Pazopanib

DFS is defined as the interval between the date of randomization and the earliest date of disease recurrence/metastasis or death due to any cause.

The PPQ is used to measure participants' preference for pazopanib or sunitinib for renal cell carcinoma management and is used to determine a participant's preference for 1 of the 2 drugs given in the 2 double-blind treatment periods. Participants were asked to select 1 of the following: 1. prefer the drug taken as the first treatment; 2. prefer the drug taken as the second treatment; or 3, no preference. Those participants who indicated a preference were asked to select the factors that had an influence on their treatment preference, as well as the most important reason for their preference.

The PPQ is used to measure participants' preference for pazopanib or sunitinib for renal cell carcinoma management and is used to determine a participant's preference for 1 of the 2 drugs given in the 2 double-blind treatment periods. Participants were asked to select 1 of the following: 1. prefer the drug taken as the first treatment; 2. prefer the drug taken as the second treatment; or 3, no preference. Those participants who indicated a preference were asked to select the factors that had an influence on their treatment preference, as well as the most important reason for their preference.

PFS is the interval between the date of randomization and the date of progression, defined by Response Evaluation Criteria in Solid Tumors (RECIST), or death due to any cause. Per RECIST, for target lesions (TLs), disease progression (PD) is defined as \>=20% increase in the sum of the longest diameters (LD) of TLs, taking as a reference, the smallest sum LD recorded since the treatment started or the appearance of \>=1 new lesions. For non-target lesions (NTLs), PD is defined as the appearance of \>=1 new lesions and/or unequivocal progression of existing NTLs. Participants (par.) who did not progress/die were censored at the date of last adequate assessment (LAA). Par. who started a new anti-cancer therapy (ACT) prior to radiological progression/death were censored at the date of LAA prior to the new ACT. Par. who progressed/died after an extended period (\>=12 months) without adequate assessment (AA) were censored at the date of their last visit with AA prior to progression/death.

PFS was defined as the interval between the date of randomization and the earliest date of progressive disease (PD), as defined by the Independent Review Committee (IRC), or death due to any cause. The IRC defined PD per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1. Per RECIST, PD is defined as a \>=20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of \>=1 new lesion.

PFS is defined as the time from the start date of pazopanib treatment to the date of the first documented progression or death due to any cause. PFS was assessed via local review according to RECIST 1.1. PFS was censored at the date of the last adequate tumor assessment if no PFS event (disease progression or death due to any cause) was observed prior to the analysis cut-off date. The PFS distribution was estimated using the Kaplan-Meier method.

ORR was defined as the percentage of participants achieving either a Complete Response (CR) or partial Response (PR) based on the Investigator review. The responses were assessed by CT or MRI based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST1.1). CR, disappearance of all target and non-target lesions; PR, at least a 30% decrease in the disease measurement, taking as reference the disease measurement done to confirm measurable disease at study enrollment, also no new lesion or progression of any non-target measurable lesion. Confirmation was based on the disease assessment at 1 cycle or at the next scheduled visit after the initial response. Only descriptive analysis performed.

Patients with high-risk, localized prostate cancer were treated with 28 days of Pazopanib or placebo, after which they underwent radical prostatectomy. During prostatectomy, benign pelvic lymph node tissue was collected and subsequently analyzed for the average number of VEGFR1-positive clusters in 8 distinct 40x microscopic fields as an indicator of pre-metastatic niche formation.

Measured from date of randomization to date of second disease progression, 'drop-out' from protocol treatment for any reason or death, associated with each of the six two-agent sequential therapies given in parallel.

The MTD of Pazopanib in combination with Everolimus 5 mg PO QD was determined by the number of patients who experience a dose limiting toxicity (DLT). See subsequent primary outcome measure for the DLT definition. The MTD is defined as the highest dose at which fewer than one-third of patients experience a DLT. If no DLTs are observed, the MTD is not reached.

A DLT was defined as an adverse event (a) with treatment attribution of possible, probable, or definite, and (b) occurs during cycle 1, and (c) meets any of the following criteria: Grade 3 or 4 non-hematologic toxicity excluding: nausea/vomiting controlled with antiemetics, Grade 3 hypertension that resolves to ≤150/90 within 7 days with supportive care, and Grade 3 asymptomatic, clinically insignificant laboratory abnormalities (LDH, alkaline phosphatase due to bone metastases, and asymptomatic hypophosphatemia). Hematologic toxicity: Grade 4 thrombocytopenia, Grade 3 thrombocytopenia with bleeding, Grade 4 neutropenia which persists for \>7 days, Grade 4 neutropenia associated with fever \>38.5C; Hematologic toxicity excluded lymphopenia or anemia of any grade. Missing more than 5 days of planned doses for drug-related intolerable grade 2 toxicity;Toxicity related to therapy severe enough to require a dose-reduction.

The objective response rate (ORR) was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.

The starting dose of HDM201 is 60 mg once every 3 weeks. The dose escalation will be conducted according to a sequential and adaptive Bayesian scheme, using the method of TITE-CRM to determine the MTD of HDM201 in combination with pazopanib. The MTD is defined as the dose associated with a probability of Dose Limiting toxicities (DLTs) the closest to 25%. Estimation of MTD will be based upon the estimation of the probability of a DLT. DLTs are defined as any of the following adverse events (AE) graded using NCI-CTCAE occurring during the DLT period (2 first cycles) and assessed as related to at least one of the study drugs: Grade (G) ≥ 4 neutropenia, G ≥ 3 febrile neutropenia, G ≥ 4 thrombocytopenia or G3 if associated with bleeding and requires platelet transfusion. Non-laboratory AEs of G ≥3 for more than 7 days. Any G3 or G4 laboratory value if: Medical intervention is required to treat the subjects, or the abnormality leads to hospitalization.

progression-free rate at 24 weeks (24W-PFR)

MTR is defined as the highest dose of pazopanib in combination with the highest dose of MK 3475 at which no more than 1 of 6 subjects experiences a DLT after a minimum of 8 weeks of treatment. DLT is defined as a drug-related AE starting in the first 8 weeks of treatment

Laboratory assessments include haematology, clinical chemistry, urine, coagulation and thyroid function test

Vital sign measurements will include heart rate, temperature and blood pressure

Cardiac assessments will include Electrocardiogram (ECG) and Echocardiograms (ECHOs)

Subjects will be monitored for anti-MK 3475 antibodies throughout the study

PFS is defined as the interval between the date of randomization and the earlier date of disease progression (using RECIST v1.1) or death due to any cause.

To evaluate the safety assessments; adverse events, vital signs, physical examinations, electrocardiograms, multi-gated acquisition scans or echocardiograms (only for patients on pazopanib and lapatinib combination therapy), and clinical laboratory assessments.