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Study Evaluating Temsirolimus (CCI-779) In Breast Neoplasms

Sponsor
Wyeth is now a wholly owned subsidiary of Pfizer (Industry)
Overall Status
Completed
CT.gov ID
NCT00062751
Collaborator
Pfizer (Industry)
108
Enrollment
3
Arms
82
Duration (Months)

Study Details

Study Description

Brief Summary

To evaluate the preliminary activity and pharmacokinetics of 2 separate doses and schedules of orally administered Temsirolimus (CCI-779) given in combination with daily letrozole, compared to letrozole alone, in the treatment of locally advanced or metastatic breast cancer in postmenopausal women. All patients must be appropriate to receive endocrine therapy as treatment for advanced disease.

Condition or Disease Intervention/Treatment Phase
  • Drug: Letrozole / Temsirolimus (CCI-779)
  • Drug: Letrozole / Temsirolimus (CCI-779)
  • Drug: Letrozole
 Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
108 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 2 Randomized Open-Label Study Of Letrozole In Combination With Two Dose Levels And Schedules Of Oral Temsirolimus (CCI-779), Or Letrozole Alone, In Postmenopausal Women With Locally Advanced Or Metastatic Breast Cancer
Study Start Date :
Dec 1, 2002
Actual Primary Completion Date :
Apr 1, 2005
Actual Study Completion Date :
Oct 1, 2009

Arms and Interventions

Arm Intervention/Treatment
Experimental: A

Drug: Letrozole / Temsirolimus (CCI-779)
Letrozole 2.5 mg daily + Temsirolimus (CCI-779) 10 mg daily
Experimental: B

Drug: Letrozole / Temsirolimus (CCI-779)
Letrozole 2.5 mg daily + Temsirolimus (CCI-779) intermittent 30 mg daily for five days every 2 weeks
Other Names:
  • Letrozole / Temsirolimus(CCI-779), Torisel

    		•
    Active Comparator: C

    Drug: Letrozole
    Letrozole 2.5 mg daily
    Other Names:
  • Letrozole alone

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Percentage of Participants With Objective Response (OR) [Baseline, every 4 cycles (1 cycle is defined as a 14 day duration) up to Cycle 25, then every 6 cycles until disease progression]

      OR measured as Complete response (CR) or Partial response (PR) confirmed by assessments performed no less than 4 weeks after the criteria for the response are first met. CR=disappearance of all target and non-target lesions with normalization of tumor marker level; PR=at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, referencing the screening sum LD. Target lesions=all measurable lesions up to 5 lesions per organ (10 lesions in total), representative of all involved organs, if possible; recorded and measured at screening. Non-target lesions=all other lesions.

    Secondary Outcome Measures

    1. Percentage of Participants With Best Overall Response (Clinical Benefit) [Baseline, every 4 cycles (1 cycle is defined as a 14 day duration) up to Cycle 25, then every 6 cycles until disease progression)]

      Best response (CR, PR, or stable disease (SD) lasting ≥6 months) recorded from baseline to disease progression or recurrence (Progressive disease [PD]). CR=disappearance of all target and non-target lesions with normalization of tumor marker level; PR is ≥30% decrease in sum of LD of target lesions; SD=neither sufficient shrinkage to=PR nor sufficient increase to=PD, referencing smallest sum LD since treatment started; PD is ≥20% increase in sum of LD of target lesions referencing smallest sum of LD; appearance of ≥1 new lesions and/or unequivocal progression of existing non-target lesions.

    2. Time to Disease Progression [Baseline, every 4 cycles (1 cycle is defined as a 14 day duration) up to Cycle 25, then every 6 cycles until disease progression)]

      Number of days to disease progression defined as the interval from the date of randomization until the first date that recurrence or progression is documented; progression (at least 20% increase in the sum of the LD of target lesions taking as reference the smallest sum of LD; appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions).

    3. Time to Treatment Failure [Baseline until Progressive disease, death, or discontinuation of study treatment]

      Number of days to treatment failure defined as interval from start of treatment to first date of progressive disease (at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD since the treatment started; appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions) or death or discontinuation of treatment due to Adverse Event, censored at last evaluation.

    4. Percentage of Participants Exhibiting Freedom From Progression [Baseline, 8 weeks, 6 months, 12 months, and 24 months]

      Freedom from progression defined as CR (disappearance of all target and non-target lesions with normalization of tumor marker level), PR (at least a 30% decrease in sum of the LD of target lesions taking as reference the screening sum LD), or SD (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD [at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD since the treatment started; appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions]).

    5. Duration of Response [Baseline, every 4 cycles (1 cycle is defined as a 14 day duration) up to Cycle 25, then every 6 cycles until disease progression)]

      Duration of response is measured from the time measurement criteria are met for CR or PR (whichever status is recorded first) until the first date that reoccurrence or PD is objectively documented, taking as reference for PD the smallest measurements recorded since the treatment started. SD is measured from the start of the treatment until the criteria for disease progression are met, taking as reference the smallest measurements recorded since the treatment started; the minimal time interval for duration of SD is 8 weeks.

    6. Number of Participants With Survival [Baseline, every 4 cycles (1 cycle is defined as a 14 day duration) until death]

      Number of participants with survival (alive) in the interval from start of treatment to last contact for participant or death as a result of any cause.

    7. Health Outcomes Assessment: EuroQol (EQ-5D) Health State Profile Score [Prior to baseline, Cycle 7 (Week 12) and final visit (within 15 days of stopping study treatment)]

      EQ-5D is a self-administered questionnaire to assess health-related quality of life in 5 domains (mobility, self care, usual activities, pain or discomfort, and anxiety or depression). Scores from the 5 domains are used to calculate the Health State Profile Score as a single index value; range: 0.0 (death) to 1.0 (perfect health); higher scores indicate a better health state.

    8. Health Outcomes Assessment: European Organization for Research and Treatment of Cancer Quality of Life Questionaire (EORTC QLQ) BR23 [Prior to baseline, Cycle 7 (Week 12) and final visit (within 15 days of stopping study treatment)]

      Assess specificity of breast cancer symptoms relevant to participant's perceived quality of life (disease related symptoms of dry mouth, eye pain, hair loss, hot flushes, attractiveness, future health, sexual activity, arm or shoulder pain, breast pain, swollen breast, and skin problems on the breast). 23-item assessment of symptoms or problems during the past week (items 1-13 and 17-23) or during the past 4 weeks (items 14-16); range from 1 (not at all) to 4 (very much). Index scores transformed and range from 0 to 100; higher scores indicate higher level of functioning and quality of life.

    9. Number of Participants With Antitumor Response in Relation to Expression of Akt Phosphorylation, Cyclin D1, PTEN, and p27 [Prior to baseline, after Cycle 4 (Week 8), after Cycle 8 (Week 14), and cross-over or final visit (within 15 days of stopping study treatment)]

      Number of participants with antitumor response (CR [disappearance of all target and non-target lesions with normalization of tumor marker level] or PR [at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, referencing the screening sum LD]) in relation to plasma levels of Akt phosphorylation, cyclin D1, PTEN, and p27.

