| Eligibility |
Inclusion Criteria:
1. Able to provide written informed consent and can understand and comply with the
requirements of the study;
2. Male or female patients, age = 18 years;
3. Patients with histologically or cytologically confirmed advanced (metastatic and/or
unresectable) solid tumors that is incurable and have progressed during or after
standard therapy or for which treatment is not available, or not tolerated;
4. Patients are able to provide fresh or archival tumor tissues (FFPE block or unstained
slides). In the absence of archival tumor tissues, a fresh biopsy of a tumor lesion at
baseline is recommended;
5. Patient must have at least one measurable lesion as defined per RECIST v1.1;
6. Eastern Cooperative Oncology Group (ECOG) Performalesce Status =1;
7. Life expectancy =12 weeks;
8. Vital organ function, defined as:
Absolute neutrophil count (ANC) = 1.5 × 109/L, platelets = 100 × 109/L, hemoglobin =
100 g/L.(Patients must not have required a blood transfusion or growth factor support
=14 days before sample collection); Serum creatinine = 1.5 × upper limit of normal
(ULN), or calculated creatinine clearance = 51 mL/min using Cockcroft-Gault equation
for patients with creatinine levels > 1.5×ULN; Aspartate transaminase (AST) and
alanine aminotransferase (ALT) = 2.5 × ULN, unless liver metastases are present, in
which case they must be = 5× ULN,ALP=2.5 TIMES ULN (=5 times ULN if tumor bone
metastasis is present); Total bilirubin (TBIL) = 1.5ULN; Patients with Gilbert
syndrome should communicate with the sponsor medical examiner whether they can be
enrolled in the group; Serum albumin = 30 g/L; International standardized ratio (INR)
or prothrombin time (PT) = 1.5X ULN and activated partial thrombin time (aPTT) = 1.5x
ULN in patients who did not receive anticoagulant therapy; For those receiving
anticoagulant therapy (e.g., low molecular weight heparin or warfarin), the
anticoagulant dose should be stable for at least 4 weeks without dose adjustment; TSH
within the normal range (if TSH is not within the normal range, free triiodothyronine
(FT3) and free thyroxine (FT4) should be within the normal range.); Urinary protein
-/+, if urinary protein =2+, additional 24-hour urine protein quantification test is
required, such as 24-hour urine protein quantification <1g can be included in the
group; Serum lipase or amylase =1.5 × ULN or >1.5 × ULN(no clinical or imaging
confirmed pancreatitis); Fridericia's QT interval (QTc) prolongation: female= 470 ms,
male= 450 ms at screening.
9. Ability to swallow oral medications (capsules and tablets) without chewing, breaking,
crushing, opening or otherwise altering the product formulation;
10. Toxicities of prior therapy (excepting alopecia) should be resolved to Grade= 1 as per
Common Terminology Criteria for Adverse Event (CTCAE) v 5.0;
11. Females of reproductive age, and males whose partners are females of reproductive age,
are required to use a medically approved contraceptive method (such as an intrauterine
device (IUD), birth control pills or condoms) during and for 90 days after the study
period; The serum HCG test of female patients of childbearing age must be negative
within 7 days before study enrollment. And must be non lactation period;
12. For Phase Ib patients, the following requirements must be met:
Cohort A: Patients with recurrent or advanced endometrial cancer must meet the following
criteria:
- Have progressed on or after platinum doublet therapy or intolerance to standard
therapy
- Have received = 2 prior lines of systemic therapies for recurrent or advanced disease.
Patients may have received up to 1 additional line of chemotherapy if given in the
neoadjuvant or adjuvant treatment setting, which may be concurrent or followed with
chemoradiation).
Note: There is no restriction regarding prior hormonal therapy.
Cohort B: HRRm HER2-negative breast cancer patients with metastatic or locally advanced
disease, which is unresectable, must meet the following criteria:
- For relapsed or advanced disease, progression follows systemic treatment of 0 to 3
lines; Hormone receptor positive (HR+) disease progressed on =1 endocrine therapy
(adjuvant or metastatic), or not suitable, prior CDK 4/6i are allowed
- Patients must have documented evidence of a known deleterious or suspected deleterious
germline orsomatic HRR gene mutations
- If patients have received platinum therapy, there should be:
In advanced setting: no evidence of objective disease progression while receiving platinum
In (neo-)adjuvant setting: disease-free interval of =6 months after the last dose
Cohort C: Patients with small cell lung cancer (SCLC) must meet the following criteria:
• Extensive small-cell lung cancer (according to the American Veterans Lung Cancer
Association VALG stage) with progression on or intolerance to standard therapy
Cohort D: Patients with recurrent or advanced stage III B-C or IV (AJCC Version 8) NSCLC
must meet the following criteria:
- No known EGFR-sensitising mutations and ALK fusion, testing is not mandatory for
patients with squamous cell cancer
- 1)PD-L1 TPS=1%, has not received any prior systemic antitumor therapy.Prior use of
neoadjuvant and/or adjuvant antitumor therapy is permitted provided that the time
between the end of the (new) adjuvant therapy and the onset of recurrence/metastasis
is =6 months. Or 2) Have progressed after at least 1 prior systemic therapy for
recurrent or advanced disease or intolerance to standard thera, first-line use of
PD-1/PD-L1 inhibitors (either monotherapy or combination chemotherapy) is allowed, but
those who have previously received PARP inhibitors cannot be included.
