Oxaliplatin and Pemetrexed Disodium in Treating Patients With Refractory Hormone-Resistant Prostate Cancer

• Sponsor: University of Southern California (Other)
• Overall Status: Completed
• CT.gov ID: NCT01338792
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 47
• Location: 1
• Arm: 1
• Duration (Months): 78
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

This phase II trial studies how well giving oxaliplatin and pemetrexed disodium together works in treating patients with refractory hormone-resistant prostate cancer. Drugs used in chemotherapy, such as oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Pemetrexed disodium may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving oxaliplatin together with pemetrexed disodium may kill more tumor cells.

Condition or Disease	Intervention/Treatment	Phase
Hormone-resistant Prostate Cancer; Recurrent Prostate Cancer	Drug: oxaliplatin; Drug: pemetrexed disodium; Other: questionnaire administration; Other: laboratory biomarker analysis; Genetic: reverse transcriptase-polymerase chain reaction; Genetic: polymorphism analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES: I. To determine the response rate by Response Evaluation Criteria In Solid Tumors (RECIST) criteria, prostate-specific antigen (PSA) response by the PSA Working Group criteria, and overall clinical benefit defined by summation of RECIST complete responses (CR) plus RECIST partial responses (PR) plus PSA PRs. SECONDARY OBJECTIVES: I. To determine time to progression in patients with hormone-refractory prostate cancer (HRPC) receiving oxaliplatin and pemetrexed. II. To describe the safety profile of this treatment.

1. Pain response will be evaluated in an exploratory manner. IV. Undertake a pilot analysis of excision repair cross-complementing 1 (ERCC1) expression levels and polymorphisms, looking at their ability to predict response to platinum therapy. OUTLINE: Patients receive oxaliplatin intravenously (IV) over 2 hours and pemetrexed disodium IV on day 1. Courses repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 47 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Oxaliplatin and Pemetrexed in Hormone Refractory Prostate Cancer
• Study Start Date: Jun 1, 2006
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: Dec 1, 2012

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (chemotherapy and enzyme inhibitor) Patients receive oxaliplatin IV over 2 hours and pemetrexed disodium IV on day 1. Courses repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity.

Drug: oxaliplatin; Given IV; Other Names: 1-OHP Dacotin Dacplat Eloxatin L-OHP ; Drug: pemetrexed disodium; Given IV; Other Names: ALIMTA LY231514 MTA ; Other: questionnaire administration; Ancillary studies; Other: laboratory biomarker analysis; Correlative studies; Genetic: reverse transcriptase-polymerase chain reaction; Correlative studies; Other Names: RT-PCR ; Genetic: polymorphism analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Best Overall Response [RECIST evaluation: Baseline, after every 2 courses, and then every 6 months after off-study, up to 1 year. PSA evaluation: baseline, day 1 of each course, final evaluation, and then every 6 months after off-study, up to 1 year]

   For patients with measurable disease, the RECIST 1.0 criteria was used to determine response. Complete Response = disappearance of all target lesions, Partial Response = greater or equal to 30% decrease in sum of longest diameter or target lesions, Stable Disease = <30% decrease or <20% increase, Progressive Disease = greater or equal to 20% increase in longest diameter of target lesions. For patients who do not have measurable disease by RECIST, the response was based on PSA response defined by Prostate Cancer Working Group criteria (1999) as 50% reduction in PSA confirmed on a second measurement at least 4 weeks later.

Secondary Outcome Measures

1. Time to Disease Progression and Overall Survival [Baseline, after every 2 courses, and then every 6 months after off-study (RECIST) until progression; or baseline, day 1 of each course, at the final evaluation, and then every 6 months after off-study (PSA) until progression]

   Progression-free survival was defined as the time from the first infusion of study treatment to the date of radiographic disease progression according to RECIST 1.0, or until two consecutive PSA rises occurred with an absolute increase of 5 ng/mL and a 50% relative increase over baseline. For patients without documented disease progression, the date of death or last follow-up without disease progression was used.

