| Eligibility |
INCLUSION CRITERIA
1. Signed informed consent form.
2. Age = 18 years.
3. 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 investigator.
4. To be enrolled in this study, only the tumor types and settings described below are
allowed:
4.1 - Cohorts 1 A-D: DNA repair deficiency, defined as bi-allelic loss-of-function
alteration (mutation and/or deletion) in at least one of the following genes: ATM,
BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, PALB2, RAD51C, RAD51D, FANCA, NBN, RAD51,
RAD54L.
4.1.1 - Cohort 1A: Non Small Cell Lung Cancer 4.1.2 - Cohort 1B: Urothelial Bladder
Cancer 4.1.3 - Cohort 1C: metastatic Castration Resistant Prostate Cancer (mCRPC)
4.1.4 - Cohort 1D: Others 4.2 - Cohorts 2A-C: Platinum-sensitive disease 4.2.1 -
Cohort 2A: Non Small Cell Lung Cancer 4.2.2 - Cohort 2B: Urothelial Bladder Cancer
4.2.3 - Cohort 2C: Gastric or gastro-esophageal junction adenocarcinoma 4.3 - Cohort
3: Metastatic Castration Resistant Prostate Cancer (mCRPC) 4.4 - Cohort 4: Clear cell
Renal Cell Carcinoma
5. Representative archival formalin-fixed paraffin-embedded (FFPE) tumor specimens in
paraffin blocks (preferred) or 20 freshly cut and unstained slides, with an associated
pathology report, for ancillary studies and central testing, is mandatory for all
cohorts. In all cases, recovery of the most recent tumor block or biopsy is encouraged
and tumor tissue has to date back from less than 3 years ago (less than 6 years for
cohort 4). Cohorts 1 and 2: if tumor tissue is more than 3 years old, a fresh tumor
biopsy is mandatory. Cohort 4: if tumor tissue is more than 6 years old, a fresh tumor
biopsy is mandatory.
- Specificities for Cohorts 1A-D:
- 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 more recent blocks are
available, these should be provided for ancillary studies, and the presence of
the mutation of interest should be confirmed on these.
- If no archival tissue is available or if tumor tissue is more than 3 years old,
feasibility of a fresh tumor biopsy at baseline (C0D1 pre-dose) should be ensured
and mutation confirmed on that tissue for cohorts 1A, 1B and 1D. 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.
- Bone biopsies are allowed for mCRPC (cohort 1C), if sufficient tumor cellularity
can be achieved.
- Specificity for cohort 3:
- If no archival tumor biopsy is available, a new fresh biopsy should be done prior
to treatment start (C0D1 pre-dose) whenever feasible; otherwise, any archival
tumor tissue will be accepted.
- Core or excisional biopsy from soft tissue or a bone biopsy is required from a
site not previously irradiated (samples from tumors progressing in a prior site
of radiation are allowed; other exceptions may be considered after Sponsor
consultation).
6. Measurable disease, defined as:
- For the non-prostate cohorts: 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.
- For prostate cohorts: At least one lesion, not previously irradiated, measurable
according to RECIST v1.1 and / or bone scan measurable disease (Cf inclusion
criteria 4) and / or measurable disease according to Prostate Cancer Working
Group Criteria 3 (PCWG3)
7. Agreement of the patient to sign the genetic analysis consent form for access to
plasma samples for ctDNA analysis.
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 with no
deterioration from registration date.
9. Estimated life expectancy of greater than 12 weeks.
10. 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).
- Platelet count = 100.000/µL (without transfusion within 2 weeks before Cycle 0
Day 1).
- Hemoglobin = 9g/dL (patients may be transfused 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 metastases.
- Albumin = 28g/L.
- Serum creatinine = 1.5 x ULN or creatinine clearance = 40mL/min .
- International normalized ratio and activated partial thromboplastin time = 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.
11. Women of childbearing potential must have a negative serum ß-HCG pregnancy test within
7 days prior to the administration of the first study treatment
12. 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 6 months after the last study
treatment administration.
13. Sexually active males patients must agree to use condom during the study and for at
least 6 months after the last study treatment administration. Also, it is recommended
their women of childbearing potential partner use a highly effective method of
contraception.
