Treating Patients With Recurrent PCNSL With Carboplatin/BBBD and Adding Rituxan To The Treatment Regimen

• Sponsor: OHSU Knight Cancer Institute (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00074165
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 17
• Locations: 2
• Arm: 1
• Duration (Months): 95
• Patients Per Site: 8.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

RATIONALE: Monoclonal antibodies, such as rituximab, can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as carboplatin, cyclophosphamide, etoposide, etoposide phosphate, and cytarabine, use different ways to stop cancer cells from dividing so they stop growing or die. Osmotic blood-brain barrier disruption uses certain drugs to open the blood vessels around the brain and allow anticancer substances to be delivered directly to the brain tumor. Chemoprotective drugs such as sodium thiosulfate may protect normal cells from the side effects of carboplatin-based chemotherapy. Combining rituximab with chemotherapy given with osmotic blood-brain barrier disruption plus sodium thiosulfate may kill more cancer cells.

PURPOSE: Phase II trial to study the effectiveness of combining rituximab with combination chemotherapy given with osmotic blood-brain barrier disruption plus sodium thiosulfate in treating patients who have refractory or recurrent primary CNS lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors; Drug/Agent Toxicity by Tissue/Organ; Lymphoma; Thrombocytopenia	Drug: Rituxan; Drug: Cyclophosphamide; Drug: Etoposide; Drug: Etoposide phosphate; Drug: Carboplatin; Drug: Sodium thiosulfate; Drug: Neupogen; Drug: Neulasta; Drug: Cytarabine	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the efficacy of rituximab, carboplatin, cyclophosphamide, etoposide or etoposide phosphate and cytarabine administered in conjunction with osmotic blood-brain barrier disruption and high-dose sodium thiosulfate, in terms of complete response rate, in patients with refractory or recurrent primary CNS lymphoma.

Secondary

• Determine the overall survival and 2-year progression-free survival of patients treated with this regimen.

• Determine the quality of life and cognitive function of patients treated with this regimen.

• Determine the neurotoxicity of this regimen in these patients.

• Determine the percentage of patients with ototoxicity over time after treatment with this regimen.

• Determine the effect of delayed administration of sodium thiosulfate on granulocyte and erythrocyte counts in these patients.

OUTLINE: This is a multicenter study.

Patients receive rituximab IV on day 1. On days 2 and 3, patients receive carboplatin intra-arterially over 10 minutes, cyclophosphamide IV over 10 minutes, and etoposide or etoposide phosphate IV over 10 minutes in conjunction with blood-brain barrier disruption. Patients also receive high-dose sodium thiosulfate IV over 15 minutes administered 4 and 8 hours after carboplatin on days 2 and 3 and intraventricular or intrathecal cytarabine on day 14. Beginning 48 hours after the last dose of chemotherapy, patients receive filgrastim (G-CSF)* subcutaneously (SC) daily for 7-10 days or until blood counts recover. Treatment repeats every 4 weeks for up to 12 courses.

NOTE: * Alternatively, patients may receive a single dose of pegfilgrastim SC, administered 48 hours after the completion of chemotherapy

Patients with intraocular lymphoma also receive methotrexate intravitreally twice weekly until the vitreous is clear of cells by slit lamp exam; once weekly for 1 month; and then monthly for 1 year.

Quality of life is assessed at baseline, every 3 months during treatment, within 30 days of final treatment, then every 6 months for 1 year, and then annually thereafter.

Patients are followed monthly for 3 months, every 2 months for 8 months, every 3 months for 1 year, and then every 6 months thereafter.

PROJECTED ACCRUAL: A total of 11-25 patients will be accrued for this study within 7-10 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial Involving Patients With Recurrent PCNSL Treated With Carboplatin/BBBD, by Adding Rituxan (Rituximab), An Anti CD-20 Antibody, To The Treatment Regimen
• Study Start Date: Jan 1, 2003
• Actual Primary Completion Date: Jun 1, 2010
• Actual Study Completion Date: Dec 1, 2010

