Local Recurrent Thymoma, Primary Inoperable Thymoma
Conditions
Keywords
primary inoperable thymoma, local recurrent thymoma, reduction of tumor size, SOM230 LAR
Brief summary
This is a monocenter, single-arm, open label phase II trial evaluating the effect of SOM230 LAR in adult patients with inoperable primary thymoma and thymoma metastasis (Masaoka II-IVa). SOM230 LAR in a dosage of 60 mg is administered i.m. once every 4 weeks. The purpose of this trial is a proof of concept.
Interventions
DRUGSOM230 LAR
SOM230 LAR in a dosage of 60 mg is administered i.m. once every 4 weeks.
Sponsors
Crolll Gmbh
Prof. Dr. Berthold Schalke
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
* Male or female patients aged ≥18 years * Diagnosis of thymoma as assessed by biopsy and/or szintigraphy * Inoperability of thymoma or loco-regional metastases. Inoperability is defined as at least adherence of the tumor to the neighbored organs, suspicious to infiltrate neighbored organs or local metastasis so that R0 resection can not be expected and /or local recurrence of thymic tumor * Tumor stage: Thymomas of all WHO based histological subtypes (WHO A, AB, B1, B2, B3) (Rosai, 1999; Travis 2004) at Masaoka stage II to IVa based on histological examination of resection specimens or core biopsies. * Patients with and without thymoma associated paraneoplastic syndrome. * Performance status 0,1, or 2 (ECOG) * Patients for whom written informed consent to participate in the study has been obtained
Exclusion criteria
* Patients having received radiolabeled somatostatin analogue therapy within the 6 months or any cytotoxic chemotherapy or interferon therapy within the 2 months prior to recording baseline symptoms * Patients who have undergone major surgery/surgical therapy for any cause within 1 month or surgical therapy of loco-regional metastases within the last 3 months before recording baseline symptoms * Patients who have received radiotherapy for any reason within the last 4 weeks and must have recovered from any side effects of radiotherapy before recording baseline symptoms * Patients who are not biochemically euthyroid * Diabetic patients on antidiabetic medications whose fasting blood glucose is poorly controlled as indicated by HbA1C \> 8% * Patients with symptomatic cholelithiasis * Patients who have congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, ventricular fibrillation, clinically significant bradycardia, advanced heart block or a history of acute myocardial infarction within the six months preceding enrollment * Patients with QT related risk factor: QTcF at screening \> 450 msec * Patients with QT related risk factor: History of syncope or family history of idiopathic sudden death * Patients with QT related risk factor:Sudden or clinically significant cardiac arrhythmias * Patients with QT related risk factor: Risk factors for Torsades de Pointes such as hypokalemia, hypomagnesemia, cardiac failure, clinically significant / symptomatic bradycardia, or high-grade AV block * Patients with QT related risk factor: Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused by diabetes or Parkinson's disease), HIV, cirrhosis, uncontrolled hypothyroidism or cardiac failure * Patients with QT related risk factor: Concomitant medication(s) known to increase the QT interval * Patients with potassium \<3.0 mmol/L at study entry, magnesium \<0.4 mmol/L at study entry, calcium \<1.75 mmol/L at study entry, family history of long QT syndrome, and concomitant medications known to prolong the QT interval. If the electrolyte abnormalities are corrected prior to study commencement, the patient may become eligible for the trial. * Patients with liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis with serum bilirubin \> 1.5 X ULN, serum albumin \< 0.67 X LLN, and/or ALT or AST more than 2 X ULN for patients without liver Confidential - 20 - Amended Clinical Study Protocol v01 / Track Changes Study No. CSOM230CIC01T metastases or ALT or AST more than 5X ULN for patients with documented liver metastases * Patients with additional active malignant disease within the last five years (with the exception of basal cell carcinoma or carcinoma in situ of the cervix) * Patients with the presence of active or suspected acute or chronic uncontrolled infection or with a history of immunocompromise, including a positive HIV test result (ELISA and Western blot). A HIV test will not be required; however, previous medical history will be reviewed * Patients with abnormal coagulation (PT or APTT elevated by 30% above normal limits) * Patients with WBC \<2.5 X 109/L; Hgb \<10 g/dL; PLT \<100 X 109/L (patients with paraneoplastic pan-, leuco-, erythro- or thrombopenia can be included if this seems to be the only reason for pan-, leuco-, erythro- or thrombopenia) * Known hypersensitivity to somatostatin analogues or any component of the pasireotide or octreotide LAR or s.c. formulations * Patients who have any current or prior medical condition that may interfere with the conduct of the study or the evaluation of its results in the opinion of the investigator * Female patients who are pregnant or lactating, or are of childbearing potential and not practicing a medically acceptable method of birth control. Female patients must use a secure method of contraception if sexually active and the partner should use a condom. If oral contraception is used, the patient must have been practicing this method for at least two months prior to enrollment and must agree to continue the oral contraceptive throughout the course of the study, and for three months after the study has ended. Male patients who are sexually active are required to use condoms during the study and for three months afterwards as a precautionary measure (available data do not suggest any increased reproductive risk with the study drugs). Female partners of these male patients should use a secondary barrier contraception. * Patients who are currently part of or have participated in any clinical investigation with an investigational drug within 1 month prior to dosing * Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study * Patient has received any other investigational agents within 28 days of first day of study drug dosing * Abnormal clinical laboratory values considered by the investigator to be clinically significant and which could affect the interpretation of the study results
