Background
Platinum-based chemotherapy is the standard of care for advanced unresectable thymic
epithelial tumors (TETs). However more than half of these patients experience disease
recurrence and require second-line therapy.
There are no approved drugs for treatment of recurrent thymoma and thymic carcinoma and new
therapeutic options are needed for patients who have disease progression on or after
platinum-containing therapy.
We have demonstrated the safety and clinical activity of immune checkpoint inhibition in
patients with recurrent TETs. In an ongoing trial (NCT03076554) we have shown that avelumab,
an anti-programmed death ligand-1 (PD-L1) antibody, induces major responses and has an
acceptable safety profile.
Combination immunotherapy is under evaluation for treatment of various cancers but has not
been studied for the treatment of TETs. Immunotherapy targeting the PD-1/PD-L1 axis can be
combined with other immune checkpoint inhibitors, cancer vaccines and anti-cytokine therapy.
Bintrafusp alfa, a bifunctional fusion protein that targets PD-L1 and transforming growth
factor-b (TGF-b) has shown activity against heavily pre-treated solid tumors including
non-small cell lung cancer previously treated with single-agent anti-PD-1/PD-L1 inhibitors.
Retrospective analysis of pre-chemotherapy tissue obtained from 20 patients with stage IV
thymic carcinoma and 13 cases of stage III/IV thymoma, showed TGF-b expression in 65% cases
of thymic carcinoma and 15% cases of thymoma with a lower median survival among patients with
thymic carcinoma (30 months versus 63 months).
As part of a phase I clinical trial, treatment with bintrafusp alfa resulted in a brief
period of disease stabilization and no immune-related adverse events in one patient with
heavily pre-treated, WHO subtype B3 thymoma with a large disease burden
Further investigation of Bintrafusp alfa in patients with recurrent TETs is needed to define
the clinical activity and safety of this drug in patients with TETs.
Primary Objectives
To determine the objective response rate (ORR) to bintrafusp alfa in participants with
relapsed or refractory thymoma and thymic carcinoma.
Eligibility
Participants (Bullet) age 18 years with histologically confirmed, unresectable thymoma or
thymic carcinoma who have previously been treated with at least one platinum-containing
chemotherapy regimen with progressive disease prior to study entry or participants who have
refused chemotherapy.
Progressive and measurable disease prior to enrollment
No history of autoimmune disease, with exception of vitiligo, autoimmune thyroid disease, or
pure red cell aplasia that are adequately managed with medical therapy
Adequate renal, hepatic and hematopoietic function
Design
This will be a single-arm, phase II study to determine the clinical activity of treatment
with Bintrafusp alfa in participants with relapsed or refractory thymoma and thymic
carcinoma.
Bintrafusp alfa will be administered at a dose of 1200 mg intravenously once every two weeks
until disease progression or development of intolerable adverse events. The two-week period
will constitute one cycle.
A Simon optimal two-stage phase II trial design will be used to rule out unacceptably low
response rate of 20% in favor of an improved response rate of 45%
Participants will be enrolled in 2 disease cohorts, thymoma and thymic carcinoma, with up to
17 evaluable participants of each tumor type. Accrual ceiling will be set at 38 participants
to account for inevaluable participants.
Participants who have completed 12 months of treatment with an ongoing response or disease
stability (for > 6 months) will be given an option of discontinuing active treatment with the
ability to reinstitute treatment on one occasion if radiological or clinical disease activity
is noted during follow-up. All eligibility criteria should be met at the time of restarting
treatment with bintrafusp alfa.
Tumor response will be assessed after completion of every third cycle (6 weeks) using
modified immune-related RECIST criteria. When possible, an optional tumor biopsy will be
conducted pre-treatment, after 3 doses in participants responding to treatment or at 6 weeks,
whichever is sooner, to evaluate treatment-related, intra-tumoral changes.
Exploratory objectives include immune correlative studies to analyze immune cell subsets,
PD-L1 expression and evaluation of soluble factors and intra-tumoral changes before and after
bintrafusp alfa treatment.
- IINCLUSION CRITERIA:
- Participants must have histologically confirmed (by the pathology department/CCR/NCI)
thymoma or thymic carcinoma.
- Participants must have had at least one prior line of platinum-based chemotherapy or
participant must have refused cytotoxic chemotherapy. Progressive disease must be
documented prior to study entry and participants must have advanced, unresectable
disease that is not amenable to surgical resection.
- Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST
1.1.
- Participants must be aged >=18 years.
- ECOG performance status <=1.
- Participants must have adequate organ and marrow function as defined below:
- absolute neutrophil count: >= 1,500/mm3 OR >= 1.5 x 10(9)/L
- platelets: >=> 100,000/mm3 OR >= 100 x 10(9)/L
- hemoglobin: >= 9g/dL (may have been transfused)
- total bilirubin: <= the upper limit of normal range (ULN) OR <= 3.0 x ULN for
participants with documented metastatic disease to the liver
- AST(SGOT)/ALT(SGPT): <= 1.5 x ULN OR <= 5 x ULN for subjects with documented
metastatic disease to the liver
- ALP: <= 2.5 x ULN
- creatinine clearance: >= 60 mL/min/1.73 m2 calculated by calculated using eGRF in
the clinical lab
- INR: normal INR, per institutional guidelines
- PT: <= 1.5 x ULN
- aPTT: <= 1.5 x ULN
- Negative serum or urine pregnancy test at screening for women of childbearing
potential (WOCBP). NOTE: WOCBP is defined as any female who has experienced menarche
and who has not undergone successful surgical sterilization or who is not
postmenopausal. If necessary, to confirm postmenopausal status an FSH level will be
included at screening. The effects of Bintrafusp alfa on the developing human fetus
are unknown. For this reason, women of childbearing potential and men must agree to
use adequate contraception (hormonal or barrier method of birth control; abstinence)
prior to study entry, for the duration of study participation and for at least 2
months after the last dose of the drug.