2. Number of Participants With Serious Adverse Events (SAEs) [Baseline, days 1 and 7 of each course, and at last evaluation, up to 1 year]

   Safety evaluation according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically confirmed prostate cancer

• Measurable disease on computed tomography (CT) or evaluable disease on bone scan with an elevated PSA

• For patients who did not initially present with metastatic disease, definitive treatment with either radical prostatectomy or external beam radiation is permitted

• Documented progression on (a) two prior hormone treatments AND (b) one or two chemotherapy regimens

• Documented progression on two prior hormone therapies is defined as orchiectomy followed by anti-adrenal medication upon progression OR gonadotropin-releasing hormone (GnRH) analog +/- androgen receptor blocker with addition or subtraction upon progression; castrate level of testosterone must be documented at study entry

• Documented progression on taxane-based chemotherapy; in addition, patients may have failed a second prior chemotherapy regimen

• Palliative radiation therapy for metastatic disease is allowed only if less than 25% of total body bone marrow was irradiated; 28 days must have elapsed since completion of radiation therapy (RT) with bone marrow recovery; soft tissue disease irradiated in the prior 2 months may not be designated as measurable disease

• ECOG performance score of 0-2

• Absolute neutrophil count (ANC) >= 1500/uL

• Platelet count >= 100,000/uL

• Creatinine clearance >= 45 mL/min

• Serum total bilirubin =<1.5 mg/dL

• Alkaline phosphatase =< 3x the upper limit of normal (ULN) for the reference lab (=< 5x the ULN for patients with known hepatic metastases) and no upper limit for patients with known bone metastases

• Serum glutamic oxaloacetic transaminase (SGOT)/serum glutamic pyruvic transaminase (SGPT) =< 3x the ULN for the reference lab (=< 5x the ULN for patients with known hepatic metastases)

• Patients must be recovered from both acute and late effects of any prior surgery, radiotherapy or other antineoplastic therapy

• Patients or their legal representatives must be able to read, understand and provide informed consent to participate in the trial

• Men of childbearing potential must consent to use barrier contraception while on treatment and for 90 days thereafter

• Patients with pleural or peritoneal effusions are eligible

• Willingness and ability to take vitamin supplementation and steroid premedication as specified in protocol

• Patients with superficial bladder cancer or skin cancer who have second malignancy within 5 years which was removed with curative intent

Exclusion Criteria:

• Active infection or with a fever >= 38.5 degrees Celsius (C) within 3 days of the first scheduled protocol treatment

• Patients with brain metastases

• Prior malignancy within the past 5 years, except for curatively treated basal cell or squamous cell carcinoma of the skin or superficial bladder cancer

• Known hypersensitivity to any of the components of oxaliplatin or pemetrexed

• Received radiotherapy to more than 25% of their bone marrow, or patients who received any radiotherapy within 4 weeks of entry

• Received treatment with strontium

• Receiving concurrent investigational therapy or who have received investigational therapy within 30 days of the first scheduled day of protocol treatment

• Life expectancy < 6 months

• Peripheral neuropathy >= Grade 2

• Any other medical condition, including mental illness or substance abuse

• History of allogeneic transplant

• Known human immunodeficiency virus (HIV) or Hepatitis B or C (active, previously treated, or both)

• Inability to stop nonsteroidal anti-inflammatory drugs (NSAIDS) for a period of 2 days before, the day of, and 2 days following administration of Alimta; 5 days before, the day of, and 2 days following administration of Alimta for long-acting NSAIDS

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	USC/Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033

Sponsors and Collaborators

• University of Southern California
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Jacek Pinski, University of Southern California

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Southern California
• ClinicalTrials.gov Identifier: NCT01338792
• Other Study ID Numbers: 4P-05-7; NCI-2011-00500
• First Posted: Apr 20, 2011
• Last Update Posted: Mar 10, 2014
• Last Verified: Feb 1, 2014

• Additional relevant MeSH terms: Prostatic Neoplasms; Oxaliplatin; Pemetrexed

Study Results

Participant Flow

Recruitment Details	The study was activated on June 14, 2006 and was closed to accrual on May 11, 2009 after accruing 47 subjects. Participants were recruited at LAC+USC Medical Center and the USC/Norris Cancer Hospital.
Pre-assignment Detail	The study had no pre-assignment criteria.

