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Phase II Study Of Oral PHA-848125AC In Patients With Thymic Carcinoma

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ClinicalTrials.gov Identifier: NCT01011439
Recruitment Status : Terminated (For the 2 last patients still on treated nominal therapeutic use of the Milciclib was approved at INT Milano.)
First Posted : November 11, 2009
Results First Posted : October 16, 2018
Last Update Posted : February 6, 2019
Sponsor:
Information provided by (Responsible Party):
Tiziana Life Sciences, PLC

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Thymic Carcinoma
Intervention Drug: Milciclib Maleate
Enrollment 72
Recruitment Details Subjects were enrolled from 22 February 2010 to 05 April 2016
Pre-assignment Details  
Arm/Group Title Milciclib Maleate (PHA-848125AC)
Hide Arm/Group Description

100 and 50 mg Capsule 150 mg/day once daily, for 7 consecutive days (days 1 to 7) followed by 7 days of rest (days 8 to 14) in a 2-week cycle

Milciclib Maleate: 150 mg/day once daily, for 7 consecutive days (days 1 to 7) followed by 7 days of rest (days 8 to 14) in a 2-week cycle.

Number of cycles: until disease progression or unacceptable toxicity.

Period Title: Overall Study
Started 72
Completed 15
Not Completed 57
Reason Not Completed
Death             37
Lost to Follow-up             4
Withdrawal by Subject             1
Sponsor's decision             15
Arm/Group Title Milciclib Maleate (PHA-848125AC)
Hide Arm/Group Description

100 and 50 mg Capsule 150 mg/day once daily, for 7 consecutive days (days 1 to 7) followed by 7 days of rest (days 8 to 14) in a 2-week cycle

Milciclib Maleate: 150 mg/day once daily, for 7 consecutive days (days 1 to 7) followed by 7 days of rest (days 8 to 14) in a 2-week cycle.

Number of cycles: until disease progression or unacceptable toxicity.

Overall Number of Baseline Participants 72
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 72 participants
<=18 years
0
   0.0%
Between 18 and 65 years
57
  79.2%
>=65 years
15
  20.8%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 72 participants
53.2  (13.3)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 72 participants
Female
37
  51.4%
Male
35
  48.6%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 72 participants
White
50
  69.4%
Black
2
   2.8%
Asian
3
   4.2%
Not Listed
10
  13.9%
Not allowed to ask per local regulation
6
   8.3%
Missing
1
   1.4%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 72 participants
United States 13
Italy 36
France 23
WHO - Classification  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 72 participants
B3 - Well differantiated thymic carcinoma
20
  27.8%
C - Thymic Carcinoma
52
  72.2%
Tumor extent at study entry  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 72 participants
Locally advanced
1
   1.4%
Metastatic
71
  98.6%
Masaoka clinical staging at study entry   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 72 participants
Stage I: grossly and microscopically encapsulated
0
   0.0%
Stage II: thymoma invades beyond the capsule
0
   0.0%
Stage III: macroscopic invasion neighboring organs
1
   1.4%
Stage IV A: pleural or pericardial dissemination
13
  18.1%
Stage IVB:hematogeneous or lymphatic dissemination
51
  70.8%
Not Listed
7
   9.7%
[1]
Measure Description: Staging used to evaluate invasiveness of the tumor.
1.Primary Outcome
Title Progression-free Survival Rate at 3 Months
Hide Description The proportion of successes (i.e. patients alive and progression free at 3 months since treatment start) out of the total number of evaluable patients
Time Frame 3 months since treatment start
Hide Outcome Measure Data
Hide Analysis Population Description

Evaluable patients: population consisting of all treated patients who fulfill the following conditions:

  • histological confirmation of thymic carcinoma by an Independent Review Committee
  • received at least 80% of drug in the first two cycles overall
  • baseline and >/= 1 on treatment tumor assessment or die before tumor re-assessment
Arm/Group Title Milciclib Maleate (PHA-848125AC)
Hide Arm/Group Description:

100 and 50 mg Capsule 150 mg/day once daily, for 7 consecutive days (days 1 to 7) followed by 7 days of rest (days 8 to 14) in a 2-week cycle

Milciclib Maleate: 150 mg/day once daily, for 7 consecutive days (days 1 to 7) followed by 7 days of rest (days 8 to 14) in a 2-week cycle.

