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A Study of Pemetrexed and Cyclophosphamide Given Every 21 Days in Advanced Breast Cancer Patients

A Phase 1/2 Dose-Escalating Study of ALIMTA and Cyclophosphamide Administered Every 21 Days in Patients With Locally Advanced or Metastatic Breast Cancer

Status
Completed
Phases
Phase 1Phase 2
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT00190671
Enrollment
103
Registered
2005-09-19
Start date
2005-06-30
Completion date
2008-03-31
Last updated
2009-11-20

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Breast Cancer

Keywords

Advanced Breast Cancer

Brief summary

This is the phase 2 portion of a phase 1/2 trial, testing the use of pemetrexed and cyclophosphamide in combination for the treatment of advanced breast cancer. A single arm Phase 1 dose finding (establish maximum tolerated dose) study precedes the randomized phase 2 portion.

Interventions

DRUGpemetrexed

Pemetrexed: 600 mg/m2, intravenous (IV), every 21 days x 8 cycles

DRUGcyclophosphamide

600 mg/m2, intravenous (IV), every 21 days x 8 cycles

Sponsors

Eli Lilly and Company
Lead SponsorINDUSTRY

Study design

Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE

Eligibility

Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No

Inclusion criteria

- You must be female and at least 18 years old. - You must have been diagnosed with breast cancer. - Your pre-study lab tests are within study requirements. - You must be willing to take folic acid and vitamin B12.

Exclusion criteria

- You are pregnant or breastfeeding. - You have another illness that your doctor thinks would make you unable to participate. - You are currently taking aspirin or aspirin-like medicine and are unable to stop for a few days during each cycle of therapy.

Design outcomes

Primary

MeasureTime frameDescription
Best Tumor Responsebaseline to measured progressive diseaseTumor response was assessed using radiological imaging, which was repeated every 6 weeks prior to every other cycle. Confirmation of response was to occur no less than 4 weeks (28 days) after the first evidence of response.

Secondary

MeasureTime frameDescription
Progression Free Survivalbaseline to measured progressive diseaseDefined as date of first treatment dose to first date of progressive disease or death from any cause. For patients not known to have died as of data cutoff date and who did not have progressive disease, the progression free survival date was censored at last contact date.
Pharmacokinetics - Maximum Observed Drug Concentration (Cmax)cycle 1 (Day 1: <1 min prior to end of pemetrexed infusion; 1/2, 1, 1.5, 2, 3, 4, 6, 8, 24, 48, 72 hours after start of pemetrexed infusion)—
Pharmacokinetics - Area Under the Curve (AUC)cycle 1 (Day 1: <1 min prior to end of pemetrexed infusion; 1/2, 1, 1.5, 2, 3, 4, 6, 8, 24, 48, 72 hours after start of pemetrexed infusion)Area under the gemcitabine concentration-time curve from zero to last quantifiable concentration \[AUC(0-t)\] was calculated by combination of linear and logarithmic trapezoidal methods. Linear trapezoidal method was employed up to tmax (time to reach maximal concentration), and then log trapezoidal method was used for those data after tmax.
Time to Progressive Diseasebaseline to measured progressive diseaseTime to progressive disease was defined as the time from the date of the first treatment dose to the first date of progressive disease or death from study disease.
Pharmacokinetics - Volume of Distributioncycle 1 (Day 1: <1 min prior to end of pemetrexed infusion; 1/2, 1, 1.5, 2, 3, 4, 6, 8, 24, 48, 72 hours after start of pemetrexed infusion)Central volume (V1) and peripheral volume (V2) of distribution.
Pharmacokinetics - Half-Life (t½)cycle 1 (Day 1: <1 min prior to end of pemetrexed infusion; 1/2, 1, 1.5, 2, 3, 4, 6, 8, 24, 48, 72 hours after start of pemetrexed infusion)The half-life associated with the terminal elimination rate constant.
Pharmacokinetics - Clearance (CL)cycle 1 (Day 1: <1 min prior to end of pemetrexed infusion; 1/2, 1, 1.5, 2, 3, 4, 6, 8, 24, 48, 72 hours after start of pemetrexed infusion)Total body clearance of drug calculated after intravenous administration.

