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Erlotinib and Temsirolimus in Treating Patients With Recurrent Malignant Glioma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00112736
Recruitment Status : Completed
First Posted : June 3, 2005
Results First Posted : June 15, 2015
Last Update Posted : June 15, 2015
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Adult Anaplastic Astrocytoma
Adult Anaplastic Oligodendroglioma
Adult Diffuse Astrocytoma
Adult Giant Cell Glioblastoma
Adult Glioblastoma
Adult Gliosarcoma
Adult Mixed Glioma
Adult Pilocytic Astrocytoma
Adult Pineal Gland Astrocytoma
Adult Subependymal Giant Cell Astrocytoma
Recurrent Adult Brain Tumor
Interventions Drug: erlotinib
Drug: temsirolimus
Procedure: therapeutic conventional surgery
Other: laboratory biomarker analysis
Other: pharmacological study
Enrollment 69
Recruitment Details Patients were enrolled between 2005 and 2008. Patients were recruited from outpatient medical clinics and referrals.
Pre-assignment Details  
Arm/Group Title Phase I (Erlotinib & Temsirolimus) Phase II (Erlotinib & Temsirolimus)
Hide Arm/Group Description

PHASE I: Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 (dose escalation). Every 28 days until disease progression or unacceptable toxicity.

erlotinib: Given orally

temsirolimus: Given IV

pharmacological study: Correlative studies

Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 at MTD phse I. Every 28 days until disease progression or unacceptable toxicity.

PHASE II (preoperative component): Patients who are surgical candidates may opt to undergo surgical resection of the tumor. Beginning 5-7 days before surgery, these patients receive oral erlotinib once daily until surgery. Patients also receive temsirolimus IV over 30 minutes at the MTD and then undergo surgical resection of the tumor 3-24 hours later. Beginning 2-4 weeks after surgery, patients receive temsirolimus at the MTD and erlotinib as in phase I.

therapeutic conventional surgery: Undergo surgical resection

laboratory biomarker analysis: Correlative studies

Period Title: Overall Study
Started 22 47
Completed 21 [1] 47 [2]
Not Completed 1 0
Reason Not Completed
1 pt never had had RX due rapid decline             1             0
[1]
12 of Phase I pts treated at MTD and hence considered part of the Phase II analysis
[2]
12 additional pts from phase 1 study were used in analysis for Phase 2 as they were treated at MTD
Arm/Group Title Phase I n=9 Phase II n=16 Phase II n=43 Total
Hide Arm/Group Description

PHASE I: Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 (dose escalation). Every 28 days until disease progression or unacceptable toxicity.

erlotinib: Given orally

temsirolimus: Given IV

Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 at MTD phse I. Every 28 days until disease progression or unacceptable toxicity.

Anaplastic Glioma

erlotinib: Given orally

temsirolimus: Given IV

Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 at MTD phse I. Every 28 days until disease progression or unacceptable toxicity.

Glioblastoma

erlotinib: Given orally

temsirolimus: Given IV

Total of all reporting groups
Overall Number of Baseline Participants 9 16 43 68
Hide Baseline Analysis Population Description
pts had to meet eligibility criteria and recieve at least one dose of treatment. 22 eligible pts enrolled in phase 1, but 1 pt declined before starting any treatment and was excluded from analysis - 12 pts were treated at MTD and thus included in the Phase 2 analysis, hence only 9 patients remained for analysis for phase 1
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 9 participants 16 participants 43 participants 68 participants
57
(33 to 74)
47
(29 to 72)
50
(20 to 69)
51
(20 to 74)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 16 participants 43 participants 68 participants
Female
4
  44.4%
4
  25.0%
12
  27.9%
20
  29.4%
Male
5
  55.6%
12
  75.0%
31
  72.1%
48
  70.6%
Karnofsky Performance Scale (KPS)   [1] 
Median (Full Range)
Unit of measure:  Units on a scale
Number Analyzed 9 participants 16 participants 43 participants 68 participants
90
(70 to 100)
90
(60 to 100)
90
(60 to 100)
90
(60 to 100)
[1]
Measure Description:

The KPS scores range from 0 (lowest score) to 100 (highest score).

