Discontinuation criteria
thrombosis, pulmonary embolism, death, diarrhoea, ®, fatigue, hypertension, toxicity, cancer, thrombocytopenia, thromboembolic, toxicities, thrombotic, febrile, nephrotic syndromeGrade, palmar-plantar, nausea, vomiting
THROMBOSIS, DISEASE PROGRESSION, PULMONARY EMBOLISM, MYOCARDIAL INFARCTION, LIVER METASTASES, HYPERTENSION, ADVERSE EVENTS, CANCER, THROMBOCYTOPENIA, EVENT, CEREBROVASCULAR ACCIDENT, CONGESTIVE HEART FAILURE, EVENTS, BILIARY OBSTRUCTION
Patients were permitted to discontinue from study treatment or from the study at any time at their own request, or by the discretion of the Investigator or Sponsor for safety, behavioural reasons, or for significant protocol violations. Further discontinuation reasons included objective disease progression, global deterioration of health, adverse events (as detailed below), loss to follow-up, refusal for further treatment, study termination by Sponsor, and death.Permanent discontinuation of sitravatinib was implemented in the following circumstances:Grade 3 or 4 febrile neutropeniaGrade 4 thrombocytopenia of any durationGrade 4 hypertensionGrade ≥3 palmar-plantar erythrodysaesthesiaGrade ≥3 haemorrhageGrade ≥2 thrombotic events (including thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular accident, and thromboembolic event)Development of nephrotic syndromeGrade ≥3 increased transaminaseImmune-mediated hepatitisUse of any radiation or earlier-than-planned surgery to manage cancer lesionsPregnancyImmune-mediated colitisIncrease in aspartate aminotransferase and/or alanine aminotransferase ≥3 × the upper limit of normal (ULN) and bilirubin ≥2 × ULN but without concurrent increases in alkaline phosphatase, that is not attributable to liver metastases or biliary obstruction.Permanent discontinuation from the study was considered in the following circumstances:If treatment with sitravatinib was withheld for ≥14 consecutive daysIf after receiving sitravatinib, but prior to any nivolumab dosing, patients developed toxicities that prevented the first nivolumab administrationIf significant hypertension recurred (this could also be addressed through medical management and/or dose reduction)In the event of treatment-related, grade ≥2 decreased ejection fractionFor patients requiring acute hospitalisation for treatment of congestive heart failure.Non-haematological toxicities of grade ≥3 and considered to be sitravatinib-related were managed with permanent discontinuation of sitravatinib. With the occurrence of grade 3 toxicities of nausea, vomiting, diarrhoea, and laboratory abnormalities that were adequately managed by routine supportive care (such as anti-emetics, anti-diarrhoeals, or electrolyte supplementation) and persisted for ≤72 hours, grade 3 fatigue lasting ≤8 days, or grade 3 amylase or lipase elevation, then sitravatinib treatment may be interrupted until resolution of toxicity to grade ≤1 or to baseline value and subsequently resumed at the same dose. Treatment with sitravatinib was discontinued in the presence of ≥2 g of proteinuria/24 h but could be restarted when protein levels decreased to <2 g/24 h.Required dose modifications (i.e., interruption, dose reduction, or discontinuation) for nivolumab were performed per the current OPDIVO® US Prescribing Information (USPI OPDIVO [nivolumab])