Thymic Carcinoma, Thymoma
Conditions
Keywords
Gene Expression, HDAC Class I and II enzymes, Thymoma, Chemotherapy, Hydroxamic Acid Deacetylase Inhibitor, Thymic Cancer
Brief summary
Background: * Tumors of the thymus are rare and can be treated with surgery, but it is often difficult to determine whether a thymic tumor is malignant based on biopsy alone and the long-term survival rate is less than 50 percent. Because thymic tumors are so rare, most treatment knowledge comes from a relatively small series of cases, and the choice of treatment usually depends on the hospital or clinic staff's experience and familiarity with a given chemotherapy and surgery regimen. * Belinostat is an investigational anticancer drug that has not yet been approved by the Food and Drug Administration for use in any cancer. Researchers are interested in determining whether belinostat can be combined with conventional chemotherapy to safely and effectively treat advanced thymic cancer. Objectives: * To determine a safe and tolerable dose of belinostat that can be given in combination with cisplatin, doxorubicin, and cyclophosphamide. * To determine if belinostat (combined with the abovementioned standard chemotherapy regimen) is effective against thymic cancer cells. Eligibility: \- Individuals at least 18 years of age who have been diagnosed with advanced or recurrent thymic malignancy that is not considered to be curable with surgery or radiation therapy, and who have not received previous chemotherapy treatment. Design: * Participants will be screened with a physical exam, blood tests, and imaging studies as directed by the study researchers. * Participants will receive six 21-day cycles (18 weeks) of treatment with belinostat in combination with cisplatin, doxorubicin, and cyclophosphamide. The treatment will require continuous infusion over 3 days, and participants will remain in the treatment center during this time. Participants will have regular blood tests, clinic visits, and imaging studies during the treatment period. * Participants who complete the six treatment cycles with no severe side effects may be offered the option to continue treatment with belinostat alone. * After the 18-week study period, participants will return for regular follow-up exams for at least 4 weeks, and will be asked to remain in contact with the study researchers once a year to continue to study long-term effects....
Detailed description
Background: * New options for the treatment of patients with advanced thymoma and thymic carcinoma are needed. * Belinostat, N-hydroxy-3-(phenylsulphamoylphenyl) acrylamide, is a hydroxamic acid deacetylase inhibitor that is able to inhibit both histone deacetylase inhibitors (HDAC) Class I and II enzymes. * An ongoing phase II study of belinostat in recurrent or metastatic thymic malignancies has shown activity which warrants further consideration of belinostat in the first line. * Belinostat alterations in target protein levels due to gene expression changes may allow increased sensitivity of cancer cells to conventional chemotherapy. Objectives: Primary Objectives * In the Phase I portion the primary objective will be to determine a safe and tolerable phase 2 dose, dose limiting toxicities (DLTs) and preliminary activity for the combination of belinostat by continuous intravenous (IV) infusion (CIVI) with cisplatin, doxorubicin and cyclophosphamide in patients with advanced thymic malignancies. * In the Phase II portion the primary objective will be to determine the clinical response rate (partial response (PR)+complete response (CR)) of belinostat in combination with cisplatin, doxorubicin and cyclophosphamide in the first line treatment of patients with advanced thymic malignancies. Secondary Objectives * To determine time to response, duration of response, progression free survival (PFS) and overall survival (OS). * To determine the toxicity profile and safety of this combination. * To assess exploratory correlative markers in relation to response to treatment (immunohistochemistry and array Comparative Genomic Hybridization (CGH)) Eligibility: * Patients with histologically confirmed advanced thymic malignancies who are chemotherapy na(SqrRoot) ve. * Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria * Adequate renal, hepatic and hematopoietic function Design: * The Phase I portion of the study will consist of four dose levels and dose escalations will follow according to traditional 3 patient cohorts. * Once the maximum tolerated doe is determined, the phase II portion of the study will begin. * Belinostat will be given as a 48h CIVI starting on day 1, doxorubicin as a slow intravenous (IV) injection on days 2 and 3, cisplatin will be infused over 1 hour on day 2 and cyclophosphamide as a slow IV infusion on Day 3. * Treatment will be given every 21 days for no more than 6 cycles or until disease progression. Treatment with belinostat alone may continue until disease progression.
Interventions
DRUGPXD101with cisplatin+doxorubicin+cyclophosphamide
PXD101 will be given as a 48h continuous intravenous infusion (CIVI) starting on day 1, doxorubicin as a slow intravenous (IV) injection on days 2 and 3, cisplatin will be infused over 1 hour on day 2 and cyclophosphamide as a slow IV infusion on Day 3. Treatment will be given every 21 days for no more than 6 cycles or until disease progression. Treatment with PXD101 alone may continue until disease progression.
