A study to evaluate the safety, pharmacokinetics, pharmacodynamics and therapeutic activity of RO7009789 (selicrelumab) in combination with vanucizumab or bevacizumab in patients with metastatic solid tumors

Part I (dose escalation):
1. Percentage of participants With Dose-Limiting Toxicities (DLTs) measured using the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.03 (NCI-CTCAE v 4.03) between 1 and 28 days. DLTs will be defined as an adverse event or abnormal laboratory value, (judged clinically significant by the investigator) considered related to selicrelumab and/or vanucizumab that occurrs during the first 28 days of treatment.
2. Maximum Tolerated Dose (MTD) of selicrelumab in combination with vanucizumab measured using the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.03 (NCI-CTCAE v 4.03) between 1 and 28 days. MTD will be defined as the dose level for which the probability of DLT (as defined above) was equal to a protocol-specified target probability.
3. Recommended Phase II Dose (RP2D) of selicrelumab in combination with vanucizumab calculated from the MTD (as defined above) which was measured between 1 and 28 days
4. Percentage of participants with Anti-Drug Antibodies (ADAs) to vanucizumab measured from serum samples taken predose (within 10 min before infusion) on day 1 of cycles 1, 2, 4, and every 2 cycles until disease progression and/or 45 days after the last dose (up to approximately 42 months).

Parts I (dose escalation) and II (expansion):
1. Percentage of Participants With Adverse Events (AEs) measured between day 1 and treatment discontinuation and/or safety follow up visit (45 days post-last dose, up to approximately 42 months). An AE will be defined as any untoward medical occurrence in a participant who received a pharmaceutical product, and which did not necessarily have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Any new disease or preexisting conditions which worsen during a study are also considered adverse events.
2. Percentage of Participants With Anti-Drug Antibodies (ADAs) to selicrelumab measured from serum samples taken predose (-1 h) on day 2 of cycles 1, 2, 3, 4, 7, and every 3 cycles until disease progression and/or 45 days after the last dose (up to approximately 42 months).

Part II (expansion):
1. Overall Response Rate (ORR) measured using local protocol for oncological imaging and evaluated using the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Criteria from baseline until the first documentation of a complete or partial response, or participant's discontinuation or death, whichever occurs first (up to approximately 42 months). The ORR will be defined as the percentage of participants with confirmed complete response (disappearance of all target lesions) and partial response (at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters) on two consecutive occasions ≥4 weeks apart, as determined by the investigator.
2. Duration of Objective Response (DOR) measured using local protocol for oncological imaging and evaluated using the RECIST v1.1 Criteria from baseline until participant's discontinuation or death, whichever occurs first (up to approximately 42 months). DOR will be defined as the time from the first occurrence of a documented objective response to the time of relapse or death from any cause, and will be analysed in participants who have a best overall response of either a complete or partial response.
3. Disease control rate (DCR) measured using local protocol for oncological imaging and evaluated using the RECIST v1.1 Criteria from baseline until participant's discontinuation or death, whichever occurs first (up to approximately 42 months). DCR will be defined as the percentage of participants who achieved a best overall response of confirmed complete response, confirmed partial response, or stable disease lasting at least 8 weeks. Where complete and partial response are defined above and stable disease is defined as neither sufficient shrinkage to qualify for partial response, nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of the diameters while on study. Progressive disease is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline.
4. Clinical Benefit Rate (CBR) measured using local protocol for oncological imaging and evaluated using the RECIST v1.1 Criteria from baseline until participant's discontinuation or death, whichever occurs first (up to approximately 42 months). CBR will be defined as the percentage of participants who achieved a best overall response of confirmed complete response, confirmed partial response, or stable disease.
5. Progression-free Survival (PFS) measured using local protocol for oncological imaging and evaluated using the RECIST v1.1 Criteria from baseline until participant's discontinuation or death, whichever occurs first (up to approximately 42 months). PFS will be defined as the time from the start of treatment to radiographical disease progression (as defined above) or death, whichever occurred first. If no disease progression was recorded and no death occurred within 100 days from the last tumor assessment, participants were censored at the last tumor assessment. If no post-baseline tumor assessment was performed, participants were not evaluable.