Arms and Interventions

Arm

Intervention/Treatment

Experimental: All subjects

Drug: Rituxan; Total dose: 375mg/m2 infused IV; Every 4 weeks for up to one year.; Other Names: Rituximab ; Drug: Cyclophosphamide; Dose 330mg/m2 x 2 days infused IV; Every 4 weeks for up to 1 year; Drug: Etoposide; Dose 200mg/m2 x 2 days infused IV; Every 4 weeks for up to one year. Etoposide phosphate may be given instead.; Drug: Etoposide phosphate; Dose 200mg/m2 infused IV x 2 days; Every 4 weeks for up to one year. Etoposide may be given instead.; Drug: Carboplatin; Dose: 200mg/m2 x 2 days infused IA with BBBD; Every 4 weeks for up to one year.; Drug: Sodium thiosulfate; Dose: 4 hrs post carboplatin = 20gm/m2; Dose: 8 hrs post carboplatin = 16gm/m2 Infused IV x 2 days; Other Names: STS ; Drug: Neupogen; 48 hours after chemotherapy, QD x 7-10 days until WBC greater than 5000. Neulasta (Pegfilgrastim) may be given instead.; Other Names: G-CSF filgrastim ; Drug: Neulasta; Dose: 6mg, 24-72 hours after chemotherapy. Neupogen may be given instead.; Other Names: Pegfilgrastim ; Drug: Cytarabine; Dose: 40mg on Day 14 following chemotherapy

Outcome Measures

Primary Outcome Measures

1. Number of Participants With a Complete Response Rate to Chemotherapy Regimen Assessed by Radiographic Response at 2 Years. [2 years]

   Per RECIST criteria (v1.1) and assessed by magnetic resonance imaging (MRI): Complete response (CR), Disappearance of all target lesions.

Secondary Outcome Measures

1. Number of Participants With Overall Survival Assessed by Clinical and Radiographic Response [5 years]

   Overall survival is measured from entry onto study until death from any cause or until death or progression of disease, respectively.

2. Progression-free Survival Assessed by Clinical and Radiographic Response From First Day of Treatment Until Tumor Progression [5 years]

3. Quality of Life Assessed by EORTC QOL Before Treatment and Then Every 3 Months [5 years]

4. Ototoxicity Assessed by Audiology Hearing Test Done Monthly During Treatment [2 years]

5. Effect of Sodium Thiosulfate (STS) on Granulocytes and Erythrocytes Assessed by Complete Blood Count Lab Values Done Weekly During Treatment [2 years]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Months to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

INCLUSION CRITERIA:

• Signed informed consent form in accordance with institutional guidelines

• Histologically or cytologically confirmed primary CNS lymphoma documented by brain biopsy or cerebrospinal fluid or vitrectomy analysis

• CD20 positive disease

• Progressive or relapsed disease during or after completion of prior methotrexate-based chemotherapy

• Aged 18 months to 75 years

• Performance status ECOG 0-3 OR Karnofsky 30-100%

• Hematocrit at least 25% (transfusion or epoetin alfa allowed)

• Absolute granulocyte count at least 1,200/mm^3

• Platelet count at least 100,000/mm^3 OR at least lower limit of normal

• Bilirubin no greater than 2.0 times upper limit of normal

• Creatinine less than 1.8 mg/dL

• Calculated Creatinine clearance (CrCl) at least 50 mL/min

• Adequate cardiac function to tolerate general anesthesia

• Adequate pulmonary function to tolerate general anesthesia

• Available for follow-up for 1 year post therapy

• Fertile patients must use effective contraception for a minimum of 2 months before and during study participation

EXCLUSION CRITERIA:

• Radiographic signs of intra-cranial herniation and/or spinal block

• HIV positive

• Systemic lymphoma

• Positive serum HCG, pregnant or lactating

• Allergy to study agents

• Hepatitis B or hepatitis C positive

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Good Samaritan Hospital Cancer Treatment Center, Hatton Institute	Cincinnati	Ohio	United States	45220
2	Knight Cancer Institute at Oregon Health and Science University	Portland	Oregon	United States	97239-3098

Sponsors and Collaborators

• OHSU Knight Cancer Institute
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Edward A. Neuwelt, MD, OHSU Knight Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Edward Neuwelt, Professor, OHSU Knight Cancer Institute
• ClinicalTrials.gov Identifier: NCT00074165
• Other Study ID Numbers: IRB00000641; 5R01CA137488-15; ONC-02059-LX; 641; 7465; OHSU-641; NCT00261651
• First Posted: Dec 11, 2003
• Last Update Posted: Apr 21, 2017
• Last Verified: Apr 1, 2017

• Keywords provided by Edward Neuwelt, Professor, OHSU Knight Cancer Institute: drug/agent toxicity by tissue/organ; thrombocytopenia; intraocular lymphoma; primary central nervous system non-Hodgkin lymphoma; primary central nervous system Hodgkin lymphoma
• Additional relevant MeSH terms: Lymphoma; Nervous System Neoplasms; Central Nervous System Neoplasms; Thrombocytopenia; Drug-Related Side Effects and Adverse Reactions; Cytarabine; Sodium thiosulfate; Cyclophosphamide; Rituximab; Carboplatin; Etoposide; Etoposide phosphate

