mg temsirolimus, the mean B/P ratio was 13.0 for temsirolimus (Table 3) and 28.0 for sirolimus (Table 4).

After 5 days of oral temsirolimus administration, temsirolimus exposure increased in a less than proportional manner with dose, while sirolimus exposure increased in a dose proportional manner (Table 5). Dose proportionality assessment indicated that the relationship between temsirolimus exposure and dose was less than proportional for Cmax (p = 0.00004) and AUC0-24 (p = 0.0026). The relationship between sirolimus exposure and temsirolimus dose was proportional for Cmax (p = 0.5689) and AUC0-24 (p = 0.5490). Limited degrees of temsirolimus accumulation occurred with multiple cycles of treatment based on analysis of variance (data not shown). In addition, no age- or gender-related effects on temsirolimus pharmacokinetics were apparent.
Table 5

Pharmacokinetic parameters of temsirolimus and sirolimus in blood in patients after oral administration of temsirolimus for 5 days daily, mean ± SD (no. patients)

Temsirolimus Dose, mg

Cmaxng/mL

tmaxh

t1/2h

AUC0-24ng·h/mL

B/P Ratio

Temsirolimus Parameters

 25

11.4 ± 4.4 (3)

3.4 ± 0.5 (3)

9.2 (1)

112.5 ± 21.6 (3)

10.9 ± 3.7 (2)

 50

15.0 ± 11.7 (3)

2.3 ± 1.2 (3)

5.9 ± 0.8 (2)

107.7 ± 6.3 (2)

4.4 ± 2.8 (2)

 75

23.0 ± 19.2 (12)

2.9 ± 1.9 (12)

9.5 ± 3.9 (10)

147.5 ± 105.2 (10)

6.2 ± 3.3 (10)

 100

20.0 ± 7.5 (6)

2.5 ± 2.8 (6)

7.4 ± 1.8 (5)

105.6 ± 34.5 (5)

7.9 ± 6.9 (6)

Sirolimus Parameters

 25

71 ± 29 (3)

4.1 ± 3.5 (3)

61.9 ± 3.2 (2)

1057 ± 956 (3)

13.7 ± 10.3 (3)

 50

144 ± 78 (3)

10.0 ± 12.0 (3)

48.6 ± 19.0 (2)

2595 ± 512 (2)

16.8 ± 11.1 (3)

 75

250 ± 150 (12)

2.9 ± 1.9 (12)

61.0 ± 26.0 (10)

3275 ± 698 (10)

23.5 ± 16.9 (12)

 100

335 ± 156 (6)

3.7 ± 3.4 (6)

45.9 ± 10.3 (4)

4431 ± 421 (5)

18.0 ± 10.8 (6)

Preliminary assessment of antitumor activity

Nineteen patients were evaluable for efficacy. None had a complete or partial response but five who received 75 mg (2 patients) or 100 mg (3) temsirolimus had minor responses, as assessed by imaging. Two patients, one who had renal cancer with lesions in the lung and one who had carcinoma of unknown primary site with disease in the lung and soft tissue (cervix and upper paratracheal), received 75 mg temsirolimus and had minor responses in cycles 3 and 4, respectively, each of which lasted for 8 weeks. The third patient, who had leiomyosarcoma with sites of disease in the soft tissue (anterior abdominal wall and pelvis), received 100 mg temsirolimus for 1 cycle and then had a dose reduction to 50 mg because of grade 3 elevated AST and ALT levels; she had a minor response in cycle 9, which lasted for 21 weeks. The fourth patient, who had mesothelioma with sites of disease in the abdomen and liver, received 100 mg temsirolimus for cycle 1 and had 2 dose reductions because of grade 1 pruritus and grade 2 stomatitis; beginning with cycle 6, she received 25 mg temsirolimus and had a minor response in cycle 21, which lasted for 8 weeks. The fifth patient, who had non-small cell lung cancer with nodal lesions, received 100 mg temsirolimus for 5 cycles and then had a dose reduction to 50 mg because of grade 2 diarrhea; he had a minor response in cycle 7, which lasted for 10 weeks.