A woman is considered of childbearing potential following menarche and until becoming
post-menopausal (= 12 months of non-therapy-induced amenorrhea) unless permanently
sterile. Permanent sterilization methods include hysterectomy, bilateral oophorectomy
and bilateral salpingectomy.
A highly effective birth control method is a one which can achieve a failure rate of
less than 1% per year when used consistently and correctly. Such methods include:
combined (estrogen and progesterone containing) hormonal contraception associated with
inhibition of ovulation; progestogen-only hormonal contraception associated with
inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-releasing
system (IUS); bilateral tubal occlusion; vasectomized partner (on the understanding
that this is the only one partner during the whole study duration), and sexual
abstinence during the entire period of risk associated with study treatment. To
prevent the risk of interaction between the study drug and hormonal contraceptives,
hormonal contraceptives should be supplemented with a barrier method (preferably male
condom). Following methods are considered as unacceptable methods (non-exhaustive
list): periodic abstinence (calendar, symptothermal, post-ovulation methods) and
withdrawal (coitus interruptus).
14. Patient should understand, sign, and date the written informed consent form prior to
any protocol-specific procedures performed.
15. Patient should be able and willing to comply with study visits and procedures as per
protocol.
16. Patients must be affiliated to a social security system or beneficiary of an
equivalent system.
NON-INCLUSION CRITERIA
Any of the following would exclude the subject from participation in the study:
1. Participation in another clinical study with an investigational product during the
last 4 weeks (excepting non-interventional clinical studies) and while on study
treatment.
2. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,
endocrine therapy (excepted androgen deprivation therapy by LHRH agonists for prostate
cancer patients), 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. Prior radiation therapy within 2 weeks 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 within
2 weeks prior to Cycle 0 Day 1, or anticipated requirements for systemic
immunosuppressive medications during the trial:
. 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. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion proteins.
9. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster
ovary cells or to any component of the atezolizumab formulation.
10. History of autoimmune/immune mediated inflammatory disease, including but not limited
to colitis, pneumonitis, hepatitis, hypophysitis, nephritis, hyperthyroidism, systemic
lupus erythematous, rheumatoid arthritis, inflammatory bowel disease, Wegener's
granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, vasculitis, or
glomerulonephritis (see Appendix 2) excepted stable hypothyroidism or stable Type 1
diabetes mellitus.
11. Active or prior documented inflammatory bowel disease (e.g. Crohn's disease,
ulcerative colitis).
12. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced
pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic
organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan -
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
13. History of allogeneic organ transplant or prior bone marrow transplantation of double
umbilical cord blood transplantation.
14. 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, uncontrolled hypertension,
unstable angina pectoris, cardiac arrhythmia, pericardial effusion.
- active peptic ulcer disease or gastritis.
- active bleeding diatheses.
15. Psychiatric illness/social situations that would limit compliance with study
requirements or compromise the ability of the subject to give written informed
consent.
16. 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.
17. Known positive test for HIV.
18. 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. Patients positive for hepatitis C
virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative
for HCV RNA.
19. Active tuberculosis.
20. Administration of a live, attenuated vaccine within 4 weeks prior to Cycle 1, Day 1 or
anticipation that such a live attenuated vaccine will be required during the study. -
Influenza vaccination should be given during influenza season only (example:
approximately October to March in the Northern Hemisphere). Patients must not receive
live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to Cycle 1,
Day 1 or at any time during the study treatment or within 5 months after the last dose
of atezolizumab.
21. Major surgical procedure within 28 days prior to Cycle 0 Day 1 or anticipation of need
for a major surgical procedure during the course of the study.
22. 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 enrollment.
23. 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.
24. 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.
25. 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
26. 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.
27. Female subjects who are pregnant, breast-feeding or male or female patients of
reproductive potential who are not employing an effective method of birth control.
28. Previous treatment with PARP inhibitors.
29. Concomitant use of strong inhibitors or inducers of CYP3A4 (See Appendix 3).
30. Treatment with systemic immunostimulatory agents (e.g. INF-a and IL-2) within 4 weeks
prior to Cycle 0 Day 1.
31. Any condition that, in the opinion of the investigator, would interfere with
evaluation of study treatment or interpretation of patient safety or study result.
32. Patient under guardianship or deprived of his liberty by a judicial or administrative
decision or incapable of giving its consent.
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