Arm/Group Title	Treatment (Chemotherapy and Enzyme Inhibitor)
Arm/Group Description	Patients receive oxaliplatin IV over 2 hours and pemetrexed disodium IV on day 1. Courses repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	47
COMPLETED	43
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Treatment (Chemotherapy and Enzyme Inhibitor)
Arm/Group Description	Patients receive oxaliplatin IV over 2 hours and pemetrexed disodium IV on day 1. Courses repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity.
Overall Participants	47
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	16 34%
>=65 years	31 66%
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	47 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	9 19.1%
Not Hispanic or Latino	38 80.9%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	4 8.5%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 2.1%
White	33 70.2%
More than one race	0 0%
Unknown or Not Reported	9 19.1%
Region of Enrollment (participants) [Number]
United States	47 100%

Outcome Measures

1. Primary Outcome

Title	Best Overall Response
Description	For patients with measurable disease, the RECIST 1.0 criteria was used to determine response. Complete Response = disappearance of all target lesions, Partial Response = greater or equal to 30% decrease in sum of longest diameter or target lesions, Stable Disease = <30% decrease or <20% increase, Progressive Disease = greater or equal to 20% increase in longest diameter of target lesions. For patients who do not have measurable disease by RECIST, the response was based on PSA response defined by Prostate Cancer Working Group criteria (1999) as 50% reduction in PSA confirmed on a second measurement at least 4 weeks later.
Time Frame	RECIST evaluation: Baseline, after every 2 courses, and then every 6 months after off-study, up to 1 year. PSA evaluation: baseline, day 1 of each course, final evaluation, and then every 6 months after off-study, up to 1 year

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 cycle of treatment were included.

Arm/Group Title	Treatment (Chemotherapy and Enzyme Inhibitor)
Arm/Group Description	Patients receive oxaliplatin IV over 2 hours and pemetrexed disodium IV on day 1. Courses repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity.
Measure Participants	47
Complete Response	0 0%
Partial Response	14 29.8%
Stable Disease	21 44.7%
Progressive Disease	8 17%
Inevaluable	4 8.5%

2. Secondary Outcome

Title	Time to Disease Progression and Overall Survival
Description	Progression-free survival was defined as the time from the first infusion of study treatment to the date of radiographic disease progression according to RECIST 1.0, or until two consecutive PSA rises occurred with an absolute increase of 5 ng/mL and a 50% relative increase over baseline. For patients without documented disease progression, the date of death or last follow-up without disease progression was used.
Time Frame	Baseline, after every 2 courses, and then every 6 months after off-study (RECIST) until progression; or baseline, day 1 of each course, at the final evaluation, and then every 6 months after off-study (PSA) until progression

Outcome Measure Data

Analysis Population Description

Participants who received at least the first infusion of treatment were included.

Arm/Group Title	Treatment (Chemotherapy and Enzyme Inhibitor)
Arm/Group Description	Patients receive oxaliplatin IV over 2 hours and pemetrexed disodium IV on day 1. Courses repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity.
Measure Participants	47
Median Survival	12.0
Median Time to Progression	5.8
Median Progression Free Survival	5.4

3. Secondary Outcome

Title	Number of Participants With Serious Adverse Events (SAEs)
Description	Safety evaluation according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
Time Frame	Baseline, days 1 and 7 of each course, and at last evaluation, up to 1 year

Outcome Measure Data

Analysis Population Description

All participants who started treatment were included.

Arm/Group Title	Treatment (Chemotherapy and Enzyme Inhibitor)
Arm/Group Description	Patients receive oxaliplatin IV over 2 hours and pemetrexed disodium IV on day 1. Courses repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity.
Measure Participants	47
Number [Participants]	35 74.5%