    10. Area Under the Concentration-time Curve (AUC) Sum [Cycle 1 Day 1 (1 cycle is defined as a 14 day duration) , Cycle 3 Day 1, and Cycle 4 Day 1, Day 6, Day 9, Day 11, and Day 12]

      Area under the concentration-time curve to infinity (AUC) measured as hours multiplied by nanograms divided by milliliters (hr*ng/mL) for CCI-779, sirolimus and letrozole. Sum is calculated as the sum of CCI-779 plus sirolimus AUCs (AUCsum).

    11. 24-hour Trough Concentration (C Trough) [Cycle 1 Day 1 (1 cycle is defined as a 14 day duration) , Cycle 3 Day 1, and Cycle 4 Day 1, Day 6, Day 9, Day 11, and Day 12]

      C trough in whole blood measured as nanograms per milliliter (ng/mL).

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    Female
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Postmenopausal women with histologically confirmed, measurable locally advanced disease or metastatic breast.

    • Must be appropriate to receive endocrine therapy as treatment for advanced disease (chemotherapy; prior adjuvant therapy with antiestrogens other than aromatase inhibitors; prior adjuvant or first-line metastatic therapy with tamoxifen or trastuzumab, are permitted).

    • Women may either present with de novo advanced or metastatic cancer, or have had tumor progression while receiving adjuvant tamoxifen or at any time after completing adjuvant tamoxifen, or have had tumor progression while receiving first-line metastatic therapy with tamoxifen.

    Exclusion Criteria:

    • Patients having known central nervous system (CNS) metastases.

    • Prior therapy with Temsirolimus (CCI-779) or aromatase inhibitors.

    • Tamoxifen, or other hormonal therapy, in the metastatic or adjuvant setting within 1 week prior to day 1 of treatment on study.

    Contacts and Locations

    Locations

    No locations specified.

    Sponsors and Collaborators

    • Wyeth is now a wholly owned subsidiary of Pfizer
    • Pfizer

    Investigators

    • Study Director: Pfizer CT.gov Call Center, Pfizer

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    , ,
    ClinicalTrials.gov Identifier:
    NCT00062751
    Other Study ID Numbers:
    • 3066A1-204
    • B1771005
    • NCT00061971
    First Posted:
    Jun 13, 2003
    Last Update Posted:
    Apr 15, 2011
    Last Verified:
    Apr 1, 2011
    Keywords provided by , ,
    breast
    neoplasms
    Additional relevant MeSH terms:
    Neoplasms
    Breast Neoplasms
    Sirolimus
    Letrozole

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail In the initial protocol, doses of CCI-779 were 25 mg daily and 75 mg intermittent; per protocol amendment, dosing was modified to 10 mg daily and 30 mg intermittent. All dose levels are included in the reporting groups.
    Arm/Group Title Let 2.5 mg Plus 10 mg Daily CCI-779 Let 2.5 mg Plus 30 mg Intermittent CCI-779 Let 2.5 mg Alone / Cross-over to 75 mg Intermittent CCI-779 Let 2.5 mg Plus 25mg Daily CCI-779 Let 2.5 mg Plus 75 mg Intermittent CCI-779
    Arm/Group Description Letrozole (Let) 2.5 milligrams (mg) daily administered with a 10 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 30 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily; permitted to cross-over at the time of progression to single-agent intermittent 75 mg dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 25 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 75 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779).
    Period Title: Overall Study
    STARTED 33 30 33 6 6
    COMPLETED 0 0 3 1 0
    NOT COMPLETED 33 30 30 5 6

    Baseline Characteristics

    Arm/Group Title Let 2.5 mg Plus 10 mg Daily CCI-779 Let 2.5 mg Plus 30 mg Intermittent CCI-779 Let 2.5 mg Alone / Cross-over to 75 mg Intermittent CCI-779 Let 2.5 mg Plus 25mg Daily CCI-779 Let 2.5 mg Plus 75 mg Intermittent CCI-779 Total
    Arm/Group Description Letrozole (Let) 2.5 milligrams (mg) daily administered with a 10 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 30 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily; permitted to cross-over at the time of progression to single-agent intermittent 75 mg dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 25 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 75 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Total of all reporting groups
    Overall Participants 33 30 33 6 6 108
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    62.21
    (11.87)
    62.83
    (8.39)
    60.85
    (9.79)
    61.83
    (9.83)
    60.00
    (9.65)
    61.82
    (9.98)
    Sex/Gender, Customized (participants) [Number]
    Female
    33
    100%
    30
    100%
    33
    100%
    6
    100%
    6
    100%
    108
    100%

    Outcome Measures

    1. Primary Outcome
    Title Percentage of Participants With Objective Response (OR)
    Description OR measured as Complete response (CR) or Partial response (PR) confirmed by assessments performed no less than 4 weeks after the criteria for the response are first met. CR=disappearance of all target and non-target lesions with normalization of tumor marker level; PR=at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, referencing the screening sum LD. Target lesions=all measurable lesions up to 5 lesions per organ (10 lesions in total), representative of all involved organs, if possible; recorded and measured at screening. Non-target lesions=all other lesions.
    Time Frame Baseline, every 4 cycles (1 cycle is defined as a 14 day duration) up to Cycle 25, then every 6 cycles until disease progression

    Outcome Measure Data

    Analysis Population Description
    Intent to treat population (ITT) defined as all participants randomized in the study. Final efficacy analysis was not conducted because the development of temsirolimus (CCI-779) for the treatment of breast cancer was terminated.
    Arm/Group Title Let 2.5 mg Plus 10 mg Daily CCI-779 Let 2.5 mg Plus 30 mg Intermittent CCI-779 Let 2.5 mg Alone / Cross-over to 75 mg Intermittent CCI-779 Let 2.5 mg Plus 25mg Daily CCI-779 Let 2.5 mg Plus 75 mg Intermittent CCI-779
    Arm/Group Description Letrozole (Let) 2.5 milligrams (mg) daily administered with a 10 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 30 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily; permitted to cross-over at the time of progression to single-agent intermittent 75 mg dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 25 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 75 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779).
    Measure Participants 0 0 0 0 0
    2. Secondary Outcome
    Title Percentage of Participants With Best Overall Response (Clinical Benefit)
    Description Best response (CR, PR, or stable disease (SD) lasting ≥6 months) recorded from baseline to disease progression or recurrence (Progressive disease [PD]). CR=disappearance of all target and non-target lesions with normalization of tumor marker level; PR is ≥30% decrease in sum of LD of target lesions; SD=neither sufficient shrinkage to=PR nor sufficient increase to=PD, referencing smallest sum LD since treatment started; PD is ≥20% increase in sum of LD of target lesions referencing smallest sum of LD; appearance of ≥1 new lesions and/or unequivocal progression of existing non-target lesions.
    Time Frame Baseline, every 4 cycles (1 cycle is defined as a 14 day duration) up to Cycle 25, then every 6 cycles until disease progression)

