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BEZ235 Phase II Trial in Patients With Advanced Pancreatic Neuroendocrine Tumors (pNET) After Failure of mTOR Inhibitor Therapy.

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ClinicalTrials.gov Identifier: NCT01658436
Recruitment Status : Completed
First Posted : August 7, 2012
Results First Posted : May 2, 2016
Last Update Posted : May 2, 2016
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Pancreatic Neuroendocrine Tumors (pNET)
Intervention Drug: BEZ235 (Stage 1)
Enrollment 31

Recruitment Details

This was a Phase II, two-stage, multicenter study, where Stage 1 was a singlearm,open label design and Stage 2 was planned to be a randomized, double-blind study.

However, at the end of Stage 1, the futility was met and hence the Stage 2 was not initiated.

Pre-assignment Details Initially , the patients were started at BEZ235 400mg bid dose regimen. The preliminary safety & tolerability data fro first 3 patients treated at this dose showed all patients reported AEs leading to dose interruption. It was decided to decrease the dose of BEZ235 to 300mg bid dose regimen.
Arm/Group Title BEZ235 300 mg BEZ235 400 mg Bid
Hide Arm/Group Description Oral BEZ235 300 mg bid was investigated in stage 1 of study Oral BEZ235 400 mg bid was investigated in stage 1 of study
Period Title: Overall Study
Started 20 11
Completed 0 0
Not Completed 20 11
Reason Not Completed
Adverse Event             6             5
Physician Decision             1             0
Progressive disease             12             4
Study terminated by sponsor             0             1
Subject/guardian decision             0             1
Death             1             0
Arm/Group Title BEZ235 300 mg/400 mg Bid
Hide Arm/Group Description Oral BEZ235 300 mg/400 mg bid was investigated in stage 1 of study
Overall Number of Baseline Participants 31
Hide Baseline Analysis Population Description
The Full Analysis Set (FAS) comprised of all patients who received at least one dose of study treatment (Stage 1). This set was known as ‘Analysis Set Stage 1’ (AS1).
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 31 participants
60.1  (11.4)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 31 participants
Female
13
  41.9%
Male
18
  58.1%
1.Primary Outcome
Title Stage 1 - Progression Free Survival (PFS) Rate Analysis at 16 Weeks as Per Local Radiology Review
Hide Description PFS rate at 16 weeks was defined as a binary variable. Patients were considered as ‘progression free’ after 16 weeks if they had an overall lesion response of complete response (CR) partial response (‘PR) or stable disease (SD)’ and “progressed” if they had an overall lesion response of ‘Progressive disease (PD) at the scan which occurred on day 105 after start of treatment, or later. Patients whose 16 weeks tumor assessment was unknown, missing or outside the window was not considered as ‘progression free’ and was considered a “failure” and counted only in the denominator for the estimation of the 16 week progression free rate.
Time Frame 16 weeks after the first BEZ235 administration.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) comprised of all patients who received at least one dose of study treatment (Stage 1). This set was known as ‘Analysis Set Stage 1’ (AS1).
Arm/Group Title BEZ235 300 mg/400 mg Bid
Hide Arm/Group Description:
Oral BEZ235 300 mg/400 mg bid was investigated in stage 1 of study
Overall Number of Participants Analyzed 31
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
51.6
(35.7 to 67.3)
2.Secondary Outcome
Title Stage 1- Overall Response Rate (ORR)
Hide Description Overall Response rate was defined as the proportion of patients with a best overall response of complete response or partial response, based on investigator's assessment as per RECIST criteria version 1.1. Based on futility analysis conducted at the end of stage 1, stage 2 was not initiated.
Time Frame Baseline, every 8 weeks up to 31 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) comprised of all patients who received at least one dose of study treatment (Stage 1). This set was known as ‘Analysis Set Stage 1’ (AS1).
Arm/Group Title BEZ235 300 mg/400 mg Bid
Hide Arm/Group Description:
Oral BEZ235 300 mg/400 mg bid was investigated in stage 1 of study
Overall Number of Participants Analyzed 31
Measure Type: Number
Unit of Measure: Percentage of participants
Complete response 0.0
Partial response 0.0
3.Secondary Outcome
Title Stage 1 - Disease Control Rate
Hide Description Disease control rate was defined as the proportion of patients with a best overall response of Complete Response, Partial response, or Stable disease, based on the investigator's assessment per RECIST version 1.1. Based on futility analysis conducted at the end of stage 1, stage 2 was not initiated.