The higher the score the better able to carry out daily activities

100-80: able to carry on normal activity and to work; No special care

70-50: Unable to work; able to live at home and care for most personal needs; varying amount of assistance needed

40-10: unable to care for self, requires equivalent of institutional or hospital care; diseases may be progressing rapidly

0: dead

Prior Chemotherapy treatments  
Median (Full Range)
Unit of measure:  Treatments
Number Analyzed 9 participants 16 participants 43 participants 68 participants
2
(0 to 3)
1
(1 to 3)
1
(0 to 3)
1
(0 to 3)
Histology  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 9 participants 16 participants 43 participants 68 participants
anaplastic glioma 3 16 0 19
glioblastoma 6 0 43 49
1.Primary Outcome
Title Maximum Tolerated Dose (Phase I)
Hide Description

Oral erlotinab at 150mg constant dose, 3 pts will be treated with temsirolimus IV with escalating doses, starting at 50mg. Doses will increase or decrease based on toxicity observed.

3 pts will be treated at each dose level - 3 dose levels were observed: 50mg, 25mg, and 15mg

Time Frame based on first 4 weeks of treatment - cycle 1
Hide Outcome Measure Data
Hide Analysis Population Description
Per protocol -
Arm/Group Title Phase I - Dose Escalation
Hide Arm/Group Description:

Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 at (dose escalation or dose de-escalation). Every 28 days until disease progression or unacceptable toxicity.

Dose levels: cohort 1 - 50mg - 3pts cohort 2 - 25mg -6pt cohort 3 - 15mg - 12pts

Overall Number of Participants Analyzed 21
Measure Type: Number
Unit of Measure: mg
15
2.Primary Outcome
Title Safety/Dose Limiting Toxities Phase I
Hide Description

Dose limiting toxities defined as: grade 3 thrombocytopenia, grade 4 anemia and neutropenia, grade >/= nonhematologic toxicity, and failure to recover from toxicites to be eligible for retreatment in 2 weeks of the last dose of either drug. Also grade 3 nonhematologic toxicities only if they wre refractory to maxiaml medical therapy.

MTD defined as dose at which fewer than one-third of patients experienced a DLT

Outcome measure defines number of participants who had a defined dose limiting toxicity.

Time Frame first 4 weeks of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Phase 1 - 50mg Phase 1 - 25 mg Phase 1 - 15mg
Hide Arm/Group Description:
Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 (50mg). Every 28 days until disease progression or unacceptable toxicity.
Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 (25mg). Every 28 days until disease progression or unacceptable toxicity.
PHASE I: Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 (15mg). Every 28 days until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 3 6 12
Measure Type: Number
Unit of Measure: participants
2 3 3
3.Primary Outcome
Title Efficacy - Response Phase 1
Hide Description

pt must have at least 8 weeks of treatment to receive MRI scan, scans are every other cycle (every 2 months). Response measured by a bidimensionally measured leison and clearly defined margins by CT or MRI scan.

Complete Response (CR): complete disappearance of all measurable and evaluable disease. No new lesions, not on any steroids Partial Response (PR): >= 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. No new lesions. Steriod dose must be no greater than max used in 1st 8wks of therapy Stable: not qualify for CR, PR, or progression. Steriod dose must be no greater than max used in 1st 8wks of therapy Progression (PD): 25% increase in the sum of products of all measurable lesions over smallest sum observed, OR clear worsening or failure to return for evalution due to death or deteriorating condition (unless clearly unrelated to brain cancer).

