Malignant Thymoma
Conditions
Keywords
B3 and C malignant thymoma
Brief summary
The intent of the study is to assess the antitumor activity of PHA-848125AC in patients with recurrent or metastatic, unresectable malignant thymoma previously treated with multiple lines of chemotherapy.
Detailed description
This is a single-arm, open-label, multicenter, phase II clinical trial design with an early stopping rules. PHA-848125AC will be administered to patients with recurrent metastatic unresectable B3 thymoma or thymic carcinoma who have received more than one line of prior systemic therapy for advanced / metastatic disease. The intent of the study is to assess the antitumor activity of PHA-848125AC and ultimately to improve the outcome of the patients. 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
* Signed and dated IRB/Approved Informed Consent * Histologically or cytologically proven diagnosis of unresectable B3 thymoma or thymic carcinoma recurrent or progressing after more than one prior systemic therapy for advanced / metastatic disease * Presence of measurable disease * Age \>=18 years old * 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 (with the exception of myasthenia gravis), 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 |
|---|---|---|
| Objective Response Rate (ORR) | Assessments were made every 6 weeks from start date until PD or up to a maximum duration of 134 weeks. | 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. |
| Disease Control Rate (ORR+SD Rate) | Assessments were made every 6 weeks from start date until PD or up to a maximum duration of 134 weeks. | 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. |
| Adverse Events (NCI CTCAE) and Hematological and Blood Chemistry Parameters | 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. | 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. |
| 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 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. |
| Progression-free Survival (PFS) | Assessments were made every 6 weeks from start date until PD or up to a maximum duration of 134 weeks. | 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. |
| Duration of Response | Assessments were made every 6 weeks from start date until PD or up to a maximum duration of 134 weeks. | Calculated in patients achieving a confirmed objective tumor response by RECIST version 1.1 criteria. |
Countries
Italy, United States
Participant flow
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.
Participants by arm
| Arm | Count |
|---|---|
| Milciclib 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. | 30 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 13 |
| Overall Study | Lost to Follow-up | 3 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Sponsor's decision | 8 |
Baseline characteristics
| Characteristic | Milciclib |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 6 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants |
| Age, Continuous | 54.2 years STANDARD_DEVIATION 11.3 |
| Masaoka clinical staging at study entry Not assessed | 6 Participants |
| Masaoka clinical staging at study entry Not available | 7 Participants |
| Masaoka clinical staging at study entry Stage I: Grossly and microscopically encapsulate | 0 Participants |
| Masaoka clinical staging at study entry Stage III: Macroscopic invasion neighboring organs | 0 Participants |
| Masaoka clinical staging at study entry Stage II: Thymoma invades beyond the capsule | 0 Participants |
| Masaoka clinical staging at study entry Stage IVA: Pleural or pericardial dissemination | 7 Participants |
| Masaoka clinical staging at study entry Stage IVB: Hematogenous or lymphatic dissemination | 10 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants |
| Race/Ethnicity, Customized Black | 2 Participants |
| Race/Ethnicity, Customized Not Listed | 2 Participants |
| Race/Ethnicity, Customized White | 23 Participants |
| Region of Enrollment Italy | 15 Participants |
| Region of Enrollment United States | 15 Participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 15 Participants |
| Tumor extent at study entry In situ | 0 Participants |
| Tumor extent at study entry Metastatic | 30 Participants |
| World Health Organization classification (International Classification of Diseases) B3 - Well Differentiated Thymic Carcinoma | 17 Participants |
| World Health Organization classification (International Classification of Diseases) C - Thymic Carcinoma | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 13 / 30 |
| other Total, other adverse events | 28 / 30 |
| serious Total, serious adverse events | 14 / 30 |
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, 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 | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Milciclib | Progression-free Survival Rate at 3 Months | Success | 13 Participants |
| Milciclib | Progression-free Survival Rate at 3 Months | Failure | 11 Participants |
Comparison: 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.p-value: <0.00195% CI: [0.33, 0.74]Fisher Exact
Secondary
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 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.
Population: All treated patients
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Milciclib | Adverse Events (NCI CTCAE) and Hematological and Blood Chemistry Parameters | N° patients with Adverse Events | 30 Participants |
| Milciclib | Adverse Events (NCI CTCAE) and Hematological and Blood Chemistry Parameters | N° patients with abnormal Hematology test | 28 Participants |
| Milciclib | Adverse Events (NCI CTCAE) and Hematological and Blood Chemistry Parameters | N° patients with abnormal Blood chemistry test | 27 Participants |
Secondary
Disease Control Rate (ORR+SD Rate)
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.
Population: Evaluable patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Milciclib | Disease Control Rate (ORR+SD Rate) | 83.3 Percentage of patients |
Secondary
Duration of Response
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.
Population: Patients achieving a confirmed objective tumor response by RECIST version 1.1 criteria.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Milciclib | Duration of Response | 2.76 Months |
Secondary
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 or up to a maximum duration of 134 weeks.
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Milciclib | Objective Response Rate (ORR) | 4.2 Percentage of patients |
Secondary
Overall Survival
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.
Population: Evaluable patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Milciclib | Overall Survival | 41.666 percentage of patients dead at 21 months |
Secondary
Progression-free Survival (PFS)
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.
Population: Evaluable patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Milciclib | Progression-free Survival (PFS) | 9.76 Months |