| Eligibility |
Inclusion Criteria:
1. Patients must have histologically confirmed metastatic uveal melanoma with measurable
disease not eligible for curative therapy.
2. Participants must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as =20 mm with conventional
techniques or as =10 mm with spiral CT scan, MRI, or calipers by clinical exam.
Patients must have at least 1 biopsiable liver metastasis.
3. Patients who are human leucocites antigen (HLA)-A02:01 positive can have received one
prior therapy with Tebentafusp for metastatic disease.
4. Patients must be 18 years of age or older at time of study entry.
5. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
6. Capable of giving signed informed consent which includes compliance with the
requirements and restrictions listed in the informed consent form (ICF) and in this
protocol. Written informed consent and any locally required authorization obtained
from the patient/legal representative prior to performing any protocol-related
procedures, including screening evaluations not performed according to normal
practice. Patients must consent for liver metastasis biopsies donation at day 0 and
day +42 since treatment initiation.
7. Adequate normal organ and marrow function as defined below:
a) Haemoglobin =9.0 g/dL b) Absolute neutrophil count (ANC) >1.5 x 109/L (> 1500 per
mm3) c) Platelet count = 100 x 109/L (>75,000 per mm3) d) Serum bilirubin =1.5 x
institutional upper limit of normal (ULN). This will not apply to patients with
confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is
predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will
be allowed only in consultation with Coordinating Investigator e) Both aspartate
aminotrnsferase (AST) and alanine aminotransferase (ALT) must be < 5 x ULN.
f) Creatinine clearance ?40 ml/min calculated by Cockcroft-Gault or another validated
method g) Urine protein:creatinine ratio (UPC) =1 or =2+ proteinuria on 2 consecutive
dipsticks taken no less than 1 week apart h) Subjects with 2+ proteinuria on dipstick
must also have UPC < 0.5 on 2 consecutive samples.
8. Females of childbearing potential must be willing to use a highly effective method of
birth control for the duration of the study, and for 6 months after the last dose of
Tislelizumab and/or Sitravatinib, and have a negative urine or serum pregnancy test =
7 days before first administration of Tislelizumab and Sitravatinib. Women will be
considered post-menopausal if they have been amenorrheic for 12 months without an
alternative medical cause. The following age-specific requirements apply:
a) Amenorrheic for =1 year in the absence of chemotherapy and/or hormonal treatments
b) Luteinizing hormone (LH) and/or follicle stimulating hormone and/or estradiol
levels in the post-menopausal range c) Radiation induced oophorectomy with last menses
>1 year ago d) Chemotherapy induced menopause with >1 year interval since last menses
e) Surgical sterilization (bilateral oophorectomy or hysterectomy) f) Women <50 years
of age would be considered post-menopausal if they have been amenorrheic for 12 months
or more following cessation of exogenous hormonal treatments and if they have
luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal
range for the institution or underwent surgical sterilization (bilateral oophorectomy
or hysterectomy) g) Women =50 years of age would be considered post-menopausal if they
have been amenorrheic for 12 months or more following cessation of all exogenous
hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had
chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical
sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
9. For both male and female patients/partners: Contraceptive use should be consistent
with local regulations regarding the methods of contraception for those participating
in clinical studies. Non-sterile males must be willing to use a highly effective
method of birth control for the duration of the study and for = 6 months after the
last dose of Tislelizumab and/or Sitravatinib. A sterile male is defined as:
1. One for whom azoospermia has been previously demonstrated in a semen sample
examination as definitive evidence of infertility.
2. Males with known "low sperm counts" (consistent with "sub-fertility") are not to
be considered sterile for purposes of this study.
10. Patient is willing and able to comply with the protocol procedures for the duration of
the study including undergoing treatment and scheduled visits and examinations
including follow up.
11. Must have a life expectancy of at least 12 weeks
12. Subjects must be able to swallow and retain oral medications and be without clinically
significant gastrointestinal illnesses that would preclude absorption of Sitravatinib.
13. Adequately controlled blood pressure (BP):
Systolic BP =140 mmHg and diastolic BP =90 mmHg in the presence or absence of a stable
regimen of antihypertensive therapy.
Exclusion Criteria:
1. Patients with concomitant malignancy other than non-melanoma skin cancer, or
superficial bladder cancer controlled with local treatment.