Cohort E: Other tumor types that may carry DNA damage repair defects that are sensitive to
PARP inhibitors or ikely to be responsive to PD-L1/PD-1 inhibitors,including but not
limited to, advanced or metastatic nasopharyngeal carcinoma, recurrent epithelial ovarian
cancer, metastatic castration-resistant prostate cancer, locally advanced or metastatic
urothelial carcinoma (muscular-invasive bladder cancer, ureteral cancer, urethral or pelvic
cancer), and advanced or metastatic pancreatic adenocarcinoma.
Exclusion Criteria:
1. Major surgery (as defined by the investigator) within 4 weeks of starting study
treatment and patient must have recovered from any effects of any major surgery; Note:
Local palliative treatment (eg. local surgery or radiotherapy) for isolated lesions is
allowed, if not affecting the efficacy evaluation;
2. Patient has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Patients with spinal cord compression unless considered to have received
definitive treatment for this and evidence of clinically stable disease for 4 weeks;
Note: Patients with previously treated brain metastases may participate provided they
are stable and have no symptoms.Asymptomatic patients with brain metastases found at
screening phase are eligible.Carcinomatous meningitis precludes a patient from study
participation regardless of clinical stability.
3. Patient has an active autoimmune disease or autoimmune disease that has required
systemic treatment in the past 2 years (ie, 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.
Note: ? Autoimmune diseases include but are not limited to systemic lupus
erythematosus, interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis,
nephritis, hyperthyroidism or multiple sclerosis; ? patients with vitiligo or in
childhood asthma has complete remission, adult patients without any intervention can
be incorporated into; ? in chronic obstructive pulmonary disease (COPD), asthma need
continuous use of bronchiectasis, inhaled corticosteroids, or local injection of
corticosteroids can into the group of patients.
4. Prior malignancy within the previous 5 years except for locally curable cancers that
have apparently been cured (eg, basal or squamous cell skin cancer, or carcinoma in
situ of the cervix, breast);
5. Patient is considered a poor medical risk due to a serious, uncontrolled medical
disorder, non-malignant systemic disease. Specific examples include, but are not
limited to, uncontrolled hypertension (systolic blood pressure >160 mmHg, diastolic
blood pressure >100 mmHg); recent (within 90 days) NYHA=3 heart failure, unstable
angina, unstable arrhythmia, myocardial infarction or cerebrovascular accident
(including transient ischemic attack), deep vein thrombosis and pulmonary embolism;
LVEF<50%;; superior vena cava syndrome; or any psychiatric or substance abuse
disorders that would interfere with cooperation with the requirements of the study
(including obtaining informed consent);
6. Severe chronic or active infections (including tuberculosis infection, etc) requiring
systemic antibacterial, antifungal, or antiviral therapy within 14 days prior to first
dose of study drugs; Patients with active tuberculosis (TB) who are receiving anti-TB
treatment or have received anti-TB treatment within 1 year prior to screening;
7. Patients who have a history of or are currently developingpneumonitisrequiring steroid
treatment, including but not limited to interstitial pneumonia, radiation pneumonia,
pulmonary fibrosis, or machine-induced pneumonia;
8. Prior bone marrow allogeneic transplantation or solid organ transplantation;
9. Patient has any known history of MDS/AML or a pre-treatment cytogenetic testing result
at risk for a diagnosis of MDS/AML;
10. Patients who had prior therapy of an anti-PD-1, anti-PD-L1, anti-PD-L2(SCLC and NSCLC
cohorts were excluded) or prior treatment with a PARPi;
11. Patient is currently participating and receiving study therapy or has participated in
a study of an investigational agent and received study therapy within 4 weeks of the
first dose of treatment;
12. Prior chemotherapy or other systemic anticancer therapy (eg, targeted therapy) within
4 weeks prior to start of study treatment; 6 weeks for nitrosoureas or mitomycin.
Hormonal therapy for cancer treatment is allowed until 7 days prior to study
treatment. Any herbal medicine used to control cancer within 14 days of the first
study treatment;
13. Requirement for systemic treatment with corticosteroids or other immunosuppressive
medications within 2 weeks of study drug administration. Intranasal, inhaled, topical
steroids, or local steroid injections (eg, intra-articular injection), or systemic
corticosteroids at physiologic doses (prednisone=10 mg/day or its equivalent), or
steroids as premedication for hypersensitivity reactions (eg, contrast agent allergy)
are allowed;
14. Concomitant use of known strong cytochrome CYP3A4 inhibitors (eg, itraconazole,
telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or
cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir). The required
washout period prior to starting senaparib is 2 weeks;
15. Concomitant use of known strong CYP3A4 inducers (eg, phenobarbital, enzalutamide,
phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's
Wort) . The required washout period prior to starting senaparib is 5 weeks for
enzalutamide or phenobarbital and 3 weeks for other agents;
16. Use of live attenuated vaccines within 30 days of initiation of study therapy; Note:
Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to
30 days after the last dose of IP;
17. Patients known to have active hepatitis (i.e., hepatitis B or C) or humales
immunodeficiency virus (HIV) positive:
- Hepatitis B core antibody (HBcAb) positive and hepatitis B surface antigen
(HBsAg) negative during screening period can participate in this study; Before
enrollment, such patients must be tested for HBV DNA, whose HBV DNA is less than
the lower limit of detection before enrollment;
- Subjects who are HBsAg positive and whose HBV DNA is below the test threshold can
be enrolled, assessed by the investigator at risk, and treated with anti-HBV
therapy to avoid viral activation throughout the study, if necessary;
- Patients with positive hepatitis C virus (HCV) antibodies can only be enrolled if
the HCV RNA test results are negative
18. Patient has a known hypersensitivity to senaparib or toripalimab components or
excipients;
19. Judgment by the investigator that the patient is unsuitable to participate in the
study and the patient is unlikely to comply with study procedures, restrictions and
requirements.
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