| Eligibility |
Inclusion Criteria:
- Age = 18 years.
- Patients must have histologically or cytologically confirmed progressive metastatic or
recurrent solid tumor (as defined below for each tumor type). Diagnosis must be stated
in a pathology report and confirmed by the physician investigator.
- Evidence of disease progression prior to trial entry.
- To be enrolled in this study, only the tumor types and settings described below are
allowed:
4.1 - Cohorts 1 A-E: DNA repair deficiency, defined as bi-allelic loss-of-function
alteration (mutation and/or deletion) in at least one of the following genes: ARID1A,
ARID2, ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, IDH1, IDH2, NBN, PALB2, PBRM1,
RAD51C, RAD51D, FANCA, NBN, RAD51, RAD54L, SMARCA4.
4.1.1 - Cohort 1A: Urothelial Bladder Cancer
- Patients must have received at least one line of prior platinum - based systemic
therapy. No more than 3 lines of previous systemic therapy for metastatic disease are
allowed.
- Relapse within 6 months of completion of adjuvant/neoadjuvant chemotherapy
containing platinum-based regimen is considered as first-line therapy.
- Previous adjuvant/neoadjuvant chemotherapy is allowed, if completed more than 6
months prior to starting the first-line therapy.
- Patients must have platinum-sensitive disease defined as disease which reaches at
least partial response after the last platinum chemotherapy line and the patient
must have progressed at least 3 months after the last cycle of chemotherapy.
- Previous exposure to one line of anti-PD-1 or anti-PD-L1 is allowed, unless
hyperprogression (Appendix 6) occurred on immunotherapy
4.1.2- Cohort 1B: Gastric or gastro-esophageal junction adenocarcinoma
- Metastatic or recurrent gastric or gastro-esophageal junction adenocarcinoma that has
progressed following at least 1 and maximum 2 prior therapies, by imaging modalities.
- Relapse within 6 months of completion of adjuvant/neoadjuvant chemotherapy is
considered as first-line therapy.
- Previous adjuvant/neoadjuvant chemotherapy is allowed, if completed more than 6 months
prior to starting the first-line therapy.
- HER2-positive and -negative amplified patients are both eligible for entry into this
study.
- Patients with HER2-positive gastric cancer must have received trastuzumab-containing
regimen prior to study entry.
- Previous exposure to anti-PD-1 or anti-PD-L1 is not allowed
4.1.3- Cohort 1C: Head and Neck Cancer
- Histologically or cytologically confirmed carcinoma of the head and neck.
- Subjects are eligible regardless of HPV status
- Relapse within 6 months of completion of adjuvant/neoadjuvant chemotherapy or
chemo-radiotherapy regimen is considered as first-line therapy
- In case of previous platinum-based therapy, tumor progression or recurrence within 6
months of last dose of platinum-based therapy is not allowed.
- Previous exposure to one line of anti-PD-1 or anti-PD-L1 is allowed, unless
hyperprogression (Appendix 6) occurred on immunotherapy
- Patients must have received at last one prior line of therapy in the advanced /
metastatic setting
- No more than 2 lines of previous systemic therapy for metastatic disease are allowed.
4.1.4- Cohort 1D: Biliary Tract Cancer and pancreatic ductal adenocarcinoma (PDAC)
- Histologically or cytologically confirmed carcinoma of the biliary tract or PDAC that
has progressed following at least 1 and maximum 2 prior therapies, by imaging
modalities.
- Previous exposure to anti-PD-1 or anti-PD-L1 is not allowed
For PDAC only:
- Patients must have received at least 16 weeks of continuous first-line platinum-based
chemotherapy without evidence of progression during that period
- Maximum of 1 prior line of therapy is allowed
4.1.5- Cohort 1E Others
- Any histology, excepted breast cancer, prostate cancer or serous ovarian cancer
(Appendix 7).
