Study of Pralatrexate to Treat Advanced or Metastatic Relapsed Transitional Cell Carcinoma of the Urinary Bladder

• Sponsor: Acrotech Biopharma LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00722553
• Collaborator: (none)
• Enrollment: 30
• Locations: 19
• Arm: 1
• Duration (Months): 38
• Patients Per Site: 1.6
• Patients Per Site Per Month: 0

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Transitional Cell; Bladder Cancer; Bladder Neoplasm	Drug: Pralatrexate Injection; Dietary Supplement: Vitamin B12; Dietary Supplement: Folic Acid	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Single-Arm Study of Pralatrexate in Patients With Advanced or Metastatic Relapsed Transitional Cell Carcinoma of the Urinary Bladder
• Study Start Date: Jul 1, 2008
• Actual Primary Completion Date: Apr 1, 2011
• Actual Study Completion Date: Sep 1, 2011

Arms and Interventions

Arm

Intervention/Treatment

Other: Dietary Supplement Vitamin B12 & Folic Acid (Vitamin B9) Vitamin 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. Folic 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.

Drug: Pralatrexate Injection; 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.; Other Names: FOLOTYN PDX Pralatrexate (RS)-10-propargyl-10-deazaaminopterin ; Dietary Supplement: Vitamin 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.; Other Names: Cyanocobalamin ; Dietary Supplement: Folic 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.; Other Names: Vitamin B9 Folate Folacin

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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)

3. 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.

4. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The University of Arizona Health Sciences Center	Tucson	Arizona	United States	85724
2	Peachtree Hematology/Oncology Consultants	Atlanta	Georgia	United States	30318
3	University of Rochester Cancer Center	Rochester	New York	United States	14642
4	University of Utah, Huntsman Cancer Institute	Salt Lake City	Utah	United States	84112
5	Centro de Terapia Radiante Cumbres (CAICI)	Rosario	Santa Fe	Argentina	2000
6	IONC (Instituto Oncológuci de Cordoba)	Cordoba		Argentina	X5004BAL
7	Algemeen Ziekenhuis Middelheim	Antwerp		Belgium	2020
8	Institut Jules Bordet	Brussels		Belgium	1000
9	CH Split Clinic of Oncology and Radiotherapy	Split		Croatia	21000
10	CHU Zagreb University Hospital Center Rebro in Zagreb	Zagreb		Croatia	10000
11	Clinic of Oncology and Nuclear Medicine, CH "Sestre Milosrdnice"	Zagreb		Croatia	10000
12	Institut Sainte Catherine	Avignon		France	84082
13	Centre Oscar Lambret	Lille Cedex		France	59020
14	Centre Hospitalier Rene Dubos	Pontoise		France	95301
15	Hopital Foch	Suresnes		France
16	Institut Gustave Roussy	Villejuif Cedex		France	94 805
17	Ciutat Sanitari de Vall d'Hebron	Barcelona		Spain	08035
18	Hospital Del Mar - Barcelona	Barcelona		Spain	8003
19	Hospital Virgen del Rocio	Sevilla		Spain	41013

Sponsors and Collaborators

• Acrotech Biopharma LLC

Investigators

• Study Director: Garry Weems, Pharm.D., Spectrum Pharmaceuticals, Inc

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Acrotech Biopharma LLC
• ClinicalTrials.gov Identifier: NCT00722553
• Other Study ID Numbers: PDX-011; 2007-004671-19
• First Posted: Jul 25, 2008
• Last Update Posted: Dec 17, 2019
• Last Verified: Dec 1, 2019

• Keywords provided by Acrotech Biopharma LLC: Transitional Cell Carcinoma of the Urinary Bladder; Transitional Cell Carcinoma; Bladder Cancer; Urinary Bladder Cancer; Bladder; Carcinoma; Urinary; Metastatic; Relapsed
• Additional relevant MeSH terms: Carcinoma; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Vitamins; Folic Acid; Vitamin B 12; Hydroxocobalamin; Vitamin B Complex; 10-deazaaminopterin; Aminopterin

Study Results

Participant Flow

Recruitment Details	Patients were enrolled between July 2008 and November 2010 across 10 study sites and 5 countries.