    Outcome Measure Data

    Analysis Population Description
    ITT; Final efficacy analysis was not conducted.
    Arm/Group Title Let 2.5 mg Plus 10 mg Daily CCI-779 Let 2.5 mg Plus 30 mg Intermittent CCI-779 Let 2.5 mg Alone / Cross-over to 75 mg Intermittent CCI-779 Let 2.5 mg Plus 25mg Daily CCI-779 Let 2.5 mg Plus 75 mg Intermittent CCI-779
    Arm/Group Description Letrozole (Let) 2.5 milligrams (mg) daily administered with a 10 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 30 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily; permitted to cross-over at the time of progression to single-agent intermittent 75 mg dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 25 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 75 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779).
    Measure Participants 0 0 0 0 0
    3. Secondary Outcome
    Title Time to Disease Progression
    Description Number of days to disease progression defined as the interval from the date of randomization until the first date that recurrence or progression is documented; progression (at least 20% increase in the sum of the LD of target lesions taking as reference the smallest sum of LD; appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions).
    Time Frame Baseline, every 4 cycles (1 cycle is defined as a 14 day duration) up to Cycle 25, then every 6 cycles until disease progression)

    Outcome Measure Data

    Analysis Population Description
    ITT; Final efficacy analysis was not conducted.
    Arm/Group Title Let 2.5 mg Plus 10 mg Daily CCI-779 Let 2.5 mg Plus 30 mg Intermittent CCI-779 Let 2.5 mg Alone / Cross-over to 75 mg Intermittent CCI-779 Let 2.5 mg Plus 25mg Daily CCI-779 Let 2.5 mg Plus 75 mg Intermittent CCI-779
    Arm/Group Description Letrozole (Let) 2.5 milligrams (mg) daily administered with a 10 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 30 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily; permitted to cross-over at the time of progression to single-agent intermittent 75 mg dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 25 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 75 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779).
    Measure Participants 0 0 0 0 0
    4. Secondary Outcome
    Title Time to Treatment Failure
    Description Number of days to treatment failure defined as interval from start of treatment to first date of progressive disease (at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD since the treatment started; appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions) or death or discontinuation of treatment due to Adverse Event, censored at last evaluation.
    Time Frame Baseline until Progressive disease, death, or discontinuation of study treatment

    Outcome Measure Data

    Analysis Population Description
    ITT; Final efficacy analysis was not conducted.
    Arm/Group Title Let 2.5 mg Plus 10 mg Daily CCI-779 Let 2.5 mg Plus 30 mg Intermittent CCI-779 Let 2.5 mg Alone / Cross-over to 75 mg Intermittent CCI-779 Let 2.5 mg Plus 25mg Daily CCI-779 Let 2.5 mg Plus 75 mg Intermittent CCI-779
    Arm/Group Description Letrozole (Let) 2.5 milligrams (mg) daily administered with a 10 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 30 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily; permitted to cross-over at the time of progression to single-agent intermittent 75 mg dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 25 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 75 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779).
    Measure Participants 0 0 0 0 0
    5. Secondary Outcome
    Title Percentage of Participants Exhibiting Freedom From Progression
    Description Freedom from progression defined as CR (disappearance of all target and non-target lesions with normalization of tumor marker level), PR (at least a 30% decrease in sum of the LD of target lesions taking as reference the screening sum LD), or SD (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD [at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD since the treatment started; appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions]).
    Time Frame Baseline, 8 weeks, 6 months, 12 months, and 24 months

    Outcome Measure Data

    Analysis Population Description
    ITT; Final efficacy analysis was not conducted.
    Arm/Group Title Let 2.5 mg Plus 10 mg Daily CCI-779 Let 2.5 mg Plus 30 mg Intermittent CCI-779 Let 2.5 mg Alone / Cross-over to 75 mg Intermittent CCI-779 Let 2.5 mg Plus 25mg Daily CCI-779 Let 2.5 mg Plus 75 mg Intermittent CCI-779
    Arm/Group Description Letrozole (Let) 2.5 milligrams (mg) daily administered with a 10 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 30 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily; permitted to cross-over at the time of progression to single-agent intermittent 75 mg dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 25 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 75 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779).
    Measure Participants 0 0 0 0 0
    6. Secondary Outcome
    Title Duration of Response
    Description Duration of response is measured from the time measurement criteria are met for CR or PR (whichever status is recorded first) until the first date that reoccurrence or PD is objectively documented, taking as reference for PD the smallest measurements recorded since the treatment started. SD is measured from the start of the treatment until the criteria for disease progression are met, taking as reference the smallest measurements recorded since the treatment started; the minimal time interval for duration of SD is 8 weeks.
    Time Frame Baseline, every 4 cycles (1 cycle is defined as a 14 day duration) up to Cycle 25, then every 6 cycles until disease progression)

    Outcome Measure Data

    Analysis Population Description
    ITT; Final efficacy analysis was not conducted.
    Arm/Group Title Let 2.5 mg Plus 10 mg Daily CCI-779 Let 2.5 mg Plus 30 mg Intermittent CCI-779 Let 2.5 mg Alone / Cross-over to 75 mg Intermittent CCI-779 Let 2.5 mg Plus 25mg Daily CCI-779 Let 2.5 mg Plus 75 mg Intermittent CCI-779
    Arm/Group Description Letrozole (Let) 2.5 milligrams (mg) daily administered with a 10 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 30 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily; permitted to cross-over at the time of progression to single-agent intermittent 75 mg dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 25 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 75 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779).
    Measure Participants 0 0 0 0 0
    7. Secondary Outcome
    Title Number of Participants With Survival
    Description Number of participants with survival (alive) in the interval from start of treatment to last contact for participant or death as a result of any cause.
    Time Frame Baseline, every 4 cycles (1 cycle is defined as a 14 day duration) until death

    Outcome Measure Data

    Analysis Population Description
    ITT; Final efficacy analysis was not conducted.
    Arm/Group Title Let 2.5 mg Plus 10 mg Daily CCI-779 Let 2.5 mg Plus 30 mg Intermittent CCI-779 Let 2.5 mg Alone / Cross-over to 75 mg Intermittent CCI-779 Let 2.5 mg Plus 25mg Daily CCI-779 Let 2.5 mg Plus 75 mg Intermittent CCI-779
    Arm/Group Description Letrozole (Let) 2.5 milligrams (mg) daily administered with a 10 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 30 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily; permitted to cross-over at the time of progression to single-agent intermittent 75 mg dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 25 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 75 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779).
    Measure Participants 0 0 0 0 0
    8. Secondary Outcome
    Title Health Outcomes Assessment: EuroQol (EQ-5D) Health State Profile Score
    Description EQ-5D is a self-administered questionnaire to assess health-related quality of life in 5 domains (mobility, self care, usual activities, pain or discomfort, and anxiety or depression). Scores from the 5 domains are used to calculate the Health State Profile Score as a single index value; range: 0.0 (death) to 1.0 (perfect health); higher scores indicate a better health state.
    Time Frame Prior to baseline, Cycle 7 (Week 12) and final visit (within 15 days of stopping study treatment)

