Bladder Cancer, Bladder Neoplasm, Carcinoma, Transitional Cell
Conditions
Keywords
Transitional Cell Carcinoma of the Urinary Bladder, Transitional Cell Carcinoma, Bladder Cancer, Urinary Bladder Cancer, Bladder, Carcinoma, Urinary, Metastatic, Relapsed
Brief summary
The purpose of this study is to determine whether pralatrexate, given with vitamin B12 and folic acid, is effective in the treatment of advanced or metastatic bladder cancer. The study will also investigate the safety of pralatrexate with vitamin B12 and folic acid in this patient population. Additionally, this study includes the collection of blood samples to investigate the pharmacokinetics (PK) of pralatrexate in this patient population (PK is the activity of a drug in the body over a period of time, including how the drug is absorbed, distributed in the body, localized in the tissues, and excreted from the body).
Interventions
Intravenous (IV) push administration over 3-5 minutes via a peripheral IV line containing normal saline (0.9% sodium chloride). Initial dose: 190 mg/m2 Dose reductions per protocol: 150 mg/m2, 120 mg/m2 and 100 mg/m2 will be allowed for defined toxicity. Administered on days 1 and 15 of a 4-week cycle (every 2 weeks) until criteria for discontinuation per the protocol are met.
DIETARY_SUPPLEMENTVitamin B12
1 mg intramuscular injection Administered within 10 weeks of enrollment, every 8-10 weeks throughout the study and for at least 30 days after last dose of pralatrexate.
DIETARY_SUPPLEMENTFolic Acid
1-1.25 mg orally Administered daily for at least 7 days prior to enrollment, throughout the study and for at least 30 days after last dose of pralatrexate.
Sponsors
Acrotech Biopharma Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed transitional cell carcinoma of the urinary bladder. Fine needle aspirate will not be accepted. * Relapsed or progressed after treatment with a platinum- and/or methotrexate-based systemic chemotherapy regimen. No more than 1 prior regimen is permitted for recurrent/metastatic disease. Patients has had a chemotherapy-free interval of ≥ 12 months from last dose if most recent prior chemotherapy was in neoadjuvant/adjuvant setting and has had ≥ 6-month chemotherapy-free interval in recurrent/metastatic setting. Patient has recovered from the toxic effects of prior therapy. Previous intravesical therapy is allowed. Prior surgical resection is allowed, as long as the patient has recovered. * Measurable disease outside a previously irradiated region, per Response Evaluation Criteria in Solid Tumors (RECIST). * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * At least 18 years of age. * Adequate blood, liver, and kidney function as defined by laboratory results. * Patient has received 1.0-1.25 mg of oral folic acid daily for at least 7 days of enrollment & 1 mg intramuscular vitamin B12 within 10 weeks of enrollment. * Women of childbearing potential have a negative serum pregnancy test within 14 days prior to enrollment and agree to use medically acceptable and effective birth control from enrollment until at least 30 days after the last dose of pralatrexate. * Men who are not surgically sterile and whose partner is of childbearing potential must use medically safe and effective birth control start of pralatrexate until at least 90 days after the last dose of pralatrexate. * Accessible for repeat dosing and follow up. * Give written informed consent.
Exclusion criteria
* Active concurrent primary malignancy or prior malignancies occurring within 5 years (except non-melanoma skin cancer, in situ carcinoma of the cervix, or occult, indolent carcinoma of the prostate). If there is a history of prior malignancies other than those exceptions listed above, the patient must be disease free for ≥ 5 years. Patients with other prior malignancies \< 5 years before study entry may still be enrolled if they have received treatment resulting in complete resolution of the cancer and currently have no clinical, radiologic, or laboratory evidence of active or recurrent disease. In the case of a single extrapelvic metastatic site, irrespective of the patient having a history of previous malignancy, a biopsy proof of the metastatic diseased organ will be necessary. * More than 1 previous regimen for recurrent/metastatic disease. * Evidence of clinically significant active third-space phenomenon * Use of investigational drugs, biologics, or devices within 28 days prior to study enrollment. * Previous exposure to other antifolates, including pralatrexate. Previous methotrexate is allowed, only if it was part of an M-VAC or MCV regimen. * Women who are pregnant or breastfeeding. * Congestive Heart Failure Class III/IV according to New York Heart Association (NYHA) Functional Classification. * Uncontrolled hypertension. * Human immunodeficiency virus (HIV)-positive diagnosis with a CD4 count of \< 100 mm3 or detectable viral load within the past 3 months, and receiving combination anti-retroviral therapy. * Central nervous system metastatic disease. * Major surgery within 2 weeks of study enrollment. * Radiation therapy (RT) within 4 weeks (within 3 months for RT to the pelvis) prior to study enrollment. * Active infection or any serious underlying medical condition, which would impair the ability of the patient to receive protocol treatment. * Dementia or significantly altered mental status that would prohibit the understanding and giving of informed consent or limit study compliance.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Assessed at the end of each even-numbered cycle (every 8 weeks), or per standard of care but no more than every 12 weeks (+/- 1 week) if treatment has ended for up to 2 years after enrollment. | The number of patients with a best overall confirmed response of either complete response (CR) or partial response (PR) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) | Measured from the first day of documented response for up to 2 years after enrollment. | Duration of time from when tumor measurement criteria were met for CR or PR (whichever status was recorded first) until the first date that recurrent disease or progressive disease (PD) or death was objectively documented. Progression is defined, using RECIST, as an increase in the smallest dimension of any target or non-target lesion, or the appearance of new lesions, since baseline. Calculated for those patients with a best overall confirmed or unconfirmed response of CR or PR. |
| Overall Survival (OS) | Assessed at the end of each even-numbered cycle (every 8 weeks), or per standard of care if treatment has ended (at least every 12 weeks) for up to 2 years after enrollment. After PD or start of subsequent treatment, OS will be assessed every 4 months. | The number of days from study day 1 to death. Patients who had not died (no record of death) or were lost to follow-up were censored at the date of last contact. |
| Clinical Benefit Rate (CBR) | Assessed at the end of each even-numbered cycle (every 8 weeks) or per standard of care, but no more than every 12 weeks (+/- 1 week) if treatment has ended, for up to 2 years after enrollment. | The number of patients with a best confirmed or unconfirmed response of CR, PR, or stable disease (SD) for at least 24 weeks (approximately 5.5 months) |
| Progression Free Survival (PFS) | Assessed at the end of each even-numbered cycle (every 8 weeks), or per standard of care but no more than every 12 weeks (+/- 1 week) if treatment has ended, for up to 2 years after enrollment. | Length of time from study day 1 to the date of radiological evidence of PD (date of computed tomography \[CT\] or magnetic resonance imaging \[MRI\] scan, whichever indicates PD) or death, regardless of cause. |
Countries
Argentina, Belgium, Croatia, France, Spain, United States
Participant flow
Recruitment details
Patients were enrolled between July 2008 and November 2010 across 10 study sites and 5 countries.
