Thalidomide and Temozolomide in Relapsed or Progressive CNS Disease or Neuroblastoma

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT00098865
• Collaborator: National Cancer Institute (NCI) (NIH), Boston Children's Hospital (Other), Celgene Corporation (Industry)
• Enrollment: 15
• Location: 1
• Arm: 1
• Duration (Months): 93
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

RATIONALE: Thalidomide may stop the growth of tumor cells by stopping blood flow to the tumor. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining thalidomide with temozolomide may kill more tumor cells.

PURPOSE: This phase II trial is studying the effectiveness of combining thalidomide with temozolomide in treating young patients who have relapsed or progressive brain tumors or recurrent neuroblastoma.

Condition or Disease	Intervention/Treatment	Phase
Central Nervous System Tumor, Pediatric; Neuroblastoma	Drug: temozolomide; Drug: thalidomide	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the feasibility of thalidomide and temozolomide in pediatric patients with relapsed or progressive poor prognosis brain tumors or recurrent neuroblastomas.

Secondary

• Determine preliminarily evidence of biologic activity of this regimen in these patients.

• Determine the toxic effects of this regimen in these patients.

STATISTICAL DESIGN: The primary data analysis will estimate the percentage of patients who can complete 6 months of therapy in the mixed population. With a target accrual of 20 patients the 90% confidence for the true feasibility rate will be no wider than 40%.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Pilot Study Of Thalidomide With Temozolomide In Patients With Relapsed Or Progressive Brain Tumors Or Neuroblastoma
• Study Start Date: Sep 1, 2002
• Actual Primary Completion Date: Jun 1, 2010
• Actual Study Completion Date: Jun 1, 2010

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Thalidomide and Temozolomide Thalidomide: Oral thalidomide on days 1-28 of a 28 day cycle initiated at 3 mg/kg and increased to maximum dose of 24 mg/kg or 1000 mg as tolerated. Temozolomide: Oral temozolomide on days 1-5 of 28 day cycle given at 200 mg/m2 or 150 mg/m2 for patients who had previously received significant therapy to the bone marrow (chemotherapy or radiation) or cranial spinal radiation. Patients were treated for 6 cycles unless disease progression or excessive toxicity. Treatment could continue beyond 6 cycles if absent disease progression

Drug: temozolomide; The lower 150/m2 Temozolomide dose was for patients who had previously received significant therapy to the bone marrow (chemotherapy or radiation) or cranial spinal raditation.; Other Names: Temodar ; Drug: thalidomide; Calculated dose was rounded down to the nearest 50mg, or up to 50mg if calculated dose was less than 50mg. Patients increased the daily dose by 50mg (one capsule) on a weekly basis unitl either unacceptable toxicity or a maximum dose.; Other Names: Thalamid

Outcome Measures

Primary Outcome Measures

1. Therapy Completion Rate [6 months]

   Feasibility in this study was defined as completion of 6 months of thalidomide with temozolomide therapy. The corresponding therapy completion rate is defined as the proportion of patients who completed 6 months of therapy.

Secondary Outcome Measures

1. Overall Response [Assessed every 8 weeks while on treatment and every 3 months for one year off-study]

   Overall response is the best response during 6 months of therapy measured by radiographic response. Complete Response (CR): Disappearance of all detectable tumors by imaging, if initially positive, as well as 2 consecutively negative CSF cytologic examinations (if the initial cytology was positive). Partial Response (PR): > 50% reduction in the sum of the products of the maximum perpendicular diameter of all measurable lesions; or 2 consecutively negative CSF cytologies and a < 50% reduction in tumor size. Stable Disease (SD): < 50% reduction in the sum of the products of the maximum perpendicular diameters of all measurable lesions, and persistently negative or positive CSF cytology Progressive Disease (PD): > 25% increase in the size of any measurable lesion, the appearance of a new radiographically demonstrable lesion, or the conversion of negative CSF cytology to positive, as confirmed by at least one repeat CSF cytology

2. Overall Survival [Assessed after treatment discontinued every 3 months up to 2 years.]

   Time from registration to death. Patients alive at last follow-up were censored.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically confirmed* diagnosis of 1 of the following:

• Poor prognosis brain tumor

• Relapsed or progressive disease

• No curative therapy exists

• Neuroblastoma

• Recurrent disease NOTE: *Histologic confirmation not required for brain stem glioma; patients with brain stem glioma must have clinical and radiographic evidence of disease

• Patients with brain stem glioma must have symptoms lasting < 3 months comprising cranial nerve deficits (often VI or VII) and/or ataxia and/or long tract signs

PATIENT CHARACTERISTICS:

Age

• 21 and under

Performance status

• Karnofsky 50-100% OR

• Lansky 50-100%

Life expectancy

• More than 2 months

Hematopoietic

• Hemoglobin ≥ 9.0 g/dL

• Platelet count > 75,000/mm^3

• WBC > 2,000/mm^3

• Absolute neutrophil count > 1,000/mm^3

Hepatic

• Bilirubin ≤ 1.5 mg/dL

• SGOT and SGPT ≤ 2 times normal (SGOT ≤ 4 times normal for patients taking Zantac)

• Alkaline phosphatase ≤ 2 times normal

• No active hepatic disease ≥ grade 3

Renal

• Creatinine < 1.5 mg/dL OR

• Creatinine clearance ≥ 70 mL/min

• No active renal disease ≥ grade 3

Cardiovascular

• No active cardiac disease ≥ grade 3

Pulmonary

• No active pulmonary disease ≥ grade 3

Other

• Not pregnant or nursing

• Fertile patients must use effective contraception during and for 4 weeks after study participation

• Willing and able to participate in the System for Thalidomide Education and Prescription Safety (S.T.E.P.S.^®) program

• No active psychiatric disease ≥ grade 3

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Prior biologic therapy allowed

• No prior thalidomide

Chemotherapy

• Prior chemotherapy allowed

• No prior temozolomide

Endocrine therapy

• Concurrent steroids allowed

Radiotherapy

• Prior radiotherapy allowed

Surgery

• Prior surgery allowed

Other

• Concurrent antiseizure medications allowed

• No other concurrent investigational agents

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• National Cancer Institute (NCI)
• Boston Children's Hospital
• Celgene Corporation

Investigators

• Study Chair: Mark W. Kieran, MD, PhD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mark W. Kieran, MD, PhD, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT00098865
• Other Study ID Numbers: 01-279 DFCI; P30CA006516; CDR0000396780
• First Posted: Dec 9, 2004
• Last Update Posted: Oct 7, 2014
• Last Verified: Sep 1, 2014

• Additional relevant MeSH terms: Neuroblastoma; Nervous System Neoplasms; Central Nervous System Neoplasms; Thalidomide; Temozolomide

Study Results

Participant Flow

Recruitment Details	15 patients were enrolled between 2002 to 2007 at the Dana-Farber Cancer Institute.
Pre-assignment Detail	For pediatric patients with relapsed or progressive brain tumors and neuroblastoma.

Arm/Group Title	Thalidomide and Temozolomide
Arm/Group Description	Thalidomide: Oral thalidomide on days 1-28 of a 28 day cycle initiated at 3 mg/kg and increased to maximum dose of 24 mg/kg or 1000 mg as tolerated. Temozolomide: Oral temozolomide on days 1-5 of 28 day cycle given at 200 mg/m2 or 150 mg/m2 for patients who had previously received significant therapy to the bone marrow (chemotherapy or radiation) or cranial spinal radiation. Patients were treated for 6 cycles unless disease progression or excessive toxicity. Treatment could continue beyond 6 cycles if absent disease progression
Period Title: Overall Study
STARTED	15
COMPLETED	6
NOT COMPLETED	9

Baseline Characteristics

Arm/Group Title	Thalidomide and Temozolomide
Arm/Group Description	Thalidomide: Oral thalidomide on days 1-28 of a 28 day cycle initiated at 3 mg/kg and increased to maximum dose of 24 mg/kg or 1000 mg as tolerated. Temozolomide: Oral temozolomide on days 1-5 of 28 day cycle given at 200 mg/m2 or 150 mg/m2 for patients who had previously received significant therapy to the bone marrow (chemotherapy or radiation) or cranial spinal radiation. Patients were treated for 6 cycles unless disease progression or excessive toxicity. Treatment could continue beyond 6 cycles if absent disease progression.
Overall Participants	15
Age (Count of Participants)
<=18 years	14 93.3%
Between 18 and 65 years	1 6.7%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	9 60%
Male	6 40%
Region of Enrollment (participants) [Number]
United States	15 100%
Disease Type (participants) [Number]
Brain Tumor	8 53.3%
Neuroblastoma	7 46.7%

Outcome Measures

1. Primary Outcome

Title	Therapy Completion Rate
Description	Feasibility in this study was defined as completion of 6 months of thalidomide with temozolomide therapy. The corresponding therapy completion rate is defined as the proportion of patients who completed 6 months of therapy.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated patients.