    Outcome Measure Data

    Analysis Population Description
    ITT; Final efficacy analysis was not conducted.
    Arm/Group Title Let 2.5 mg Plus 10 mg Daily CCI-779 Let 2.5 mg Plus 30 mg Intermittent CCI-779 Let 2.5 mg Alone / Cross-over to 75 mg Intermittent CCI-779 Let 2.5 mg Plus 25mg Daily CCI-779 Let 2.5 mg Plus 75 mg Intermittent CCI-779
    Arm/Group Description Letrozole (Let) 2.5 milligrams (mg) daily administered with a 10 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 30 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily; permitted to cross-over at the time of progression to single-agent intermittent 75 mg dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 25 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 75 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779).
    Measure Participants 0 0 0 0 0
    9. Secondary Outcome
    Title Health Outcomes Assessment: European Organization for Research and Treatment of Cancer Quality of Life Questionaire (EORTC QLQ) BR23
    Description Assess specificity of breast cancer symptoms relevant to participant's perceived quality of life (disease related symptoms of dry mouth, eye pain, hair loss, hot flushes, attractiveness, future health, sexual activity, arm or shoulder pain, breast pain, swollen breast, and skin problems on the breast). 23-item assessment of symptoms or problems during the past week (items 1-13 and 17-23) or during the past 4 weeks (items 14-16); range from 1 (not at all) to 4 (very much). Index scores transformed and range from 0 to 100; higher scores indicate higher level of functioning and quality of life.
    Time Frame Prior to baseline, Cycle 7 (Week 12) and final visit (within 15 days of stopping study treatment)

    Outcome Measure Data

    Analysis Population Description
    ITT; Final efficacy analysis was not conducted.
    Arm/Group Title Let 2.5 mg Plus 10 mg Daily CCI-779 Let 2.5 mg Plus 30 mg Intermittent CCI-779 Let 2.5 mg Alone / Cross-over to 75 mg Intermittent CCI-779 Let 2.5 mg Plus 25mg Daily CCI-779 Let 2.5 mg Plus 75 mg Intermittent CCI-779
    Arm/Group Description Letrozole (Let) 2.5 milligrams (mg) daily administered with a 10 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 30 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily; permitted to cross-over at the time of progression to single-agent intermittent 75 mg dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 25 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 75 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779).
    Measure Participants 0 0 0 0 0
    10. Secondary Outcome
    Title Number of Participants With Antitumor Response in Relation to Expression of Akt Phosphorylation, Cyclin D1, PTEN, and p27
    Description Number of participants with antitumor response (CR [disappearance of all target and non-target lesions with normalization of tumor marker level] or PR [at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, referencing the screening sum LD]) in relation to plasma levels of Akt phosphorylation, cyclin D1, PTEN, and p27.
    Time Frame Prior to baseline, after Cycle 4 (Week 8), after Cycle 8 (Week 14), and cross-over or final visit (within 15 days of stopping study treatment)

    Outcome Measure Data

    Analysis Population Description
    ITT; Final analysis was not conducted.
    Arm/Group Title Let 2.5 mg Plus 10 mg Daily CCI-779 Let 2.5 mg Plus 30 mg Intermittent CCI-779 Let 2.5 mg Alone / Cross-over to 75 mg Intermittent CCI-779 Let 2.5 mg Plus 25mg Daily CCI-779 Let 2.5 mg Plus 75 mg Intermittent CCI-779
    Arm/Group Description Letrozole (Let) 2.5 milligrams (mg) daily administered with a 10 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 30 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily; permitted to cross-over at the time of progression to single-agent intermittent 75 mg dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 25 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 75 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779).
    Measure Participants 0 0 0 0 0
    11. Secondary Outcome
    Title Area Under the Concentration-time Curve (AUC) Sum
    Description Area under the concentration-time curve to infinity (AUC) measured as hours multiplied by nanograms divided by milliliters (hr*ng/mL) for CCI-779, sirolimus and letrozole. Sum is calculated as the sum of CCI-779 plus sirolimus AUCs (AUCsum).
    Time Frame Cycle 1 Day 1 (1 cycle is defined as a 14 day duration) , Cycle 3 Day 1, and Cycle 4 Day 1, Day 6, Day 9, Day 11, and Day 12

    Outcome Measure Data

    Analysis Population Description
    ITT; Final analysis was not conducted.
    Arm/Group Title Let 2.5 mg Plus 10 mg Daily CCI-779 Let 2.5 mg Plus 30 mg Intermittent CCI-779 Let 2.5 mg Alone / Cross-over to 75 mg Intermittent CCI-779 Let 2.5 mg Plus 25mg Daily CCI-779 Let 2.5 mg Plus 75 mg Intermittent CCI-779
    Arm/Group Description Letrozole (Let) 2.5 milligrams (mg) daily administered with a 10 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 30 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily; permitted to cross-over at the time of progression to single-agent intermittent 75 mg dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 25 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 75 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779).
    Measure Participants 0 0 0 0 0
    12. Secondary Outcome
    Title 24-hour Trough Concentration (C Trough)
    Description C trough in whole blood measured as nanograms per milliliter (ng/mL).
    Time Frame Cycle 1 Day 1 (1 cycle is defined as a 14 day duration) , Cycle 3 Day 1, and Cycle 4 Day 1, Day 6, Day 9, Day 11, and Day 12

    Outcome Measure Data

    Analysis Population Description
    ITT; Final analysis was not conducted.
    Arm/Group Title Let 2.5 mg Plus 10 mg Daily CCI-779 Let 2.5 mg Plus 30 mg Intermittent CCI-779 Let 2.5 mg Alone / Cross-over to 75 mg Intermittent CCI-779 Let 2.5 mg Plus 25mg Daily CCI-779 Let 2.5 mg Plus 75 mg Intermittent CCI-779
    Arm/Group Description Letrozole (Let) 2.5 milligrams (mg) daily administered with a 10 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 30 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily; permitted to cross-over at the time of progression to single-agent intermittent 75 mg dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 25 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 75 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779).
    Measure Participants 0 0 0 0 0