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
-INCLUSION CRITERIA: 1. Both the phase I and phase II portions of the protocol will be only open to patients with histologically confirmed advanced stage (Masaoka stage III or IV) thymic malignancies. 2. Patients must be chemotherapy na(SqrRoot) ve for the treatment of advanced thymic malignancies. 3. Age \> 18 years. 4. Eastern Cooperative Oncology Group (ECOG) performance status \< 2 (Karnofsky \> 60%). 5. Life expectancy of greater than 3 months. 6. Patients must have normal organ and marrow function as defined below: * leukocytes \> 3,000/mcL * absolute neutrophil count \> 1,500/mcL * platelets \> 100,000/mcL * total bilirubin within normal institutional limits * Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamic pyruvic transaminase(SGPT) less than or equal to 5 times the institutional upper limit of normal with evidence of metastatic disease to the liver or less than or equal to 3 times the institutional upper limit of normal without evidence of metastatic disease to the liver * creatinine less than or equal to 1.5 times institutional upper limits of normal OR \- creatinine clearance \> 45 mL/min/1.73 m(2) for patients with creatinine levels above institutional normal. 7. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \> 20 mm with conventional techniques or as \> 10 mm with spiral computed tomography (CT) scan. 8. Patients must have recovered from toxicity related to prior therapy (surgery or radiation) to grade less than or equal to 1 and must be at least 28 days since any prior radiation or major surgery. Target lesions cannot be selected within previously irradiated areas, if not newly arising or clearly progressing after irradiation as proven by repeat scanning. 9. Concurrent corticosteroids for myasthenia gravis, or other paraneoplastic syndromes, or other chronic conditions are allowed. Eligibility of patients receiving any medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of belinostat or cisplatin, doxorubicin or cyclophosphamide will be determined following review of their case by the Principal Investigator. Efforts should be made to switch patients with brain metastases who are taking enzyme-inducing anticonvulsant agents to other medications. 10. The effects of belinostat on the developing human fetus are unknown. For this reason and because histone deacetylase inhibitors (HDAC) inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. 11. Ability to understand and the willingness to sign a written informed consent document. Inclusion of Women and Minorities Both men and women of all races and ethnic groups are eligible for this trial
Exclusion criteria
1. Patients who have had major surgery or radiotherapy within 3 weeks of enrollment. 2. Patients may not be receiving any other investigational agents. 3. Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. However, patients who have had treatment for their brain metastases and whose brain metastatic disease status has remained stable for at least 1 month without steroids may be enrolled at the discretion of the principal investigator. 4. History of allergic reactions attributed to compounds of similar chemical or biologic composition to belinostat or other agents used in study. 5. Patients with prior treatment with drugs of the HDAC inhibitor class are excluded, except for valproic acid (VPA) where prior treatment is accepted as long as it is not within the last 2 weeks before enrolment. 6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. 7. Pregnant women are excluded from this study because belinostat is an HDAC inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with belinostat, breastfeeding should be discontinued if the mother is treated with belinostat. These potential risks may also apply to other agents used in this study. 8. Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with belinostat. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated. 9. Marked baseline prolongation of Q wave, T wave (QT)/corrected QT interval (QTc) interval, e.g., repeated demonstration of a QTc interval \> 500 ms; Long QT Syndrome. Patients taking medications that may cause QTc prolongation will be eligible as long as they comply with the recommendations in appendix D. 10. History of another invasive malignancy in the last five years. Adequately treated non-invasive, non-melanoma skin cancers as well as in situ carcinoma of the cervix will be allowed. 11. Patients with tumor amenable to potentially curative therapy as assessed by the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of Belinostat | 2 years | The MTD is defined as the highest dose at which less than 2 out of 6 patients experienced a dose limiting toxicity (DLT). A DLT is defined as grade 4 neutropenia lasting more than 7 days despite prophylactic or therapeutic use of granulocyte colony-stimulating factor (G-CSF), febrile neutropenia defined as absolute neutrophil count (ANC) less than 1000/mm(3) and temperature more than 38.5 degrees Celsius or 100.4 degrees Fahrenheit or life threatening sepsis, grade 4 thrombocytopenia or grade 3 thrombocytopenia associated with bleeding during the first cycle of therapy. Any grade 3 or 4 non-hematologic toxicity was considered dose limiting with the following exceptions: grade 3 diarrhea lasting less than 48 hours, grade 3 nausea and/or vomiting lasting less than 48 hours, grade 3 electrolyte abnormalities lasting less than 48 hours, grade 3 creatinine elevation lasting less than 48 hours. |