Number of cycles: until disease progression or unacceptable toxicity.

Overall Number of Participants Analyzed 54
Measure Type: Count of Participants
Unit of Measure: Participants
Success
24
  44.4%
Failure
30
  55.6%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Milciclib Maleate (PHA-848125AC)
Comments H0:p</=17% vs. H1:p>17%, with an interesting PFS-3 rate of 33% or higher; Power=80%; Alpha(1-sided)=5%, 54 evaluable patients are required for a Simon optimal two stage design trial. If at least 4 successes among the first 17 evaluable patients are observed in the 1st stage, patients’ enrollment proceed up to the final analysis where at least 14/54 successes (PFS-3 rate ≥ 25.9%) must be required to reject the null hypothesis.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Method of Estimation Estimation Parameter Single proportion
Estimated Value 0.44
Confidence Interval (2-Sided) 95%
0.31 to 0.59
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Confirmed Objective Response Rate (ORR)
Hide Description Point and 95% confidence interval estimates was calculated for the objective tumor response rate (confirmed CRs or PRs). The determination of antitumor efficacy was based on objective tumor assessments made according to the RECIST guideline (version 1.1) The analysis was performed in the evaluable population.
Time Frame Assessments were made every 6 weeks from start date until PD to a maximum duration of 242 weeks or until PD.
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable patients
Arm/Group Title Milciclib Maleate (PHA-848125AC)
Hide Arm/Group Description:

100 and 50 mg Capsule 150 mg/day once daily, for 7 consecutive days (days 1 to 7) followed by 7 days of rest (days 8 to 14) in a 2-week cycle

Milciclib Maleate: 150 mg/day once daily, for 7 consecutive days (days 1 to 7) followed by 7 days of rest (days 8 to 14) in a 2-week cycle.

Number of cycles: until disease progression or unacceptable toxicity.

Overall Number of Participants Analyzed 54
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of patients
3.7
(0.45 to 12.75)
3.Secondary Outcome
Title Disease Control Rate
Hide Description Point and 95% confidence interval estimates was calculated for the disease control rate (confirmed CRs / PRs and SD>/= 6 weeks). The analysis was performed in the evaluable populations.
Time Frame Assessments were made every 6 weeks from start date until PD to a maximum duration of 242 weeks or until PD.
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable patients
Arm/Group Title Milciclib Maleate (PHA-848125AC)
Hide Arm/Group Description:

100 and 50 mg Capsule 150 mg/day once daily, for 7 consecutive days (days 1 to 7) followed by 7 days of rest (days 8 to 14) in a 2-week cycle

Milciclib Maleate: 150 mg/day once daily, for 7 consecutive days (days 1 to 7) followed by 7 days of rest (days 8 to 14) in a 2-week cycle.

Number of cycles: until disease progression or unacceptable toxicity.

Overall Number of Participants Analyzed 54
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of patients
75.9
(62.36 to 86.51)
4.Secondary Outcome
Title Progression-free Survival
Hide Description The length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse. In a clinical trial, measuring the progression-free survival is one way to see how well a new treatment works.
Time Frame Assessments were made every 6 weeks from start date until PD to a maximum duration of 242 weeks or until PD.
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable patients
Arm/Group Title Milciclib Maleate (PHA-848125AC)
Hide Arm/Group Description:

100 and 50 mg Capsule 150 mg/day once daily, for 7 consecutive days (days 1 to 7) followed by 7 days of rest (days 8 to 14) in a 2-week cycle

Milciclib Maleate: 150 mg/day once daily, for 7 consecutive days (days 1 to 7) followed by 7 days of rest (days 8 to 14) in a 2-week cycle.