Time Frame Baseline, every 8 weeks up to 31 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) comprised of all patients who received at least one dose of study treatment (Stage 1). This set was known as ‘Analysis Set Stage 1’ (AS1).
Arm/Group Title BEZ235 300 mg/400 mg Bid
Hide Arm/Group Description:
Oral BEZ235 300 mg/400 mg bid was investigated in stage 1 of study
Overall Number of Participants Analyzed 31
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
71.0
(54.8 to 83.9)
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title BEZ235 300 mg Bid BEZ235 400 mg Bid
Hide Arm/Group Description BEZ235 300 mg bid BEZ235 400 mg bid
All-Cause Mortality
BEZ235 300 mg Bid BEZ235 400 mg Bid
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
BEZ235 300 mg Bid BEZ235 400 mg Bid
Affected / at Risk (%) Affected / at Risk (%)
Total   8/20 (40.00%)   5/11 (45.45%) 
Blood and lymphatic system disorders     
ANAEMIA  1  1/20 (5.00%)  0/11 (0.00%) 
Cardiac disorders     
CARDIAC ARREST  1  1/20 (5.00%)  0/11 (0.00%) 
LEFT VENTRICULAR HYPERTROPHY  1  0/20 (0.00%)  1/11 (9.09%) 
SYSTOLIC DYSFUNCTION  1  0/20 (0.00%)  1/11 (9.09%) 
Gastrointestinal disorders     
ABDOMINAL PAIN  1  2/20 (10.00%)  0/11 (0.00%) 
CONSTIPATION  1  0/20 (0.00%)  1/11 (9.09%) 
DIARRHOEA  1  0/20 (0.00%)  1/11 (9.09%) 
VOMITING  1  1/20 (5.00%)  0/11 (0.00%) 
General disorders     
PYREXIA  1  1/20 (5.00%)  0/11 (0.00%) 
Hepatobiliary disorders     
CHOLESTASIS  1  0/20 (0.00%)  1/11 (9.09%) 
HEPATIC PAIN  1  0/20 (0.00%)  1/11 (9.09%) 
Infections and infestations     
ERYSIPELAS  1  1/20 (5.00%)  0/11 (0.00%) 
INFECTION  1  1/20 (5.00%)  0/11 (0.00%) 
SEPSIS  1  2/20 (10.00%)  0/11 (0.00%) 
STAPHYLOCOCCAL INFECTION  1  1/20 (5.00%)  0/11 (0.00%) 
Metabolism and nutrition disorders     
HYPONATRAEMIA  1  1/20 (5.00%)  0/11 (0.00%) 
Musculoskeletal and connective tissue disorders     
SPINAL COLUMN STENOSIS  1  1/20 (5.00%)  0/11 (0.00%) 
Nervous system disorders     
SPINAL CORD COMPRESSION  1  0/20 (0.00%)  1/11 (9.09%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
BEZ235 300 mg Bid BEZ235 400 mg Bid
Affected / at Risk (%) Affected / at Risk (%)
Total   20/20 (100.00%)   11/11 (100.00%) 
Blood and lymphatic system disorders     
ANAEMIA  1  0/20 (0.00%)  1/11 (9.09%) 
LYMPHOPENIA  1  1/20 (5.00%)  0/11 (0.00%) 
NEUTROPENIA  1  0/20 (0.00%)  2/11 (18.18%) 
THROMBOCYTOPENIA  1  0/20 (0.00%)  1/11 (9.09%) 
Cardiac disorders     
ATRIAL FIBRILLATION  1  1/20 (5.00%)  0/11 (0.00%) 
CARDIAC FAILURE  1  1/20 (5.00%)  0/11 (0.00%) 
PALPITATIONS  1  0/20 (0.00%)  1/11 (9.09%) 
Ear and labyrinth disorders     