- Previous exposure to one line of anti-PD-1 or anti-PD-L1 is allowed, unless
hyperprogression (Appendix 6) occurred on immunotherapy 4.2 - Cohorts 2:
Platinum-sensitive urothelial bladder cancer
- Patients must have received at least one line of prior platinum - based systemic
therapy. No more than 3 lines of previous systemic therapy for metastatic disease are
allowed.
- Platinum-sensitive disease is defined as disease which reached at least partial
response after the last platinum chemotherapy line and progressed at least 3 months
after the last cycle of chemotherapy
- Relapse within 6 months of completion of adjuvant/neoadjuvant chemotherapy containing
platinum-based regimen is considered as first-line therapy.
- Previous adjuvant/neoadjuvant chemotherapy is allowed, if completed more than 6 months
prior to starting the first-line therapy.
- Previous exposure to one line of anti-PD-1 or anti-PD-L1 is allowed, unless
hyperprogression (Appendix 6) occurred on immunotherapy 4.3 - Cohort 3: Clear cell
Renal Cell Carcinoma
- Patients must have received at least one line of previous therapy. No more than 4
previous lines of therapy are allowed.
- Patients must have received anti-PD-1 (or anti-PD-L1) in combination with an
anti-CTLA-4 or an anti-angiogenic agent, and an antiangiogenic agent.
- Previous exposure to one line of anti-PD-1 or anti-PD-L1 is allowed unless
hyperprogression (Appendix 6) occurred on immunotherapy For all cohorts:
Representative archival formalin-fixed paraffin-embedded (FFPE) tumor specimens in
paraffin blocks (preferred) or 20 (ideally) freshly cut and unstained slides, with an
associated pathology report, for ancillary studies and/or central testing. If less
than 20 slides are available, inclusion must be discussed with the Coordinating
Investigator. In all cases, recovery of the most recent tumor block or biopsy is
encouraged. If no material is available (blocks or slides), a biopsy will be mandatory
at baseline (before the start of the treatment).
For Cohorts 1A-E:
- For patients with DNA repair gene mutation already identified by local testing,
mutational testing must have been done less than one year prior to inclusion in the
trial (i.e. signing of informed consent). Tumor block should correspond to the one
that has been used for the original testing. If no archival tissue available
feasibility of a fresh tumor biopsy at baseline should be ensured and mutation
confirmed on that tissue. Only tissue from core needle, punch or excisional biopsy
sample collection will be accepted. Other methods such as fine-needle aspiration,
brushing, bone tissue or lavage samples are not acceptable.
- For patients whose tissue will be evaluated by the Gustave Roussy DNA repair gene
panel, original or more recent tumor blocks can be used.
- At least one lesion, not previously irradiated, measurable according to RECIST
v1.1) as =10 mm in the longest diameter (except lymph nodes which must have short
axis = 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI)
and suitable for repeated assessment.
- Patients must have progressed following standard of care or not eligible to
effective standard therapy
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 with no
deterioration from registration date.
- Estimated life expectancy of greater than 12 weeks.
- Adequate hematologic and organ function, defined by the following laboratory
results obtained within 3 days prior to the first study treatment (Cycle 0 Day
1):
- Absolute neutrophil count (ANC) = 1500 cells/µL (without granulocyte
colony-stimulating factor support within 2 weeks before cycle 0 day 1).
- Lymphocyte count = 500/µL.
- Platelet count = 100.000/µL (without platelets transfusion within 2 weeks before
Cycle 0 Day 1).
- Hemoglobin = 9g/dL (patients are not allowed to be transfused with RBC or receive
erythropoietic treatment to meet this criterion).
- Total bilirubin = 1.5 ULN (subjects with documented/suspected Gilbert's disease
or liver metastases may be enrolled with bilirubin = 3 × ULN).
- Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) = 2.5 x upper
normal limit (ULN) or = 5 × ULN in case of liver involvement.
- Albumin = 28g/L.
- Serum creatinine = 1.5 x ULN or creatinine clearance = 40 mL/min (according to
Cockroft and Gault formula).