Number of cycles: until disease progression or unacceptable toxicity.

Overall Number of Participants Analyzed 54
Median (95% Confidence Interval)
Unit of Measure: Months
6.83
(4.11 to 8.71)
5.Secondary Outcome
Title Duration of Response
Hide Description Assessed in patients achieving a confirmed objective tumor response by RECIST version 1.1 criteria.
Time Frame Assessments were made every 6 weeks from start date until PD to a maximum duration of 242 weeks or until PD.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Milciclib Maleate (PHA-848125AC)
Hide Arm/Group Description:

100 and 50 mg Capsule 150 mg/day once daily, for 7 consecutive days (days 1 to 7) followed by 7 days of rest (days 8 to 14) in a 2-week cycle.

Milciclib Maleate: 150 mg/day once daily, for 7 consecutive days (days 1 to 7) followed by 7 days of rest (days 8 to 14) in a 2-week cycle.

Number of cycles: until disease progression or unacceptable toxicity.

Overall Number of Participants Analyzed 2
Median (95% Confidence Interval)
Unit of Measure: Months
8.41
(6.90 to 9.92)
6.Secondary Outcome
Title Overall Survival
Hide Description The length of time from the start of treatment for a disease, such as cancer, to the date in which the patients diagnosed with the disease were still alive.
Time Frame Every 6 weeks during Follow-Up until PD or new therapy start; every 6 months thereafter, up to 2 years from the last dose of study drug.
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable patients
Arm/Group Title Milciclib Maleate (PHA-848125AC)
Hide Arm/Group Description:

100 and 50 mg Capsule 150 mg/day once daily, for 7 consecutive days (days 1 to 7) followed by 7 days of rest (days 8 to 14) in a 2-week cycle

Milciclib Maleate: 150 mg/day once daily, for 7 consecutive days (days 1 to 7) followed by 7 days of rest (days 8 to 14) in a 2-week cycle.

Number of cycles: until disease progression or unacceptable toxicity.

Overall Number of Participants Analyzed 54
Median (95% Confidence Interval)
Unit of Measure: Months
24.18
(16.89 to 36.57)
7.Secondary Outcome
Title Overall Safety Profile (Adverse Events (NCI CTCAE) and Hematological and Blood Chemistry Parameters)
Hide Description

The adverse events (AEs) were coded with the Medical Dictionary for Regulatory Activities (MedDRA) and their severity graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. The following subsets of AEs were considered: serious AEs, AEs with CTCAE grade 3-5, AEs with a relationship to study treatment classified by the Investigator as possible or probable or definite and AEs reported as leading to discontinuation from treatment.

Laboratory test values were graded according to the NCI CTCAE scale, v3.0, whenever possible. For each laboratory test included in the NCI CTCAE system, the incidence of abnormalities was evaluated by considering the worst occurrence for each patient throughout the whole treatment period.

Time Frame Adverse events: from date treatment consent signed to 28 days after last dose of study drug; hematology/blood chemistry tests: at baseline and between Day 11-14 of each cycle of a total of 135 two-week cycles.
Hide Outcome Measure Data
Hide Analysis Population Description
All treated patients
Arm/Group Title Milciclib Maleate (PHA-848125AC)
Hide Arm/Group Description:

100 and 50 mg Capsule 150 mg/day once daily, for 7 consecutive days (days 1 to 7) followed by 7 days of rest (days 8 to 14) in a 2-week cycle

Milciclib Maleate: 150 mg/day once daily, for 7 consecutive days (days 1 to 7) followed by 7 days of rest (days 8 to 14) in a 2-week cycle.

Number of cycles: until disease progression or unacceptable toxicity.

