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Study Of Oral PHA-848125AC In Patients With Malignant Thymoma Previously Treated With Multiple Lines Of Chemotherapy

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ClinicalTrials.gov Identifier: NCT01301391
Recruitment Status : Terminated (For the last patient still on treated nominal therapeutic use of the Milciclib was approved at INT Milano.)
First Posted : February 23, 2011
Results First Posted : October 4, 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 Malignant Thymoma
Intervention Drug: Milciclib Maleate
Enrollment 30
Recruitment Details Subjects were enrolled from 02 Feb 2011 to 28 Jan 2016 by 2 centers in US and one in Italy.
Pre-assignment Details Four patients were screening failure.
Arm/Group Title Milciclib
Hide Arm/Group Description

Milciclib Maleate capsules

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 30 [1]
Completed [2] 4
Not Completed 26
Reason Not Completed
Death             13
Lost to Follow-up             3
Physician Decision             2
Sponsor's decision             8
[1]
On treatment until disease progression, patient withdrawal of consent, or unacceptable toxicity.
[2]
Follow up for survival: up to the end of study or for no more than 2 years from end of treatment.
Arm/Group Title Milciclib
Hide Arm/Group Description

Milciclib Maleate capsules

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 30
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants
<=18 years
0
   0.0%
Between 18 and 65 years
24
  80.0%
>=65 years
6
  20.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 30 participants
54.2  (11.3)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants
Female
15
  50.0%
Male
15
  50.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants
White
23
  76.7%
Black
2
   6.7%
Asian
3
  10.0%
Not Listed
2
   6.7%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants
United States
15
  50.0%
Italy
15
  50.0%
World Health Organization classification (International Classification of Diseases)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants
B3 - Well Differentiated Thymic Carcinoma
17
  56.7%
C - Thymic Carcinoma
13
  43.3%
Tumor extent at study entry  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants
Metastatic
30
 100.0%
In situ
0
   0.0%
Masaoka clinical staging at study entry   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants
Stage I: Grossly and microscopically encapsulate
0
   0.0%
Stage II: Thymoma invades beyond the capsule
0
   0.0%
Stage III: Macroscopic invasion neighboring organs
0
   0.0%
Stage IVA: Pleural or pericardial dissemination
7
  23.3%
Stage IVB: Hematogenous or lymphatic dissemination
10
  33.3%
Not assessed
6
  20.0%
Not available
7
  23.3%
[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
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Hide Analysis Population Description
Evaluable patients, i.e., consists of all eligible and treated patients who fulfill the following additional conditions: 1) they receive at least 80% of drug in the first two cycles overall; 2) they have baseline and > or = 1 on-treatment tumor/oncologic assessment(s) or die before tumor re-assessment.
Arm/Group Title Milciclib
Hide Arm/Group Description:

Milciclib Maleate capsules

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 24
Measure Type: Count of Participants
Unit of Measure: Participants
Success
13
  54.2%
Failure
11
  45.8%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Milciclib
Comments H0:p≤ 25% vs H1:p> 25% with an interesting PFS-3 rate of 50% (median PFS of 3 months), alpha=0.05 and beta=0.10, 30 evaluable patients are required for a single stage trial. If at the end of the trial 12 or more out of 30 evaluable patients are alive and progression-free at 3 months since the treatment start date, the null hypothesis are rejected. A Fleming multiple-testing procedure is applied. If >=4 successes out of the first 15 patients are observed, accrual will continue up to 30.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments A priori threshold for statistical significance = 0.05
Method Fisher Exact
Comments [Not Specified]
Method of Estimation Estimation Parameter Single proportion
Estimated Value 0.54
Confidence Interval (2-Sided) 95%
0.33 to 0.74
Estimation Comments [Not Specified]
2.Secondary Outcome
Title 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 were 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 treatment; hematology/blood chemistry tests: at baseline and between Day 11-14 of each cycle of a maximum total of 48 two-week cycles.
Hide Outcome Measure Data
Hide Analysis Population Description
All treated patients
Arm/Group Title Milciclib
Hide Arm/Group Description:

Milciclib Maleate capsules

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 30
Measure Type: Count of Participants
Unit of Measure: Participants
N° patients with Adverse Events
30
 100.0%
N° patients with abnormal Hematology test
28
  93.3%
N° patients with abnormal Blood chemistry test
27
  90.0%
3.Secondary Outcome
Title 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 or up to a maximum duration of 134 weeks.
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable population: the patient population consists of all eligible and treated patients who fulfill the following additional conditions: 1) they receive at least 80% of drug in the first two cycles overall; 2) they have baseline and > or = 1 on-treatment tumor/oncologic assessment(s) or die before tumor re-assessment.
Arm/Group Title Milciclib
Hide Arm/Group Description:

Milciclib Maleate capsules

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 24
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of patients
4.2
(0.11 to 21.12)
4.Secondary Outcome
Title Disease Control Rate (ORR+SD Rate)
Hide Description Point and 95% confidence interval estimates was calculated for the disease control rate (confirmed CRs / PRs and SD > or = 6 weeks). The analysis was performed in the evaluable patient populations.
Time Frame Assessments were made every 6 weeks from start date until PD or up to a maximum duration of 134 weeks.
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable patients
Arm/Group Title Milciclib
Hide Arm/Group Description:

Milciclib Maleate capsules

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 24
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of patients
83.3
(62.62 to 95.26)
5.Secondary Outcome
Title Duration of Response
Hide Description Calculated 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 or up to a maximum duration of 134 weeks.
Hide Outcome Measure Data
Hide Analysis Population Description
Patients achieving a confirmed objective tumor response by RECIST version 1.1 criteria.
Arm/Group Title Milciclib
Hide Arm/Group Description:

Milciclib Maleate capsules

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 1
Measure Type: Number
Unit of Measure: Months
2.76
6.Secondary Outcome
Title Overall Survival
Hide Description The length of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, and to the date in which the patients diagnosed with the disease are still alive. Kaplan-Meier estimates as percentage of patients 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
Hide Arm/Group Description:

Milciclib Maleate capsules

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 24
Measure Type: Number
Unit of Measure: percentage of patients dead at 21 months
41.666
7.Secondary Outcome
Title Progression-free Survival (PFS)
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 or up to a maximum duration of 134 weeks.
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable patients
Arm/Group Title Milciclib
Hide Arm/Group Description:

Milciclib Maleate capsules

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 24
Median (95% Confidence Interval)
Unit of Measure: Months
9.76
(4.11 to 17.45)
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 5.1 weeks to 141.3 weeks with a median of 19.28 weeks.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Milciclib
Hide Arm/Group Description