- International normalized ratio (INR) and activated partial thromboplastin time
(aPTT) = 1.5 x ULN. This applies only to patients who do not receive therapeutic
anticoagulation; patients receiving therapeutic anticoagulation (such as
low-molecular weight heparin or warfarin) should be on stable dose.
- Women of childbearing potential must have a negative serum ß-HCG pregnancy test
within 14 days prior to the administration of the first study treatment.Pregnancy
testing must be repeated within 72 hours prior to the first dose and while on
study.
- Sexually active women of childbearing potential must agree to use a highly
effective method of contraception supplemented by a barrier method, or to abstain
from sexual activity during the study and for at least 180 days after the last
study treatment administration.
- Participant must agree to not breastfeed during the study or for 180 days after
the last dose of study treatment.
- Participant must agree to not donate blood during the study or for 90 days after
the last dose of study treatment.
- Sexually active males patients must agree to use condom during the study and for
at least 180 days after the last study treatment administration. Also, it is
recommended their women of childbearing potential partner use a highly effective
method of contraception for the same duration.
- Patient should understand, sign, and date the written informed consent form prior
to any protocol-specific procedures performed.
- Patient should be able and willing to comply with study visits and procedures as
per protocol.
- Patients must be affiliated to a social security system or beneficiary of an
equivalent system.
Exclusion Criteria:
1. Participation in another clinical study with an investigational product simultaneously
and/or during the last 4 weeks (excepting observational or non-interventional clinical
studies).
2. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,
endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
antibodies, other investigational agent) 28 days prior to the first dose of study
drug, or five half lives of the previous agent, whichever is the shorter.
3. Participant has had radiation therapy encompassing >20% of the bone marrow within 2
weeks prior to Cycle 0 Day 1; or any radiation therapy within 1 week prior to Cycle 0
Day 1.
4. History of another primary malignancy within 5 years prior to Cycle 0 Day 1 except
for:
- Malignancy treated with curative intent and with no known active disease =5 years
before the first dose of study drug and of low potential risk for recurrence.
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease.
- Adequately treated carcinoma in situ without evidence of disease (eg, carcinoma
in situ of the cervix, localized prostate cancer treated surgically with curative
intent, ductal carcinoma in situ treated surgically with curative intent).
5. Treatment with systemic corticosteroids or other immunosuppressive medications
(including but not limited to prednisone, dexamethasone, cyclophosphamide,
azathioprine, methotrexate, thalidomide, and antitumor necrosis factor agents) within
2 weeks prior to Cycle 0 Day 1, or anticipated requirements for systemic
immunosuppressive medications during the trial:
o The use of inhaled corticosteroids for chronic obstructive pulmonary disease,
mineralocorticoids for patients with orthostatic hypotension, low-dose supplemental
corticosteroids for adrenocortical insufficiency and topical steroids for cutaneous
diseases are allowed.
6. Acute toxicities from previous therapies that have not resolved to Grade = 1, with the
exception of alopecia.
7. Any prior Grade =3 immune-related adverse event (irAE) while receiving any previous
immunotherapy agent, or any unresolved irAE > Grade 1.
8. Participant must not have received a platelet transfusion = 4 weeks prior to Cycle 0
Day 1.
9. Participants must not have received colony stimulating factors (eg, granulocyte
colony-stimulating factor, granulocyte macrophage colony stimulating factor, or
recombinant erythropoietin) within 4 weeks prior to Cycle 0 Day 1.
10. Participant has had any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia due
to prior chemotherapy that persisted > 4 weeks and was related to the most recent
treatment.
11. Participant must not have any known history of myelodysplastic syndrome (MDS) or acute
myeloid leukemia (AML).
12. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion proteins.
13. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster
ovary cells or to any component of the TSR-042 formulation, or to niraparib or its
components.
14. History of autoimmune disease, including but not limited to myasthenia gravis,
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid
syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome,
multiple sclerosis, vasculitis or glomerulonephritis.