Overall Number of Participants Analyzed 72
Measure Type: Count of Participants
Unit of Measure: Participants
N° patients with Adverse Events
72
 100.0%
N° patients with abnormal Hematology test
70
  97.2%
N° patients with abnormal Blood Chemistry test
70
  97.2%
Time Frame Adverse events were reported for patients from consent signed to 28 days after last dose of study drug. Individual patient adverse event reporting ranged from 4.8 weeks to 281.7 weeks with a median of 24.07 weeks.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Milciclib Maleate (PHA-848125AC)
Hide Arm/Group Description

100 and 50 mg Capsule 150 mg/day once daily, for 7 consecutive days (days 1 to 7) followed by 7 days of rest (days 8 to 14) in a 2-week cycle

Milciclib Maleate: 150 mg/day once daily, for 7 consecutive days (days 1 to 7) followed by 7 days of rest (days 8 to 14) in a 2-week cycle.

Number of cycles: until disease progression or unacceptable toxicity.

All-Cause Mortality
Milciclib Maleate (PHA-848125AC)
Affected / at Risk (%)
Total   37/72 (51.39%)    
Show Serious Adverse Events Hide Serious Adverse Events
Milciclib Maleate (PHA-848125AC)
Affected / at Risk (%) # Events
Total   22/72 (30.56%)    
Blood and lymphatic system disorders   
Red cell aplasia * 1  1/72 (1.39%)  1
Cardiac disorders   
Atrial fibrillation * 1  1/72 (1.39%)  1
Supraventricular tachycardia * 1  1/72 (1.39%)  1
Eye disorders   
Retinal detachment * 1  1/72 (1.39%)  1
Gastrointestinal disorders   
Diarrhoea * 1  2/72 (2.78%)  2
Vomiting * 1  2/72 (2.78%)  2
Nausea * 1  1/72 (1.39%)  1
General disorders   
Pyrexia * 1  2/72 (2.78%)  2
Sudden death * 1  2/72 (2.78%)  2
Asthenia * 1  1/72 (1.39%)  1
Oedema peripheral * 1  1/72 (1.39%)  1
Hepatobiliary disorders   
Biliary dilatation * 1  1/72 (1.39%)  1
Infections and infestations   
Infection NOS * 1  1/72 (1.39%)  1
Metabolism and nutrition disorders   
Dehydratation * 1  1/72 (1.39%)  1
Musculoskeletal and connective tissue disorders   
Polymyositis * 1  1/72 (1.39%)  1
Nervous system disorders   
Syncope * 1  2/72 (2.78%)  2
Cerebral ischaemia * 1  1/72 (1.39%)  1
Epilepsy NOS * 1  1/72 (1.39%)  1
Muscle contractions involuntary * 1  1/72 (1.39%)  2
Myasthenia gravis * 1  1/72 (1.39%)  1
Myasthenic syndrome * 1  1/72 (1.39%)  1
Neuralgia NOS * 1  1/72 (1.39%)  1
Neurological symptoms * 1  1/72 (1.39%)  1
Psychiatric disorders   
Confusional state * 1  1/72 (1.39%)  1
Renal and urinary disorders   
Nephrolithiasis * 1  1/72 (1.39%)  1
Respiratory, thoracic and mediastinal disorders   
Pleural effusion * 1  2/72 (2.78%)  2
Bronchitis NOS * 1  1/72 (1.39%)  1
Dyspnoea NOS * 1  1/72 (1.39%)  1
Vascular disorders   
Subclavian vein thrombosis * 1  1/72 (1.39%)  1
Superior vena caval occclusion * 1  1/72 (1.39%)  1
1
Term from vocabulary, MedDRA (5.1)
*
Indicates events were collected by non-systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Milciclib Maleate (PHA-848125AC)
Affected / at Risk (%) # Events
Total   72/72 (100.00%)    