VERTIGO  1  0/20 (0.00%)  1/11 (9.09%) 
Gastrointestinal disorders     
ABDOMINAL DISTENSION  1  2/20 (10.00%)  0/11 (0.00%) 
ABDOMINAL PAIN  1  6/20 (30.00%)  2/11 (18.18%) 
ABDOMINAL PAIN UPPER  1  2/20 (10.00%)  4/11 (36.36%) 
ANAL FISSURE  1  0/20 (0.00%)  1/11 (9.09%) 
ASCITES  1  1/20 (5.00%)  0/11 (0.00%) 
CHEILITIS  1  0/20 (0.00%)  1/11 (9.09%) 
CONSTIPATION  1  4/20 (20.00%)  1/11 (9.09%) 
DIARRHOEA  1  16/20 (80.00%)  6/11 (54.55%) 
DRY MOUTH  1  2/20 (10.00%)  1/11 (9.09%) 
DYSPEPSIA  1  2/20 (10.00%)  2/11 (18.18%) 
GASTROINTESTINAL MOTILITY DISORDER  1  0/20 (0.00%)  1/11 (9.09%) 
GASTROOESOPHAGEAL REFLUX DISEASE  1  1/20 (5.00%)  0/11 (0.00%) 
HAEMORRHOIDS  1  1/20 (5.00%)  0/11 (0.00%) 
MELAENA  1  1/20 (5.00%)  0/11 (0.00%) 
NAUSEA  1  9/20 (45.00%)  6/11 (54.55%) 
OESOPHAGITIS  1  1/20 (5.00%)  2/11 (18.18%) 
PROCTALGIA  1  0/20 (0.00%)  1/11 (9.09%) 
STOMATITIS  1  6/20 (30.00%)  5/11 (45.45%) 
TOOTH DISCOLOURATION  1  0/20 (0.00%)  1/11 (9.09%) 
VOMITING  1  6/20 (30.00%)  4/11 (36.36%) 
General disorders     
ASTHENIA  1  4/20 (20.00%)  3/11 (27.27%) 
FACE OEDEMA  1  1/20 (5.00%)  0/11 (0.00%) 
FATIGUE  1  7/20 (35.00%)  3/11 (27.27%) 
INFLUENZA LIKE ILLNESS  1  2/20 (10.00%)  0/11 (0.00%) 
NON-CARDIAC CHEST PAIN  1  1/20 (5.00%)  2/11 (18.18%) 
OEDEMA  1  0/20 (0.00%)  1/11 (9.09%) 
OEDEMA PERIPHERAL  1  4/20 (20.00%)  3/11 (27.27%) 
PAIN  1  0/20 (0.00%)  1/11 (9.09%) 
PYREXIA  1  4/20 (20.00%)  1/11 (9.09%) 
Hepatobiliary disorders     
HEPATIC FUNCTION ABNORMAL  1  0/20 (0.00%)  1/11 (9.09%) 
HEPATIC PAIN  1  2/20 (10.00%)  1/11 (9.09%) 
HYPERTRANSAMINASAEMIA  1  0/20 (0.00%)  2/11 (18.18%) 
PORTAL VEIN THROMBOSIS  1  1/20 (5.00%)  0/11 (0.00%) 
Immune system disorders     
HYPERSENSITIVITY  1  1/20 (5.00%)  0/11 (0.00%) 
Infections and infestations     
BRONCHITIS  1  2/20 (10.00%)  0/11 (0.00%) 
CONJUNCTIVITIS  1  0/20 (0.00%)  1/11 (9.09%) 
FOLLICULITIS  1  1/20 (5.00%)  0/11 (0.00%) 
GASTROINTESTINAL INFECTION  1  1/20 (5.00%)  0/11 (0.00%) 
GINGIVITIS  1  0/20 (0.00%)  1/11 (9.09%) 
INFLUENZA  1  0/20 (0.00%)  1/11 (9.09%) 
NASOPHARYNGITIS  1  1/20 (5.00%)  0/11 (0.00%) 
ORAL CANDIDIASIS  1  0/20 (0.00%)  1/11 (9.09%) 
ORAL HERPES  1  1/20 (5.00%)  2/11 (18.18%) 
PARONYCHIA  1  1/20 (5.00%)  0/11 (0.00%) 
PHARYNGITIS  1  0/20 (0.00%)  1/11 (9.09%) 
RHINITIS  1  1/20 (5.00%)  0/11 (0.00%) 
SUBCUTANEOUS ABSCESS  1  1/20 (5.00%)  0/11 (0.00%) 
URINARY TRACT INFECTION  1  1/20 (5.00%)  0/11 (0.00%) 
VULVOVAGINAL CANDIDIASIS  1  0/20 (0.00%)  1/11 (9.09%) 
Injury, poisoning and procedural complications     
CONTRAST MEDIA REACTION  1  1/20 (5.00%)  0/11 (0.00%) 