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Tumor Volume From Baseline to EOS | at least 6 months | To evaluate whether SOM230 LAR is effective in patients with inoperable thymoma with respect to shrinkage of tumor volume. Response is defined as the decrease in tumor volume of 20 % at EOS as compared to baseline. Tumor shrinkage is assessed by CT or MRI. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Resection Status | at least 6 months | To evaluate the resection status based on the categories R0, R1 and ≥ R2 at EOS using CT or MRI imaging. R0 resection means no residual tumor tissue (best status); R1 indicates microscopic residual tumor tissue and R2 indicates macroscopic residual tumor tissue (worst status). |
| Assessment of Tumor Operability | at least 6 months | Assessment if patients reaching operability at the EOS. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Safety: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | at least 6 months | — |
| Health Related Quality of Life | at least 6 months | Health related quality of life information was collected at Baseline and EOS using SF-36 questionnaire. Questionnaires had to be completed by the patients. All questions are scored on a scale from 0 to 100, with 100 representing the highest level of functioning possible. Patient reported answers were transformed into domain scores according to the guidelines provided by RAND/MOS. Statistical significance of the result was tested with a paired Wilcoxon rang sum test with a significance level of 0.05 considering only paired values (n=11) using PSPP Version 0.10.1. |
| Assessment of Myasthenia Gravis (MG) Status by Determining Titin-antibody Status | at least 6 months | MG severity status is assessed by determining Titin-antibody status at Baseline and EOS. |
| Assessment of Myasthenia Gravis (MG) Status by Measuring ACHR-antibody Concentrations | at least 6 months | MG severity status is assessed by measuring ACHR-antibody concentrations at Baseline and EOS. |
Countries
Germany
Participant flow
Recruitment details
This monocentric trial was conducted in Regensburg, Germany. The patients were asked for study participation by the investigator.
Participants by arm
| Arm | Count |
|---|---|
| SOM230 LAR SOM230 LAR in a dosage of 60 mg i.m. once every 4 weeks | 16 |
| Total | 16 |
Baseline characteristics
| Characteristic | SOM230 LAR |
|---|---|
| Age, Continuous | 52.6 years STANDARD_DEVIATION 12.7 |
| Region of Enrollment Germany | 16 Participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 16 |
| other Total, other adverse events | 16 / 16 |
| serious Total, serious adverse events | 7 / 16 |
Outcome results
Primary
Percent Change in Tumor Volume From Baseline to EOS
To evaluate whether SOM230 LAR is effective in patients with inoperable thymoma with respect to shrinkage of tumor volume. Response is defined as the decrease in tumor volume of 20 % at EOS as compared to baseline. Tumor shrinkage is assessed by CT or MRI.
Time frame: at least 6 months
Population: Initial diagnosis of thymoma for one patient could not be confirmed, but a squamous cell carcinoma was diagnosed by the central pathologist. Tumor voume was 320.99 cm\^3 at screening. Tumor size was reduced to 176.87 cm\^3 at month 2 (-44.9 % compared to baseline). At month 4 (EOS) tumor volume was slightly increased compared to month 2 (189 cm\^3).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| SOM230 LAR | Percent Change in Tumor Volume From Baseline to EOS | -37.38 percentage of tumor volume |
Secondary
Assessment of Tumor Operability
Assessment if patients reaching operability at the EOS.
Time frame: at least 6 months
Population: Operability of the tumor at the EOS was based on the decision of the treating surgeon. In addition the response criteria had to be fulfilled.~The tumors of 11 patients (68.75%) were operable. One of these patients decided not to undergo surgery. Tumors of 5 patients were inoperable (31.25%) at the EOS.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| SOM230 LAR | Assessment of Tumor Operability | Tumor assesed as operable. | 11 Participants |
| SOM230 LAR | Assessment of Tumor Operability | Tumor assesed as not operable. | 5 Participants |
Secondary
Tumor Resection Status
To evaluate the resection status based on the categories R0, R1 and ≥ R2 at EOS using CT or MRI imaging. R0 resection means no residual tumor tissue (best status); R1 indicates microscopic residual tumor tissue and R2 indicates macroscopic residual tumor tissue (worst status).
Time frame: at least 6 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| SOM230 LAR | Tumor Resection Status | Surgery performed with resection status R0 | 6 Participants |
| SOM230 LAR | Tumor Resection Status | Surgery performed with resection status R1 | 4 Participants |
| SOM230 LAR | Tumor Resection Status | No surgery performed | 6 Participants |
Other Pre-specified
Assessment of Myasthenia Gravis (MG) Status by Determining Titin-antibody Status
MG severity status is assessed by determining Titin-antibody status at Baseline and EOS.
