Ritonavir and Lopinavir in Treating Patients With Progressive or Recurrent High-Grade Glioma

• Sponsor: Case Comprehensive Cancer Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01095094
• Collaborator: (none)
• Enrollment: 19
• Location: 1
• Arm: 1
• Duration (Months): 34
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

RATIONALE: Ritonavir and lopinavir may stop the growth of gliomas by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. PURPOSE: This phase II trial is studying how well giving ritonavir together with lopinavir works in treating patients with progressive or recurrent high-grade glioma.

Condition or Disease	Intervention/Treatment	Phase
Brain Tumor; Anaplastic Astrocytoma; Anaplastic Ependymoma; Anaplastic Oligodendroglioma; Brain Stem Glioma; Giant Cell Glioblastoma; Glioblastoma; Gliosarcoma; Mixed Glioma	Drug: ritonavir; Drug: lopinavir	Phase 2

Detailed Description

PRIMARY OBJECTIVES: I. To evaluate the 6-month progression-free survival in patients with recurrent or progressive high grade gliomas treated with ritonavir and lopinavir. SECONDARY OBJECTIVES: I. To evaluate the toxicity of ritonavir and lopinavir in this patient population. OUTLINE: Patients receive oral ritonavir and lopinavir twice daily in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed periodically.

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Ritonavir/Lopinavir in Patients With Progressive of Recurrent High-Grade Gliomas
• Study Start Date: Jan 1, 2009
• Actual Primary Completion Date: Jun 1, 2010
• Actual Study Completion Date: Nov 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I Patients receive oral ritonavir and lopinavir twice daily in the absence of disease progression or unacceptable toxicity.	Drug: ritonavir; Given orally; Other Names: Norvir RIT ; Drug: lopinavir; Given orally; Other Names: ABT-378/r

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival [At 6 months]

   Number of patients that remained disease free at 6 months from start of treatment.

Secondary Outcome Measures

1. Grade 3-5 Toxicity as Assessed by NCI CTC v3.0 [at 6 months from start of treatment]

   Number of participants with adverse events grades 3-5. For a detailed list of adverse events see the adverse event module.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically proven high grade glioma (WHO grade 3-4) which is progressive or recurrent following radiation therapy with or without chemotherapy

• Patients with previous low grade glioma who progressed after radiotherapy and chemotherapy and are biopsied and found to have a high grade glioma are eligible

• Patients must have recovered from toxicity of prior therapy - An interval of >= 3 months must have elapsed since the completion of the most recent course of radiation therapy

• Minimum interval since last drug therapy: 2 weeks since last non-cytotoxic therapy; 3 weeks must have elapsed since the completion of a non-nitrosourea containing chemotherapy regimen; 6 weeks since the completion of a nitrosourea containing chemotherapy regimen

• Patients must have a Karnofsky performance status >= 60% (i.e., must be able to care for himself/herself with the occasional help of others)

• Patients must have normal hematologic, renal, and liver function (i.e., absolute neutrophil count >= 1500/mm^{3, platelets >= 100,000/mm}3, HgB > 9 d/dl, creatinine =< 1.5mg/dl, total bilirubin =< 1.5mg/dl, transaminases =< 2.5 times the upper limits of the institutional norm)

• Patients must be able to provide written informed consent

• Patients with the potential for pregnancy or impregnating their partner must agree to follow acceptable birth control methods to avoid contraception - Female patients of child-bearing potential must have a negative pregnancy test

• Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin of carcinoma in situ of the cervix and breast, adequately treated stage I or II cancer from which the patient is in complete remission

• Patients with other prior malignancies must be disease-free for >= 3 years

• Patients must be maintained on a stable corticosteroid regimen from the time of their baseline scan until the start of treatment

• Patients must have a Mini mental state exam score >= 15

Exclusion Criteria:

• Patients with serious concurrent infection or medical illness, which would jeopardize the ability of the patient to receive the treatment outlines in this protocol with reasonable safety

• Patients who are pregnant or breast-feeding

• Patients receiving concurrent therapy for their tumor (with the exception of steroids)