| Number of Participants With Grade 3 and 4 Dose Limiting Toxicity (DLT) at 2000mg/m(2) Belinostat | up to 122 months | A DLT is defined as grade 4 neutropenia lasting more than 7 days despite prophylactic or therapeutic use of granulocyte colony-stimulating factor (G-CSF), febrile neutropenia defined as absolute neutrophil count (ANC) less than 1000/mm(3) and temperature more than 38.5 degrees Celsius or 100.4 degrees Fahrenheit or life threatening sepsis, grade 4 thrombocytopenia or grade 3 thrombocytopenia associated with bleeding during the first cycle of therapy. Any grade 3 or 4 non-hematologic toxicity was considered dose limiting with the following exceptions: grade 3 diarrhea lasting less than 48 hours, grade 3 nausea and/or vomiting lasting less than 48 hours, grade 3 electrolyte abnormalities lasting less than 48 hours, grade 3 creatinine elevation lasting less than 48 hours. |
| Objective Response Rate (Partial Response (PR) + Complete Response (CR) of Belinostat in Combination With Cisplatin, Doxorubicin and Cyclophosphamide in the First Line Treatment of Patients With Advanced Thymic Malignancies | 43 months | Objective response rate is the number of participants with a best objective response of partial response (PR) + complete response (CR) per the Response Criteria in Solid Tumors (RECIST) divided by the number of participants who had treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | 43 months | DCR is defined as stable disease (SD) + partial response (PR) + complete response (CR) per the Response Criteria in Solid Tumors (RECIST). |
| Time to Response | From the first day of treatment until the date of first documented response, assessed up to 43 months | Time to response is the time between the first day of treatment until first date of response (complete response (CR) + partial response (PR)) (whichever is first recorded). |
| Duration of Response | From the time of first response until date of progression, assessed up to 43 months | Duration of response is measured from the time measurement criteria (e.g. Response Evaluation Criteria in Solid Tumors (RECIST)) are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). |
| Progression Free Survival (PFS) | Start of treatment to time of disease progression or death whichever occurs first, assessed up to 43 months | Duration of time from start of treatment to time of progression or death whichever occurs first. |
| Overall Survival (OS) | Start of treatment to time of death, assessed up to 43 months | Overall survival is defined as the on-study date until the date of death or progression as appropriate. |
| Time to Half Life (t1/2) of Belinostat | on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose. | Half life is the duration of time for the drug to be reduced to half the original amount. |
| Total Clearance (CL) of Belinostat | on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose | Clearance is the amount of time for the drug to be eliminated from the body. |
| Number of Participants With Serious and Non-serious Adverse Events | up to 122 months | Here is the number of participants with serious and non-serious adverse events. For a detailed list of events, see the adverse event module. |
| Maximum Plasma Concentration (Cmax)/Dose | on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose | Plasma concentrations of Belinostat were measured using a newly designed and validated ultra high-performance liquid chromatography (HPLC) with tandem mass spectrometric (MS/MS) assay, with a lower limit of quantification of 5ng/mL. |
| Time to Maximum Plasma Concentration (Tmax) | on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose | Time to reach peak concentration after drug administration. |
| Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF)) | on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose | AUC is a measure of the serum concentration of Belinostat over time. It is used to characterize drug absorption. |
| Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF)/Dose | on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose | AUC is a measure of the serum concentration of Belinostat over time. It is used to characterize drug absorption. |
| Relative Change Observed in Total Protein Hyperacetylation of Cluster of Differentiation 3 (CD3)+T Cells With Belinostat | Baseline Cycle 1 Day 1 (C1D1), Cycle 1 Day 2 (C1D2), Cycle 1 Day 3 (C1D3), and Cycle 2 Day 1 (C2D1) | Changes in marker levels from baseline. All pre values were set to 1 so that we could measure changes relative to the baseline. |