Arm/Group Title	Full Population
Arm/Group Description	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.
Period Title: Overall Study
STARTED	30
COMPLETED	30
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Full Population
Arm/Group Description	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.
Overall Participants	30
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	14 46.7%
>=65 years	16 53.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.8 (9)
Sex: Female, Male (Count of Participants)
Female	3 10%
Male	27 90%
Region of Enrollment (participants) [Number]
France	14 46.7%
United States	4 13.3%
Argentina	1 3.3%
Spain	10 33.3%
Belgium	1 3.3%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate (ORR)
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evaluable Population
Arm/Group Description	All patients who received at least 1 dose of pralatrexate, had histologically confirmed transitional cell carcinoma (TCC) (> 50% TCC in tumor) of the urinary bladder, and had measurable disease at baseline.
Measure Participants	30
Number [participants]	1 3.3%

2. Secondary Outcome

Title	Duration of Response (DOR)
Description	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.

Outcome Measure Data

Analysis Population Description

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/Group Title	Evaluable Patients
Arm/Group Description	All patients who received at least 1 dose of pralatrexate, had histologically confirmed TCC (> 50% TCC in tumor) of the urinary bladder, and had measurable disease at baseline.
Measure Participants	5
Median (95% Confidence Interval) [Days]	82

3. Secondary Outcome

Title	Clinical Benefit Rate (CBR)
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evaluable Population
Arm/Group Description	All patients who received at least 1 dose of pralatrexate, had histologically confirmed TCC (> 50% TCC in tumor) of the urinary bladder, and had measurable disease at baseline.
Measure Participants	30
Number [participants]	3 10%

4. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	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.

Outcome Measure Data

Analysis Population Description

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/Group Title	Evaluable Population
Arm/Group Description	All patients who received at least 1 dose of pralatrexate, had histologically confirmed TCC (> 50% TCC in tumor) of the urinary bladder, and had measurable disease at baseline.
Measure Participants	30
Median (95% Confidence Interval) [Months]	4.0

5. Secondary Outcome

Title	Overall Survival (OS)
Description	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.

Outcome Measure Data

Analysis Population Description

Analysis per protocol. Patients who had not died or were lost to follow-up were censored

Arm/Group Title	Evaluable Population
Arm/Group Description	All patients who received at least 1 dose of pralatrexate, had histologically confirmed TCC (> 50% TCC in tumor) of the urinary bladder, and had measurable disease at baseline.
Measure Participants	30
Median (95% Confidence Interval) [Months]	9.3

