Sitravatinib and Tislelizumab in Patients With Metastatic Uveal Melanoma With Liver Metastases.

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.
• •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.