| Relative Changes in the Number of Tregs With Treatment | Baseline Cycle 1 Day 1 (C1D1), Cycle 1 Day 2 (C1D2), Cycle 1 Day 3 (C1D3), and Cycle 2 Day 1 (C2D1) | Changes in marker levels from baseline. All pre values were set to 1 so that we could measure changes relative to the baseline. |
| Relative Changes in T Cell Immunoglobulin Domain and Mucin Domain-3 (TIM3)-Expressing Cluster of Differentiation 8 (CD8)+Tcells | Baseline Cycle 1 Day 1 (C1D1), Cycle 1 Day 2 (C1D2), Cycle 1 Day 3 (C1D3), and Cycle 2 Day 1 (C2D1) | Changes in marker levels from baseline. All pre values were set to 1 so that we could measure changes relative to the baseline. |
| Maximum Observed Plasma Concentration (Cmax) of Belinostat | on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose | Plasma concentrations of Belinostat were measured using a newly designed and validated ultra high-performance liquid chromatography (HPLC) with tandem mass spectrometric (MS/MS) assay, with a lower limit of quantification of 5ng/mL. |
| Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | up to 122 months | Here are the number of patients with treatment -related grade 3 and 4 adverse events (highest grade per event per patient). |
| Clinical Response | 43 months | Response is defined by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants All participants who had at least one dose of Belinostat. | 26 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Dose Escalation Phase 1 Dose Level 1 | Adverse Event | 2 | 0 | 0 |
| Dose Escalation Phase 1 Dose Level 1 | Discontinued due to treatment delay | 1 | 0 | 0 |
| Dose Escalation Phase 1 Dose Level 1 | Progressive Disease | 1 | 0 | 0 |
| Dose Escalation Phase 1 Dose Level 2 | Adverse Event | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 6 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants |
| Age, Continuous | 53.9 years STANDARD_DEVIATION 13.3 |
| ECOG Performance Status Grade 0 | 18 Participants |
| ECOG Performance Status Grade 1 | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Prior Neoadjuvant or Adjuvant Chemotherapy | 4 Participants |
| Prior Radiation | 7 Participants |
| Prior Surgery Debulking | 2 Participants |
| Prior Surgery Radical | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 20 Participants |
| Region of Enrollment United States | 26 participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 13 Participants |
| Stage at Enrolment IVA | 12 Participants |
| Stage at Enrolment IVB | 14 Participants |
| Tumor Type B1 | 2 Participants |
| Tumor Type B2 | 7 Participants |
| Tumor Type B3 | 3 Participants |
| Tumor Type Thymic carcinoma | 14 Participants |
| Tumor Type Thymoma | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 13 / 26 |
| other Total, other adverse events | 26 / 26 |
| serious Total, serious adverse events | 20 / 26 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of Belinostat
The MTD is defined as the highest dose at which less than 2 out of 6 patients experienced a dose limiting toxicity (DLT). A DLT is defined as grade 4 neutropenia lasting more than 7 days despite prophylactic or therapeutic use of granulocyte colony-stimulating factor (G-CSF), febrile neutropenia defined as absolute neutrophil count (ANC) less than 1000/mm(3) and temperature more than 38.5 degrees Celsius or 100.4 degrees Fahrenheit or life threatening sepsis, grade 4 thrombocytopenia or grade 3 thrombocytopenia associated with bleeding during the first cycle of therapy. Any grade 3 or 4 non-hematologic toxicity was considered dose limiting with the following exceptions: grade 3 diarrhea lasting less than 48 hours, grade 3 nausea and/or vomiting lasting less than 48 hours, grade 3 electrolyte abnormalities lasting less than 48 hours, grade 3 creatinine elevation lasting less than 48 hours.
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Dose Level 1 & Phase I Dose Level 2 | Maximum Tolerated Dose (MTD) of Belinostat | 1000 mg/m(2) |
Primary
Number of Participants With Grade 3 and 4 Dose Limiting Toxicity (DLT) at 2000mg/m(2) Belinostat
A DLT is defined as grade 4 neutropenia lasting more than 7 days despite prophylactic or therapeutic use of granulocyte colony-stimulating factor (G-CSF), febrile neutropenia defined as absolute neutrophil count (ANC) less than 1000/mm(3) and temperature more than 38.5 degrees Celsius or 100.4 degrees Fahrenheit or life threatening sepsis, grade 4 thrombocytopenia or grade 3 thrombocytopenia associated with bleeding during the first cycle of therapy. Any grade 3 or 4 non-hematologic toxicity was considered dose limiting with the following exceptions: grade 3 diarrhea lasting less than 48 hours, grade 3 nausea and/or vomiting lasting less than 48 hours, grade 3 electrolyte abnormalities lasting less than 48 hours, grade 3 creatinine elevation lasting less than 48 hours.