Time Frame at least 8 weeks of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Response was reviewed only in those patients treated at the MTD (15mg temsirolimus)
Arm/Group Title Phase I 15mg Temsirolimus (MTD Dose)
Hide Arm/Group Description:

PHASE I: Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 (15mg). Every 28 days until disease progression or unacceptable toxicity.

erlotinib: Given orally

temsirolimus: Given IV

Overall Number of Participants Analyzed 12
Measure Type: Number
Unit of Measure: participants
Complete Response 0
Partial response 1
Stable 2
Progressive Disease 9
4.Primary Outcome
Title Pharmacokinetics (Phase I)
Hide Description

Tersirolimus Cmax (ng/mL) for cycle 1 is presented in the outcome measure table below for the 3 dose levels

blood samples (5ml) was collected in EDTA containing tubes on days 1 and 2 of cycle 1

Collection time points: prior to dosing of both drugs, at end of temsirolimus infusion and at 1,2,4,6, and 24 hr after erlotinib administration

Time Frame Days 1, 2 of cycle 1, prior to dosing of both drugs, at end of temsirolimus infusion and at 1,2,4,6, and 24 hr after erlotinib administration
Hide Outcome Measure Data
Hide Analysis Population Description
per protocol
Arm/Group Title Phase 1 - 15mg Phase 1 - 25 mg Phase 1 - 50mg
Hide Arm/Group Description:
PHASE I: Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 (15mg). Every 28 days until disease progression or unacceptable toxicity.
Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 (25mg). Every 28 days until disease progression or unacceptable toxicity.
Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 (50mg). Every 28 days until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 11 6 3
Mean (Standard Deviation)
Unit of Measure: ng/mL
460  (219) 428  (115) 451  (281)
5.Primary Outcome
Title Progression-free Survival at 6 Months (Phase II)
Hide Description

Progression (PD): 25% increase in the sum of products of all measurable lesions over smallest sum observed, OR clear worsening or failure to return for evalution due to death or deteriorating condition (unless clearly unrelated to brain cancer).

Responses had to be present on 2 consecutive scans and were centrally reviewed.

Time Frame Evaluated at baseline and every other cycle, till Month 6
Hide Outcome Measure Data
Hide Analysis Population Description
Primary endpoint PFS6 date of registration; Sample size chosen to discriminate between 15% & 35% PFS6 rates for GBM patients. With accrual 32 GBM patients, trial would be considered successful if 8 achieved PFS6. This yields 0.92 power to detect a 35% PFS6 rate, with 0.90 probability of rejecting the treatment regimen if the PFS6 rate is only 15%.
Arm/Group Title Phase II n=43
Hide Arm/Group Description:

Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 at MTD phse I. Every 28 days until disease progression or unacceptable toxicity.

Glioblastoma

erlotinib: Given orally

temsirolimus: Given IV

Overall Number of Participants Analyzed 43
Measure Type: Number
Unit of Measure: participants
6
Time Frame Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Phase I (Erlotinib & Temsirolimus) Phase II (Erlotinib & Erlotinib)
Hide Arm/Group Description

PHASE I: Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 (dose escalation). Every 28 days until disease progression or unacceptable toxicity.

erlotinib: Given orally

temsirolimus: Given IV

pharmacological study: Correlative studies

Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 at MTD phse I. Every 28 days until disease progression or unacceptable toxicity.

PHASE II (preoperative component): Patients who are surgical candidates may opt to undergo surgical resection of the tumor. Beginning 5-7 days before surgery, these patients receive oral erlotinib once daily until surgery. Patients also receive temsirolimus IV over 30 minutes at the MTD and then undergo surgical resection of the tumor 3-24 hours later. Beginning 2-4 weeks after surgery, patients receive temsirolimus at the MTD and erlotinib as in phase I.

