Thymic Carcinoma
Conditions
Keywords
B3 and C malignant thymoma
Brief summary
The intent of the study is to assess the antitumor activity of PHA-848125AC as second-line treatment in patients with recurrent or metastatic, unresectable thymic carcinoma previously treated with chemotherapy.
Detailed description
The Simon's optimal 2 stage design is adopted for this single-arm, open-label, multicenter phase II clinical trial of PHA-848125AC administered to patients with recurrent or metastatic, unresectable thymic carcinoma previously treated with chemotherapy (only one prior systemic therapy allowed). The intent of the study is to assess the antitumor activity of PHA-848125AC and ultimately to improve the outcome of patients with thymic carcinoma who have already exploited one chemotherapy option. The primary end point for this study is a progression free survival rate of 3 months.
Interventions
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.
Sponsors
Tiziana Life Sciences LTD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically proven diagnosis of unresectable B3 thymoma or thymic carcinoma recurrent or progressing after prior chemotherapy (only one prior systemic therapy allowed) * Presence of measurable disease * Age \>=18 years * ECOG performance status 0-1 * Negative pregnancy test (if female in reproductive years) * Use of effective contraceptive methods if men and women of child producing potential * Adequate liver function Total Serum Bilirubin \<=1.5 x upper limit of normal (ULN) Transaminases (AST/ALT) \<=2.5ULN (if liver metastases are present, then \<=5ULN is allowed) ALP \<=2.5ULN (if liver and/or bone metastases are present, then \<=5ULN is allowed) * Adequate renal function Serum Creatinine \<=ULN or Creatinine Clearance calculated by Cockcroft and Gault's formula \> 60 mL/min. * Adequate hematologic status ANC \>=1,500cells/mm3 Platelet Count \>=100,000cells/mm3 Hemoglobin \>=9.0g/dL * Two weeks must have elapsed since completion of prior chemotherapy, minor surgery, radiotherapy (provided that no more than 25% of bone marrow reserve has been irradiated) * Resolution of all acute toxic effects of any prior treatments to NCI CTC (Version 3.0) grade \<=1
Exclusion criteria
* Any of the following in the past 6 months: myocardial infarction, uncontrolled cardiac arrhythmia, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis * Grade \>1 retinopathy * Known brain metastases * Known active infections * Pregnant or breast feeding women * Diabetes mellitus uncontrolled * Gastrointestinal disease that would impact on drug absorption * Patients under treatment with anticoagulants or with coagulation disorders or with signs of hemorrhage at baseline * Patients with previous history or current presence of neurological disorders, including epilepsy (although controlled by anticonvulsant therapy), Parkinson's disease and extra-pyramidal syndromes * Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that make the patient inappropriate for entry into this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival Rate at 3 Months | 3 months since treatment start | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate | Assessments were made every 6 weeks from start date until PD to a maximum duration of 242 weeks or until PD. | 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. |
| Progression-free Survival | Assessments were made every 6 weeks from start date until PD to a maximum duration of 242 weeks or until PD. | 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. |
| Confirmed Objective Response Rate (ORR) | Assessments were made every 6 weeks from start date until PD to a maximum duration of 242 weeks or until PD. | 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. |
| Overall Survival | 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. | 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. |
| Overall Safety Profile (Adverse Events (NCI CTCAE) and Hematological and Blood Chemistry Parameters) | 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. | 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. |
| Duration of Response | Assessments were made every 6 weeks from start date until PD to a maximum duration of 242 weeks or until PD. | Assessed in patients achieving a confirmed objective tumor response by RECIST version 1.1 criteria. |
Countries
France, Italy, United States
Participant flow
Recruitment details
Subjects were enrolled from 22 February 2010 to 05 April 2016
Participants by arm
| Arm | Count |
|---|---|
| Milciclib Maleate (PHA-848125AC) 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. | 72 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 37 |