2. Previous treatment with targeted therapies and/or anti-angiogenic agents such as
VEGFR, MEK, BRAF, ERK inhibitors, with the exception of Tebentafusp.
3. Previous treatment with immune checkpoint inhibitors, either anti-PD1/PD-L1 (Including
Tislelizumab), anti-CTLA-4, or other treatments.
4. Presence of brain or leptomeningeal involvement unless previously treated, off
steroids at least 2 weeks, and considered stable. Patients with untreated central
nervous system (CNS) metastases and/or carcinomatous meningitis identified either on
the baseline brain imaging [RECIST]) obtained during the screening period or
identified prior to signing the ICF. Patients whose brain metastases have been treated
may participate provided they show radiographic stability (defined as 2 brain images,
both of which are obtained after treatment to the brain metastases. These imaging
scans should both be obtained at least four weeks apart and show no evidence of
intracranial progression). In addition, any neurologic symptoms that developed either
as a result of the brain metastases or their treatment must have resolved or be stable
either, without the use of steroids, or are stable on a steroid dose of =10mg/day of
prednisone or its equivalent and anticonvulsants, for at least 14 days prior to the
start of treatment. Brain metastases will not be recorded as RECIST Target Lesions at
baseline.
5. Patients weighing <30kg will be excluded from enrollment.
6. Participation in another clinical study with an investigational product during the
last 4 weeks.
7. Concurrent enrollment in another clinical study, unless it is an observational
(non-interventional) clinical study or during the follow-up period of an
interventional study.
8. Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine
therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
antibodies) =28 days prior to the first dose of study drug. If sufficient wash-out
time has not occurred due to the schedule or Pharmacokinetic properties of an agent, a
longer wash-out period will be required, as agreed by Sponsor designated Coordinating
Investigator and Principal Investigator.
9. Any unresolved toxicity NCI CTCAE Grade =2 from previous anticancer therapy with the
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
criteria
1. Patients with Grade =2 neuropathy will be evaluated on a case-by-case basis after
consultation with the Coordinating Investigator.
2. Patients with irreversible toxicity not reasonably expected to be exacerbated by
treatment with Tislelizumab may be included only after consultation with the
Coordinating Investigator.
3. Known toxicity on prior checkpoint inhibitor treatment:
I) Grade = 3 immune-related adverse event (AE) related to checkpoint inhibitors.
II) Grade 2 immune-related AE associated with checkpoint inhibitor unless the AE
resolved or was well III) controlled by withholding the checkpoint inhibitor
and/or treatment with steroids, with the exception of prior colitis, myocarditis,
and pneumonitis, which are exclusionary.
CNS or ocular AE of any grade related to checkpoint inhibitors. Note: Patients
with a prior endocrine AE are permitted to enroll if they are stably maintained
on appropriate replacement therapy and are asymptomatic.
10. Any concurrent chemotherapy, investigational medicinal product (IMP), biologic, or
hormonal therapy for cancer treatment different to Sitravatinib and/or Tislelizumab.
Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone
replacement therapy) is acceptable.
11. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of
radiation within 4 weeks of the first dose of study drug.
12. Major surgery within a minimum of 4 weeks prior to inclusion; patients must have
recovered from any effects of any major surgery prior to inclusion. Note: Local
surgery of isolated lesions for palliative intent and minor surgeries performed to
obtain biological material for the study (i.e. liver biopsy) are acceptable.
13. History of allogeneic organ transplantation.
14. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this
criterion:
1. Patients with vitiligo or alopecia
2. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
hormone replacement
3. Any chronic skin condition that does not require systemic therapy
4. Patients without active disease in the last 5 years may be included but only
after consultation with the Coordinating Investigator
5. Patients with celiac disease controlled by diet alone
15. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled/malignant hypertension,
unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious
chronic gastrointestinal conditions associated with diarrhea, or psychiatric
illness/social situations that would limit compliance with study requirement,
compromise Sitravatinib absorption, substantially increase risk of incurring AEs or
compromise the ability of the patient to give written informed consent.
16. History of another primary malignancy except for:
1. Malignancy treated with curative intent and with no known active disease =5 years
before the first dose of IMP and of low potential risk for recurrence
2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease
3. Adequately treated carcinoma in situ without evidence of disease
17 -History of active primary immunodeficiency.