Adverse Events

Time Frame	Assessed every 2 weeks while on treatment through safety follow-up visit (35 +/-5 days post-last dose) or early termination visit (at time of withdrawal).
Adverse Event Reporting Description	Serious AEs and AEs regardless of causality and all grades presented below. Symptoms present at baseline, AEs, and intercurrent illnesses were monitored at every study visit. Patients were instructed to report AEs to the investigator. All AEs including observed or volunteered problems, complaints, or symptoms were recorded.
Arm/Group Title	Full Population
Arm/Group Description	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.
All Cause Mortality
	Full Population
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Full Population
	Affected / at Risk (%)	# Events
Total	17/30 (56.7%)
Blood and lymphatic system disorders
anaemia	2/30 (6.7%)
neutropenia	2/30 (6.7%)
thrombocytopenia	1/30 (3.3%)
Cardiac disorders
pericarditis	1/30 (3.3%)
Gastrointestinal disorders
stomatitis	6/30 (20%)
ascites	1/30 (3.3%)
diarrhoea	1/30 (3.3%)
vomiting	1/30 (3.3%)
General disorders
asthenia	2/30 (6.7%)
general physical health deterioration	2/30 (6.7%)
pyrexia	2/30 (6.7%)
fatigue	1/30 (3.3%)
mucosal inflammation	1/30 (3.3%)
Hepatobiliary disorders
hyperbilirubinaemia	1/30 (3.3%)
Infections and infestations
cellulitis	1/30 (3.3%)
infection	1/30 (3.3%)
Injury, poisoning and procedural complications
renal injury	1/30 (3.3%)
Metabolism and nutrition disorders
anorexia	2/30 (6.7%)
hypercalcaemia	1/30 (3.3%)
Musculoskeletal and connective tissue disorders
arthralgia	2/30 (6.7%)
pain in extremity	1/30 (3.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
lung infiltration malignant	1/30 (3.3%)
Renal and urinary disorders
haematuria	1/30 (3.3%)
renal failure	1/30 (3.3%)
Respiratory, thoracic and mediastinal disorders
atelectasis	1/30 (3.3%)
pulmonary oedema	1/30 (3.3%)
Skin and subcutaneous tissue disorders
toxic skin eruption	2/30 (6.7%)
rash pruritic	1/30 (3.3%)
Other (Not Including Serious) Adverse Events
	Full Population
	Affected / at Risk (%)	# Events
Total	30/30 (100%)
Blood and lymphatic system disorders
anaemia	11/30 (36.7%)
neutropenia	7/30 (23.3%)
thrombocytopenia	5/30 (16.7%)
leukopenia	3/30 (10%)
Cardiac disorders
arrhythmia	2/30 (6.7%)
Gastrointestinal disorders
stomatitis	23/30 (76.7%)
constipation	10/30 (33.3%)
vomiting	10/30 (33.3%)
nausea	8/30 (26.7%)
abdominal pain	6/30 (20%)
diarrhoea	4/30 (13.3%)
aphthous stomatitis	3/30 (10%)
abdominal distension	2/30 (6.7%)
ascites	2/30 (6.7%)
dry mouth	2/30 (6.7%)
dysphagia	2/30 (6.7%)
General disorders
asthenia	15/30 (50%)
pyrexia	9/30 (30%)
fatigue	6/30 (20%)
oedema peripheral	6/30 (20%)
general physical health deterioration	3/30 (10%)
chest pain	2/30 (6.7%)
hypothermia	2/30 (6.7%)
localised oedema	2/30 (6.7%)
mucosal inflammation	2/30 (6.7%)
Infections and infestations
infection	2/30 (6.7%)
Investigations
weight decreased	4/30 (13.3%)
Metabolism and nutrition disorders
anorexia	10/30 (33.3%)
dehydration	3/30 (10%)
hypokalaemia	3/30 (10%)
hyperglycaemia	2/30 (6.7%)
Musculoskeletal and connective tissue disorders
back pain	3/30 (10%)
arthralgia	2/30 (6.7%)
musculoskeletal chest pain	2/30 (6.7%)
pain in extremity	2/30 (6.7%)
Nervous system disorders
dizziness	2/30 (6.7%)
headache	2/30 (6.7%)
Psychiatric disorders
confusional state	2/30 (6.7%)
Renal and urinary disorders
renal failure	5/30 (16.7%)
haematuria	4/30 (13.3%)
Reproductive system and breast disorders
oedema genital	2/30 (6.7%)
pelvic pain	2/30 (6.7%)
Respiratory, thoracic and mediastinal disorders
dyspnoea	6/30 (20%)
cough	3/30 (10%)
epistaxis	3/30 (10%)
dysphonia	2/30 (6.7%)
pharyngolaryngeal pain	2/30 (6.7%)
Skin and subcutaneous tissue disorders
alopecia	4/30 (13.3%)
rash papular	2/30 (6.7%)
toxic skin eruption	2/30 (6.7%)
Vascular disorders
hot flush	2/30 (6.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Allos agreements with investigators (PIs) may vary. The PI may publish/make public data from the trial after the earlier of publication by Allos or 18 months after study completion. Allos can review results communications prior to public release and can embargo communications regarding trial results for a period less than or equal to 90 days from submission for review. Allos can request changes to the communication related to confidential or patent information, or to ensure accuracy.