- Patients with autoimmune hypothyroidism on a stable dose of thyroid replacement
hormone are eligible.
- Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen are
eligible.
15. Active or prior documented inflammatory bowel disease (e.g. Crohn's disease,
ulcerative colitis).
16. History of interstitial lung disease, idiopathic pulmonary fibrosis, drug-induced
pneumonitis, organizing pneumonia or evidence of active pneumonitis on screening chest
CT scan.
17. History of allogeneic organ transplant or prior bone marrow transplantation of double
umbilical cord blood transplantation.
18. Uncontrolled intercurrent illness including, but not limited to:
- ongoing or active infection or severe infection requiring hospitalization or IV
antibiotics within 2 weeks of starting treatment (with the exception of
prophylactic antibiotics).
- symptomatic congestive heart failure > NYHA II, superior vena cava syndrome,
uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia,
pericardial effusion, myocardial infarction within 90 days.
- active peptic ulcer disease or gastritis.
- active bleeding diatheses.
- major seizure disorder
19. Psychiatric illness/social situations that would limit compliance with study
requirements or compromise the ability of the subject to give written informed
consent.
20. Patients with known left ventricular ejection fraction (LVEF) < 40%; patients with
known coronary artery disease, congestive heart failure not meeting the above
criteria, or LVEF < 50% must be on a stable cardiologic treatment.
21. Known positive test for HIV.
22. Patients with active hepatitis B (defined as positive HBsAg test at screening) or
hepatitis C (HCV).Patients with past hepatitis B virus (HBV) infection or resolved HBV
infection (defined as having a negative HBsAg test and a positive antibody to
hepatitis B core antigen anti-HBc) are eligible.
23. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase
chain reaction (PCR) is negative for HCV RNA.
24. Active tuberculosis.
25. Administration of attenuated or live vaccine within 4 weeks prior to Cycle 0 Day 1 or
anticipation that such a live attenuated vaccine will be required during the study.
26. Major surgical procedure within 20 days prior ty Cycle 0 Day 1 or anticipation of need
for a major surgical procedure during the course of the study.
27. Uncontrolled tumor-related pain: patients requiring pain medication must be on a
stable regimen at study entry and symptomatic lesions amenable to palliative
radiotherapy should be treated prior to enrolment.
28. Uncontrolled effusion (pleural, pericardial or ascites) requiring recurrent drainage
procedures (once a month or more frequently); patients with indwelling catheters (e.g.
PleurX) are allowed.
29. Uncontrolled hypercalcemia (>1.5mmol/L ionized calcium or Ca > 12mg/dL or corrected
serum calcium >ULN) or symptomatic hypercalcemia requiring continued use of
bisphosphonate therapy or denosumab.
- Patients who are receiving bisphosphonate therapy or denosumab specifically to
prevent skeletal events and who do not have a history or clinically significant
hypercalcemia are eligible.
- Patients who are receiving denosumab prior to enrollment must be willing and
eligible to receive a bisphosphonate instead while on study.
30. History of leptomeningeal disease
- Symptomatic CNS metastasis or uncontrolled CNS metastasis, requiring increasing
doses of steroids or stable dose of steroids > 10mg prednisone qd.
- Spinal cord compression without evidence that disease has been clinically stable
for = 2 weeks prior to Cycle 0 Day 1.
31. Previous treatment with PARP inhibitors.
32. Treatment with systemic immunostimulatory agents (e.g. INF-a and IL-2) within 4 weeks
prior to Cycle 0 Day 1.
33. Patients with rare hereditary problems of galactose intolerance, the lapp lactase
deficiency or glucose galactose malabsorption
34. Any condition that, in the opinion of the investigator, would interfere with
evaluation of study treatment or interpretation of patient safety or study result.
35. Patient under guardianship or deprived of his liberty by a judicial or administrative
decision or incapable of giving its consent.
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