    Adverse Events

    Time Frame
    Adverse Event Reporting Description An Adverse Event (AE) term may be reported as both a serious and non-serious AE, but are distinct events. AE may = serious for 1 subject and = non-serious for another subject or subject may have experienced both a serious and non-serious episode of the same event.
    Arm/Group Title Let 2.5 mg Plus 10 mg Daily CCI-779 Let 2.5 mg Plus 30 mg Intermittent CCI-779 Let 2.5 mg Alone Prior to Cross-over to 75 mg Intermit CCI-779 After Cross-over to 75 mg Intermittent CCI-779 Let 2.5 mg Plus 25mg Daily CCI-779 Let 2.5 mg Plus 75 mg Intermittent CCI-779
    Arm/Group Description Letrozole (Let) 2.5 milligrams (mg) daily administered with a 10 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 30 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily; permitted to cross-over at the time of progression to single-agent intermittent (intermit)75 mg dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). Includes events reported prior to the cross-over date for cross-over participants. Letrozole (Let) 2.5 mg administered daily with a 25 mg daily dose of Temsirolimus (CCI-779). Includes events reported after the cross-over date for cross-over participants. Letrozole (Let) 2.5 mg administered daily with a 25 mg daily dose of Temsirolimus (CCI-779). Letrozole (Let) 2.5 mg administered daily with a 75 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779).
    All Cause Mortality
    Let 2.5 mg Plus 10 mg Daily CCI-779 Let 2.5 mg Plus 30 mg Intermittent CCI-779 Let 2.5 mg Alone Prior to Cross-over to 75 mg Intermit CCI-779 After Cross-over to 75 mg Intermittent CCI-779 Let 2.5 mg Plus 25mg Daily CCI-779 Let 2.5 mg Plus 75 mg Intermittent CCI-779
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Let 2.5 mg Plus 10 mg Daily CCI-779 Let 2.5 mg Plus 30 mg Intermittent CCI-779 Let 2.5 mg Alone Prior to Cross-over to 75 mg Intermit CCI-779 After Cross-over to 75 mg Intermittent CCI-779 Let 2.5 mg Plus 25mg Daily CCI-779 Let 2.5 mg Plus 75 mg Intermittent CCI-779
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 12/33 (36.4%) 10/30 (33.3%) 9/33 (27.3%) 1/18 (5.6%) 2/6 (33.3%) 1/6 (16.7%)
    Blood and lymphatic system disorders
    Anemia 0/33 (0%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 1/6 (16.7%) 0/6 (0%)
    Neutropenia 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Cardiac disorders
    Angina pectoris 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Atrial fibrillation 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Cardiomyopathy 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Congestive heart failure 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Coronary artery disorder 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Deep vein thrombosis 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hematoma 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hemorrhage 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hypertension 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Peripheral vascular disorder 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Pulmonary embolus 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Endocrine disorders
    Diabetes mellitus 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Gastrointestinal disorders
    Diarrhea 0/33 (0%) 1/30 (3.3%) 1/33 (3%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Mucositis 0/33 (0%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 1/6 (16.7%) 1/6 (16.7%)
    Colitis 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Duodenal ulcer 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Gastroenteritis 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Gastrointestinal carcinoma 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hepatic failure 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Ileus 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Intestinal obstruction 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Pancreatitis 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Stomach ulcer 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    General disorders
    Cellulitis 2/33 (6.1%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Death 1/33 (3%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Infection 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 1/6 (16.7%)
    Sepsis 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 1/6 (16.7%)
    Accidental injury 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Chest pain 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Septic shock 0/33 (0%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 1/6 (16.7%) 0/6 (0%)
    Investigations
    Reaction unevaluable 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Metabolism and nutrition disorders
    Hypercalcemia 1/33 (3%) 1/30 (3.3%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hyperglycemia 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hypomagnesemia 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Nervous system disorders
    Spinal cord compression 0/33 (0%) 0/30 (0%) 2/33 (6.1%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Delirium 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Renal and urinary disorders
    Acute kidney failure 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hydronephrosis 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnea 3/33 (9.1%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Lung edema 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Lung infiltration NOS 0/33 (0%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 1/6 (16.7%) 0/6 (0%)
    Pneumonia 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Pneumonitis 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Respiratory failure 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Other (Not Including Serious) Adverse Events
    Let 2.5 mg Plus 10 mg Daily CCI-779 Let 2.5 mg Plus 30 mg Intermittent CCI-779 Let 2.5 mg Alone Prior to Cross-over to 75 mg Intermit CCI-779 After Cross-over to 75 mg Intermittent CCI-779 Let 2.5 mg Plus 25mg Daily CCI-779 Let 2.5 mg Plus 75 mg Intermittent CCI-779
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 33/33 (100%) 30/30 (100%) 32/33 (97%) 16/18 (88.9%) 6/6 (100%) 6/6 (100%)
    Blood and lymphatic system disorders
    Anemia 6/33 (18.2%) 4/30 (13.3%) 3/33 (9.1%) 1/18 (5.6%) 5/6 (83.3%) 2/6 (33.3%)
    Neutropenia 4/33 (12.1%) 4/30 (13.3%) 0/33 (0%) 1/18 (5.6%) 3/6 (50%) 1/6 (16.7%)
    Leukopenia 5/33 (15.2%) 2/30 (6.7%) 2/33 (6.1%) 1/18 (5.6%) 2/6 (33.3%) 0/6 (0%)
    Lymphopenia 4/33 (12.1%) 2/30 (6.7%) 2/33 (6.1%) 3/18 (16.7%) 2/6 (33.3%) 0/6 (0%)
    Thrombocytopenia 2/33 (6.1%) 2/30 (6.7%) 1/33 (3%) 2/18 (11.1%) 3/6 (50%) 0/6 (0%)
    Lymphedema 2/33 (6.1%) 3/30 (10%) 0/33 (0%) 2/18 (11.1%) 2/6 (33.3%) 0/6 (0%)
    Lymphadenopathy 1/33 (3%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 1/6 (16.7%)
    Ecchymosis 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Granulocytosis 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Iron deficiency anemia 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Monocytosis 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Cardiac disorders
    Vasodilatation 6/33 (18.2%) 2/30 (6.7%) 11/33 (33.3%) 1/18 (5.6%) 1/6 (16.7%) 0/6 (0%)
    Hypertension 4/33 (12.1%) 5/30 (16.7%) 2/33 (6.1%) 0/18 (0%) 1/6 (16.7%) 0/6 (0%)
