A Pilot Study to Investigate the Safety and Clinical Activity of Avelumab (MSB0010718C) in Thymoma and Thymic Carcinoma After Progression on Platinum-Based Chemotherapy
A Pilot Study to Investigate the Safety and Clinical Activity of Avelumab (MSB0010718C) in Thymoma and Thymic Carcinoma After Progression on Platinum-Based Chemotherapy
Background:
Thymoma and thymic carcinoma are cancers originating in the thymus gland. Platinum-based chemotherapy is standard treatment for them. But not uncommonly, the disease returns and people need more treatment to keep the cancer from growing. The drug Avelumab could help the immune system fight cancer.
Objective:
To test if avelumab is safe and well-tolerated, and is effective in treating relapsed or refractory thymoma and thymic carcinoma.
Eligibility:
People ages 18 and older with thymoma or thymic carcinoma that has returned or progressed after platinum-containing chemotherapy
Design:
Participants will be screened with:
Participants will have treatment in 2-week cycles. They will continue until the side effects are not tolerable or their disease gets worse. Visits at the following time points are required per protocol. Patients who respond to treatment or have durable stability after at least 12 months of therapy may undergo a dose de-escalation regimen to continue on therapy.
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. The clinical activity of checkpoint blockade targeting programmed death 1 (PD-1) and its ligand (PD-L1) has been demonstrated against various tumor types. We have demonstrated the ability of avelumab to induce major responses in patients with advanced thymoma in a phase I dose escalation study. Further investigation of avelumab in patients with TETs is needed to define the clinical activity and safety of immune checkpoint blockade in patients with TETs.
Primary Objectives
To determine the safety and tolerability of avelumab in participants with relapsed or refractory thymoma and thymic carcinoma.
To determine the objective response rate (ORR) to avelumab in participants with relapsed or refractory thymoma and thymic carcinoma.
Eligibility
Participants 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
Prior treatment with immune checkpoint inhibitors is permitted if the reason for discontinuation was not disease progression or life-threatening adverse events (laboratory abnormalities alone with prior therapy will not exclude participants from this trial)
Measurable disease by RECIST 1.1 criteria
Adequate renal, hepatic and hematopoietic function
No major surgery, radiotherapy, chemotherapy or biologic therapy within 28 days of avelumab
No prior thymic tumor-associated autoimmune disease with the exception of pure red cell aplasia and vitiligo.
Design
This will be a single-arm, pilot study to determine the clinical activity and safety of treatment with avelumab in participants with relapsed or refractory thymoma and thymic carcinoma.
Avelumab will be administered at a dose of 10 mg/kg intravenously once every two weeks until disease progression or development of intolerable adverse events. The two week period will constitute one cycle.
Per the study team s discretion, participants who respond to treatment or have durable stability after at least 12 months of therapy may undergo a dose de-escalation regimen to continue on therapy.
Toxicity will be assessed every cycle by CTCAE version 5.0.
Tumor response will be assessed after completion of every third cycle (6 weeks) using RECIST criteria, version 1.1.
When possible, a tumor biopsy will be conducted pre-treatment and on C4D43 to evaluate treatment-related, intra-tumoral changes.
INCLUSION CRITERIA:
Participants must have histologically confirmed thymoma or thymic carcinoma by the pathology department/CCR/NCI.
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.
Prior treatment of PD-1 or PD-L1-directed immune checkpoint blockade is permitted if treatment was not discontinued due to disease progression or lifethreatening adverse events per the investigators discretion (laboratory abnormalities alone with prior therapy will not exclude participants from this trial).
Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1.
Individuals aged greater than or equal to 18 years
-- Because no dosing or adverse event data are currently available on the use of Avelumab in participants <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
ECOG performance status less than or equal to 1.
Participants must have normal organ and marrow function as defined below:
Highly effective contraception for all individuals if the risk of conception exists. (Note: The effects of the study drug on the developing human fetus are unknown. Thus, individuals of childbearing potential and those able to father a child must agree to use highly effective contraception, defined as 2 barrier methods, or 1 barrier method with a spermicide, an intrauterine device or use of oral female
contraceptive. Effective contraception must be used 30 days prior to first study drug administration, for the duration of trial participation, and at least 30 days after last avelumab treatment administration if the risk of conception exists. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this trial, the treating physician should be informed immediately.)
EXCLUSION CRITERIA:
Concurrent treatment with a non-permitted drug
Concurrent anticancer treatment within 28 days before the start of trial 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 28 days before the start of trial treatment (excluding prior diagnostic biopsy); concurrent systemic therapy with immunosuppressive agents within 28 days before the start of trial treatment; use of hormonal agents for the treatment of thymic cancer within 7 days before the start of trial treatment; or use of any investigational drug within 28 days before the start of trial treatment.
--Note: Individuals receiving bisphosphonate or denosumab are eligible provided treatment was initiated at least 14 days before the first dose of avelumab.
History of previous malignant disease within the last 2 years with the following exceptions: basal or squamous cell carcinoma of the skin, cervical carcinoma in situ, ductal carcinoma in situ of the breast, papillary or follicular thyroid carcinoma, and non-muscle invasive bladder cancer.
Active autoimmune disease that might deteriorate when receiving an immune-stimulatory agent. Participants with diabetes type 1, vitiligo, psoriasis, pure red cell aplasia, Good s syndrome or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible. Anti-acetylcholine receptor antibodies will be checked during screening. Participants will be ineligible if results are positive, even if there is no clinical history of autoimmune disease.
Participants with symptomatic brain metastases will be excluded from trial secondary to poor prognosis. However, participants who have had treatment for their brain metastasis and whose brain disease has remained stable for 3 months without steroid therapy may be enrolled.
Active infection requiring systemic therapy or significant acute or chronic infections including, among others:
Prior organ transplantation including allogenic stem-cell transplantation.
Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v5 Grade greater than or equal to 3).
Persisting toxicity related to prior therapy (NCI CTCAE v5Grade > 1) however, alopecia, sensory neuropathy Grade less than or equal to 2, or other Grade less than or equal to 2 not constituting a safety risk based on investigator s judgment are acceptable.
Pregnancy or lactation period. Note: a negative pregnancy test is required for individuals of childbearing potential. Individuals who are postmenopausal (age-related amenorrhea greater than or equal to 12 consecutive months or follicle-stimulating hormone (FSH) > 40 milli international units per milliliter [mIU/ml]), or who had undergone hysterectomy or bilateral oophorectomy are exempt from pregnancy testing. If necessary to confirm postmenopausal status a FSH level will be included at screening.
Pregnant individuals are excluded from this study because Avelumab 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 Avelumab, breastfeeding should be discontinued if the mother is treated with Avelumab.