Thymoma, Thymus Cancer, Thymic Carcinoma
Conditions
Brief summary
A research study of the drug amrubicin in patients with cancer of the thymus (thymoma or thymic carcinoma). We hope to learn whether this drug is an effective and safe treatment for thymic cancers.
Detailed description
Amrubicin, a synthetic 9-aminoanthracycline, is structurally similar to doxorubicin, but has a different primary mode of action. It acts primarily as an inhibitor of DNA topoisomerase II, exerting its cytotoxic effects by stabilizing a topoisomerase II mediated cleavable complex. This inhibition is significantly more than that seen in doxorubicin, which, in contrast, tends to demonstrate more DNA intercalation than amrubicin. It has not yet been evaluated for use in thymic malignancies, but given its efficacy in NSCLC and small cell lung cancer (SCLC), as well as the known efficacy of other anthracyclines and topoisomerase II inhibitors in first-line thymoma treatment, it warrants study for use in the second line and beyond in refractory or relapsed patients. Unlike doxorubicin, amrubicin has had minimal cardiotoxicity even with ongoing use, which also makes it a promising agent for use in the second line even for patients who have previously been exposed to, and potentially helped by, doxorubicin.
Interventions
DRUGAmrubicin
35 mg/m2; IV on days 1-3 each 3 week cycle
Sponsors
Celgene
Heather Wakelee
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed invasive or metastatic thymoma or thymic carcinoma. Locally invasive disease is acceptable, provided it is not resectable. * Previous treatment with at least one prior chemotherapy regimen. * Documented progressive disease after the most recent chemotherapy regimen. * Presence of measurable disease on imaging within 4 weeks prior to first dose * Completion of prior systemic therapy at least 4 weeks prior to first dose. * Any prior immunotherapy therapy completed at least 8 weeks prior to first dose. * Any prior surgery completed at least 4 weeks prior to first dose, with adequate recovered from surgery. * Any prior radiation therapy must have no residual toxic effects of therapy. Chest radiotherapy with curative intent to the primary disease complex must have been completed ≥ 28 days prior to first dose. Cranial radiation must have been completed ≥ 21 days prior to first dose. Radiotherapy to all other areas must have been completed ≥ 7 days prior to first dose. * Age ≥ 18 years. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * Leukocytes ≥ 3000/mm³ * Absolute neutrophil count ≥ 1500/mm³ * Platelets ≥ 100,000/mm³ * Hemoglobin ≥ 9 g/d * Serum bilirubin \< 1.5 x institutional upper limit of normal (ULN) * Aspartate transaminase (AST) and alanine transaminase (ALT) ratio \< 3 x ULN * Serum creatinine \< 1.5 times institutional upper limit of normal if serum creatinine above institutional upper limit of normal, calculated serum creatinine clearance by the Cockcroft Gault method \> 60 mL/min * Left ventricular ejection fraction (LVEF) ≥ 50% by transthoracic echocardiogram (TTE) or multiple gated acquisition scan (MUGA) * For females of childbearing potential, negative serum pregnancy test within 4 weeks of first dose. * For males and females of childbearing potential, use of effective contraceptive methods during the study. * Ability to understand and willingness to sign a written informed consent document.