18- Active infection including tuberculosis (TB) (clinical evaluation that includes
clinical history, physical examination and radiographic findings, and TB testing in line
with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),
hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a
past or resolved HBV infection (defined as the presence of hepatitis B core antibody
[anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV)
antibodies are eligible only if polymerase chain reaction is negative for HCV RNA.
19- Current or prior use of immunosuppressive medication within 14 days before the first
dose of Tislelizumab. The following are exceptions to this criterion:
a) Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
articular injection) b) Systemic corticosteroids at physiologic doses not to exceed 10
mg/day of prednisone or its equivalent c) Steroids as premedication for hypersensitivity
reactions (e.g., CT scan premedication)
20- Receipt of live attenuated vaccine within 30 days prior to the first dose of IMP. Note:
Patients, if enrolled, should not receive live vaccines whilst receiving IMP and up to 30
days after the last dose of IMP.
21- Female patients who are pregnant (confirmed with positive pregnancy test) or
breastfeeding or male or female patients of reproductive potential who are not willing to
employ effective birth control from screening to 6 months after the last dose of
Tislelizumab and/or Sitravatinib therapy.
22- History of severe allergic reaction attributed to Sitravatinib or a similar VEGFR
inhibitor or known hypersensitivity to any component of Sitravatinib dose composition
23- Known allergy or hypersensitivity to Tislelizumab or Sitravatinib or any of the
excipients.
24- History of gastrointestinal perforation. Subjects with a history of abdominal fistula
will be eligible if:
a) the fistula has been surgically repaired, b) there is no evidence of fistula for at
least 6 months prior to inclusion, and c) the subject is deemed to be at low risk of
recurrent fistula in the opinion of the Investigator.
25- History of intra-abdominal abscess within 3 months prior to inclusion
26- Clinically significant signs and/or symptoms of bowel obstruction within 3 months prior
to inclusion
27- Resting ECG with clinically significant abnormal findings. i.e. Mean QT interval
corrected for heart rate using Fridericia's formula (QTcF) =470 ms calculated from 3 ECGs
(within 15 minutes at 5 minutes apart).
28- Subjects with any one or more of the following:
a)History of myocardial infarction within 6 months prior to inclusion; patients with a
history of myocardial infarction within 6 to 12 months prior to inclusion may be allowed
following assessment b) Unstable angina within 6 months prior to inclusion c) Known
significant cardiac disease (New York Heart Association [NYHA] classification of III or
IV).
d) Concomitant medication known to cause prolonged QT which cannot be discontinued or
changed to a different medication prior to enrollment
29- Left ventricular ejection fraction < lower limit of normal (LLN) per institutional
guidelines, or <55%, if threshold for normal is not otherwise specified by institutional
guidelines, for patients with the following risk factors:
a) Prior or planned treatment with anthracyclines (ie, PLD) b) Prior treatment with
trastuzumab c) Prior central thoracic radiation therapy (RT), including exposure of heart
to therapeutic doses of ionizing RT d) History of myocardial infarction within 6 to 12
months prior to inclusion e) Prior history of other significant impaired cardiac function.
30- History of stroke or transient ischemic attack within 6 months prior to inclusion.
31- History of significant hemorrhage within 4 weeks of first dose date.
32- Patients with:
1. With uncontrolled diabetes or > Grade 1 laboratory test abnormalities in potassium,
sodium, or corrected calcium despite standard medical management or = Grade 3
hypoalbuminemia = 14 days before
2. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent
drainage (recurrence = 14 days after intervention)
3. History of interstitial lung disease, non-infectious pneumonitis or uncontrolled lung
diseases including pulmonary fibrosis, or acute lung diseases. Patients with
significantly impaired pulmonary function, or who require supplemental oxygen at
baseline must undergo an assessment of pulmonary function at screening
33- Evidence of any other disease, physical examination or laboratory finding giving
reasonable suspicion of a disease or condition that puts the subject at high risk for
treatment-related complication.
34- Prior enrollment or treatment in a previous Tislelizumab and/or Sitravatinib
clinical study regardless of treatment arm assignment.
35- Any serious medical condition or psychiatric illness that would interfere in
understanding of the informed consent form.
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