Participants by arm
| Arm | Count |
|---|---|
| Full Population Population consists of all patients who received at least 1 dose of pralatrexate. Pralatrexate was administered on days 1 and 15 of a 4-week cycle as an intravenous (IV) push over 3-5 minutes via a peripheral IV line containing normal saline at an initial dose of 190 mg/m2. These patients received a 1 mg intramuscular injection of Vitamin B12 within 10 weeks of enrollment and every 8-10 weeks throughout the study, and for at least 30 days after the last dose of pralatrexate. These patients were also administered 1-1.25 mg of Folic Acid orally for at least 7 days prior to enrollment, throughout the study and for at least 30 days after the last dose of pralatrexate. | 30 |
| Total | 30 |
Baseline characteristics
| Characteristic | Full Population |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 16 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants |
| Age, Continuous | 65.8 years STANDARD_DEVIATION 9 |
| Region of Enrollment Argentina | 1 participants |
| Region of Enrollment Belgium | 1 participants |
| Region of Enrollment France | 14 participants |
| Region of Enrollment Spain | 10 participants |
| Region of Enrollment United States | 4 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 30 / 30 |
| serious Total, serious adverse events | 17 / 30 |
Outcome results
Primary
Objective Response Rate (ORR)
The number of patients with a best overall confirmed response of either complete response (CR) or partial response (PR)
Time frame: Assessed at the end of each even-numbered cycle (every 8 weeks), or per standard of care but no more than every 12 weeks (+/- 1 week) if treatment has ended for up to 2 years after enrollment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Evaluable Population | Objective Response Rate (ORR) | 1 participants |
Secondary
Clinical Benefit Rate (CBR)
The number of patients with a best confirmed or unconfirmed response of CR, PR, or stable disease (SD) for at least 24 weeks (approximately 5.5 months)
Time frame: Assessed at the end of each even-numbered cycle (every 8 weeks) or per standard of care, but no more than every 12 weeks (+/- 1 week) if treatment has ended, for up to 2 years after enrollment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Evaluable Population | Clinical Benefit Rate (CBR) | 3 participants |
Secondary
Duration of Response (DOR)
Duration of time from when tumor measurement criteria were met for CR or PR (whichever status was recorded first) until the first date that recurrent disease or progressive disease (PD) or death was objectively documented. Progression is defined, using RECIST, as an increase in the smallest dimension of any target or non-target lesion, or the appearance of new lesions, since baseline. Calculated for those patients with a best overall confirmed or unconfirmed response of CR or PR.
Time frame: Measured from the first day of documented response for up to 2 years after enrollment.
Population: Analysis was per protocol, based on the number of all responding patients both confirmed and unconfirmed (n=5) in the evaluable population (n=30)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Evaluable Population | Duration of Response (DOR) | 82 Days |
Secondary
Overall Survival (OS)
The number of days from study day 1 to death. Patients who had not died (no record of death) or were lost to follow-up were censored at the date of last contact.
Time frame: Assessed at the end of each even-numbered cycle (every 8 weeks), or per standard of care if treatment has ended (at least every 12 weeks) for up to 2 years after enrollment. After PD or start of subsequent treatment, OS will be assessed every 4 months.
Population: Analysis per protocol. Patients who had not died or were lost to follow-up were censored
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Evaluable Population | Overall Survival (OS) | 9.3 Months |
Secondary
Progression Free Survival (PFS)
Length of time from study day 1 to the date of radiological evidence of PD (date of computed tomography \[CT\] or magnetic resonance imaging \[MRI\] scan, whichever indicates PD) or death, regardless of cause.
Time frame: Assessed at the end of each even-numbered cycle (every 8 weeks), or per standard of care but no more than every 12 weeks (+/- 1 week) if treatment has ended, for up to 2 years after enrollment.
Population: Analysis was per protocol, based on the number of patients (pts) who had an event of progressive disease (PD) or death. Pts who did not have an event at the time of data cut-off were censored.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Evaluable Population | Progression Free Survival (PFS) | 4.0 Months |