Prostate Cancer
Conditions
Keywords
Prostate Cancer
Brief summary
Docetaxel-based therapy has been shown to prolong survival as first-line therapy for patients with hormone refractory prostate cancer (HRPC), and has become the standard of care. The beneficial effects of any therapy in HRPC may be diverse and include reduction in tumor bulk (when measurable), reduction in prostate-specific antigen PSA, reduction in symptoms (particularly pain), or stabilization of disease. Clear reductions in tumor bulk or PSA may provide objective evidence of a treatment effect, and stabilization of disease may be just as clinically meaningful in patients who are actively progressing prior to starting therapy. Pemetrexed has shown a broad array of activity in many diseases that until now were thought to be non-responsive to chemotherapy in the second-line setting. This trial is designed to further assess the efficacy, safety, tolerability, and pharmacogenetics of pemetrexed as a single agent in subjects with HRPC whose disease has progressed following one prior taxane-based chemotherapy regimen for HRPC.
Detailed description
OUTLINE: This is a multi-center study. * Pemetrexed 500mg/m2 will be administered intravenously over approximately 10-minutes on Day 1 of a 21-day cycle. * Folic Acid (350-1000 mcg. PO daily) will be taken by patients to reduce toxicity. At least 5 daily doses of folic acid must be taken during the 7-day period preceding the first dose of pemetrexed, and dosing should continue during the full course of therapy and for 21 days after the last dose of pemetrexed. * Vitamin B12 (1000 µg) will be administered as an intramuscular injection during the week preceding the first dose of pemetrexed and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as pemetrexed. Performance Status: Karnofsky Performance Status 70-100 Life expectancy \> 12 weeks Hematopoietic: * Absolute Neutrophil Count (ANC) \> 1500/mm3 * Platelet count \> 100,000/mm3 * Hemoglobin \> 9 g/dL Hepatic: * Bilirubin \< 1.5 X upper limit of normal (unless due to Gilbert's disease) * Alkaline phosphatase and Alanine Transanimase (ALT) (SGPT) \< 3 X upper limit of normal (ULN); may be \< 5 X ULN for patients with liver metastases. Alkaline phosphatase may be any value for patients with bone metastases. Renal: * Calculated creatinine clearance \>45 mL/min based on the standard Cockroft and Gault formula Cardiovascular: * No congestive heart failure requiring therapy or New York Heart Association (NYHA) class II or greater or active angina or known myocardial infarction within 12 months prior to study * No unstable angina, uncontrolled congestive heart failure, or unstable symptomatic arrhythmia requiring medication within 6 months prior to being registered for protocol therapy * Subjects with chronic atrial arrhythmia, i.e., atrial fibrillation, paroxysmal supraventricular tachycardia, or controlled hypertension are eligible Pulmonary: * Not specified
Interventions
DRUGPemetrexed
Pemetrexed 500 mg/m2 IV over 10 minutes, day 1 of 21-day cycle
DIETARY_SUPPLEMENTFolic Acid
All participants received oral Folic Acid 350-100ug once per day for 7 days preceding the first pemetrexed dose and continuing throughout the study and and for 21 days after the last dose of pemetrexed.
DIETARY_SUPPLEMENTVitamin B12
All patients received vitamin B12 1000ug intramuscular injection the week preceding the first pemetrexed dose and received additional 1000ug intramuscular injections every three cycles thereafter on the same day of pemetrexed administration.
Sponsors
Eli Lilly and Company
Walther Cancer Institute
Christopher Sweeney, MBBS
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically documented adenocarcinoma of the prostate * Clinically refractory or resistant to hormone therapy as assessed by progression following at least one hormonal therapy (orchiectomy or luteinizing hormone-releasing hormone (LHRH) agonist) * One prior taxane based chemotherapy regimen for HRPC * Documented progression of disease after one taxane based prior chemotherapy regimen for HRPC. Progression is defined as at least one of the following: * An increase in PSA \> 50% over nadir value on prior Taxane-based therapy * Progression of measurable disease as defined by RECIST * Progression of bone disease as defined by the appearance of one or more new bone lesions or worsening symptoms * Orchiectomy or testosterone levels \< 50 ng/dL maintained by LHRH agonist * Prior chemotherapy, or other experimental anticancer agents must be completed \> 4 weeks prior to being registered for protocol therapy * Palliative radiotherapy must be completed at least 14 days prior to registration.
