| Eligibility |
Inclusion Criteria:
Relapsed/advanced thymoma B3 and 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 surgical 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 within 28 days of study enrollment. If clinically indicated,
brain imaging must be performed
- At least 18 years;
- WHO Performance Status (PS) 0-2 Note: for the cohort of patient that will be treated
with nivolumab and ipilimumab: PS 0-1
- Availability of FFPE tumor tissue (a tumour block or 10 unstained slides), notably for
PD-L1 Immunohistochemistry (IHC) expression assessment. Archival material is allowed.
Patients will be eligible to participate regardless of the level of PD-L1 expression,
however 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);
- ALT 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. 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
- Female patients who are breast feeding should discontinue nursing prior to the first
dose of study medication and must not be breast feeding 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
Exclusion Criteria:
- No 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 the enrollment and any neurologic symptoms have returned to
baseline), and have not received steroids (for a total equivalent dose of more than
10mg 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;
- Current participation to any other clinical research nor treatment with an
investigational agent or use of an investigational device within 4 weeks of the
enrollment;
- Known history or current evidence of active Hepatitis B (e.g., HBsAg reactive) or C
(e.g., HCV RNA[qualitative] is detected) or Human Immunodeficiency Virus (HIV)
(HIV-1/2 antibodies);
- 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 othe corticosteroid
is allowed for example as replacement therapy
- No 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 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.
A specific attention should be given in order to detect any minor myasthenia signs at
enrollment; acetylcholine receptor antibodies will be systematically tested when
symptoms are suggestive of a myasthenia;
- History of any other hematologic or primary solid tumor malignancy, unless in
remission for at least 5 years. A pT1-2 prostatic cancer Gleason score < 6,
superficial bladder cancer, non melanomatous skin cancer or carcinoma in situ of the
cervix is eligible;
- Previous allogeneic tissue/solid organ transplant;
- Active infection requiring therapy;
- Surgery or chemotherapy related toxicity (toxicity resolved to 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 the
participation to the study and/or the 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;
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