- Participants with previously treated brain or CNS metastases are eligible provided
that the subject has recovered from any acute side effects of radiotherapy and does
not require treatment with steroids, and any whole brain radiation therapy was
completed at least 2 weeks prior to enrollment.
- Ability of subject to understand and the willingness to sign a written informed
consent document.
EXCLUSION CRITERIA:
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to bintrafusp alfa.
- History of anaphylaxis or recent (within 5 months) history of uncontrollable asthma.
- Prior treatment with PD-1 or PD-L1-directed immune checkpoint blockade is not
permitted. Prior treatment with other immunomodulating drugs such as cancer vaccines
is permitted based on investigators discretion as long as treatment was not
discontinued due to life-threatening adverse events (laboratory abnormalities alone
with prior therapy will not exclude participants from this trial).
- Concurrent treatment with a non-permitted drug
- Prior anticancer treatment within 14 days before treatment (e.g., cytoreductive
therapy, radiotherapy [with the exception of palliative bone directed radiotherapy],
immune therapy, or cytokine therapy except for erythropoietin); major surgery within
14 days before treatment (excluding prior diagnostic biopsy); prior systemic therapy
(or 5 half-lives of a drug, whichever is shorter) with immunosuppressive agents within
14 days before treatment; use of hormonal agents for anti-cancer therapy within 7 days
before treatment; or use of any investigational drug within 14 days before treatment.
Note: Subjects receiving bisphosphonate or denosumab are eligible provided treatment was
initiated at least 14 days before treatment.
- History of previous malignant disease within the last 3 years with the following
exceptions: basal or squamous cell carcinoma in situ of the skin treated with curative
intent, endoscopically resected GI cancers limited to the mucosal layer without
recurrence in > 1 year, cervical carcinoma in situ, ductal carcinoma in situ of the
breast, papillary or follicular thyroid carcinoma, and superficial/non-muscle invasive
bladder cancer.
- Active brain or CNS metastases causing clinical symptoms or metastases that require
therapeutic intervention.
- Active or history of autoimmune disease that might deteriorate when receiving an
immune-stimulatory agent, with the exception of diabetes type I, vitiligo, psoriasis,
autoimmune thyroid disease not requiring immunosuppressive treatment, or pure red cell
aplasia that are adequately managed with medical therapy. In addition,
anti-acetylcholine receptor binding and anti-striational antibodies will be checked
during screening and participants will be ineligible if results are positive, even if
there is no clinical history of autoimmune disease.
- Participants receiving systemic corticosteroids at doses > 10 mg daily prednisone
equivalent will be excluded. However, participants on inhaled steroids and adrenal
replacement steroid doses up to 10 mg daily prednisone equivalents are permitted in
the absence of autoimmune disease
- Active infection requiring systemic therapy or significant acute or chronic infections
including, among others:
- Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening
(positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test
positive).
- Known history of testing positive for HIV or testing positive for HIV at
screening or known acquired immunodeficiency syndrome.
HIV-positive TET participants are ineligible because of the risk of developing
opportunistic infections after treatment with an immune checkpoint inhibitor. Additionally,
TET participants are at higher risk of developing opportunistic infections due to
underlying immune defects. Prior cases of disseminated herpes virus, cytomegalovirus and
fungal infections have been documented in this patient population.
- Prior organ transplantation including allogenic stem-cell transplantation,
Participants who have had prior transplants that do not require immunosuppression are
eligible.
- Persisting toxicity related to prior therapy (NCI CTCAE v. 5 Grade > 1); however,
alopecia, sensory neuropathy Grade <= 2, or other Grade <= 2 not constituting a safety
risk based on investigator s judgment are acceptable.
- Participants unwilling to accept blood products as medically indicated.
- Pregnant or lactating women. Pregnant women are excluded from this study because
Bintrafusp alfa is in the class of agents known as antineoplastics/monoclonal
antibodies 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 Bintrafusp alfa, breastfeeding should be discontinued if
the mother is treated with Bintrafusp alfa.
- Known alcohol or drug abuse.
- Uncontrolled intercurrent illness including, but not limited to, symptomatic
congestive heart failure, unstable angina pectoris, cardiac arrhythmia, cerebral
vascular accident/stroke < 6 months prior to enrollment, myocardial infarction < 6
months prior to enrollment, or psychiatric illness/social situations that would limit
compliance with study requirements. All other severe acute or chronic medical
conditions including immune colitis, inflammatory bowel disease, immune pneumonitis,
drug-induced pneumonitis requiring oral or IV steroids, interstitial lung disease,
pulmonary fibrosis or psychiatric conditions including recent (within the past year)
or active suicidal ideation or behavior; or laboratory abnormalities that may increase
the risk associated with study participation or study treatment administration or may
interfere with the interpretation of study results and, in the judgment of the
investigator, would make the patient inappropriate for entry into this study.
Participants with history of bleeding diathesis or recent major bleeding events
considered by the Investigator as high risk for investigational drug treatment are
also excluded.
- Administration of live vaccine within 4 weeks prior to treatment, with the exception
of vaccination against COVID-19