Time frame: up to 122 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I Dose Level 1 & Phase I Dose Level 2 | Number of Participants With Grade 3 and 4 Dose Limiting Toxicity (DLT) at 2000mg/m(2) Belinostat | Grade 3 Nausea | 2 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Number of Participants With Grade 3 and 4 Dose Limiting Toxicity (DLT) at 2000mg/m(2) Belinostat | Grade 3 Diarrhea | 2 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Number of Participants With Grade 3 and 4 Dose Limiting Toxicity (DLT) at 2000mg/m(2) Belinostat | Grade 4 Neutropenia | 2 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Number of Participants With Grade 3 and 4 Dose Limiting Toxicity (DLT) at 2000mg/m(2) Belinostat | Grade 4 Thrombocytopenia | 2 Participants |
Primary
Objective Response Rate (Partial Response (PR) + Complete Response (CR) of Belinostat in Combination With Cisplatin, Doxorubicin and Cyclophosphamide in the First Line Treatment of Patients With Advanced Thymic Malignancies
Objective response rate is the number of participants with a best objective response of partial response (PR) + complete response (CR) per the Response Criteria in Solid Tumors (RECIST) divided by the number of participants who had treatment.
Time frame: 43 months
Population: One patient hospitalized for viral meningoencephalitis during the first cycle was not evaluable for response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Dose Level 1 & Phase I Dose Level 2 | Objective Response Rate (Partial Response (PR) + Complete Response (CR) of Belinostat in Combination With Cisplatin, Doxorubicin and Cyclophosphamide in the First Line Treatment of Patients With Advanced Thymic Malignancies | 21 percentage of participants |
| Thymoma Participants | Objective Response Rate (Partial Response (PR) + Complete Response (CR) of Belinostat in Combination With Cisplatin, Doxorubicin and Cyclophosphamide in the First Line Treatment of Patients With Advanced Thymic Malignancies | 64 percentage of participants |
| Thymic and Thymoma Participants | Objective Response Rate (Partial Response (PR) + Complete Response (CR) of Belinostat in Combination With Cisplatin, Doxorubicin and Cyclophosphamide in the First Line Treatment of Patients With Advanced Thymic Malignancies | 40 percentage of participants |
Secondary
Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF))
AUC is a measure of the serum concentration of Belinostat over time. It is used to characterize drug absorption.
Time frame: on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I Dose Level 1 & Phase I Dose Level 2 | Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF)) | 19756 hr*ng/ml | Standard Deviation 7634 |
| Thymoma Participants | Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF)) | 29686 hr*ng/ml | — |
Secondary
Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF)/Dose
AUC is a measure of the serum concentration of Belinostat over time. It is used to characterize drug absorption.
Time frame: on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I Dose Level 1 & Phase I Dose Level 2 | Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF)/Dose | 10.78 hr*ng/ml/mg | Standard Deviation 5.57 |
| Thymoma Participants | Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF)/Dose | 7.57 hr*ng/ml/mg | — |
Secondary
Clinical Response
Response is defined by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time frame: 43 months
Population: One patient hospitalized for viral meningoencephalitis during the first cycle was not evaluable for response.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I Dose Level 1 & Phase I Dose Level 2 | Clinical Response | Complete Response (CR) | 0 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Clinical Response | Partial Response (PR) | 3 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Clinical Response | Stable Disease (SD) | 10 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Clinical Response | Progressive Disease (PD) | 1 Participants |
| Thymoma Participants | Clinical Response | Progressive Disease (PD) | 0 Participants |
| Thymoma Participants | Clinical Response | Complete Response (CR) | 1 Participants |
| Thymoma Participants | Clinical Response | Stable Disease (SD) | 4 Participants |
| Thymoma Participants | Clinical Response | Partial Response (PR) | 6 Participants |
| Thymic and Thymoma Participants | Clinical Response | Progressive Disease (PD) | 1 Participants |
| Thymic and Thymoma Participants | Clinical Response | Partial Response (PR) | 9 Participants |
| Thymic and Thymoma Participants | Clinical Response | Stable Disease (SD) | 14 Participants |
| Thymic and Thymoma Participants | Clinical Response | Complete Response (CR) | 1 Participants |
Secondary
Disease Control Rate (DCR)
DCR is defined as stable disease (SD) + partial response (PR) + complete response (CR) per the Response Criteria in Solid Tumors (RECIST).
Time frame: 43 months
Population: One patient hospitalized for viral meningoencephalitis during the first cycle was not evaluable for response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Dose Level 1 & Phase I Dose Level 2 | Disease Control Rate (DCR) | 93 percentage of participants |
| Thymoma Participants | Disease Control Rate (DCR) | 100 percentage of participants |
| Thymic and Thymoma Participants | Disease Control Rate (DCR) | 96 percentage of participants |
Secondary
Duration of Response
Duration of response is measured from the time measurement criteria (e.g. Response Evaluation Criteria in Solid Tumors (RECIST)) are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).
