A Phase 2 Study of Amrubicin in Relapsed or Refractory Thymic Malignancies

• ClinicalTrials.gov Identifier: NCT01364727
• Recruitment Status: Completed
• First Posted: June 2, 2011
• Results First Posted: March 14, 2017
• Last Update Posted: April 16, 2019
• Sponsor: Heather Wakelee
• Collaborator: Celgene
• Information provided by (Responsible Party): Heather Wakelee, Stanford University

Tracking Information

• First Submitted Date: May 31, 2011
• First Posted Date: June 2, 2011
• Results First Submitted Date: January 23, 2017
• Results First Posted Date: March 14, 2017
• Last Update Posted Date: April 16, 2019
• Actual Study Start Date: June 2011
• Actual Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 17, 2017)

Overall Response Rate (ORR) [ Time Frame: 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

Original Primary Outcome Measures (submitted: May 31, 2011)

• Evaluate the Overall response rate (ORR) = (CR+PR) in patients with thymic malignancies. ORR will be assessed radiographically by RECIST criteria. [ Time Frame: 2 years ]
• Evaluate progression-free survival in patients with thymic malignancies treated with amrubicin [ Time Frame: 2 years ]

Current Secondary Outcome Measures (submitted: January 23, 2017)

• Median Progression-free Survival (PFS) [ Time Frame: 2 years ]
  Median Progression-free survival in patients with thymic malignancies treated with amrubicin
• Disease Control Rate (DCR) [ Time Frame: 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.

• Original Secondary Outcome Measures (submitted: May 31, 2011): Evaluate disease control rate (DCR = CR+PR+SD) in patients with thymic malignancies treated with amrubicin. [ Time Frame: 2 years ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase 2 Study of Amrubicin in Relapsed or Refractory Thymic Malignancies
• Official Title: A Phase II Study of Amrubicin in Relapsed or Refractory Thymic Malignancies
• 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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Other

Condition

• Thymoma
• Thymus Cancer
• Thymic Carcinoma

Intervention

Drug: Amrubicin

35 mg/m2; IV on days 1-3 each 3 week cycle

Other Name: Calsed

Study Arms

Experimental: Amrubicin

Amrubicin 35mg/m2 IV days 1-3 every 3 weeks

Intervention: Drug: Amrubicin

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 20, 2016): 33
• Original Estimated Enrollment (submitted: May 31, 2011): 39
• Actual Study Completion Date: December 31, 2018
• Actual Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01364727
• Other Study ID Numbers: IRB-20444; SU-01142011-7369 ( Other Identifier: Stanford University ); THOR0003 ( Other Identifier: OnCore )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Heather Wakelee, Stanford University
• Original Responsible Party: Heather A. Wakelee, Stanford University School of Medicine
• Current Study Sponsor: Heather Wakelee
• Original Study Sponsor: Stanford University
• Collaborators: Celgene

Investigators

• Principal Investigator: Heather A. Wakelee; Stanford University

• PRS Account: Stanford University
• Verification Date: April 2019