Single-arm, multicenter, phase II study of immunotherapy in patients with type B3 thymoma and thymic carcinoma previously treated with chemotherapy - (Nivothym)

*Relapsed/advanced thymoma B3 or thymic carcinoma not amenable to
curative-intent radical treatment; *At least one previous line of
platinum-based chemotherapy for advanced disease - Patients treated with
neo-adjuvant or adjuvant platinum-based chemotherapy combined with radical
surgery or as part of radical chemoradiotherapy are eligible if chemotherapy
was completed less than 6 months before enrollment; *Radiological progression
documented per RECIST 1.1 during or after completion of previous line therapy;
*Presence of measurable disease according to RECIST 1.1.; -Disease status must
be documented by full chest and upper abdomen (including adrenal glands) CT
and/or MRI and brain CT and/or MRI within 28 days prior study enrollment. *At
least 18 years; *WHO Performance Status (PS) 0-2; *Availability of FFPE tumor
tissue (preferentially a tumor block or 10 unstained slides), notably for PD-L1
immunohistochemistry (IHC) expression assessment. Archival material is allowed.
Tissue must be considered adequate (assessed by a local pathologist) for
characterization of PD-L1 status as per procedure manual; *Adequate
hematological function: -White blood count >= 2 × 109/L; -Haemoglobin >9 g/dL;
-Platelet count >100 × 109/L; *Adequate liver function: -Total bilirubin <1.5 ×
ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0
mg/dL); -LT and/or AST <2.5 × ULN (< 4 x ULN in case of liver metastasis)
-Alkaline phosphatase <5 × ULN; *Adequate renal function: calculated creatinine
clearance >=50 mL/min (according to Cockroft-Gault, see below); -Female CrCl =
((140 - age in years) x weight in kg x 0.85)/ 72 x serum creatinine in mg/dL;
-Male CrCl = ((140 - age in years) x weight in kg x 1.00)/72 x serum creatinine
in mg/dL; *Women of child bearing potential (WOCBP) must have a negative serum
pregnancy test within 72 hours prior to the first dose of study treatment;
-Note: women of childbearing potential are defined as premenopausal females
capable of becoming pregnant (i.e. females who have had any evidence of menses
in the past 12 months, with the exception of those who had prior hysterectomy).
However, women who have been amenorrheic for 12 or more months are still
considered to be of childbearing potential if the amenorrhea is possibly due to
prior chemotherapy, antiestrogens, low body weight, ovarian suppression or
other reasons; *Patients of childbearing / reproductive potential should use
adequate birth control measures, as defined by the investigator, during the
study treatment period and for at least 5 months for a woman and 7 months for a
man after the last study treatment. Note:A highly effective method of birth
control is defined as a method which results in a low failure rate (i.e. less
than 1% per year) when used consistently and correctly. Such methods include:
-Combined (estrogen and progestogen containing) hormonal contraception
associated with inhibition of ovulation (oral, intravaginal, transdermal)
-Progestogen-only hormonal contraception associated with inhibition of
ovulation (oral, injectable, implantable) -Intrauterine device (IUD)
-Intrauterine hormone-releasing system (IUS) -Bilateral tubal occlusion
-Vasectomized partner -Sexual abstinence (sexual abstinence is only acceptable
if this is in line with the preferred and usual lifestyle of the patient)
Acceptable birth control methods that result in a failure rate of more than 1%
per year include: -Progestogen-only oral hormonal contraception, where
inhibition of ovulation is not the primary mode of action -Male or female
condom with or without spermicide -Cap, diaphragm or sponge with spermicide A
combination of male condom with either cap, diaphragm or sponge with spermicide
(double barrier methods) are also considered acceptable, but not highly
effective, birth control methods *Female patients who are breast feeding should
discontinue nursing prior to the first dose of study medication and must not
breast feed during the trial treatment and for a period of at least 5 months
following the last administration of trial drug(s); *Before patient
registration, written informed consent must be given according to ICH/GCP, and
national/local regulations.

*Any evidence of active central nervous system (CNS) metastases and/or
carcinomatous meningitis. Patients with previously treated brain metastases may
participate provided they are clinically stable (i.e. without evidence of
progression by imaging for at least four weeks prior to enrollment and any
neurologic symptoms have returned to baseline), and have not received steroids
(for a total equivalent dose of more than 10 mg of prednisone per day) for at
least 7 days prior to enrollment; *Prior treatment with anti-PD-1,
anti-PD-L1/2, anti-CD137, CTLA-4 modulators; *Presence of acetylcholine
receptor antibodies; *Current participation in any other clinical research or
treatment with an investigational agent or use of an investigational device
within 4 weeks of enrollment; *Known active Hepatitis B (e.g., positive HBsAg
result) or C (e.g., HCV RNA[qualitative] is detected) or known history or
current evidence of Human Immunodeficiency Virus (HIV) (HIV-1/2 antibodies);
*If CT has to be used, known contra-indications for CT with IV contrast;
*Chronic use of immunosuppressive agents and/or systemic corticosteroids or any
use in the last 15 days prior to enrollment; -Corticosteroid use as
premedication for IV contrast allergies/reactions is allowed; -Daily prednisone
at doses up to 10 mg or equivalent doses of any other corticosteroid is allowed
for example as replacement therapy; *History of interstitial lung disease (ILD)
OR pneumonitis (other than COPD exacerbation) that has required oral or IV
steroids; *Active autoimmune disease that has required systemic treatment in
the past 2 years (i.e. with use of disease modifying agents, corticosteroids or
immunosuppressive drugs). Replacement therapy (i.e., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment and is
allowed; *Live vaccines within 30 days prior to the first dose of study therapy
and while participating in study. Examples of live vaccines include, but are
not limited to, the following: measles, mumps, rubella, chicken pox, yellow
fever, H1N1 flu, rabies, BCG, and typhoid vaccine. *Autoimmune paraneoplastic
syndrome requiring immunosuppressive or dedicated treatment. Particular
attention should be given to detecting any minor myasthenia signs or positive
autoantibodies at enrollment; *History of any other hematologic or primary
solid tumor malignancy, unless in remission for at least 5 years. pT1-2
prostatic cancer Gleason score < 6, superficial bladder cancer, non
melanomatous skin cancer or carcinoma in situ of the cervix are allowed;
*Previous allogeneic tissue/solid organ transplant; *Active infection requiring
therapy; *Surgery or chemotherapy related toxicity that have not resolved to a
grade 1, with the exception of alopecia, fatigue, neuropathy and lack of
appetite /nausea; *Severe comorbidities that in the opinion of the investigator
might hamper participation to the study and/or treatment administration; *Any
psychological, familial, sociological or geographical condition potentially
hampering compliance with the study protocol and follow-up schedule; those
conditions should be discussed with the patient before registration in the
trial.