Countries

Austria, Czechia, Hungary, Poland, Romania, Russia

Participant flow

Pre-assignment details

This was a Phase 1/2 study. Phase 1 determined the doses to use in the Phase 2 portion. In this 2-stage Simon's optimal design study, enrollment in the 600 mg/m2 arm was stopped at the end of Stage 1 because of lack of efficacy; ongoing patients were allowed to continue treatment. Secondary efficacy endpoints were evaluated for 1800 mg/m2 arm only.

Participants by arm

ArmCount
Pemetrexed 600mg/m2
Pemetrexed: 600 mg/m2, intravenous, every 21 days x 8 cycles Cyclophosphamide: 600 mg/m2, intravenous, every 21 days x 8 cycles
42
Pemetrexed 1800mg/m2
Pemetrexed: 1800 mg/m2, intravenous, every 21 days x 8 cycles Cyclophosphamide: 600 mg/m2, intravenous, every 21 days x 8 cycles
61
Total103

Withdrawals & dropouts

PeriodReasonFG000FG001
Overall StudyAdverse Event32
Overall StudyClinical Relapse01
Overall StudyDeath from Other Causes02
Overall StudyDeath from Study Disease11
Overall StudyDeath from Study-Drug Toxicity02
Overall StudyLack of Efficacy1924
Overall StudyProtocol Violation01
Overall StudySatisfactory Response47
Overall StudyWithdrawal by Subject02

Baseline characteristics

CharacteristicTotalPemetrexed 600mg/m2Pemetrexed 1800mg/m2
Age Continuous58.0 years59.0 years56.0 years
Body Surface Area1.7 square meters1.8 square meters1.7 square meters
Estrogen-Receptor Status
Missing
12.0 participants3 participants9 participants
Estrogen-Receptor Status
Negative
31.0 participants10 participants21 participants
Estrogen-Receptor Status
Positive
49.0 participants22 participants27 participants
Estrogen-Receptor Status
Unknown
11.0 participants7 participants4 participants
Height160.0 centimeters160.0 centimeters160.0 centimeters
Human Epidermal Growth Factor Receptor 2 (HER-2/NEU) Status
Negative
38.0 participants11 participants27 participants
Human Epidermal Growth Factor Receptor 2 (HER-2/NEU) Status
Not Done
41.0 participants18 participants23 participants
Human Epidermal Growth Factor Receptor 2 (HER-2/NEU) Status
Positive
7.0 participants4 participants3 participants
Human Epidermal Growth Factor Receptor 2 (HER-2/NEU) Status
Unknown
17.0 participants9 participants8 participants
Pathological Diagnosis
Adenocarcinoma of the Breast
44.0 participant17 participant27 participant
Pathological Diagnosis
Inflammatory Breast Carcinoma
17.0 participant7 participant10 participant
Pathological Diagnosis
Other
42.0 participant18 participant24 participant
Progesterone-Receptor Status
Missing
12.0 participants3 participants9 participants
Progesterone-Receptor Status
Negative
36.0 participants13 participants23 participants
Progesterone-Receptor Status
Positive
44.0 participants19 participants25 participants
Progesterone-Receptor Status
Unknown
11.0 participants7 participants4 participants
Race/Ethnicity
Caucasian
103.0 participants42 participants61 participants
Region of Enrollment
Austria
14.0 participants3 participants11 participants
Region of Enrollment
Czech Republic
4.0 participants2 participants2 participants
Region of Enrollment
Hungary
22.0 participants11 participants11 participants
Region of Enrollment
Poland
20.0 participants9 participants11 participants
Region of Enrollment
Romania
18.0 participants9 participants9 participants
Region of Enrollment
Russian Federation
25.0 participants8 participants17 participants
Sex: Female, Male
Female
103.0 Participants42 Participants61 Participants
Sex: Female, Male
Male
0.0 Participants0 Participants0 Participants
Weight70.0 kilograms71.5 kilograms70.0 kilograms
World Health Organization Performance Status
0 - Asymptomatic, fully active
58.0 participants18 participants40 participants
World Health Organization Performance Status
1 - Symptomatic, fully ambulatory, light activity
40.0 participants22 participants18 participants
World Health Organization Performance Status
2 - Symptomatic, ambulatory, no work activities
5.0 participants2 participants3 participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
deaths
Total, all-cause mortality
— / —— / —
other
Total, other adverse events
38 / —59 / —
serious
Total, serious adverse events
6 / —13 / —