    Tachycardia 3/33 (9.1%) 2/30 (6.7%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hemorrhage 2/33 (6.1%) 0/30 (0%) 2/33 (6.1%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Angina pectoris 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Atrial fibrillation 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Congestive heart failure 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Peripheral vascular disorder 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Spider vein 1/33 (3%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Bradycardia 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Cardiovascular physical finding 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Deep vein thrombosis 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hypotension 0/33 (0%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 1/6 (16.7%)
    Migraine 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Palpitation 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Shock 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Sinus bradycardia 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Valvular heart disease 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Varicose vein 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Vascular disorder 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Ventricular extrasystoles 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Pericardial effusion 0/33 (0%) 0/30 (0%) 0/33 (0%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Phlebitis 0/33 (0%) 0/30 (0%) 0/33 (0%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Ear and labyrinth disorders
    Ear pain 1/33 (3%) 1/30 (3.3%) 2/33 (6.1%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Ear disorder 0/33 (0%) 2/30 (6.7%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Tinnitus 0/33 (0%) 1/30 (3.3%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Deafness 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Otitis externa 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Endocrine disorders
    Diabetes mellitus 1/33 (3%) 2/30 (6.7%) 0/33 (0%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Goiter 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Eye disorders
    Conjunctivitis 5/33 (15.2%) 3/30 (10%) 2/33 (6.1%) 3/18 (16.7%) 1/6 (16.7%) 0/6 (0%)
    Abnormal vision 1/33 (3%) 3/30 (10%) 1/33 (3%) 0/18 (0%) 1/6 (16.7%) 0/6 (0%)
    Eye disorder 2/33 (6.1%) 2/30 (6.7%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 1/6 (16.7%)
    Dry eyes 1/33 (3%) 2/30 (6.7%) 0/33 (0%) 1/18 (5.6%) 2/6 (33.3%) 0/6 (0%)
    Cataract specified 0/33 (0%) 3/30 (10%) 0/33 (0%) 1/18 (5.6%) 1/6 (16.7%) 0/6 (0%)
    Eye pain 1/33 (3%) 0/30 (0%) 0/33 (0%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Glaucoma 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Gastrointestinal disorders
    Diarrhea 13/33 (39.4%) 15/30 (50%) 6/33 (18.2%) 9/18 (50%) 4/6 (66.7%) 2/6 (33.3%)
    Mucositis 10/33 (30.3%) 15/30 (50%) 2/33 (6.1%) 10/18 (55.6%) 4/6 (66.7%) 4/6 (66.7%)
    Nausea 7/33 (21.2%) 11/30 (36.7%) 10/33 (30.3%) 5/18 (27.8%) 2/6 (33.3%) 3/6 (50%)
    Anorexia 9/33 (27.3%) 12/30 (40%) 6/33 (18.2%) 5/18 (27.8%) 2/6 (33.3%) 2/6 (33.3%)
    Constipation 9/33 (27.3%) 3/30 (10%) 6/33 (18.2%) 1/18 (5.6%) 3/6 (50%) 1/6 (16.7%)
    Stomatitis 5/33 (15.2%) 8/30 (26.7%) 2/33 (6.1%) 4/18 (22.2%) 4/6 (66.7%) 3/6 (50%)
    Vomiting 6/33 (18.2%) 5/30 (16.7%) 5/33 (15.2%) 4/18 (22.2%) 1/6 (16.7%) 2/6 (33.3%)
    Dry mouth 3/33 (9.1%) 3/30 (10%) 2/33 (6.1%) 2/18 (11.1%) 1/6 (16.7%) 3/6 (50%)
    Dyspepsia 3/33 (9.1%) 5/30 (16.7%) 3/33 (9.1%) 1/18 (5.6%) 0/6 (0%) 1/6 (16.7%)
    Aphthous stomatitis 2/33 (6.1%) 3/30 (10%) 0/33 (0%) 1/18 (5.6%) 3/6 (50%) 0/6 (0%)
    Gastroenteritis 1/33 (3%) 2/30 (6.7%) 2/33 (6.1%) 0/18 (0%) 1/6 (16.7%) 0/6 (0%)
    Dysphagia 2/33 (6.1%) 2/30 (6.7%) 0/33 (0%) 1/18 (5.6%) 1/6 (16.7%) 1/6 (16.7%)
    Flatulence 1/33 (3%) 0/30 (0%) 2/33 (6.1%) 0/18 (0%) 1/6 (16.7%) 1/6 (16.7%)
    Gingivitis 0/33 (0%) 3/30 (10%) 0/33 (0%) 1/18 (5.6%) 0/6 (0%) 2/6 (33.3%)
    Oral moniliasis 1/33 (3%) 1/30 (3.3%) 2/33 (6.1%) 0/18 (0%) 1/6 (16.7%) 0/6 (0%)
    Rectal disorder 2/33 (6.1%) 3/30 (10%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Mouth ulceration 3/33 (9.1%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Gamma glutamyl transpeptidase increased 1/33 (3%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 1/6 (16.7%) 0/6 (0%)
    Gastroesophageal reflux disease 1/33 (3%) 1/30 (3.3%) 0/33 (0%) 1/18 (5.6%) 1/6 (16.7%) 0/6 (0%)
    Glossitis 2/33 (6.1%) 1/30 (3.3%) 0/33 (0%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Colitis 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Mouth pain 1/33 (3%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Stomach ulcer 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Abdominal distension 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Cheilitis 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Esophagitis 0/33 (0%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 1/6 (16.7%) 0/6 (0%)
    Gastrointestinal disorder 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Gastrointestinal physical finding 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Gum hemorrhage 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Gum hyperplasia 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hepatitis 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hiatal hernia 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Periodontal abscess 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Rectal hemorrhage 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Stools abnormal 1/33 (3%) 0/30 (0%) 0/33 (0%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Tooth disorder 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Esophageal stenosis 0/33 (0%) 0/30 (0%) 0/33 (0%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    General disorders
    Asthenia 15/33 (45.5%) 21/30 (70%) 20/33 (60.6%) 10/18 (55.6%) 5/6 (83.3%) 6/6 (100%)
    Pain 12/33 (36.4%) 12/30 (40%) 12/33 (36.4%) 4/18 (22.2%) 1/6 (16.7%) 1/6 (16.7%)
    Headache 11/33 (33.3%) 11/30 (36.7%) 10/33 (30.3%) 4/18 (22.2%) 2/6 (33.3%) 2/6 (33.3%)
    Back pain 9/33 (27.3%) 10/30 (33.3%) 12/33 (36.4%) 3/18 (16.7%) 1/6 (16.7%) 1/6 (16.7%)
    Infection 9/33 (27.3%) 8/30 (26.7%) 9/33 (27.3%) 1/18 (5.6%) 3/6 (50%) 2/6 (33.3%)
    Abdominal pain 3/33 (9.1%) 9/30 (30%) 9/33 (27.3%) 1/18 (5.6%) 2/6 (33.3%) 1/6 (16.7%)
    Chest pain 6/33 (18.2%) 4/30 (13.3%) 3/33 (9.1%) 1/18 (5.6%) 0/6 (0%) 1/6 (16.7%)
    Fever 4/33 (12.1%) 3/30 (10%) 5/33 (15.2%) 3/18 (16.7%) 0/6 (0%) 1/6 (16.7%)
    Accidental injury 1/33 (3%) 5/30 (16.7%) 4/33 (12.1%) 2/18 (11.1%) 0/6 (0%) 0/6 (0%)
    Flu syndrome 4/33 (12.1%) 1/30 (3.3%) 2/33 (6.1%) 2/18 (11.1%) 1/6 (16.7%) 0/6 (0%)
    Neck pain 2/33 (6.1%) 3/30 (10%) 3/33 (9.1%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Cellulitis 2/33 (6.1%) 2/30 (6.7%) 1/33 (3%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Chills 2/33 (6.1%) 3/30 (10%) 2/33 (6.1%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Face edema 4/33 (12.1%) 2/30 (6.7%) 1/33 (3%) 3/18 (16.7%) 0/6 (0%) 0/6 (0%)
    Pelvic pain 2/33 (6.1%) 3/30 (10%) 1/33 (3%) 1/18 (5.6%) 0/6 (0%) 1/6 (16.7%)
    Lab test abnormal 2/33 (6.1%) 2/30 (6.7%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Malaise 2/33 (6.1%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 1/6 (16.7%)
    Neoplasm 0/33 (0%) 2/30 (6.7%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Sepsis 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 1/6 (16.7%)