Time frame: From the time of first response until date of progression, assessed up to 43 months
Population: One patient hospitalized for viral meningoencephalitis during the first cycle was not evaluable for response. The reason median was not reached is that patients with thymoma have a more indolent disease with a longer survival, therefore a longer duration of response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Dose Level 1 & Phase I Dose Level 2 | Duration of Response | 7.4 months |
| Thymoma Participants | Duration of Response | NA months |
| Thymic and Thymoma Participants | Duration of Response | 7.4 months |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Belinostat
Plasma concentrations of Belinostat were measured using a newly designed and validated ultra high-performance liquid chromatography (HPLC) with tandem mass spectrometric (MS/MS) assay, with a lower limit of quantification of 5ng/mL.
Time frame: on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose
Population: One patient was excluded from pharmacokinetic analysis due to insufficient sampling in dose level 2. Dose normalized parameters are normalized to absolute total dose (over 48 hours continuous intravenous infusion (CIVI)) for that patient, not dose level.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I Dose Level 1 & Phase I Dose Level 2 | Maximum Observed Plasma Concentration (Cmax) of Belinostat | 650.6 ng/ml | Standard Deviation 288.1 |
| Thymoma Participants | Maximum Observed Plasma Concentration (Cmax) of Belinostat | 1202 ng/ml | — |
Secondary
Maximum Plasma Concentration (Cmax)/Dose
Plasma concentrations of Belinostat were measured using a newly designed and validated ultra high-performance liquid chromatography (HPLC) with tandem mass spectrometric (MS/MS) assay, with a lower limit of quantification of 5ng/mL.
Time frame: on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I Dose Level 1 & Phase I Dose Level 2 | Maximum Plasma Concentration (Cmax)/Dose | 0.36 ng/ml/mg | Standard Deviation 0.21 |
| Thymoma Participants | Maximum Plasma Concentration (Cmax)/Dose | 0.31 ng/ml/mg | — |
Secondary
Number of Participants With Serious and Non-serious Adverse Events
Here is the number of participants with serious and non-serious adverse events. For a detailed list of events, see the adverse event module.
Time frame: up to 122 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I Dose Level 1 & Phase I Dose Level 2 | Number of Participants With Serious and Non-serious Adverse Events | Serious | 20 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Number of Participants With Serious and Non-serious Adverse Events | Non-serious | 26 Participants |
Secondary
Overall Survival (OS)
Overall survival is defined as the on-study date until the date of death or progression as appropriate.
Time frame: Start of treatment to time of death, assessed up to 43 months
Population: One patient hospitalized for viral meningoencephalitis during the first cycle was not evaluable. The reason median was not reached is that patients with thymoma have a more indolent disease with a longer survival, therefore a longer duration of response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Dose Level 1 & Phase I Dose Level 2 | Overall Survival (OS) | 21.4 months |
| Thymoma Participants | Overall Survival (OS) | NA months |
| Thymic and Thymoma Participants | Overall Survival (OS) | 28.5 months |
Secondary
Progression Free Survival (PFS)
Duration of time from start of treatment to time of progression or death whichever occurs first.
Time frame: Start of treatment to time of disease progression or death whichever occurs first, assessed up to 43 months
Population: One patient hospitalized for viral meningoencephalitis during the first cycle was not evaluable. The reason median was not reached is that patients with thymoma have a more indolent disease with a longer survival, therefore a longer duration of response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Dose Level 1 & Phase I Dose Level 2 | Progression Free Survival (PFS) | 7.2 months |
| Thymoma Participants | Progression Free Survival (PFS) | NA months |
| Thymic and Thymoma Participants | Progression Free Survival (PFS) | 9 months |
p-value: 0.021Wilcoxon (Mann-Whitney)
Secondary
Relative Change Observed in Total Protein Hyperacetylation of Cluster of Differentiation 3 (CD3)+T Cells With Belinostat
Changes in marker levels from baseline. All pre values were set to 1 so that we could measure changes relative to the baseline.
Time frame: Baseline Cycle 1 Day 1 (C1D1), Cycle 1 Day 2 (C1D2), Cycle 1 Day 3 (C1D3), and Cycle 2 Day 1 (C2D1)
Population: One patient hospitalized for viral meningoencephalitis during the first cycle was not evaluable. Two samples could not be analyzed since they were of poor quality with too few cells for immune cell subset analysis or the samples could not be collected in time for pharmacodynamics analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase I Dose Level 1 & Phase I Dose Level 2 | Relative Change Observed in Total Protein Hyperacetylation of Cluster of Differentiation 3 (CD3)+T Cells With Belinostat | C1D2 | 3.45 Relative fold change |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Relative Change Observed in Total Protein Hyperacetylation of Cluster of Differentiation 3 (CD3)+T Cells With Belinostat | C1D3 | 2.49 Relative fold change |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Relative Change Observed in Total Protein Hyperacetylation of Cluster of Differentiation 3 (CD3)+T Cells With Belinostat | C2D1 | 1.15 Relative fold change |
p-value: 0.3Wilcoxon signed rank test
p-value: 0.0001Wilcoxon signed rank test
p-value: 0.0001Wilcoxon signed rank test
Secondary
Relative Changes in T Cell Immunoglobulin Domain and Mucin Domain-3 (TIM3)-Expressing Cluster of Differentiation 8 (CD8)+Tcells
Changes in marker levels from baseline. All pre values were set to 1 so that we could measure changes relative to the baseline.