therapeutic conventional surgery: Undergo surgical resection

laboratory biomarker analysis: Correlative studies

All-Cause Mortality
Phase I (Erlotinib & Temsirolimus) Phase II (Erlotinib & Erlotinib)
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Hide Serious Adverse Events
Phase I (Erlotinib & Temsirolimus) Phase II (Erlotinib & Erlotinib)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/21 (14.29%)      2/59 (3.39%)    
Cardiac disorders     
Myocardial infarction * 1 [1]  1/21 (4.76%)  1 0/59 (0.00%)  0
Eye disorders     
retinopathy * 1  0/21 (0.00%)  0 1/59 (1.69%)  1
General disorders     
fever * 1  1/21 (4.76%)  1 0/59 (0.00%)  0
Musculoskeletal and connective tissue disorders     
generalized muscle weakness * 1  0/21 (0.00%)  0 1/59 (1.69%)  1
Respiratory, thoracic and mediastinal disorders     
Upper respiratory infection * 1 [2]  1/21 (4.76%)  1 0/59 (0.00%)  0
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, CTCAE (3.0)
[1]
Cardiac ischemia
[2]
normal ANC
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Phase I (Erlotinib & Temsirolimus) Phase II (Erlotinib & Erlotinib)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   21/21 (100.00%)      37/59 (62.71%)    
Cardiac disorders     
hypotension  1  2/21 (9.52%)  2 0/59 (0.00%)  0
Gastrointestinal disorders     
diarrhea * 1  2/21 (9.52%)  2 0/59 (0.00%)  0
Mucositis oral * 1  6/21 (28.57%)  6 5/59 (8.47%)  5
Nausea * 1  1/21 (4.76%)  1 0/59 (0.00%)  0
Vomiting * 1  1/21 (4.76%)  1 0/59 (0.00%)  0
General disorders     
fatigue * 1  2/21 (9.52%)  2 2/59 (3.39%)  2
Infections and infestations     
Mucosal infection * 1  1/21 (4.76%)  1 0/59 (0.00%)  0
Investigations     
White blood Cells  1 [1]  2/21 (9.52%)  2 0/59 (0.00%)  0
Platelets  1 [2]  4/21 (19.05%)  4 2/59 (3.39%)  2
Liver Function Test abnormality  1 [3]  3/21 (14.29%)  3 1/59 (1.69%)  1
Lymphocyte count decrease  1 [4]  0/21 (0.00%)  0 5/59 (8.47%)  5
Metabolism and nutrition disorders     
Anorexia  1  2/21 (9.52%)  2 0/59 (0.00%)  0
dehydration * 1  3/21 (14.29%)  3 0/59 (0.00%)  0
hypercholesterolemia  1  1/21 (4.76%)  1 1/59 (1.69%)  1
hypertriglyceridemia  1  2/21 (9.52%)  2 1/59 (1.69%)  1
hypocalcemia  1  2/21 (9.52%)  2 1/59 (1.69%)  1
hypophosphatemia  1  5/21 (23.81%)  5 4/59 (6.78%)  4
hyperglycemia * 1  0/21 (0.00%)  0 2/59 (3.39%)  2
hypernatremia  1  0/21 (0.00%)  0 1/59 (1.69%)  1
Musculoskeletal and connective tissue disorders     
Pain in extremity * 1 [5]  0/21 (0.00%)  0 1/59 (1.69%)  1
Skin and subcutaneous tissue disorders     
Pruritus * 1  2/21 (9.52%)  2 0/59 (0.00%)  0
Dry Skin * 1  0/21 (0.00%)  0 1/59 (1.69%)  1
Rash * 1  8/21 (38.10%)  8 10/59 (16.95%)  10
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, CTCAE (3.0)
[1]
Leukopenia
[2]
Thrombocytopenia
[3]
SGOT, SGPT
[4]
lymphopenia
[5]
Pain in Limb
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Patrick Y Wen
Organization: Adult Brain Tumor Consortium (ABTC)
EMail: pwen@partners.org
Layout table for additonal information
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00112736    
Obsolete Identifiers: NCT00267878
Other Study ID Numbers: NCI-2012-02921
NCI-2012-02921 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CDR0000429553
NABTC04-02 ( Other Identifier: Adult Brain Tumor Consortium )
NABTC-04-02 ( Other Identifier: CTEP )
U01CA062399 ( U.S. NIH Grant/Contract )
First Submitted: June 2, 2005
First Posted: June 3, 2005
Results First Submitted: April 28, 2015
Results First Posted: June 15, 2015
Last Update Posted: June 15, 2015