Study Results

Participant Flow

Arm/Group Title	Rituximab and Carboplatin
Arm/Group Description	Rituximab: (i.v.) 375 mg/m^2 given the evening before blood brain barrier disruption(BBBD) procedure day 1 Carboplatin: (i.a.) 200 mg/m^2 /day x 2 days = 400 mg/m^2
Period Title: Overall Study
STARTED	17
COMPLETED	17
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Rituximab and Carboplatin
Arm/Group Description	Rituximab: (i.v.) 375 mg/m^2 given the evening before blood brain barrier disruption(BBBD) procedure day 1 Carboplatin: (i.a.) 200 mg/m^2 /day x 2 days = 400 mg/m^2
Overall Participants	17
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	12 70.6%
>=65 years	5 29.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.235 (12.799)
Sex: Female, Male (Count of Participants)
Female	8 47.1%
Male	9 52.9%
Region of Enrollment (participants) [Number]
United States	17 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With a Complete Response Rate to Chemotherapy Regimen Assessed by Radiographic Response at 2 Years.
Description	Per RECIST criteria (v1.1) and assessed by magnetic resonance imaging (MRI): Complete response (CR), Disappearance of all target lesions.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rituximab and Carboplatin
Arm/Group Description	Rituximab: (i.v.) 375 mg/m^2 given the evening before blood brain barrier disruption(BBBD) procedure day 1 Carboplatin: (i.a.) 200 mg/m^2 /day x 2 days = 400 mg/m^2
Measure Participants	17
Number [Participants]	1 5.9%

2. Secondary Outcome

Title	Number of Participants With Overall Survival Assessed by Clinical and Radiographic Response
Description	Overall survival is measured from entry onto study until death from any cause or until death or progression of disease, respectively.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

Inadequate sample size to determine overall survival

Arm/Group Title	Rituximab and Carboplatin
Arm/Group Description	Rituximab: (i.v.) 375 mg/m^2 given the evening before blood brain barrier disruption(BBBD) procedure day 1 Carboplatin: (i.a.) 200 mg/m^2 /day x 2 days = 400 mg/m^2
Measure Participants	0

3. Secondary Outcome

Title	Progression-free Survival Assessed by Clinical and Radiographic Response From First Day of Treatment Until Tumor Progression
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Quality of Life Assessed by EORTC QOL Before Treatment and Then Every 3 Months
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Ototoxicity Assessed by Audiology Hearing Test Done Monthly During Treatment
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Effect of Sodium Thiosulfate (STS) on Granulocytes and Erythrocytes Assessed by Complete Blood Count Lab Values Done Weekly During Treatment
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	Rituximab and Carboplatin
Arm/Group Description	Rituximab: (i.v.) 375 mg/m^2 given the evening before blood brain barrier disruption(BBBD) procedure day 1 Carboplatin: (i.a.) 200 mg/m^2 /day x 2 days = 400 mg/m^2
All Cause Mortality
	Rituximab and Carboplatin
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Rituximab and Carboplatin
	Affected / at Risk (%)	# Events
Total	16/17 (94.1%)
Blood and lymphatic system disorders
Neutropenic Fever	2/17 (11.8%)
Anemia	1/17 (5.9%)
Carotid Artery Tear	1/17 (5.9%)
Electrolyte Imbalance and Increased Blood Sodium	1/17 (5.9%)
Cardiac disorders
Atrial Fibrillation	1/17 (5.9%)
General disorders
Unresponsiveness	1/17 (5.9%)
Death	1/17 (5.9%)
Injury, poisoning and procedural complications
Hospitalized for Fall	1/17 (5.9%)
Investigations
Extended Hospitalization	2/17 (11.8%)
Musculoskeletal and connective tissue disorders
Superficial Epidermolysis	1/17 (5.9%)
Psychiatric disorders
Neurological Symptoms	1/17 (5.9%)
Respiratory, thoracic and mediastinal disorders
Bronchitis	1/17 (5.9%)
Vascular disorders
Stroke	1/17 (5.9%)
Chemical Meningitis and Seizures	1/17 (5.9%)
Other (Not Including Serious) Adverse Events
	Rituximab and Carboplatin
	Affected / at Risk (%)	# Events
Total	1/17 (5.9%)
General disorders
Leg Pain	1/17 (5.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.