PRIMARY OBJECTIVES:
I. To assess the safety and tolerability of the combination of trabectedin and avelumab in
subjects with advanced leiomyosarcoma and liposarcoma.
II. To assess the objective response rate of advanced L-type sarcoma patients receiving the
combination regimen of avelumab and trabectedin.
SECONDARY OBJECTIVE:
I. To further explore the clinical activity and safety profile of avelumab and trabectedin as
a combination therapy.
OUTLINE:
Avelumab will be administered every 2 weeks. Trabectedin will be administered every 3 weeks
for the first two doses (Week 1 and Week 4), and then every four weeks (Week 7, Week 11,…)
moving forward. After Cycle 2 of trabectedin, dosing may extend to every 5 weeks at
investigator discretion, for management of trabectedin-associated toxicity only. Delays of
trabectedin beyond 5 weeks may be allowed but require written approval from the
Sponsor-Investigator. On days where both drugs are scheduled to be administered, avelumab
will be administered first. This will continue until unacceptable toxicity or confirmed
disease progression.
After completion of study treatment, patients are followed up at 30 and 90 days, then every
12 weeks for 2 years.
Inclusion Criteria:
- Must have a histologically confirmed diagnosis of advanced (metastatic or
unresectable) soft tissue sarcoma with one of the following subtypes:
- Leiomyosarcoma
- Liposarcoma
- Subject must be clinically indicated to receive trabectedin therapy as part of routine
care. Subjects may be first line, or have receive any number of prior systemic
therapies
- Total bilirubin level =< 1.5 x the upper limit of normal (ULN) mg/dL
- Aspartate aminotransferase (AST) =< 2.5 x ULN and alanine aminotransferase (ALT) =<
2.5 x ULN
- Alkaline phosphatase < 2.5 x ULN
- Serum creatinine =< 1.5 x ULN
- Calculated creatinine clearance >= 30 mL/min using the Cockcroft-Gault formula may be
included
- Creatinine phosphokinase (CPK) =< 2.5 x ULN
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
- Platelet count >= 100,000/mm^3 (100 x 10^9/L)
- Hemoglobin >= 9 g/dL
- Subject must demonstrate a left ventricular ejection fraction (LVEF) > 45% by
echocardiography (ECHO) or multigated acquisition scan (MUGA)
- Male or non-pregnant and non-breast feeding female:
- Females of child-bearing potential must agree to use highly effective
contraception without interruption from initiation of therapy and while on study
medication and have a negative serum pregnancy test (beta - human chorionic
gonadotropin [hCG]) result at screening and agree to ongoing pregnancy testing
during the course of the study, and at the end of study treatment; a highly
effective method of contraception is defined as one that results in a low failure
rate (that is, < 1% per year), when used consistently and correctly, such as
implants, injectables, combined oral contraceptives, some intrauterine
contraceptive devices, sexual abstinence, or a vasectomized partner
- Male subjects must practice abstinence or agree to use a condom during sexual
contact with a pregnant female or a female of childbearing potential while
participating in the study
- All ongoing toxicities related to prior therapies must be resolved to grade 1 or
better (except alopecia)
- Subject must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 1
or Karnofsky performance scale >= 70
- Subjects must have one or more measurable lesions, as determined by Response
Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 assessed by computed
tomography (CT) or magnetic resonance imaging (MRI)
- Subjects must have a life expectancy of >= 6 months, as determined by the treating
physician
- Ability to understand and sign informed consent document
- Willingness and ability to comply with the scheduled visits, laboratory tests, and
other study procedures
Exclusion Criteria:
- Known active, uncontrolled, or symptomatic central nervous system (CNS) metastases; a
subject with controlled and asymptomatic CNS metastases may participate in this study;
as such, the subject must have completed any prior treatment for CNS metastases >= 28
days (including radiotherapy and/or surgery) prior to the start of treatment in this
study and should not be receiving chronic corticosteroid therapy in excess of 10 mg
daily prednisone (or equivalent) for CNS metastases; subjects with known CNS
metastases must be confirmed radiographically stable by at least one imaging study, at
least 28 days from last treatment
- Receipt of any type of cytotoxic, biologic, or other systemic anticancer therapy
(including investigational) within 2 weeks of enrollment
- Prior organ transplantation, including allogeneic stem cell transplantation
- Prior treatment with trabectedin
- Significant acute or chronic infections including, among others:
- Known history of testing positive test for human immunodeficiency virus (HIV) or
known acquired immunodeficiency syndrome (AIDS)
- Known active infection with hepatitis B or hepatitis C
- Active autoimmune disease that might deteriorate when receiving an immunostimulatory
agent:
- Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease
not requiring immunosuppressive treatment are eligible
- Subjects requiring hormone replacement with corticosteroids are eligible if the
steroids are administered only for the purpose of hormonal replacement and at
doses =< 10 mg or 10 mg equivalent prednisone per day
- Administration of steroids through a route known to result in a minimal systemic
exposure (topical, intranasal, introocular, or inhalation) are acceptable
- Known severe hypersensitivity reactions to monoclonal antibodies (grade >= 3 National
Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version
[v] 5.0), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more
features of partially controlled asthma)
- Pregnancy or lactating females
- Known alcohol or drug abuse
- All other significant diseases (for example, inflammatory bowel disease, uncontrolled
asthma), which, in the opinion of the investigator, might impair the subject's
tolerance of trial treatment
- Any vaccination within 4 weeks of the first dose of avelumab, with the following
exceptions:
* Administration of inactivated vaccines, including inactivated flu vaccines, are
allowable; however, they should not be given within 2 weeks prior to starting study
treatment
- Clinically significant cardiovascular disease including cerebral vascular
accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months
prior to enrollment), congestive heart failure with New York Heart Association (NYHA)
class II or greater or serious cardiac arrhythmia requiring medication
- Severe (requiring active treatment) acute or chronic medical conditions including:
colitis, inflammatory bowel disease, pneumonitis, or pulmonary fibrosis
- Recent (within the past year) or active suicidal ideation or behavior