    Allergic reaction 2/33 (6.1%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Cyst 1/33 (3%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Generalized edema 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 1/6 (16.7%) 0/6 (0%)
    Abscess 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Chest pain substernal 0/33 (0%) 0/30 (0%) 1/33 (3%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    General physical health deterioration 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hypothermia 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Moniliasis 0/33 (0%) 0/30 (0%) 0/33 (0%) 2/18 (11.1%) 0/6 (0%) 0/6 (0%)
    Investigations
    Reaction unevaluable 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Local reaction to procedure 1/33 (3%) 2/30 (6.7%) 1/33 (3%) 2/18 (11.1%) 0/6 (0%) 0/6 (0%)
    Allergic reaction other than drug 2/33 (6.1%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Laboratory events not classified 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Metabolism and nutrition disorders
    Peripheral edema 16/33 (48.5%) 11/30 (36.7%) 5/33 (15.2%) 4/18 (22.2%) 4/6 (66.7%) 2/6 (33.3%)
    Hyperlipemia 9/33 (27.3%) 9/30 (30%) 4/33 (12.1%) 3/18 (16.7%) 3/6 (50%) 3/6 (50%)
    Hypercholesteremia 8/33 (24.2%) 11/30 (36.7%) 4/33 (12.1%) 1/18 (5.6%) 1/6 (16.7%) 2/6 (33.3%)
    Hyperglycemia 7/33 (21.2%) 10/30 (33.3%) 2/33 (6.1%) 2/18 (11.1%) 0/6 (0%) 1/6 (16.7%)
    Weight loss 8/33 (24.2%) 5/30 (16.7%) 1/33 (3%) 2/18 (11.1%) 1/6 (16.7%) 1/6 (16.7%)
    SGOT increased 3/33 (9.1%) 5/30 (16.7%) 4/33 (12.1%) 3/18 (16.7%) 0/6 (0%) 2/6 (33.3%)
    SGPT increased 3/33 (9.1%) 5/30 (16.7%) 3/33 (9.1%) 4/18 (22.2%) 0/6 (0%) 2/6 (33.3%)
    Hypokalemia 7/33 (21.2%) 4/30 (13.3%) 0/33 (0%) 3/18 (16.7%) 0/6 (0%) 1/6 (16.7%)
    Edema 5/33 (15.2%) 3/30 (10%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hypophosphatemia 5/33 (15.2%) 1/30 (3.3%) 1/33 (3%) 1/18 (5.6%) 2/6 (33.3%) 0/6 (0%)
    Lactic dehydrogenase increased 4/33 (12.1%) 1/30 (3.3%) 3/33 (9.1%) 1/18 (5.6%) 0/6 (0%) 1/6 (16.7%)
    Alkaline phosphatase increased 2/33 (6.1%) 3/30 (10%) 3/33 (9.1%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Hypocalcemia 4/33 (12.1%) 3/30 (10%) 0/33 (0%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Creatinine increased 1/33 (3%) 2/30 (6.7%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Dehydration 1/33 (3%) 3/30 (10%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hypercalcemia 0/33 (0%) 2/30 (6.7%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hyperchloremia 2/33 (6.1%) 2/30 (6.7%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hyperuricemia 0/33 (0%) 1/30 (3.3%) 3/33 (9.1%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    BUN increased 1/33 (3%) 1/30 (3.3%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hypomagnesemia 2/33 (6.1%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Bilirubinemia 1/33 (3%) 0/30 (0%) 1/33 (3%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Hypernatremia 1/33 (3%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hypoglycemia 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 1/6 (16.7%) 0/6 (0%)
    Hyponatremia 2/33 (6.1%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hypoproteinemia 1/33 (3%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Weight gain 0/33 (0%) 0/30 (0%) 2/33 (6.1%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hyperkalemia 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hypochloremia 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Respiratory acidosis 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Thirst 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 11/33 (33.3%) 13/30 (43.3%) 12/33 (36.4%) 5/18 (27.8%) 4/6 (66.7%) 2/6 (33.3%)
    Myalgia 7/33 (21.2%) 7/30 (23.3%) 7/33 (21.2%) 2/18 (11.1%) 0/6 (0%) 1/6 (16.7%)
    Bone pain 5/33 (15.2%) 8/30 (26.7%) 6/33 (18.2%) 3/18 (16.7%) 0/6 (0%) 0/6 (0%)
    Arthrosis 1/33 (3%) 5/30 (16.7%) 1/33 (3%) 2/18 (11.1%) 0/6 (0%) 0/6 (0%)
    Musculoskeletal stiffness 0/33 (0%) 4/30 (13.3%) 1/33 (3%) 1/18 (5.6%) 0/6 (0%) 1/6 (16.7%)
    Joint disorder 0/33 (0%) 2/30 (6.7%) 2/33 (6.1%) 0/18 (0%) 0/6 (0%) 1/6 (16.7%)
    Arthritis 0/33 (0%) 1/30 (3.3%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Bursitis 0/33 (0%) 2/30 (6.7%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Intervertebral disc protrusion 0/33 (0%) 2/30 (6.7%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Leg cramps 1/33 (3%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Musculoskeletal anomaly 0/33 (0%) 2/30 (6.7%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Osteopenia 1/33 (3%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Osteoporosis 1/33 (3%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Tenosynovitis 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 1/6 (16.7%) 0/6 (0%)
    Bone necrosis 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Coccydynia 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Muscle spasms 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Myasthenia 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Tetany 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Tendon disorder 0/33 (0%) 0/30 (0%) 0/33 (0%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Nervous system disorders
    Insomnia 7/33 (21.2%) 7/30 (23.3%) 5/33 (15.2%) 2/18 (11.1%) 0/6 (0%) 0/6 (0%)
    Depression 5/33 (15.2%) 5/30 (16.7%) 6/33 (18.2%) 1/18 (5.6%) 1/6 (16.7%) 1/6 (16.7%)
    Paresthesia 3/33 (9.1%) 4/30 (13.3%) 3/33 (9.1%) 1/18 (5.6%) 1/6 (16.7%) 1/6 (16.7%)
    Dizziness 0/33 (0%) 4/30 (13.3%) 5/33 (15.2%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Anxiety 2/33 (6.1%) 1/30 (3.3%) 3/33 (9.1%) 0/18 (0%) 1/6 (16.7%) 0/6 (0%)
    Vertigo 2/33 (6.1%) 1/30 (3.3%) 2/33 (6.1%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Somnolence 1/33 (3%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 1/6 (16.7%) 1/6 (16.7%)
    Hypesthesia 0/33 (0%) 2/30 (6.7%) 1/33 (3%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Ataxia 0/33 (0%) 2/30 (6.7%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Carpal tunnel syndrome 0/33 (0%) 1/30 (3.3%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Emotional lability 0/33 (0%) 2/30 (6.7%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hyperesthesia 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 1/6 (16.7%) 0/6 (0%)
    Neuropathic pain 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 1/6 (16.7%) 0/6 (0%)
    Neuropathy 0/33 (0%) 1/30 (3.3%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Tremor 0/33 (0%) 1/30 (3.3%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Abnormal gait 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Confusion 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Facial paralysis 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hostility 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hypotonia 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Incoordination 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Libido decreased 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    emory impairment 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Nervousness 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Neuralgia 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Neuritis 0/33 (0%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 1/6 (16.7%)