| Overall Study | Lost to Follow-up | 4 |
| Overall Study | Sponsor's decision | 15 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Milciclib Maleate (PHA-848125AC) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 15 Participants |
| Age, Categorical Between 18 and 65 years | 57 Participants |
| Age, Continuous | 53.2 years STANDARD_DEVIATION 13.3 |
| Masaoka clinical staging at study entry Not Listed | 7 Participants |
| Masaoka clinical staging at study entry Stage I: grossly and microscopically encapsulated | 0 Participants |
| Masaoka clinical staging at study entry Stage III: macroscopic invasion neighboring organs | 1 Participants |
| Masaoka clinical staging at study entry Stage II: thymoma invades beyond the capsule | 0 Participants |
| Masaoka clinical staging at study entry Stage IV A: pleural or pericardial dissemination | 13 Participants |
| Masaoka clinical staging at study entry Stage IVB:hematogeneous or lymphatic dissemination | 51 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants |
| Race/Ethnicity, Customized Black | 2 Participants |
| Race/Ethnicity, Customized Missing | 1 Participants |
| Race/Ethnicity, Customized Not allowed to ask per local regulation | 6 Participants |
| Race/Ethnicity, Customized Not Listed | 10 Participants |
| Race/Ethnicity, Customized White | 50 Participants |
| Region of Enrollment France | 23 participants |
| Region of Enrollment Italy | 36 participants |
| Region of Enrollment United States | 13 participants |
| Sex: Female, Male Female | 37 Participants |
| Sex: Female, Male Male | 35 Participants |
| Tumor extent at study entry Locally advanced | 1 Participants |
| Tumor extent at study entry Metastatic | 71 Participants |
| WHO - Classification B3 - Well differantiated thymic carcinoma | 20 Participants |
| WHO - Classification C - Thymic Carcinoma | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 37 / 72 |
| other Total, other adverse events | 72 / 72 |
| serious Total, serious adverse events | 22 / 72 |
Outcome results
Primary
Progression-free Survival Rate at 3 Months
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
Population: 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 | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Milciclib Maleate (PHA-848125AC) | Progression-free Survival Rate at 3 Months | Success | 24 Participants |
| Milciclib Maleate (PHA-848125AC) | Progression-free Survival Rate at 3 Months | Failure | 30 Participants |
Comparison: 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.p-value: <0.00195% CI: [0.31, 0.59]Fisher Exact
Secondary
Confirmed Objective Response Rate (ORR)
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.
Population: Evaluable patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Milciclib Maleate (PHA-848125AC) | Confirmed Objective Response Rate (ORR) | 3.7 Percentage of patients |
Secondary
Disease Control Rate
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.
Population: Evaluable patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Milciclib Maleate (PHA-848125AC) | Disease Control Rate | 75.9 Percentage of patients |
Secondary
Duration of Response
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Milciclib Maleate (PHA-848125AC) | Duration of Response | 8.41 Months |
Secondary
Overall Safety Profile (Adverse Events (NCI CTCAE) and Hematological and Blood Chemistry Parameters)
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.
Population: All treated patients
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Milciclib Maleate (PHA-848125AC) | Overall Safety Profile (Adverse Events (NCI CTCAE) and Hematological and Blood Chemistry Parameters) | N° patients with Adverse Events | 72 Participants |
| Milciclib Maleate (PHA-848125AC) | Overall Safety Profile (Adverse Events (NCI CTCAE) and Hematological and Blood Chemistry Parameters) | N° patients with abnormal Hematology test | 70 Participants |
| Milciclib Maleate (PHA-848125AC) | Overall Safety Profile (Adverse Events (NCI CTCAE) and Hematological and Blood Chemistry Parameters) | N° patients with abnormal Blood Chemistry test | 70 Participants |
Secondary
Overall Survival
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.
Population: Evaluable patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Milciclib Maleate (PHA-848125AC) | Overall Survival | 24.18 Months |
Secondary
Progression-free Survival
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.
Population: Evaluable patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Milciclib Maleate (PHA-848125AC) | Progression-free Survival | 6.83 Months |