SPINAL COMPRESSION FRACTURE  1  1/20 (5.00%)  0/11 (0.00%) 
Investigations     
ALANINE AMINOTRANSFERASE INCREASED  1  2/20 (10.00%)  0/11 (0.00%) 
ASPARTATE AMINOTRANSFERASE INCREASED  1  2/20 (10.00%)  0/11 (0.00%) 
BLOOD ALKALINE PHOSPHATASE INCREASED  1  1/20 (5.00%)  0/11 (0.00%) 
BLOOD BILIRUBIN INCREASED  1  0/20 (0.00%)  1/11 (9.09%) 
BLOOD CHLORIDE DECREASED  1  1/20 (5.00%)  0/11 (0.00%) 
BLOOD CREATININE INCREASED  1  1/20 (5.00%)  1/11 (9.09%) 
BLOOD IRON DECREASED  1  1/20 (5.00%)  0/11 (0.00%) 
BLOOD LACTATE DEHYDROGENASE INCREASED  1  1/20 (5.00%)  0/11 (0.00%) 
BLOOD POTASSIUM INCREASED  1  1/20 (5.00%)  0/11 (0.00%) 
C-REACTIVE PROTEIN INCREASED  1  1/20 (5.00%)  0/11 (0.00%) 
EJECTION FRACTION DECREASED  1  1/20 (5.00%)  0/11 (0.00%) 
ELECTROCARDIOGRAM QT PROLONGED  1  1/20 (5.00%)  0/11 (0.00%) 
GAMMA-GLUTAMYLTRANSFERASE INCREASED  1  3/20 (15.00%)  2/11 (18.18%) 
HEPATIC ENZYME INCREASED  1  0/20 (0.00%)  1/11 (9.09%) 
LIVER FUNCTION TEST ABNORMAL  1  1/20 (5.00%)  0/11 (0.00%) 
NEUTROPHIL COUNT INCREASED  1  1/20 (5.00%)  0/11 (0.00%) 
PLATELET COUNT DECREASED  1  1/20 (5.00%)  0/11 (0.00%) 
WEIGHT DECREASED  1  2/20 (10.00%)  2/11 (18.18%) 
WHITE BLOOD CELLS URINE  1  0/20 (0.00%)  1/11 (9.09%) 
Metabolism and nutrition disorders     
DECREASED APPETITE  1  6/20 (30.00%)  2/11 (18.18%) 
HYPERCALCAEMIA  1  1/20 (5.00%)  0/11 (0.00%) 
HYPERCHOLESTEROLAEMIA  1  0/20 (0.00%)  1/11 (9.09%) 
HYPERGLYCAEMIA  1  7/20 (35.00%)  4/11 (36.36%) 
HYPERKALAEMIA  1  1/20 (5.00%)  0/11 (0.00%) 
HYPOGLYCAEMIA  1  2/20 (10.00%)  1/11 (9.09%) 
HYPONATRAEMIA  1  1/20 (5.00%)  0/11 (0.00%) 
Musculoskeletal and connective tissue disorders     
ARTHRALGIA  1  1/20 (5.00%)  3/11 (27.27%) 
BACK PAIN  1  1/20 (5.00%)  1/11 (9.09%) 
FLANK PAIN  1  3/20 (15.00%)  0/11 (0.00%) 
JOINT SWELLING  1  1/20 (5.00%)  1/11 (9.09%) 
MUSCLE ATROPHY  1  1/20 (5.00%)  0/11 (0.00%) 
MUSCLE SPASMS  1  2/20 (10.00%)  1/11 (9.09%) 
MUSCULAR WEAKNESS  1  1/20 (5.00%)  1/11 (9.09%) 
MUSCULOSKELETAL CHEST PAIN  1  1/20 (5.00%)  0/11 (0.00%) 
MUSCULOSKELETAL PAIN  1  3/20 (15.00%)  1/11 (9.09%) 
MYALGIA  1  2/20 (10.00%)  0/11 (0.00%) 
NECK PAIN  1  1/20 (5.00%)  0/11 (0.00%) 
PAIN IN EXTREMITY  1  1/20 (5.00%)  0/11 (0.00%) 
Nervous system disorders     
DIZZINESS  1  1/20 (5.00%)  0/11 (0.00%) 
DYSGEUSIA  1  0/20 (0.00%)  1/11 (9.09%) 
HEADACHE  1  1/20 (5.00%)  0/11 (0.00%) 
LETHARGY  1  0/20 (0.00%)  2/11 (18.18%) 
LOSS OF CONSCIOUSNESS  1  0/20 (0.00%)  1/11 (9.09%) 
MIGRAINE  1  1/20 (5.00%)  0/11 (0.00%) 
PARAESTHESIA  1  0/20 (0.00%)  1/11 (9.09%) 