    Parkinson's disease 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Phantom pain 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Ptosis 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Speech disorder 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Thinking abnormal 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Abnormal dreams 0/33 (0%) 0/30 (0%) 0/33 (0%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Restless legs syndrome 0/33 (0%) 0/30 (0%) 0/33 (0%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Stupor 0/33 (0%) 0/30 (0%) 0/33 (0%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Taste loss 3/33 (9.1%) 0/30 (0%) 1/33 (3%) 2/18 (11.1%) 2/6 (33.3%) 2/6 (33.3%)
    Taste perversion 0/33 (0%) 2/30 (6.7%) 0/33 (0%) 2/18 (11.1%) 0/6 (0%) 1/6 (16.7%)
    Renal and urinary disorders
    Urinary tract infection 3/33 (9.1%) 3/30 (10%) 1/33 (3%) 5/18 (27.8%) 2/6 (33.3%) 1/6 (16.7%)
    Dysuria 3/33 (9.1%) 2/30 (6.7%) 2/33 (6.1%) 1/18 (5.6%) 1/6 (16.7%) 1/6 (16.7%)
    Cystitis 3/33 (9.1%) 2/30 (6.7%) 0/33 (0%) 0/18 (0%) 1/6 (16.7%) 0/6 (0%)
    Vaginal moniliasis 4/33 (12.1%) 1/30 (3.3%) 0/33 (0%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Vaginal dryness 2/33 (6.1%) 1/30 (3.3%) 1/33 (3%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Metrorrhagia 1/33 (3%) 1/30 (3.3%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Vaginal hemorrhage 0/33 (0%) 3/30 (10%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Breast pain 1/33 (3%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Leukorrhea 0/33 (0%) 2/30 (6.7%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Endometrial hyperplasia 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hematuria 0/33 (0%) 0/30 (0%) 0/33 (0%) 1/18 (5.6%) 0/6 (0%) 1/6 (16.7%)
    Polyuria 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Urinary frequency 0/33 (0%) 0/30 (0%) 1/33 (3%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Urinary hesitation 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Urinary incontinence 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Urine abnormality 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Vaginitis 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Vulvovaginal disorder 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnea 8/33 (24.2%) 7/30 (23.3%) 7/33 (21.2%) 2/18 (11.1%) 2/6 (33.3%) 1/6 (16.7%)
    Cough increased 7/33 (21.2%) 7/30 (23.3%) 7/33 (21.2%) 4/18 (22.2%) 2/6 (33.3%) 1/6 (16.7%)
    Epistaxis 8/33 (24.2%) 11/30 (36.7%) 0/33 (0%) 2/18 (11.1%) 1/6 (16.7%) 2/6 (33.3%)
    Pharyngitis 4/33 (12.1%) 5/30 (16.7%) 7/33 (21.2%) 3/18 (16.7%) 1/6 (16.7%) 3/6 (50%)
    Rhinitis 3/33 (9.1%) 4/30 (13.3%) 5/33 (15.2%) 1/18 (5.6%) 1/6 (16.7%) 2/6 (33.3%)
    Upper respiratory infection 3/33 (9.1%) 7/30 (23.3%) 3/33 (9.1%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Sinusitis 2/33 (6.1%) 2/30 (6.7%) 4/33 (12.1%) 1/18 (5.6%) 1/6 (16.7%) 0/6 (0%)
    Bronchitis 5/33 (15.2%) 1/30 (3.3%) 1/33 (3%) 1/18 (5.6%) 0/6 (0%) 1/6 (16.7%)
    Sinus congestion 4/33 (12.1%) 1/30 (3.3%) 2/33 (6.1%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Pneumonia 3/33 (9.1%) 2/30 (6.7%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Voice alteration 1/33 (3%) 2/30 (6.7%) 0/33 (0%) 1/18 (5.6%) 1/6 (16.7%) 0/6 (0%)
    Lung infiltration NOS 1/33 (3%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Rhinitis allergic 0/33 (0%) 2/30 (6.7%) 1/33 (3%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Atelectasis 0/33 (0%) 2/30 (6.7%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Laryngitis 0/33 (0%) 1/30 (3.3%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Nose dryness 1/33 (3%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Sputum increased 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 1/6 (16.7%)
    Apnea 0/33 (0%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 1/6 (16.7%)
    Hemoptysis 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hypoxia 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Lung disorder 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Lung fibrosis 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Pleural effusion 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Pleuritic pain 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Pneumothorax 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Pulmonary physical finding 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Skin and subcutaneous tissue disorders
    Rash 7/33 (21.2%) 13/30 (43.3%) 6/33 (18.2%) 7/18 (38.9%) 4/6 (66.7%) 2/6 (33.3%)
    Nail disorder 10/33 (30.3%) 9/30 (30%) 0/33 (0%) 3/18 (16.7%) 2/6 (33.3%) 1/6 (16.7%)
    Pruritus 5/33 (15.2%) 7/30 (23.3%) 0/33 (0%) 5/18 (27.8%) 2/6 (33.3%) 2/6 (33.3%)
    Skin disorder 4/33 (12.1%) 6/30 (20%) 1/33 (3%) 1/18 (5.6%) 0/6 (0%) 3/6 (50%)
    Acne 3/33 (9.1%) 7/30 (23.3%) 1/33 (3%) 4/18 (22.2%) 0/6 (0%) 0/6 (0%)
    Erythema 3/33 (9.1%) 5/30 (16.7%) 3/33 (9.1%) 1/18 (5.6%) 0/6 (0%) 0/6 (0%)
    Dry skin 1/33 (3%) 4/30 (13.3%) 2/33 (6.1%) 3/18 (16.7%) 2/6 (33.3%) 1/6 (16.7%)
    Skin ulcer 0/33 (0%) 3/30 (10%) 1/33 (3%) 1/18 (5.6%) 1/6 (16.7%) 2/6 (33.3%)
    Alopecia 2/33 (6.1%) 1/30 (3.3%) 3/33 (9.1%) 3/18 (16.7%) 0/6 (0%) 0/6 (0%)
    Fungal dermatitis 2/33 (6.1%) 1/30 (3.3%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 1/6 (16.7%)
    Maculopapular rash 2/33 (6.1%) 1/30 (3.3%) 2/33 (6.1%) 2/18 (11.1%) 0/6 (0%) 0/6 (0%)
    Sweating 0/33 (0%) 2/30 (6.7%) 3/33 (9.1%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Exfoliative dermatitis 0/33 (0%) 3/30 (10%) 0/33 (0%) 0/18 (0%) 1/6 (16.7%) 0/6 (0%)
    Folliculitis 2/33 (6.1%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 1/6 (16.7%)
    Herpes simplex 3/33 (9.1%) 1/30 (3.3%) 0/33 (0%) 4/18 (22.2%) 0/6 (0%) 0/6 (0%)
    Pruritic rash 1/33 (3%) 3/30 (10%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Skin discoloration 2/33 (6.1%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 1/6 (16.7%) 0/6 (0%)
    Herpes zoster 1/33 (3%) 0/30 (0%) 1/33 (3%) 1/18 (5.6%) 1/6 (16.7%) 0/6 (0%)
    Night sweats 1/33 (3%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Pustular rash 1/33 (3%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Skin hypertrophy 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 1/18 (5.6%) 0/6 (0%) 1/6 (16.7%)
    Vesiculobullous rash 0/33 (0%) 2/30 (6.7%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Hirsutism 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Melanosis 0/33 (0%) 0/30 (0%) 1/33 (3%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Skin necrosis 1/33 (3%) 0/30 (0%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)
    Urticaria 0/33 (0%) 1/30 (3.3%) 0/33 (0%) 0/18 (0%) 0/6 (0%) 0/6 (0%)

    Limitations/Caveats

    Clinical development of oral temsirolimus for treatment of locally advanced or metastatic breast cancer was terminated by Wyeth based on the results of a phase 3 clinical study with the combination temsirolimus and letrozole.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Pfizer has the right to review disclosures, requesting a delay of < 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), < 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.

    Results Point of Contact

    Name/Title Pfizer ClinicalTrials.gov Call Center
    Organization Pfizer, Inc.
    Phone 1-800-718-1021
    Email ClinicalTrials.govCallCenter@pfizer.com
    Responsible Party:
    , ,
    ClinicalTrials.gov Identifier:
    NCT00062751
    Other Study ID Numbers:
    • 3066A1-204
    • B1771005
    • NCT00061971
    First Posted:
    Jun 13, 2003
    Last Update Posted:
    Apr 15, 2011
    Last Verified:
    Apr 1, 2011