• HIV positive

• Prior therapy with HIV protease inhibitors

• Concurrent therapy with hepatic enzyme inducing anticonvulsant

• Inability to be followed closely at the Cleveland Clinic

• Patients requiring the use of medication well-known contraindicated for concomitant use with lopinavir/ritonavir: amiodarone, astemizole, bepridil, bupropione, cisapride, clorazepate, clozapim, diazepam, encainide, flecainide, flurazepam, meperidine, midazolam, primozide, piroxicam, propafenone, propoxifeno, quinidine, rifabutin, terfenadine, triazolam, zolpidem, dihydroergotamine, ergotamine

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cleveland Clinic Taussig Institute, Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44195

Sponsors and Collaborators

• Case Comprehensive Cancer Center

Investigators

• Principal Investigator: David Peereboom, MD, Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Case Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT01095094
• Other Study ID Numbers: CASE2307; NCI-2009-01288; NCT00792987
• First Posted: Mar 29, 2010
• Last Update Posted: Jun 10, 2013
• Last Verified: Apr 1, 2013

• Keywords provided by Case Comprehensive Cancer Center: adult brain tumor; adult anaplastic astrocytoma; adult anaplastic ependymoma; adult anaplastic oligodendroglioma; adult brain stem glioma; adult giant cell glioblastoma; adult glioblastoma; adult gliosarcoma; adult mixed glioma; recurrent adult brain tumor
• Additional relevant MeSH terms: Glioblastoma; Glioma; Brain Neoplasms; Astrocytoma; Ependymoma; Gliosarcoma; Oligodendroglioma; Ritonavir; Lopinavir

Study Results

Participant Flow

Recruitment Details	Patients were recruited from medical clinic May 2008 to May 2009.

Arm/Group Title	Arm I
Arm/Group Description	Patients receive oral ritonavir and lopinavir twice daily in the absence of disease progression or unacceptable toxicity. ritonavir : Given orally lopinavir : Given orally
Period Title: Overall Study
STARTED	19
COMPLETED	16
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Arm I
Arm/Group Description	Patients receive oral ritonavir and lopinavir twice daily in the absence of disease progression or unacceptable toxicity. ritonavir : Given orally lopinavir : Given orally
Overall Participants	19
Age, Customized (Number) [Number]
30-39 years	4 21.1%
40-49 years	5 26.3%
50-59 years	7 36.8%
60-69 years	1 5.3%
70-79 years	2 10.5%
Sex: Female, Male (Count of Participants)
Female	7 36.8%
Male	12 63.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 5.3%
Not Hispanic or Latino	18 94.7%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	19 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	19 100%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival
Description	Number of patients that remained disease free at 6 months from start of treatment.
Time Frame	At 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I
Arm/Group Description	Patients receive oral ritonavir and lopinavir twice daily in the absence of disease progression or unacceptable toxicity. ritonavir : Given orally lopinavir : Given orally
Measure Participants	16
Number [participants]	4 21.1%

2. Secondary Outcome

Title	Grade 3-5 Toxicity as Assessed by NCI CTC v3.0
Description	Number of participants with adverse events grades 3-5. For a detailed list of adverse events see the adverse event module.
Time Frame	at 6 months from start of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I
Arm/Group Description	Patients receive oral ritonavir and lopinavir twice daily in the absence of disease progression or unacceptable toxicity. ritonavir : Given orally lopinavir : Given orally
Measure Participants	19
Number [participants]	7 36.8%