Arm/Group Title	Thalidomide and Temozolomide
Arm/Group Description	Thalidomide: Oral thalidomide on days 1-28 of a 28 day cycle initiated at 3 mg/kg and increased to maximum dose of 24 mg/kg or 1000 mg as tolerated. Temozolomide: Oral temozolomide on days 1-5 of 28 day cycle given at 200 mg/m2 or 150 mg/m2 for patients who had previously received significant therapy to the bone marrow (chemotherapy or radiation) or cranial spinal radiation. Patients were treated for 6 cycles unless disease progression or excessive toxicity. Treatment could continue beyond 6 cycles if absent disease progression temozolomide: The lower 150/m2 Temozolomide dose was for patients who had previously received significant therapy to the bone marrow (chemotherapy or radiation) or cranial spinal raditation. thalidomide: Calculated dose was rounded down to the nearest 50mg, or up to 50mg if calculated dose was less than 50mg. Patients increased the daily dose by 50mg (one capsule) on a weekly basis unitl either unacceptable toxicity or a maximum dose.
Measure Participants	15
Number (90% Confidence Interval) [proportion of participants]	.40 2.7%

2. Secondary Outcome

Title	Overall Response
Description	Overall response is the best response during 6 months of therapy measured by radiographic response. Complete Response (CR): Disappearance of all detectable tumors by imaging, if initially positive, as well as 2 consecutively negative CSF cytologic examinations (if the initial cytology was positive). Partial Response (PR): > 50% reduction in the sum of the products of the maximum perpendicular diameter of all measurable lesions; or 2 consecutively negative CSF cytologies and a < 50% reduction in tumor size. Stable Disease (SD): < 50% reduction in the sum of the products of the maximum perpendicular diameters of all measurable lesions, and persistently negative or positive CSF cytology Progressive Disease (PD): > 25% increase in the size of any measurable lesion, the appearance of a new radiographically demonstrable lesion, or the conversion of negative CSF cytology to positive, as confirmed by at least one repeat CSF cytology
Time Frame	Assessed every 8 weeks while on treatment and every 3 months for one year off-study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Thalidomide and Temozolomide
Arm/Group Description	Thalidomide: Oral thalidomide on days 1-28 of a 28 day cycle initiated at 3 mg/kg and increased to maximum dose of 24 mg/kg or 1000 mg as tolerated. Temozolomide: Oral temozolomide on days 1-5 of 28 day cycle given at 200 mg/m2 or 150 mg/m2 for patients who had previously received significant therapy to the bone marrow (chemotherapy or radiation) or cranial spinal radiation. Patients were treated for 6 cycles unless disease progression or excessive toxicity. Treatment could continue beyond 6 cycles if absent disease progression temozolomide: The lower 150/m2 Temozolomide dose was for patients who had previously received significant therapy to the bone marrow (chemotherapy or radiation) or cranial spinal raditation. thalidomide: Calculated dose was rounded down to the nearest 50mg, or up to 50mg if calculated dose was less than 50mg. Patients increased the daily dose by 50mg (one capsule) on a weekly basis unitl either unacceptable toxicity or a maximum dose.
Measure Participants	15
Partial Response	1 6.7%
Stable Disease	9 60%
Progressive Disease	4 26.7%
Unevaluable	1 6.7%

3. Secondary Outcome

Title	Overall Survival
Description	Time from registration to death. Patients alive at last follow-up were censored.
Time Frame	Assessed after treatment discontinued every 3 months up to 2 years.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated patients.

Arm/Group Title	Thalidomide and Temozolomide
Arm/Group Description	Thalidomide: Oral thalidomide on days 1-28 of a 28 day cycle initiated at 3 mg/kg and increased to maximum dose of 24 mg/kg or 1000 mg as tolerated. Temozolomide: Oral temozolomide on days 1-5 of 28 day cycle given at 200 mg/m2 or 150 mg/m2 for patients who had previously received significant therapy to the bone marrow (chemotherapy or radiation) or cranial spinal radiation. Patients were treated for 6 cycles unless disease progression or excessive toxicity. Treatment could continue beyond 6 cycles if absent disease progression temozolomide: The lower 150/m2 Temozolomide dose was for patients who had previously received significant therapy to the bone marrow (chemotherapy or radiation) or cranial spinal raditation. thalidomide: Calculated dose was rounded down to the nearest 50mg, or up to 50mg if calculated dose was less than 50mg. Patients increased the daily dose by 50mg (one capsule) on a weekly basis unitl either unacceptable toxicity or a maximum dose.
Measure Participants	15
Median (95% Confidence Interval) [months]	12.8

