Pemetrexed as Second-Line Therapy in Treating Patients With Hormone Refractory Prostate Cancer

Phase 2

Completed

Conditions: Prostate Cancer

Interventions: Drug: Pemetrexed
Dietary Supplement: Folic Acid
Dietary Supplement: Vitamin B12

Registration Number: NCT00216099

Lead Sponsor: Christopher Sweeney, MBBS

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

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 49

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Investigational Treatment	Folic Acid	* Pemetrexed 500 mg/m2 IV over 10 minutes, day 1 of 21-day cycle * Oral Folic Acid, once per day for 7 days preceding pemetrexed dose, continued daily, and for 21 days after the last dose of pemetrexed. * Vitamin B12, 1000ug intramuscular injection 7 days preceding pemetrexed dose, and every three cycles thereafter on the same day of pemetrexed administration
Investigational Treatment	Vitamin B12	* Pemetrexed 500 mg/m2 IV over 10 minutes, day 1 of 21-day cycle * Oral Folic Acid, once per day for 7 days preceding pemetrexed dose, continued daily, and for 21 days after the last dose of pemetrexed. * Vitamin B12, 1000ug intramuscular injection 7 days preceding pemetrexed dose, and every three cycles thereafter on the same day of pemetrexed administration
Investigational Treatment	Pemetrexed	* Pemetrexed 500 mg/m2 IV over 10 minutes, day 1 of 21-day cycle * Oral Folic Acid, once per day for 7 days preceding pemetrexed dose, continued daily, and for 21 days after the last dose of pemetrexed. * Vitamin B12, 1000ug intramuscular injection 7 days preceding pemetrexed dose, and every three cycles thereafter on the same day of pemetrexed administration

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
Overall Survival	From study enrollment until death (for life)
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.
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
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.
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
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\

Trial Locations

Locations (15): Pennsylvania Oncology-Hematology Associates
🇺🇸
Philadelphia, Pennsylvania, United States
Medical & Surgical Specialists, LLC
🇺🇸
Galesburg, Illinois, United States
Indiana University Cancer Center
🇺🇸
Indianapolis, Indiana, United States
Quality Cancer Center (MCGOP)
🇺🇸
Indianapolis, Indiana, United States
Northern Indiana Cancer Research Consortium
🇺🇸
South Bend, Indiana, United States
AP&S Clinic
🇺🇸
Terre Haute, Indiana, United States
Elkhart Clinic
🇺🇸
Elkhart, Indiana, United States
Fort Wayne Oncology & Hematology, Inc
🇺🇸
Fort Wayne, Indiana, United States
Community Regional Cancer Center
🇺🇸
Indianapolis, Indiana, United States
Medical Consultants, P.C.
🇺🇸
Muncie, Indiana, United States
Arnett Cancer Care
🇺🇸
Lafayette, Indiana, United States
Hematology Oncology Associates S.J., P.A.
🇺🇸
Mt. Holly, New Jersey, United States
Consultants in Medical Oncology & Hematology
🇺🇸
Drexel Hill, Pennsylvania, United States
Methodist Cancer Center
🇺🇸
Omaha, Nebraska, United States
Center for Hematology/Oncology of S. Michigan
🇺🇸
Jackson, Michigan, United States