Outcome results

Primary

Best Tumor Response

Tumor response was assessed using radiological imaging, which was repeated every 6 weeks prior to every other cycle. Confirmation of response was to occur no less than 4 weeks (28 days) after the first evidence of response.

Time frame: baseline to measured progressive disease

Population: Number of randomized participants.

ArmMeasureGroupValue (NUMBER)
Pemetrexed 600mg/m2Best Tumor ResponseComplete Response0 participants
Pemetrexed 600mg/m2Best Tumor ResponsePartial Response8 participants
Pemetrexed 600mg/m2Best Tumor ResponseStable Disease18 participants
Pemetrexed 600mg/m2Best Tumor ResponseProgressive Disease13 participants
Pemetrexed 600mg/m2Best Tumor ResponseUnknown3 participants
Pemetrexed 600mg/m2Best Tumor ResponseNot Assessed0 participants
Pemetrexed 1800mg/m2Best Tumor ResponseUnknown5 participants
Pemetrexed 1800mg/m2Best Tumor ResponseComplete Response0 participants
Pemetrexed 1800mg/m2Best Tumor ResponseProgressive Disease8 participants
Pemetrexed 1800mg/m2Best Tumor ResponsePartial Response20 participants
Pemetrexed 1800mg/m2Best Tumor ResponseNot Assessed2 participants
Pemetrexed 1800mg/m2Best Tumor ResponseStable Disease26 participants
Secondary

Pharmacokinetics - Area Under the Curve (AUC)

Area under the gemcitabine concentration-time curve from zero to last quantifiable concentration \[AUC(0-t)\] was calculated by combination of linear and logarithmic trapezoidal methods. Linear trapezoidal method was employed up to tmax (time to reach maximal concentration), and then log trapezoidal method was used for those data after tmax.

Time frame: cycle 1 (Day 1: <1 min prior to end of pemetrexed infusion; 1/2, 1, 1.5, 2, 3, 4, 6, 8, 24, 48, 72 hours after start of pemetrexed infusion)

Population: Number of participants included in the pharmacokinetic analyses.

ArmMeasureValue (GEOMETRIC_MEAN)Dispersion
Pemetrexed 600mg/m2Pharmacokinetics - Area Under the Curve (AUC)375 hour times microgram per milliliterFull Range 13
Pemetrexed 1800mg/m2Pharmacokinetics - Area Under the Curve (AUC)1050 hour times microgram per milliliterFull Range 17
Secondary

Pharmacokinetics - Clearance (CL)

Total body clearance of drug calculated after intravenous administration.

Time frame: cycle 1 (Day 1: <1 min prior to end of pemetrexed infusion; 1/2, 1, 1.5, 2, 3, 4, 6, 8, 24, 48, 72 hours after start of pemetrexed infusion)

Population: Number of participants included in the pharmacokinetic analyses.