Two patients had stable disease for at least 24 weeks. One patient, who had renal cancer, received 75 mg temsirolimus for 2 cycles, had a dose reduction to 50 mg because of grade 2 hypertriglyceridemia, and had stable disease lasting for 35 weeks. The second patient, who had chondrosarcoma, received 100 mg temsirolimus and had stable disease lasting for 36 weeks. Thus, 7 of the 19 efficacy-evaluable patients (37%) had minor response or stable disease for at least 35 weeks.

The median time to tumor progression for the 19 evaluable patients was 15.7 weeks (95% confidence interval, 12.0 to 30.0). No relationships were evident between time to tumor progression or best tumor response and AUCsum or temsirolimus or sirolimus Cmax or AUC0-24.

Discussion

In this study, we determined if an oral formulation of temsirolimus could be used as a treatment for patients with advanced cancer. When the 100-mg dose of temsirolimus was evaluated during the first 2-week cycle of treatment, DLTs of grade 3 elevations of AST and ALT occurred in one patient and grade 3 rash occurred in a second patient. No DLTs in the first cycle occurred when patients were subsequently treated with the 75-mg dose so that the MTD of the oral formulation of temsirolimus was determined to be 75 mg administered once a day for 5 days every 2 weeks.

The most common grade 1 to 3 temsirolimus-related adverse events that occurred in all patients in any cycle of treatment were mucositis (58% patients), rash/maculopapular rash (58%), and asthenia (46%). These occurred in patients treated with the MTD with a frequency similar to that of the total population. Mucositis and rash also were frequent causes for dose reductions. Temsirolimus-related adverse events were the cause of dose reductions in 50% of patients in the 75-mg cohort and 83% of patients in the 100-mg cohort.

When administered orally, temsirolimus underwent a 7- to 24-fold greater conversion to the sirolimus metabolite than when administered intravenously. This finding and the similar tmax values for temsirolimus and sirolimus suggest that oral temsirolimus is subject to substantial first-pass metabolism. Consequently, oral bioavailability of temsirolimus was low, 1.5% to 2.5%, but, with the contribution of equipotent sirolimus, the relative exposure of the oral formulation was 8.8% to 26.5%. This relative exposure is similar to the bioavailability obtained with administration of oral sirolimus of 18% [27].

Seven patients with renal cancer, leiomyosarcoma, mesothelioma, non-small cell carcinoma, and chondrosarcoma had minor responses or stable disease lasting for at least 35 weeks. Two patients who received the 75-mg dose without dose reductions had minor responses. Thus, the MTD of the oral formulation of temsirolimus administered once daily for 5 days every 2 weeks was associated with antitumor activity.

This temsirolimus dose and schedule were used in combination with an oral, daily 2.5-mg dose of letrozole for the treatment of patients with locally advanced or metastatic breast cancer, in a phase II study [28]. However, the temsirolimus dose had to be reduced to 30 mg because a number of patients required dose delays or reductions. When 30 mg temsirolimus was used in combination with letrozole (n = 30) and compared with letrozole alone (n=29), the combination was tolerable and showed promising efficacy [29]. However, when a phase III study was conducted with similar patients treated with either the combination of oral temsirolimus, 30 mg for 5 days every 2 weeks, plus oral letrozole, 2.5 mg daily (n = 493), or letrozole alone (n = 499), it was terminated early because of lack of efficacy in the combination arm [30]. Thus, the oral formulation of temsirolimus is no longer under development. However, the IV formulation of temsirolimus has shown acceptable safety and significant efficacy in the treatment of patients with poor-prognosis, advanced RCC compared with interferon-α [16] and has been approved in the United States for the treatment of patients with advanced RCC and in Europe for the first-line treatment of patients with advanced RCC who have at least 3 of 6 poor-prognostic risk factors [31, 32]. The IV formulation of temsirolimus also is being studied as a possible treatment for other kinds of cancer [1721, 24, 33, 34].

Acknowledgments

This study was supported by research funding from Wyeth Research, Collegeville, PA. We thank the patients, their families, and the clinical personnel who participated in this study and, of Wyeth Research, Bonnie Marshall and Maria Cincotta for study management and Susan Leinbach for assistance with manuscript preparation.

Copyright information

© Springer Science+Business Media, LLC 2009