Blood and lymphatic system disorders   
Leukopenia NOS * 1  12/72 (16.67%)  32
Neutropenia * 1  12/72 (16.67%)  39
Anaemia NOS * 1  8/72 (11.11%)  12
Cardiac disorders   
Palpitations * 1  4/72 (5.56%)  6
Ear and labyrinth disorders   
Vertigo * 1  10/72 (13.89%)  108
Eye disorders   
Photopsia * 1  7/72 (9.72%)  14
Vision blurred * 1  6/72 (8.33%)  6
Conjunctivitis * 1  5/72 (6.94%)  8
Lacrimation increased * 1  4/72 (5.56%)  5
Visual disturbance NOS * 1  4/72 (5.56%)  5
Gastrointestinal disorders   
Nausea * 1  65/72 (90.28%)  448
Diarrhoea NOS * 1  56/72 (77.78%)  457
Vomiting NOS * 1  47/72 (65.28%)  192
Abdominal pain NOS * 1  11/72 (15.28%)  28
Abdominal pain upper * 1  8/72 (11.11%)  10
Constipation * 1  8/72 (11.11%)  15
Dysphagia * 1  4/72 (5.56%)  4
Stomatitis * 1  4/72 (5.56%)  5
General disorders   
Asthenia * 1  48/72 (66.67%)  249
Chest pain * 1  14/72 (19.44%)  30
Fatigue * 1  14/72 (19.44%)  34
Pyrexia * 1  10/72 (13.89%)  13
Mucosal imflammation * 1  7/72 (9.72%)  14
Oedema peripheral * 1  5/72 (6.94%)  10
Rigors * 1  5/72 (6.94%)  5
Infections and infestations   
Influenza * 1  4/72 (5.56%)  7
Investigations   
Alanine aminotransferase increased * 1  9/72 (12.50%)  12
Blood amylase increased * 1  8/72 (11.11%)  32
Lipase increased * 1  7/72 (9.72%)  33
Aspartate aminotransferase increased * 1  6/72 (8.33%)  7
Weight decreased * 1  5/72 (6.94%)  5
Metabolism and nutrition disorders   
Anorexia * 1  23/72 (31.94%)  45
Hypophosphataemia * 1  17/72 (23.61%)  72
Musculoskeletal and connective tissue disorders   
Back pain * 1  15/72 (20.83%)  19
Arthralgia * 1  12/72 (16.67%)  15
Myalgia * 1  5/72 (6.94%)  5
Flank pain * 1  4/72 (5.56%)  5
Neck pain * 1  4/72 (5.56%)  5
Nervous system disorders   
Tremor * 1  25/72 (34.72%)  159
Headache * 1  15/72 (20.83%)  34
Dysgeusia * 1  13/72 (18.06%)  37
Dizziness * 1  12/72 (16.67%)  28
Paraesthesia * 1  8/72 (11.11%)  10
Dysphonia * 1  6/72 (8.33%)  6
Psychiatric disorders   
Anxiety * 1  6/72 (8.33%)  12
Insomnia * 1  6/72 (8.33%)  12
Depression * 1  4/72 (5.56%)  5
Respiratory, thoracic and mediastinal disorders   
Cough * 1  24/72 (33.33%)  35
Dyspnoea * 1  20/72 (27.78%)  28
Rhinitis NOS * 1  9/72 (12.50%)  13
Bronchitis * 1  6/72 (8.33%)  10
Skin and subcutaneous tissue disorders   
Rash NOS * 1  5/72 (6.94%)  5
Sweating increased * 1  4/72 (5.56%)  7
1
Term from vocabulary, MedDRA (5.1)
*
Indicates events were collected by non-systematic assessment
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. Cristina Davite
Organization: CLIOSS S.r.l.
Phone: +39 0031 58 ext 1482
EMail: regulatory@clioss.com
Layout table for additonal information
Responsible Party: Tiziana Life Sciences, PLC
ClinicalTrials.gov Identifier: NCT01011439     History of Changes
Other Study ID Numbers: CDKO-125a-006
2009-014338-79 ( EudraCT Number )
First Submitted: November 10, 2009
First Posted: November 11, 2009
Results First Submitted: May 31, 2018
Results First Posted: October 16, 2018
Last Update Posted: February 6, 2019