Time frame: Baseline Cycle 1 Day 1 (C1D1), Cycle 1 Day 2 (C1D2), Cycle 1 Day 3 (C1D3), and Cycle 2 Day 1 (C2D1)
Population: One patient hospitalized for viral meningoencephalitis during the first cycle was not evaluable. Three samples could not be analyzed since they were of poor quality with too few cells for immune cell subset analysis or the samples could not be collected in time for pharmacodynamics analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase I Dose Level 1 & Phase I Dose Level 2 | Relative Changes in T Cell Immunoglobulin Domain and Mucin Domain-3 (TIM3)-Expressing Cluster of Differentiation 8 (CD8)+Tcells | C1D2 | 0.81 Relative fold change |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Relative Changes in T Cell Immunoglobulin Domain and Mucin Domain-3 (TIM3)-Expressing Cluster of Differentiation 8 (CD8)+Tcells | C1D3 | 0.66 Relative fold change |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Relative Changes in T Cell Immunoglobulin Domain and Mucin Domain-3 (TIM3)-Expressing Cluster of Differentiation 8 (CD8)+Tcells | C2D1 | 1.01 Relative fold change |
p-value: 0.95Wilcoxon signed rank test
p-value: 0.0001Wilcoxon signed rank test
p-value: 0.0001Wilcoxon signed rank test
Secondary
Relative Changes in the Number of Tregs With Treatment
Changes in marker levels from baseline. All pre values were set to 1 so that we could measure changes relative to the baseline.
Time frame: Baseline Cycle 1 Day 1 (C1D1), Cycle 1 Day 2 (C1D2), Cycle 1 Day 3 (C1D3), and Cycle 2 Day 1 (C2D1)
Population: One patient hospitalized for viral meningoencephalitis during the first cycle was not evaluable. Three samples could not be analyzed since they were of poor quality with too few cells for immune cell subset analysis or the samples could not be collected in time for pharmacodynamics analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase I Dose Level 1 & Phase I Dose Level 2 | Relative Changes in the Number of Tregs With Treatment | C2D1 | 1.12 relative fold change |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Relative Changes in the Number of Tregs With Treatment | C1D2 | 0.58 relative fold change |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Relative Changes in the Number of Tregs With Treatment | C1D3 | 0.47 relative fold change |
p-value: 0.76Wilcoxon signed rank test
p-value: 0.0009Wilcoxon signed rank test
p-value: 0.0001Wilcoxon signed rank test
Secondary
Time to Half Life (t1/2) of Belinostat
Half life is the duration of time for the drug to be reduced to half the original amount.
Time frame: on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I Dose Level 1 & Phase I Dose Level 2 | Time to Half Life (t1/2) of Belinostat | 0.47 Hour | Standard Deviation 0.19 |
| Thymoma Participants | Time to Half Life (t1/2) of Belinostat | 0.40 Hour | — |
Secondary
Time to Maximum Plasma Concentration (Tmax)
Time to reach peak concentration after drug administration.
Time frame: on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I Dose Level 1 & Phase I Dose Level 2 | Time to Maximum Plasma Concentration (Tmax) | 25.28 Hour | Standard Deviation 22.29 |
| Thymoma Participants | Time to Maximum Plasma Concentration (Tmax) | 50.0 Hour | — |
Secondary
Time to Response
Time to response is the time between the first day of treatment until first date of response (complete response (CR) + partial response (PR)) (whichever is first recorded).
Time frame: From the first day of treatment until the date of first documented response, assessed up to 43 months
Population: One patient hospitalized for viral meningoencephalitis during the first cycle was not evaluable for response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Dose Level 1 & Phase I Dose Level 2 | Time to Response | 44.5 days |
Secondary
Total Clearance (CL) of Belinostat
Clearance is the amount of time for the drug to be eliminated from the body.
Time frame: on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I Dose Level 1 & Phase I Dose Level 2 | Total Clearance (CL) of Belinostat | 133.5 L/hr | Standard Deviation 145.1 |
| Thymoma Participants | Total Clearance (CL) of Belinostat | 132.1 L/hr | — |
Secondary
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient)
Here are the number of patients with treatment -related grade 3 and 4 adverse events (highest grade per event per patient).