ArmMeasureValue (GEOMETRIC_MEAN)Dispersion
Pemetrexed 600mg/m2Pharmacokinetics - Clearance (CL)45.9 milliliters per minuteFull Range 15
Pemetrexed 1800mg/m2Pharmacokinetics - Clearance (CL)51.8 milliliters per minuteFull Range 27
Secondary

Pharmacokinetics - Half-Life (t½)

The half-life associated with the terminal elimination rate constant.

Time frame: cycle 1 (Day 1: <1 min prior to end of pemetrexed infusion; 1/2, 1, 1.5, 2, 3, 4, 6, 8, 24, 48, 72 hours after start of pemetrexed infusion)

Population: Number of participants included in the pharmacokinetic analyses.

ArmMeasureValue (GEOMETRIC_MEAN)
Pemetrexed 600mg/m2Pharmacokinetics - Half-Life (t½)4.19 hours
Pemetrexed 1800mg/m2Pharmacokinetics - Half-Life (t½)3.79 hours
Secondary

Pharmacokinetics - Maximum Observed Drug Concentration (Cmax)

Time frame: cycle 1 (Day 1: <1 min prior to end of pemetrexed infusion; 1/2, 1, 1.5, 2, 3, 4, 6, 8, 24, 48, 72 hours after start of pemetrexed infusion)

Population: Number of participants included in the pharmacokinetic analyses.

ArmMeasureValue (GEOMETRIC_MEAN)Dispersion
Pemetrexed 600mg/m2Pharmacokinetics - Maximum Observed Drug Concentration (Cmax)125 micrograms per millilitersFull Range 15
Pemetrexed 1800mg/m2Pharmacokinetics - Maximum Observed Drug Concentration (Cmax)369 micrograms per millilitersFull Range 14
Secondary

Pharmacokinetics - Volume of Distribution

Central volume (V1) and peripheral volume (V2) of distribution.

Time frame: cycle 1 (Day 1: <1 min prior to end of pemetrexed infusion; 1/2, 1, 1.5, 2, 3, 4, 6, 8, 24, 48, 72 hours after start of pemetrexed infusion)

Population: Number of participants included in the pharmacokinetic analyses.

ArmMeasureGroupValue (GEOMETRIC_MEAN)Dispersion
Pemetrexed 600mg/m2Pharmacokinetics - Volume of DistributionCentral Volume of Distribution (V1)7.46 LitersFull Range 16
Pemetrexed 600mg/m2Pharmacokinetics - Volume of DistributionPeripheral Volume of Distribution (V2)3.58 LitersFull Range 37
Pemetrexed 1800mg/m2Pharmacokinetics - Volume of DistributionCentral Volume of Distribution (V1)8.14 LitersFull Range 25
Pemetrexed 1800mg/m2Pharmacokinetics - Volume of DistributionPeripheral Volume of Distribution (V2)3.33 LitersFull Range 16
Secondary

Progression Free Survival

Defined as date of first treatment dose to first date of progressive disease or death from any cause. For patients not known to have died as of data cutoff date and who did not have progressive disease, the progression free survival date was censored at last contact date.

Time frame: baseline to measured progressive disease

Population: All randomized participants in the Phase 2 portion of the trial (enrollment in 600mg/m2 arm stopped during Phase 1 and was not continued in Phase 2). The Progression Free Survival date was censored for 22 (35.07%) participants.

ArmMeasureValue (MEDIAN)
Pemetrexed 600mg/m2Progression Free Survival6.26 months
Secondary

Time to Progressive Disease

Time to progressive disease was defined as the time from the date of the first treatment dose to the first date of progressive disease or death from study disease.

Time frame: baseline to measured progressive disease

Population: All randomized participants in the Phase 2 portion of the trial (enrollment in 600mg/m2 arm stopped during Phase 1 and was not continued in Phase 2). Time to disease progression was censored for 26 (42.6%) participants.

ArmMeasureValue (MEDIAN)
Pemetrexed 600mg/m2Time to Progressive Disease6.56 months

Source: ClinicalTrials.gov · Data processed: Mar 26, 2026