Exclusion criteria
* Intravenous radio-isotopes therapy must be completed at least 6 weeks prior to registration * No brain metastasis that are untreated and/or not controlled and/or still requiring corticosteroids * No history of other malignancies within 5 years prior to being registered for protocol therapy, except for adequately treated basal or squamous cell skin cancer * No history of uncontrolled psychiatric illness or serious systemic disease, including active infection, uncontrolled hypertension * No surgery or significant traumatic injury within 21 days prior to being registered for protocol therapy * Patients must be willing to interrupt aspirin or other non-steroidal anti-inflammatory agents for a 5-day period (8 day period for long acting agents such as piroxicam) * Patients must be willing to take folic acid or vitamin B12 supplementation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall PSA Response | Start of treatment until disease progression/recurrence (for life) | Best overall Prostate-Specific Antigen (PSA) response PSA response is defined by a greater than or equal to 50% decline in PSA confirmed by a second PSA value at least 4 weeks after the first PSA response timepoint PSA Stable Disease is defined as less than a 50% decline in PSA and less than a 50% increase in PSA from baseline PSA progression is defined as greater than or equal to a 50% increase in PSA compared to baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| OBJECTIVE Overall Response Rate | Start of treatment until disease progression/recurrence (for life) | Response Evaluation Criteria in Solid Tumors (RECIST). Objective overall response rate is defined as Complete Response (CR) + Partial Response (PR) Per RECIST: CR= Disappearance of all target and non-target lesions and normalization of tumor marker level PR= Disappearance of all target lesions and persistence of non-target lesion(s) or maintenance of tumor marker level above normal limits OR at least a 30% decrease in the sum of the longest diameter, taking as reference the baseline sum longest diameter and disappearance of all non-target lesions or persistence of non-target lesion(s) or maintenance of tumor marker level above normal limits |
| Rate of Clinical Benefit | Any time among evaluable subjects (for life) | A clinical benefit is defined as an improvement for at least 3 consecutive weeks in at least one of the following parameters without any sustained worsening in any other: \> 50% reduction in analgesic consumption or \> 50% reduction in pain intensity or \> 20 point gain in performance status. |
| Safety and Tolerability | 18 months | Safety and Tolerability was evaluated by reporting the percentage of patient who experienced grade 3 or 4 toxicities using Common Terminology Criteria for Adverse Events CTCAE v3.0 criteria. CTCAE grades the severity of an adverse event from 1-5 where 1=least severe and 5=death. |
| Overall Survival | From study enrollment until death (for life) | — |
| Time to Progression | Study enrollment until progression per RECIST or PSA (for life) | Progression per Response Evaluation Criteria in Solid Tumors (RECIST) or Prostate-Specific Antigen (PSA) Progression RECIST PD=at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions or Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions PSA progression=increase in PSA to \>50% above lowest level recorded on study. Two consecutive increases required at least 4 weeks apart, but time to progression will be determined at time of first PSA showing increase \> 50% above baseline \*Note, upper confidence interval was not reached\* |
| Time to Prostate-Specific Antigen (PSA)/Serological Progression | From study enrollment to progression per PSA criteria (for life) | Serological Progression (sPD) - increase in PSA to \>50% above lowest level recorded on study. Two consecutive increases required at least 4 weeks apart, but time to progression will be determined at time of first PSA showing increase \> 50% above baseline |
| RFC1 G80A Genotype | Screening | Samples for RFC1 G80A pharmacogenetic analysis were collected at screening |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pemetrexed 500mg/m^2 Pemetrexed 500 mg/m2 IV over 10 minutes, day 1 of 21-day cycle
Pemetrexed: Pemetrexed 500 mg/m2 IV over 10 minutes, day 1 of 21-day cycle | 49 |
| Total | 49 |
Baseline characteristics
| Characteristic | Pemetrexed 500mg/m^2 |
|---|---|
| Age, Continuous | 68 years |
| Baseline Karnofsky Performance Status (KPS) | 90 units on a scale |
| Baseline Opiate Use | 9.6 Intramuscular morphine equivalents |
| Baseline Pain Score | 2 units on a scale |
| Baseline Prostate-Specific Antigen (PSA) | 72.2 ng/mL |
| Days Since Last Docetaxel 0-28 | 30 participants |
| Days Since Last Docetaxel >180 | 6 participants |
| Days Since Last Docetaxel 29-90 | 7 participants |
| Days Since Last Docetaxel 91-180 | 5 participants |
| Days Since Last Docetaxel unknown | 1 participants |
| Metastatic Sites Bone | 31 participants |
| Metastatic Sites Lymph Node | 16 participants |
| Metastatic Sites Visceral | 7 participants |
| Region of Enrollment United States | 49 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 48 / 49 |
| serious Total, serious adverse events | 15 / 49 |