Adverse Events

Time Frame	Baseline, days 1 and 7 of each course, and at last evaluation
Arm/Group Title	Treatment (Chemotherapy and Enzyme Inhibitor)
Arm/Group Description	Patients receive oxaliplatin IV over 2 hours and pemetrexed disodium IV on day 1. Courses repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Treatment (Chemotherapy and Enzyme Inhibitor)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Chemotherapy and Enzyme Inhibitor)
	Affected / at Risk (%)	# Events
Total	35/47 (74.5%)
Blood and lymphatic system disorders
Hemoglobin	6/47 (12.8%)	8
General disorders
Death not associated with CTCAE term (Disease progression NOS)	2/47 (4.3%)	2
Fatigue (asthenia, lethargy, malaise)	7/47 (14.9%)	7
Immune system disorders
Allergic reaction/hypersensitivity (including drug fever)	1/47 (2.1%)	1
Infections and infestations
Infection - Other	1/47 (2.1%)	1
Infection (documented clinically or microbiologically) with Gr 3 or 4 neutrophis (ANC <1.0 x 10e9/L)	1/47 (2.1%)	1
Infection with normal ANC or Gr 1 or 2 neutrophils (Blood)	1/47 (2.1%)	1
Infection with normal ANC or Gr 1 or 2 neutrophils (Upper airway NOS)	1/47 (2.1%)	1
Investigations
Alkaline Phosphatase	5/47 (10.6%)	9
AST, SGOT (serum glutamic oxaloacetic transaminase)	2/47 (4.3%)	2
Leukocytes (total WBC)	7/47 (14.9%)	10
Lymphopenia	9/47 (19.1%)	20
Neutrophils/granulocytes (ANC/AGC)	9/47 (19.1%)	25
Platelets	2/47 (4.3%)	3
Metabolism and nutrition disorders
Anorexia	1/47 (2.1%)	1
Glucose, serum-high (hyperglycemia)	6/47 (12.8%)	6
Sodium, serum-low (hyponatremia)	1/47 (2.1%)	1
Musculoskeletal and connective tissue disorders
Muscle weakness, generalized or specific area (not due to neuropathy) (Whole body/generalized)	1/47 (2.1%)	1
Pain (Back)	1/47 (2.1%)	1
Pain (Bone)	1/47 (2.1%)	1
Pain (Extremity-limb)	1/47 (2.1%)	1
Pain (Joint)	6/47 (12.8%)	6
Pain (Muscle)	6/47 (12.8%)	6
Nervous system disorders
Ataxia	1/47 (2.1%)	1
Dizziness	3/47 (6.4%)	4
Neuropathy: sensory	2/47 (4.3%)	2
Seizure	1/47 (2.1%)	1
Syncope (fainting)	1/47 (2.1%)	1
Psychiatric disorders
Confusion	3/47 (6.4%)	3
Respiratory, thoracic and mediastinal disorders
Bronchospasm, wheezing	1/47 (2.1%)	1
Dyspsnea (shortness of breath)	2/47 (4.3%)	2
Pleural effusion (non-malignant)	1/47 (2.1%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Chemotherapy and Enzyme Inhibitor)
	Affected / at Risk (%)	# Events
Total	47/47 (100%)
Blood and lymphatic system disorders
Hemoglobin-decreased	47/47 (100%)	103
Cardiac disorders
Supraventricular and nodal arrhythmia (Sinus tachycardia)	1/47 (2.1%)	1
Ear and labyrinth disorders
Hearing: patients with/without baseline audiogram and enrolled in a monitoring program	10/47 (21.3%)	10
Hearing: patients without baseline audiogram and not enrolled in a monitoring program	10/47 (21.3%)	16
Tinnitus	5/47 (10.6%)	7
Eye disorders
Dry eye syndrome	1/47 (2.1%)	2
Blurred vision	1/47 (2.1%)	1
Watery eye (epiphora, tearing)	1/47 (2.1%)	1
Gastrointestinal disorders
Constipation	11/47 (23.4%)	13
Diarrhea	17/47 (36.2%)	35
Distension/bloating, abdominal	2/47 (4.3%)	2
Dry mouth/salivary gland (xerostomia)	2/47 (4.3%)	2
Dysphagia (difficulty swallowing)	1/47 (2.1%)	2
Incontinence, anal	1/47 (2.1%)	1
Nausea	31/47 (66%)	53
Pain (Abdomen NOS)	4/47 (8.5%)	5
Pain (Oral cavity)	1/47 (2.1%)	1
Pain (Stomach)	2/47 (4.3%)	2
Vomiting	16/47 (34%)	21
General disorders
