ACSÉ PEMBROLIZUMAB

UNICANCER

Pr Jean-Charles Soria     Mail Soria

Clichy, Villejuif, Lyon, Marseille, Toulouse

The primary objective of the trial is to evaluate the response to pembrolizumab monotherapy in cohorts of patients with unresectable locally advanced or metastatic, rare sarcoma, rare ovarian cancer, PCNSL, rare thyroid cancer, rare malignant neuroendocrine cancer or germ-cell cancer, which is resistant or refractory to standard therapy, and for which no other treatment options are available.

Objectifs secondaires:
•    To identify populations, for which the IP is expected to have a clinical benefit.
•    To assess the efficacy of pembrolizumab monotherapy in each cohort in terms of survival, progression occurrence and quality of response.
•    To assess the safety profile of pembrolizumab monotherapy.
•    To define predictive factors including biomarkers related to the response to pembrolizumab; in particular to explore whether the immunohistochemical expression of PD-L1 and other immune markers (CD3, CD4, FOXP3, CD8 or CD68/CD163) in the tumour samples (both in the tumour cells and the immune cells) is correlated with response to pembrolizumab.
•    To test if the mutational load measured in tumour samples from some of the studied cohorts can be correlated with response to pembrolizumab.

Phase 2, non-randomised, open-label, multicentric study

1. Patient information sheet and written informed consent form signed.
2. Histologically confirmed diagnosis of a pathology corresponding to one of the following selected cancer types:
– Rare thyroid cancer: differentiated thyroid carcinoma (Papillary, follicular, Hurthle cell (oncocytic), poorly differentiated thyroid carcinoma), medullary thyroid carcinoma, anaplastic thyroid carcinoma.
– Rare malignant neuroendocrine cancer:
•    poorly differentiated tumours refractory after 2 lines of chemotherapy,
•    well differentiated tumours refractory after 4 lines of treatment,
•    carcinoid tumours after 2 lines of treatment.
3. Metastatic disease or unresectable locally advanced malignancy that is resistant or refractory to standard therapy or for which standard therapy does not exist or is not considered appropriate by the Investigator.
4. Aged ? 18 years old.
5. Measurable disease according to RECIST v1.1 guidelines for solid tumours (Eisenhauer, 2009); or IPCG response criteria (Abrey, 2005) for patients in the PCNSL cohort. For patients with germ-cell cancer measurable disease is defined as measurable according to RECIST v1.1 and / or abnormal levels of AFP, hCG and LDH.
6. Able to provide a FFPE biopsy sample of a metastatic site or primitive tumour tissue.
7. Patients must have a mandatory treatment-free interval of at least 21 days following previous systemic anti-cancer treatments.
8. Patients who have received previous systemic anticancer treatment and/or radiotherapy should have recovered from any treatment related toxicity, to a level of ? grade 1 (according to National Cancer Institute [NCI] common terminology criteria for adverse events, version 4 (CTCAE v4) with the exception of Grade 2 alopecia.
9. Adequate hematologic function (absolute neutrophil count ? 1.0 x109/L, platelets ? 100 x109/L, haemoglobin ? 9 g/L) measured within 14 days of treatment initiation.
10. Adequate renal function (creatinine clearance ? 50 mL/min using the MDRD or CKI EPI method) measured within 14 days of treatment initiation.
11. Adequate hepatic function (serum bilirubin ? 1.5 xULN unless due to Gilbert’s syndrome; aspartate aminotransferase [ASAT] and alanine aminotransferase [ALAT] ? 3 xULN) measured within 14 days of treatment initiation. For patients with documented liver metastasis ASAT/ALAT ? 5x ULN is acceptable.
12. Strictly normal blood levels of calcium and magnesium, measured within 14 days of treatment initiation.
13. Eastern Cooperative Oncology Group Performance Status of ? 1.
14. Estimated life expectancy ? 90 days.
15. Patients who are sexually active must agree to use a medically accepted method of contraception (e.g. implants, injectables, combined oral contraceptives, some intrauterine devices or vasectomized partner, for participating women; condoms for participating men) or practice complete abstinence, beginning 14 days before the first administration of IP, while on treatment and for at least 5 months after the last administration of IP for female patients, and 7 months after the last administration of IP for male patients.
16. Women of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to the first administration of IP. If urine test results are positive or cannot be confirmed as negative, a serum pregnancy test will be required.
17. Women who are breastfeeding should discontinue nursing prior to the first administration of IP and for at least 120 days after the last administration of IP.
18. Patients must be affiliated to a Social Security System or equivalent.

Patients meeting any of the following criteria will be excluded from participation in the study:
1. Prior treatment with an anti-PD1 or anti-PD-L1 antibody.
2. Eligible, and willing, to participate in a clinical trial of an alternative anticancer therapy targeting their disease, which is open to accrual in France.
3. Concurrent steroid medication at a dose greater than prednisone 10 mg/day or equivalent. For patients with PCNSL or germ-cell cancer, concurrent steroid medication at a dose greater than prednisone 20 mg/day or equivalent.
4. Has 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 (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
5. History of (non-infectious) pneumonitis that required steroids, or current pneumonitis.
6. History of severe hypersensitivity reaction to any monoclonal antibody therapy
7. Radiotherapy (except for brain and extremities) within 21 days prior to the first administration of IP.
8. Treatment with other investigational drugs or participation in another clinical trial within 21 days prior to the first administration of IP or concomitantly with the trial.
9. Has known symptomatic central nervous system (CNS) metastases. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment.
10. Has known carcinomatous meningitis or a history of leptomeningeal disease except for patients with primary CNS lymphoma.
11. Serum creatinine > 1.5 xULN or glomerular filtration rate < 50 ml/min.
12. Lymphocytes count below 1,000/mm3 and CD4+ count below 500/mm3 as assessed by routine blood phenotyping.
13. Other malignancies within the past 5 years other than basal cell skin cancer or in situ carcinoma of the cervix.
14. Active serious infections in particular if requiring systemic antibiotic or antimicrobial therapy.
15. Active or chronic hepatitis B, hepatitis C and/or human immunodeficiency virus infection (HIV 1/2 antibodies), or a known history of active Tuberculosis bacillus.
16. Live vaccine received within 30 days of planned start of study treatment.
17. Active alcohol or drug abuse.
18. Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule.
19. Any condition which in the Investigator’s opinion makes it undesirable for the subject to participate in the trial or which would jeopardize compliance with the protocol.

300 au total, 20-50 par cohorte