Time frame: at least 6 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| SOM230 LAR | Assessment of Myasthenia Gravis (MG) Status by Determining Titin-antibody Status | Change from positive to negative | 2 Participants |
| SOM230 LAR | Assessment of Myasthenia Gravis (MG) Status by Determining Titin-antibody Status | Missing data at baseline or EOS | 8 Participants |
| SOM230 LAR | Assessment of Myasthenia Gravis (MG) Status by Determining Titin-antibody Status | Change from negative to negative | 4 Participants |
| SOM230 LAR | Assessment of Myasthenia Gravis (MG) Status by Determining Titin-antibody Status | Change from negative to positive | 0 Participants |
| SOM230 LAR | Assessment of Myasthenia Gravis (MG) Status by Determining Titin-antibody Status | Change from positive to positive | 2 Participants |
Other Pre-specified
Assessment of Myasthenia Gravis (MG) Status by Measuring ACHR-antibody Concentrations
MG severity status is assessed by measuring ACHR-antibody concentrations at Baseline and EOS.
Time frame: at least 6 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| SOM230 LAR | Assessment of Myasthenia Gravis (MG) Status by Measuring ACHR-antibody Concentrations | Missing data at baseline or EOS | 8 Participants |
| SOM230 LAR | Assessment of Myasthenia Gravis (MG) Status by Measuring ACHR-antibody Concentrations | ACHR-antibody level increased | 1 Participants |
| SOM230 LAR | Assessment of Myasthenia Gravis (MG) Status by Measuring ACHR-antibody Concentrations | ACHR-antibody level decreased | 4 Participants |
| SOM230 LAR | Assessment of Myasthenia Gravis (MG) Status by Measuring ACHR-antibody Concentrations | ACHR-antibody level constant | 3 Participants |
Other Pre-specified
Health Related Quality of Life
Health related quality of life information was collected at Baseline and EOS using SF-36 questionnaire. Questionnaires had to be completed by the patients. All questions are scored on a scale from 0 to 100, with 100 representing the highest level of functioning possible. Patient reported answers were transformed into domain scores according to the guidelines provided by RAND/MOS. Statistical significance of the result was tested with a paired Wilcoxon rang sum test with a significance level of 0.05 considering only paired values (n=11) using PSPP Version 0.10.1.
Time frame: at least 6 months
Population: 5 out of 16 patients were excluded from analysis due to missing EOS data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SOM230 LAR | Health Related Quality of Life | Physical function (SCR) | 58.6 units on a scale | Standard Deviation 28.9 |
| SOM230 LAR | Health Related Quality of Life | Physical function (EOS) | 49.1 units on a scale | Standard Deviation 25.6 |
| SOM230 LAR | Health Related Quality of Life | Role limitations due to physical health (SCR) | 31.8 units on a scale | Standard Deviation 38.9 |
| SOM230 LAR | Health Related Quality of Life | Role limitations due to physical health (EOS) | 34.1 units on a scale | Standard Deviation 45.1 |
| SOM230 LAR | Health Related Quality of Life | Pain (SCR) | 57.3 units on a scale | Standard Deviation 28.8 |
| SOM230 LAR | Health Related Quality of Life | Pain (EOS) | 52.3 units on a scale | Standard Deviation 35.7 |
| SOM230 LAR | Health Related Quality of Life | General health (SCR) | 53.2 units on a scale | Standard Deviation 12.9 |
| SOM230 LAR | Health Related Quality of Life | General health (EOS) | 47.1 units on a scale | Standard Deviation 14.5 |
| SOM230 LAR | Health Related Quality of Life | Energy/Fatigue (SCR) | 43.6 units on a scale | Standard Deviation 15.5 |
| SOM230 LAR | Health Related Quality of Life | Energy/Fatigue (EOS) | 39.2 units on a scale | Standard Deviation 21.3 |
| SOM230 LAR | Health Related Quality of Life | Social functioning (SCR) | 61.4 units on a scale | Standard Deviation 27.6 |
| SOM230 LAR | Health Related Quality of Life | Social functioning (EOS) | 60.2 units on a scale | Standard Deviation 30.5 |
| SOM230 LAR | Health Related Quality of Life | Role limitations due to emotional problems (SCR) | 63.6 units on a scale | Standard Deviation 45.8 |
| SOM230 LAR | Health Related Quality of Life | Role limitations due to emotional problems (EOS) | 60.6 units on a scale | Standard Deviation 44.3 |
| SOM230 LAR | Health Related Quality of Life | Emotional well-being (SCR) | 60.4 units on a scale | Standard Deviation 18.7 |
| SOM230 LAR | Health Related Quality of Life | Emotional well-being (EOS) | 56.6 units on a scale | Standard Deviation 20.9 |
| SOM230 LAR | Health Related Quality of Life | Change in health (general) (SCR) | 38.6 units on a scale | Standard Deviation 20.5 |
| SOM230 LAR | Health Related Quality of Life | Change in health (general) (EOS) | 50.0 units on a scale | Standard Deviation 15.8 |
Other Pre-specified
Safety: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
Time frame: at least 6 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| SOM230 LAR | Safety: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | Number of participants with AEs | 16 Participants |
| SOM230 LAR | Safety: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | Number of participants with SAEs | 7 Participants |