TREMOR  1  1/20 (5.00%)  1/11 (9.09%) 
Psychiatric disorders     
AGITATION  1  0/20 (0.00%)  1/11 (9.09%) 
DEPRESSED MOOD  1  0/20 (0.00%)  1/11 (9.09%) 
DEPRESSION  1  1/20 (5.00%)  0/11 (0.00%) 
HALLUCINATION  1  0/20 (0.00%)  1/11 (9.09%) 
INSOMNIA  1  1/20 (5.00%)  1/11 (9.09%) 
Renal and urinary disorders     
ACUTE KIDNEY INJURY  1  1/20 (5.00%)  0/11 (0.00%) 
DYSURIA  1  1/20 (5.00%)  0/11 (0.00%) 
POLLAKIURIA  1  0/20 (0.00%)  1/11 (9.09%) 
Reproductive system and breast disorders     
BENIGN PROSTATIC HYPERPLASIA  1  1/20 (5.00%)  0/11 (0.00%) 
SCROTAL PAIN  1  1/20 (5.00%)  0/11 (0.00%) 
VAGINAL DISCHARGE  1  0/20 (0.00%)  1/11 (9.09%) 
VULVOVAGINAL DRYNESS  1  0/20 (0.00%)  1/11 (9.09%) 
Respiratory, thoracic and mediastinal disorders     
CATARRH  1  0/20 (0.00%)  1/11 (9.09%) 
DYSPNOEA  1  6/20 (30.00%)  1/11 (9.09%) 
EPISTAXIS  1  1/20 (5.00%)  2/11 (18.18%) 
HICCUPS  1  0/20 (0.00%)  1/11 (9.09%) 
NASAL CONGESTION  1  1/20 (5.00%)  0/11 (0.00%) 
OROPHARYNGEAL PAIN  1  1/20 (5.00%)  0/11 (0.00%) 
RHINORRHOEA  1  1/20 (5.00%)  1/11 (9.09%) 
SNEEZING  1  0/20 (0.00%)  1/11 (9.09%) 
THROAT IRRITATION  1  0/20 (0.00%)  1/11 (9.09%) 
Skin and subcutaneous tissue disorders     
ALOPECIA  1  1/20 (5.00%)  0/11 (0.00%) 
DRY SKIN  1  3/20 (15.00%)  0/11 (0.00%) 
HAND DERMATITIS  1  1/20 (5.00%)  0/11 (0.00%) 
HYPERHIDROSIS  1  1/20 (5.00%)  0/11 (0.00%) 
NAIL DISORDER  1  1/20 (5.00%)  0/11 (0.00%) 
NAIL TOXICITY  1  1/20 (5.00%)  0/11 (0.00%) 
NIGHT SWEATS  1  1/20 (5.00%)  0/11 (0.00%) 
PAIN OF SKIN  1  1/20 (5.00%)  0/11 (0.00%) 
PHOTOSENSITIVITY REACTION  1  0/20 (0.00%)  1/11 (9.09%) 
PRURITUS  1  1/20 (5.00%)  2/11 (18.18%) 
RASH  1  2/20 (10.00%)  3/11 (27.27%) 
ROSACEA  1  0/20 (0.00%)  1/11 (9.09%) 
SKIN FISSURES  1  0/20 (0.00%)  1/11 (9.09%) 
Vascular disorders     
FLUSHING  1  0/20 (0.00%)  1/11 (9.09%) 
HOT FLUSH  1  0/20 (0.00%)  1/11 (9.09%) 
HYPERTENSION  1  3/20 (15.00%)  0/11 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
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.
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e.,data from all sites) in clinical trial or disclosure of trial results in their entirety.
Results Point of Contact
Name/Title: Clinical Disclosure Office
Organization: Novartis Pharmaceuticals
Phone: 862-778-8300
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01658436     History of Changes
Other Study ID Numbers: CBEZ235F2201
2012-000675-16 ( EudraCT Number )
First Submitted: July 6, 2012
First Posted: August 7, 2012
Results First Submitted: March 11, 2016
Results First Posted: May 2, 2016
Last Update Posted: May 2, 2016