Milciclib Maleate capsules

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
Affected / at Risk (%)
Total   13/30 (43.33%)    
Show Serious Adverse Events Hide Serious Adverse Events
Milciclib
Affected / at Risk (%) # Events
Total   14/30 (46.67%)    
Cardiac disorders   
Pericardial effusion * 1  1/30 (3.33%)  1
Gastrointestinal disorders   
Abdominal pain NOS * 1  1/30 (3.33%)  1
Gastrointestinal obstruction NOS * 1  1/30 (3.33%)  1
General disorders   
Fatigue * 1  1/30 (3.33%)  1
Pyrexia * 1  1/30 (3.33%)  1
Hepatobiliary disorders   
Hyperbilirubinaemia * 1  1/30 (3.33%)  1
Infections and infestations   
Pneumonia NOS * 1  2/30 (6.67%)  2
Sepsis NOS * 1  1/30 (3.33%)  1
Staphylococcal infection * 1  1/30 (3.33%)  1
Injury, poisoning and procedural complications   
Fracture * 1  1/30 (3.33%)  1
Investigations   
Alanine aminotransferase increased * 1  1/30 (3.33%)  1
Aspartate aminotransferase increased * 1  1/30 (3.33%)  1
Blood alkaline phosphatase NOS increased * 1  1/30 (3.33%)  1
Blood bilirubin increased * 1  1/30 (3.33%)  1
Metabolism and nutrition disorders   
Hypoglycaemia * 1  1/30 (3.33%)  1
Musculoskeletal and connective tissue disorders   
Arthralgia * 1  1/30 (3.33%)  1
Myalgia * 1  1/30 (3.33%)  1
Nervous system disorders   
Extrapyramidal disorder * 1  1/30 (3.33%)  1
Syncope * 1  1/30 (3.33%)  1
Reproductive system and breast disorders   
Epididymitis NOS * 1  1/30 (3.33%)  1
Respiratory, thoracic and mediastinal disorders   
Haemoptisys * 1  2/30 (6.67%)  2
Cough * 1  1/30 (3.33%)  1
Dyspnoea NOS * 1  1/30 (3.33%)  1
Dyspnoea exertional * 1  1/30 (3.33%)  1
Hypoxia * 1  1/30 (3.33%)  1
Skin and subcutaneous tissue disorders   
Erythema multiforme * 1  1/30 (3.33%)  1
Sweating increased * 1  1/30 (3.33%)  1
Vascular disorders   
Deep vein thrombosis * 1  1/30 (3.33%)  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
Affected / at Risk (%) # Events
Total   28/30 (93.33%)    
Blood and lymphatic system disorders   
Anaemia * 1  8/30 (26.67%)  8
Leukopenia * 1  4/30 (13.33%)  5
Neutropenia * 1  4/30 (13.33%)  7
Cardiac disorders   
Tachycardia * 1  2/30 (6.67%)  2
Ear and labyrinth disorders   
Tinnitus * 1  2/30 (6.67%)  3
Eye disorders   
Conjunctivitis * 1  2/30 (6.67%)  3
Ocular discomfort * 1  2/30 (6.67%)  2
Photopsia * 1  2/30 (6.67%)  3
Gastrointestinal disorders   
Nausea * 1  25/30 (83.33%)  92
Diarrhoea NOS * 1  18/30 (60.00%)  70
Vomiting NOS * 1  17/30 (56.67%)  66
Constipation * 1  4/30 (13.33%)  4
Abdominal pain upper * 1  3/30 (10.00%)  3
Abdominal pain NOS * 1  2/30 (6.67%)  4
Dysphagia * 1  2/30 (6.67%)  2
Gastrointestinal disorder NOS * 1  2/30 (6.67%)  4
General disorders   
Asthenia * 1  11/30 (36.67%)  22
Fatigue * 1  11/30 (36.67%)  17
Pyrexia * 1  7/30 (23.33%)  9
Oedema peripheral * 1  5/30 (16.67%)  5
Chest pain * 1  3/30 (10.00%)  3
Pain NOS * 1  2/30 (6.67%)  4
Pain exacerbated * 1  2/30 (6.67%)  2
Infections and infestations   
Influenza * 1  3/30 (10.00%)  4
Investigations   
Lipase increased * 1  4/30 (13.33%)  11
Alanine aminotransferase increased * 1  3/30 (10.00%)  5
Blood amylase increased * 1  3/30 (10.00%)  6
Weight decreased * 1  3/30 (10.00%)  3
Aspartate aminotransferase increased * 1  2/30 (6.67%)  3
Lymphocyte count decreased * 1  2/30 (6.67%)  5
Metabolism and nutrition disorders   
Anorexia * 1  8/30 (26.67%)  8
Appetite decreased NOS * 1  2/30 (6.67%)  3
Dehydratation * 1  2/30 (6.67%)  4
Hypokalaemia * 1  2/30 (6.67%)  5
Hypomagnesaemia * 1  2/30 (6.67%)  3
Hypophosphataemia * 1  2/30 (6.67%)  4
Musculoskeletal and connective tissue disorders   
Arthralgia * 1  4/30 (13.33%)  5
Flank pain * 1  2/30 (6.67%)  2
Muscle spasms * 1  2/30 (6.67%)  5
Myalgia * 1  2/30 (6.67%)  3
Nervous system disorders   
Tremor * 1  11/30 (36.67%)  30
Dizziness * 1  7/30 (23.33%)  12
Paraesthesia * 1  4/30 (13.33%)  5
Dysgeusia * 1  3/30 (10.00%)  3
Haedache * 1  3/30 (10.00%)  3
Psychiatric disorders   
Anxiety * 1  2/30 (6.67%)  2
Renal and urinary disorders   
Azotaemia * 1  2/30 (6.67%)  2
Respiratory, thoracic and mediastinal disorders   
Cough * 1  6/30 (20.00%)  8
Dyspnoea NOS * 1  2/30 (6.67%)  2
Dyspnoea exertional * 1  2/30 (6.67%)  2
Epistaxis * 1  2/30 (6.67%)  2
Productive cough * 1  2/30 (6.67%)  2
Skin and subcutaneous tissue disorders   
Pruritus * 1  3/30 (10.00%)  3
Rash maculo-papular * 1  3/30 (10.00%)  5
Dry skin * 1  2/30 (6.67%)  2
Nail disorder NOS * 1  2/30 (6.67%)  2
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. Davite Cristina
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: NCT01301391     History of Changes
Other Study ID Numbers: CDKO-125a-007
First Submitted: February 15, 2011
First Posted: February 23, 2011
Results First Submitted: May 31, 2018
Results First Posted: October 4, 2018
Last Update Posted: February 6, 2019