Constitutional Symptoms	1/47 (2.1%)	1
Edema: limb	7/47 (14.9%)	9
Fatigue (asthenia, lethargy, malaise)	47/47 (100%)	129
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	2/47 (4.3%)	3
Flu-like syndrome	4/47 (8.5%)	4
Injection site reaction/extravasation changes	2/47 (4.3%)	2
Immune system disorders
Allergic reaction/hypersensitivity (including drug fever)	14/47 (29.8%)	18
Infections and infestations
Infection with normal ANC or Grade 1 or 2 neutrophils (Bladder [urinary])	2/47 (4.3%)	2
Infection with unknown ANC (Bladder [urinary])	1/47 (2.1%)	1
Nasal cavity/paranasal sinus reactions	1/47 (2.1%)	1
Injury, poisoning and procedural complications
Bruising (in absence of Grade 3 or 4 thrombocytopenia)	1/47 (2.1%)	1
Vascular access complication	1/47 (2.1%)	1
Investigations
Alkaline Phosphatase	39/47 (83%)	69
ALT, SGPT (serum glutamic pyruvic transaminase)	20/47 (42.6%)	33
AST, SGOT (serum glutamic oxaloacetic transaminase)	35/47 (74.5%)	64
Bilirubin (hyperbilirubinemia)	1/47 (2.1%)	5
Creatinine Increased	12/47 (25.5%)	24
Leucocytes (total WBC)-decreased	29/47 (61.7%)	95
Lymphopenia	3/47 (6.4%)	3
Neutrophils/granulocytes (ANC/AGC)	24/47 (51.1%)	43
Platelet count decreased	19/47 (40.4%)	58
Weight loss	3/47 (6.4%)	3
Metabolism and nutrition disorders
Albumin, serum-low (hypoalbuminemia)	19/47 (40.4%)	41
Anorexia	35/47 (74.5%)	71
Calcium, serum-high (hypercalcemia)	3/47 (6.4%)	3
Calcium, serum-low (hypocalcemia)	9/47 (19.1%)	12
Glucose, serum-high (hyperglycemia)	36/47 (76.6%)	76
Phosphate, serum-low (hypophosphatemia)	1/47 (2.1%)	1
Potassium, serum-high (hyperkalemia)	6/47 (12.8%)	8
Potassium, serum-low (hypokalemia)	3/47 (6.4%)	4
Sodium, serum-low (hyponatremia)	25/47 (53.2%)	36
Musculoskeletal and connective tissue disorders
Muscle weakness, generalized or specific area (not due to neuropathy) - Extremity-lower	1/47 (2.1%)	1
Muscle weakness, generalized or specific area (not due to neuropathy) (Whole body/generalized)	3/47 (6.4%)	3
Pain (Back)	7/47 (14.9%)	8
Pain (Bone)	2/47 (4.3%)	2
Pain (Chest/thorax NOS)	1/47 (2.1%)	1
Pain (Extremity-limb)	7/47 (14.9%)	9
Pain (Joint)	29/47 (61.7%)	51
Pain (Muscle)	29/47 (61.7%)	45
Nervous system disorders
Dizziness	20/47 (42.6%)	24
Memory impairment	1/47 (2.1%)	1
Neuropathy: cranial (CN VIII Hearing and balance)	1/47 (2.1%)	1
Neuropathy: sensory	40/47 (85.1%)	87
Pain (Head/headache)	2/47 (4.3%)	2
Taste alteration (dysgeusia)	3/47 (6.4%)	3
Psychiatric disorders
Confusion	2/47 (4.3%)	2
Psychosis (hallucinations/delusions)	1/47 (2.1%)	1
Renal and urinary disorders
Incontinence, urinary	1/47 (2.1%)	1
Urinary frequency/urgency	2/47 (4.3%)	2
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	1/47 (2.1%)	1
Bronchospasm, wheezing	4/47 (8.5%)	7
Cough	4/47 (8.5%)	4
Dyspnea (shortness of breath)	4/47 (8.5%)	6
Hiccoughs (hiccups, singultus)	1/47 (2.1%)	1
Pleural effusion (non-malignant)	2/47 (4.3%)	2
Skin and subcutaneous tissue disorders
Dermatology/Skin - Other	1/47 (2.1%)	2
Hair loss/alopecia (scalp or body)	1/47 (2.1%)	1
Nail changes	1/47 (2.1%)	3
Petechiae/purpura (hemorrhage/bleeding into skin or mucosa)	7/47 (14.9%)	11
Photosensitivity	5/47 (10.6%)	5
Rash/desquamation	3/47 (6.4%)	3
Rash: acne/acneiform	1/47 (2.1%)	1
Sweating (diaphoresis)	1/47 (2.1%)	1
Vascular disorders
Hypertension	1/47 (2.1%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.