Adverse Events

Time Frame	Adverse Event data was collected on all patients while on study over a 3 year 5 month period.
Arm/Group Title	Arm I
Arm/Group Description	Patients receive oral ritonavir and lopinavir twice daily in the absence of disease progression or unacceptable toxicity. ritonavir : Given orally lopinavir : Given orally
All Cause Mortality
	Arm I
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Arm I
	Affected / at Risk (%)	# Events
Total	5/19 (26.3%)
Gastrointestinal disorders
Vomiting	1/19 (5.3%)
Nausea	1/19 (5.3%)
General disorders
Edema: limb	1/19 (5.3%)
Death not associated with CTCAE term - Disease progression NOS	4/19 (21.1%)
Musculoskeletal and connective tissue disorders
Muscle weakness, generalized or specific area (not due to neuropathy) - Whole body/generalized	1/19 (5.3%)
Nervous system disorders
Neuropathy: motor	1/19 (5.3%)
Renal and urinary disorders
Incontinence, urinary	1/19 (5.3%)
Other (Not Including Serious) Adverse Events
	Arm I
	Affected / at Risk (%)	# Events
Total	17/19 (89.5%)
Blood and lymphatic system disorders
Leukopenia	1/19 (5.3%)
Neutropenia	1/19 (5.3%)
Endocrine disorders
Cushingoid appearance (e.g., moon face, buffalo hump, centripetal obesity, cutaneous striae)	1/19 (5.3%)
hot Flashes/Flushes	1/19 (5.3%)
Eye disorders
Ocular/Visual - Other (Specify, Foggy Vision)	2/19 (10.5%)
Gastrointestinal disorders
Diarrhea	11/19 (57.9%)
Dysphagia (difficulty swallowing)	4/19 (21.1%)
Bad Breath	1/19 (5.3%)
Heartburn/dyspepsia	2/19 (10.5%)
Mucositis/stomatitis (clinical exam) - Oral cavity	4/19 (21.1%)
Nausea	3/19 (15.8%)
Salivary gland changes/ increased saliva	2/19 (10.5%)
Vomiting	1/19 (5.3%)
General disorders
Edema: limb	2/19 (10.5%)
Fatigue (asthenia, lethargy, malaise)	7/19 (36.8%)
Flu-like syndrome	1/19 (5.3%)
Rigors/chills	1/19 (5.3%)
Sweating (diaphoresis)	1/19 (5.3%)
Immune system disorders
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	1/19 (5.3%)
Investigations
Elevated AST, SGOT(serum glutamic oxaloacetic transaminase)	1/19 (5.3%)
Thrombocytopenia	3/19 (15.8%)
Potassium, serum-low (hypokalemia)	1/19 (5.3%)
Weight Loss	1/19 (5.3%)
Metabolism and nutrition disorders
Anorexia	2/19 (10.5%)
Cholesterol, serum-high (hypercholesteremia)	5/19 (26.3%)
Glucose, serum-high (hyperglycemia)	2/19 (10.5%)
Triglyceride, serum-high (hypertriglyceridemia)	7/19 (36.8%)
Musculoskeletal and connective tissue disorders
Muscle weakness, generalized or specific area (not due to neuropathy) - Extremity-lower	3/19 (15.8%)
Pain - Bone	1/19 (5.3%)
Pain - Extremity-limb	1/19 (5.3%)
Pain - Neck	1/19 (5.3%)
Nervous system disorders
Ataxia	1/19 (5.3%)
Cognitive disturbance	2/19 (10.5%)
Confusion	2/19 (10.5%)
Memory impairment	4/19 (21.1%)
Mood alteration - Anxiety	1/19 (5.3%)
Neuropathy: cranial - CN XII Motor-tongue	1/19 (5.3%)
Neuropathy: motor	4/19 (21.1%)
Pain - Head/headache	3/19 (15.8%)
Seizure	3/19 (15.8%)
Somnolence/depressed level of consciousness	1/19 (5.3%)
Speech impairment (e.g., dysphasia or aphasia)	4/19 (21.1%)
Neuropathy: sensory	1/19 (5.3%)
Dizziness	2/19 (10.5%)
Psychiatric disorders
Mood alteration - Depression	1/19 (5.3%)
Renal and urinary disorders
Incontinence, urinary	1/19 (5.3%)
Respiratory, thoracic and mediastinal disorders
Voice changes/dysarthria (e.g., hoarseness, loss or alteration in voice, laryngitis)	1/19 (5.3%)
Skin and subcutaneous tissue disorders
Dry skin	1/19 (5.3%)
Rash/desquamation	2/19 (10.5%)
Rash: acne/acneiform	1/19 (5.3%)
Vascular disorders
Thrombosis/thrombus/embolism	1/19 (5.3%)

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.