Exclusion criteria
* Current use, or use within 4 weeks prior to first dose, of any other investigational agents. * Known history of allergic reactions attributed to compounds of similar chemical or biologic composition to amrubicin. * Active malignancy requiring treatment other than thymic malignancy. * Pregnant or nursing females due to unknown toxic effects of amrubicin on the developing fetus or in breast milk. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. * Symptomatic central nervous system metastatic disease. Patients with asymptomatic brain metastases allowed. If treated with surgical resection or radiation therapy, the patient must be stable for \>= 2 weeks after completion of therapy. If the patient is on corticosteroids, the dose of corticosteroids, the dose of corticosteroids must have been stable for \>= 2 weeks prior to first dose of study treatment, or be in the process of being tapered. * Concurrent severe or uncontrolled medical disease (including but not limited to active systemic infection, diabetes, hypertension, coronary artery disease, congestive hear failure and mental illness) that in the opinion of the investigator would compromise the safety of the patient or compromise the ability of the patient to complete the study. * Known history of seropositive human immunodeficiency virus (HIV) or use of immunosuppressive medications for other conditions that would, in the opinion of the investigator, increase the risk of serious neutropenic complications.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | 2 years | Participants received amrubicin 35 mg/m2 IV days 1 to 3, every 3 weeks, until progression or toxicity. Tumor response rate was assessed radiographically by the Response Evaluation Criteria In Solid Tumors (RECIST), and the overall response rate (ORR) was expressed as the sum of the Complete Response (CR) rate and the Partial Response (PR) rate. RECIST criteria define when cancer patients improve (respond); stay the same (stable); or worsen (progression) during treatments. The criteria presume that linear measures are an adequate substitute for 2-dimensional (2D) methods and includes 4 response categories: * CR = Disappearance of all target lesions * PR = 30% decrease in the sum of the longest diameter of target lesions * Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions * Stable disease (SD) = Small changes that do not meet above criteria |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression-free Survival (PFS) | 2 years | Median Progression-free survival in patients with thymic malignancies treated with amrubicin |
| Disease Control Rate (DCR) | 2 years | Disease control rate (DCR) is the sum of Complete Response (CR) rate + Partial Response (PR) rate + Stable Disease (SD) rate , and is expressed here as the sum of the Overall Response Rate (ORR = CR + PR) plus the Stable Disease (SD) rate, ORR + SD. Response was assessed by the RECIST criteria, elaborated above. |
Countries
United States
Participant flow
Pre-assignment details
35 participants were fully screened for this study,and all 35 are included in Baseline Characteristics. However, 2 were ineligible and did not receive treatment, and so are not included in Outcomes nor Adverse Events.
Participants by arm
| Arm | Count |
|---|---|
| Amrubicin Amrubicin 35mg/m2 IV days 1-3 every 3 weeks until progression or toxicity | 35 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Not Eligible | 2 |
Baseline characteristics
| Characteristic | Amrubicin |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 11 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Histology Thymic Carcinoma | 20 Participants |
| Histology Thymoma | 14 Participants |
| Histology Unknown | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 10 Participants |
| Race (NIH/OMB) Black or African American | 2 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 | 23 Participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 33 / 33 |
| serious Total, serious adverse events | 16 / 33 |
Outcome results
Primary
Overall Response Rate (ORR)
Participants received amrubicin 35 mg/m2 IV days 1 to 3, every 3 weeks, until progression or toxicity. Tumor response rate was assessed radiographically by the Response Evaluation Criteria In Solid Tumors (RECIST), and the overall response rate (ORR) was expressed as the sum of the Complete Response (CR) rate and the Partial Response (PR) rate. RECIST criteria define when cancer patients improve (respond); stay the same (stable); or worsen (progression) during treatments. The criteria presume that linear measures are an adequate substitute for 2-dimensional (2D) methods and includes 4 response categories: * CR = Disappearance of all target lesions * PR = 30% decrease in the sum of the longest diameter of target lesions * Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions * Stable disease (SD) = Small changes that do not meet above criteria
Time frame: 2 years
Population: Includes those participants with Complete Response (CR) plus those with Partial Response (PR).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Amrubicin | Overall Response Rate (ORR) | Partial Response (PR) | 6 Participants |
| Amrubicin | Overall Response Rate (ORR) | Complete Response (CR) | 0 Participants |
| Amrubicin | Overall Response Rate (ORR) | Overall response rate (ORR) | 6 Participants |
Secondary
Disease Control Rate (DCR)
Disease control rate (DCR) is the sum of Complete Response (CR) rate + Partial Response (PR) rate + Stable Disease (SD) rate , and is expressed here as the sum of the Overall Response Rate (ORR = CR + PR) plus the Stable Disease (SD) rate, ORR + SD. Response was assessed by the RECIST criteria, elaborated above.
Time frame: 2 years
Population: Includes those participants with Complete Response (CR) plus those with Partial Response (PR), plus those with Stable Disease).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Amrubicin | Disease Control Rate (DCR) | Stable Disease (SD) | 23 Participants |
| Amrubicin | Disease Control Rate (DCR) | Disease control rate (DCR) | 29 Participants |
| Amrubicin | Disease Control Rate (DCR) | Overall Response Rate (ORR) | 6 Participants |
Secondary
Median Progression-free Survival (PFS)
Median Progression-free survival in patients with thymic malignancies treated with amrubicin
Time frame: 2 years
Population: Some participants (2) continue to survive without progression, although a median and the 95% confidence interval (95% CI) for the 33 participants have been defined.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Amrubicin | Median Progression-free Survival (PFS) | 8.5 Months |