Outcome results
Primary
Best Overall PSA Response
Best overall Prostate-Specific Antigen (PSA) response PSA response is defined by a greater than or equal to 50% decline in PSA confirmed by a second PSA value at least 4 weeks after the first PSA response timepoint PSA Stable Disease is defined as less than a 50% decline in PSA and less than a 50% increase in PSA from baseline PSA progression is defined as greater than or equal to a 50% increase in PSA compared to baseline
Time frame: Start of treatment until disease progression/recurrence (for life)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pemetrexed 500mg/m^2 | Best Overall PSA Response | >50% decline in PSA | 8 percentage of participatns |
| Pemetrexed 500mg/m^2 | Best Overall PSA Response | Stable PSA | 20 percentage of participatns |
| Pemetrexed 500mg/m^2 | Best Overall PSA Response | PSA progression | 65 percentage of participatns |
Secondary
OBJECTIVE Overall Response Rate
Response Evaluation Criteria in Solid Tumors (RECIST). Objective overall response rate is defined as Complete Response (CR) + Partial Response (PR) Per RECIST: CR= Disappearance of all target and non-target lesions and normalization of tumor marker level PR= Disappearance of all target lesions and persistence of non-target lesion(s) or maintenance of tumor marker level above normal limits OR at least a 30% decrease in the sum of the longest diameter, taking as reference the baseline sum longest diameter and disappearance of all non-target lesions or persistence of non-target lesion(s) or maintenance of tumor marker level above normal limits
Time frame: Start of treatment until disease progression/recurrence (for life)
Population: Patients who had measurable disease per RECIST 1.1 at baseline. Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension with longest diameter \>20 mm using conventional techniques or \>10 mm with spiral CT scan.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pemetrexed 500mg/m^2 | OBJECTIVE Overall Response Rate | Participants with PR with meas. dis. per RECIST | 8 percentage of participants |
| Pemetrexed 500mg/m^2 | OBJECTIVE Overall Response Rate | participants with SD maintained at 12 weeks | 39 percentage of participants |
Secondary
Overall Survival
Time frame: From study enrollment until death (for life)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed 500mg/m^2 | Overall Survival | 14 months |
Secondary
Rate of Clinical Benefit
A clinical benefit is defined as an improvement for at least 3 consecutive weeks in at least one of the following parameters without any sustained worsening in any other: \> 50% reduction in analgesic consumption or \> 50% reduction in pain intensity or \> 20 point gain in performance status.
Time frame: Any time among evaluable subjects (for life)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pemetrexed 500mg/m^2 | Rate of Clinical Benefit | 33 percentage of participants |
Secondary
RFC1 G80A Genotype
Samples for RFC1 G80A pharmacogenetic analysis were collected at screening
Time frame: Screening
Population: Samples were available from 46 patients
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pemetrexed 500mg/m^2 | RFC1 G80A Genotype | A/A Genotype | 6 participants |
| Pemetrexed 500mg/m^2 | RFC1 G80A Genotype | A/G Genotype | 22 participants |
| Pemetrexed 500mg/m^2 | RFC1 G80A Genotype | G/G Genotype | 18 participants |
Secondary
Safety and Tolerability
Safety and Tolerability was evaluated by reporting the percentage of patient who experienced grade 3 or 4 toxicities using Common Terminology Criteria for Adverse Events CTCAE v3.0 criteria. CTCAE grades the severity of an adverse event from 1-5 where 1=least severe and 5=death.
Time frame: 18 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pemetrexed 500mg/m^2 | Safety and Tolerability | Grade 3 | 42.9 percentage of participants |
| Pemetrexed 500mg/m^2 | Safety and Tolerability | Grade 4 | 8.2 percentage of participants |
Secondary
Time to Progression
Progression per Response Evaluation Criteria in Solid Tumors (RECIST) or Prostate-Specific Antigen (PSA) Progression RECIST PD=at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions or Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions PSA progression=increase in PSA to \>50% above lowest level recorded on study. Two consecutive increases required at least 4 weeks apart, but time to progression will be determined at time of first PSA showing increase \> 50% above baseline \*Note, upper confidence interval was not reached\*
Time frame: Study enrollment until progression per RECIST or PSA (for life)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed 500mg/m^2 | Time to Progression | 5 months |
Secondary
Time to Prostate-Specific Antigen (PSA)/Serological Progression
Serological Progression (sPD) - increase in PSA to \>50% above lowest level recorded on study. Two consecutive increases required at least 4 weeks apart, but time to progression will be determined at time of first PSA showing increase \> 50% above baseline
Time frame: From study enrollment to progression per PSA criteria (for life)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed 500mg/m^2 | Time to Prostate-Specific Antigen (PSA)/Serological Progression | 2 months |