Time frame: up to 122 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic and Renal: Hypokalemia | 3 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hematologic: Lymphocyte count decreased | 24 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Other: Febrile neutropenia | 3 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic and Renal: Hypermagnesemia | 3 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Limb edema | 0 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Nausea | 1 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic and Renal: Hypoalbuminemia | 1 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Pain in extremity | 1 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Cardiovascular: Electrocardiogram QTc prolonged | 1 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic and Renal: Hypocalcemia | 1 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hematologic: White blood cell decreased | 22 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Cardiovascular: Ejection fraction decreased | 1 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic and Renal: Hyponatremia | 1 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Otehrs: Entercolitis infectious | 1 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Cardiovascular: Atrial fibrillation | 0 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Cardiovascular: Thromboembolic event | 3 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Non-cardiac chest pain | 1 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hematologic: Neutrophil count decreased | 19 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic and Renal: Hypomagnesemia | 1 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Hypoxia | 1 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hematologic: Platelet count decreased | 10 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Syncope | 1 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Hearing impaired | 1 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hematologic: Anemia | 7 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Tumor lysis syndrome | 0 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Fatigue | 2 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic and Renal: Hypophosphatemia | 4 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Vomiting | 0 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Lung infection | 2 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic and Renal: Aspartate aminotransferase incr | 4 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic/Renal: Alanine aminotransferase increased | 3 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Urinary tract infection | 1 Participants |
| Phase I Dose Level 1 & Phase I Dose Level 2 | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Diarrhea | 1 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Fatigue | 0 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic and Renal: Hypomagnesemia | 0 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Otehrs: Entercolitis infectious | 1 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Vomiting | 1 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hematologic: Lymphocyte count decreased | 2 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hematologic: White blood cell decreased | 2 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hematologic: Neutrophil count decreased | 2 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hematologic: Platelet count decreased | 2 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hematologic: Anemia | 2 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic and Renal: Hypophosphatemia | 2 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic/Renal: Alanine aminotransferase increased | 1 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic and Renal: Hypokalemia | 1 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic and Renal: Hypermagnesemia | 0 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic and Renal: Hypoalbuminemia | 1 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic and Renal: Hypocalcemia | 1 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic and Renal: Hyponatremia | 0 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Cardiovascular: Thromboembolic event | 0 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Cardiovascular: Atrial fibrillation | 1 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Cardiovascular: Ejection fraction decreased | 0 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Cardiovascular: Electrocardiogram QTc prolonged | 0 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Nausea | 2 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Other: Febrile neutropenia | 0 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Diarrhea | 1 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Lung infection | 0 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic and Renal: Aspartate aminotransferase incr | 2 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Hearing impaired | 0 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Hypoxia | 0 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Non-cardiac chest pain | 0 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Pain in extremity | 0 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Syncope | 0 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Tumor lysis syndrome | 1 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Limb edema | 1 Participants |
| Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Urinary tract infection | 0 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic/Renal: Alanine aminotransferase increased | 4 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Syncope | 1 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Diarrhea | 2 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic and Renal: Hypophosphatemia | 6 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic and Renal: Aspartate aminotransferase incr | 6 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Lung infection | 2 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Otehrs: Entercolitis infectious | 2 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hematologic: Anemia | 9 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Vomiting | 1 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Fatigue | 2 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hematologic: Platelet count decreased | 12 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Tumor lysis syndrome | 1 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Hearing impaired | 1 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hematologic: Neutrophil count decreased | 21 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic and Renal: Hypomagnesemia | 1 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Hypoxia | 1 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hematologic: White blood cell decreased | 24 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Cardiovascular: Thromboembolic event | 3 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic and Renal: Hyponatremia | 1 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Urinary tract infection | 1 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Cardiovascular: Atrial fibrillation | 1 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic and Renal: Hypocalcemia | 2 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Non-cardiac chest pain | 1 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Cardiovascular: Ejection fraction decreased | 1 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic and Renal: Hypoalbuminemia | 2 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hematologic: Lymphocyte count decreased | 26 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Cardiovascular: Electrocardiogram QTc prolonged | 1 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic and Renal: Hypermagnesemia | 3 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Limb edema | 1 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Nausea | 3 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Hepatic and Renal: Hypokalemia | 4 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Others: Pain in extremity | 1 Participants |
| Thymic and Thymoma Participants | Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Other: Febrile neutropenia | 3 Participants |