Adverse Events

Time Frame	Clinical assessment of drug toxicities was performed every clinic visit including CBC and serum biochemistries were collected every 2 weeks for the first 8 weeks of therapy and then monthly.
Arm/Group Title	Thalidomide and Temzolomide
Arm/Group Description	Thalidomide: Oral thalidomide on days 1-28 of a 28 day cycle initiated at 3 mg/kg and increased to maximum dose of 24 mg/kg or 1000 mg as tolerated. Temozolomide: Oral temozolomide on days 1-5 of 28 day cycle given at 200 mg/m2 or 150 mg/m2 for patients who had previously received significant therapy to the bone marrow (chemotherapy or radiation) or cranial spinal radiation. Patients were treated for 6 cycles unless disease progression or excessive toxicity. Treatment could continue beyond 6 cycles if absent disease progression.
All Cause Mortality
	Thalidomide and Temzolomide
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Thalidomide and Temzolomide
	Affected / at Risk (%)	# Events
Total	9/15 (60%)
Blood and lymphatic system disorders
Hemoglobin	2/15 (13.3%)
Hematologic-other	1/15 (6.7%)
Febrile neutropenia	1/15 (6.7%)
Eye disorders
Vision-blurred	1/15 (6.7%)
Gastrointestinal disorders
Constipation	1/15 (6.7%)
General disorders
Fatigue	1/15 (6.7%)
Immune system disorders
Allergic reaction	1/15 (6.7%)
Infections and infestations
Infection w/ unk ANC catheter related	1/15 (6.7%)
Infection-other	1/15 (6.7%)
Investigations
Leukocytes	4/15 (26.7%)
Lymphopenia	2/15 (13.3%)
Neutrophils	5/15 (33.3%)
Platelets	4/15 (26.7%)
ALT, SGPT	2/15 (13.3%)
Metabolism and nutrition disorders
Hypokalemia	1/15 (6.7%)
Psychiatric disorders
Depression	1/15 (6.7%)
Skin and subcutaneous tissue disorders
Rash/desquamation	1/15 (6.7%)
Vascular disorders
Hypotension	1/15 (6.7%)
Other (Not Including Serious) Adverse Events
	Thalidomide and Temzolomide
	Affected / at Risk (%)	# Events
Total	14/15 (93.3%)
Blood and lymphatic system disorders
Hemoglobin	8/15 (53.3%)
Cardiac disorders
Cardiac-other	2/15 (13.3%)
Ear and labyrinth disorders
Hearing-other	1/15 (6.7%)
Gastrointestinal disorders
Constipation	6/15 (40%)
Diarrhea w/o prior colostomy	1/15 (6.7%)
Nausea	2/15 (13.3%)
Vomiting	5/15 (33.3%)
Abdomen, pain	1/15 (6.7%)
General disorders
Fatigue	8/15 (53.3%)
Fever w/o neutropenia	3/15 (20%)
Rigors/chills	1/15 (6.7%)
Constitutional, other	3/15 (20%)
Pain-other	1/15 (6.7%)
Infections and infestations
Infection-other	1/15 (6.7%)
Investigations
Leukocytes	9/15 (60%)
Lymphopenia	5/15 (33.3%)
Neutrophils	6/15 (40%)
Platelets	7/15 (46.7%)
Alkaline phosphatase	2/15 (13.3%)
ALT, SGPT	8/15 (53.3%)
AST, SGOT	6/15 (40%)
Creatinine	3/15 (20%)
Metabolism and nutrition disorders
Bicarbonate	8/15 (53.3%)
Hypocalcemia	2/15 (13.3%)
Hyperglycemia	2/15 (13.3%)
Hypermagnesemia	1/15 (6.7%)
Hypomagnesemia	1/15 (6.7%)
Hypophosphatemia	1/15 (6.7%)
Hyperkalemia	3/15 (20%)
Hyponatremia	1/15 (6.7%)
Musculoskeletal and connective tissue disorders
Musculoskeletal/soft tissue-other	1/15 (6.7%)
Nervous system disorders
Ataxia	1/15 (6.7%)
Memory impairment	1/15 (6.7%)
Neuropathy-motor	1/15 (6.7%)
Neuropathy-sensory	1/15 (6.7%)
Neurologic-other	1/15 (6.7%)
Head/headache	3/15 (20%)
Psychiatric disorders
Insomnia	1/15 (6.7%)
Euphoria	1/15 (6.7%)
Renal and urinary disorders
Incontinence urinary	1/15 (6.7%)
Respiratory, thoracic and mediastinal disorders
Cough	3/15 (20%)
Skin and subcutaneous tissue disorders
Dry skin	1/15 (6.7%)
Alopecia	2/15 (13.3%)
Rash/desquamation	3/15 (20%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.