Part I (dose escalation):
1. Overall Response Rate (ORR) measured using local protocol for oncological imaging and evaluated using the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Criteria during tumor assessments at baseline and on day 1 of cycle 3, 5, and 7, and every 12 weeks thereafter, until disease progression until the first documentation of a complete or partial response, or participant's discontinuation or death, whichever occurs first (up to approximately 42 months). The ORR will be defined as the percentage of participants with confirmed complete response (disappearance of all target lesions) and partial response (at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters) on two consecutive occasions ≥4 weeks apart, as determined by the investigator.
2. Duration of Objective Response (DOR) measured using local protocol for oncological imaging and evaluated using the RECIST v1.1 Criteria during tumor assessments at baseline and on day 1 of cycle 3, 5, and 7, and every 12 weeks thereafter, until disease progression until the first documentation of a complete or partial response, or participant's discontinuation or death, whichever occurs first (up to approximately 42 months). DOR will be defined as the time from the first occurrence of a documented objective response to the time of relapse or death from any cause, and will be analysed in participants who have a best overall response of either a complete or partial response.
3. Disease control rate (DCR) measured using local protocol for oncological imaging and evaluated using the RECIST v1.1 Criteria during tumor assessments at baseline and on day 1 of cycle 3, 5, and 7, and every 12 weeks thereafter, until disease progression until the first documentation of a complete or partial response, or participant's discontinuation or death, whichever occurs first (up to approximately 42 months). DCR will be defined as the percentage of participants who achieved a best overall response of confirmed complete response, confirmed partial response, or stable disease lasting at least 8 weeks. Where complete and partial response are defined above and stable disease is defined as neither sufficient shrinkage to qualify for partial response, nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of the diameters while on study. Progressive disease is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline.
4. Clinical Benefit Rate (CBR) measured using local protocol for oncological imaging and evaluated using the RECIST v1.1 Criteria during tumor assessments at baseline and on day 1 of cycle 3, 5, and 7, and every 12 weeks thereafter, until disease progression until the first documentation of a complete or partial response, or participant's discontinuation or death, whichever occurs first (up to approximately 42 months). CBR will be defined as the percentage of participants who achieved a best overall response of confirmed complete response, confirmed partial response, or stable disease.
5. Progression-free Survival (PFS) measured using local protocol for oncological imaging and evaluated using the RECIST v1.1 Criteria during tumor assessments at baseline and on day 1 of cycle 3, 5, and 7, and every 12 weeks thereafter, until disease progression until the first documentation of a complete or partial response, or participant's discontinuation or death, whichever occurs first (up to approximately 42 months). PFS will be defined as the time from the start of treatment to radiographical disease progression (as defined above) or death, whichever occurred first. If no disease progression was recorded and no death occurred within 100 days from the last tumor assessment, participants were censored at the last tumor assessment. If no post-baseline tumor assessment was performed, participants were not evaluable.
6. Area Under the concentration-time Curve from time 0 to last measurable concentration of vanucizumab (AUClast) following subcutaneous (SC) administration measured from serum samples taken at predose on day 1 of cycle 1, 2, 4, 6, 8, and every 2 cycles thereafter until disease progression and/or 45 days after last dose, predose and at end of infusion on day 15 of each cycle until disease progression and/or 45 days after last dose, and 6 and 24 h postdose on day 15 of cycle 1 and 8
7. Area Under the concentration-time Curve from time 0 to infinity (until participant's discontinuation or death, whichever occurs first, up to approximately 42 months) of vanucizumab (AUCinf) following subcutaneous (SC) administration measured from serum samples taken at predose on day 1 of cycle 1, 2, 4, 6, 8, and every 2 cycles thereafter until disease progression and/or 45 days after last dose, predose and at end of infusion on day 15 of each cycle until disease progression and/or 45 days after last dose, and 6 and 24 h postdose on day 15 of cycle 1 and 8
8. Concentration at the end of infusion (Cend) of vanucizumab measured from serum samples taken at predose on day 1 of cycle 1, 2, 4, 6, 8, and every 2 cycles thereafter until disease progression and/or 45 days after last dose, predose and at end of infusion on day 15 of each cycle until disease progression and/or 45 days after last dose, and 6 and 24 h postdose on day 15 of cycle 1 and 8
9. Apparent Clearance (CL/F) of vanucizumab measured from serum samples taken at predose on day 1 of cycle 1, 2, 4, 6, 8, and every 2 cycles thereafter until disease progression and/or 45 days after last dose, predose and at end of infusion on day 15 of each cycle until disease progression and/or 45 days after last dose, and 6 and 24 h postdose on day 15 of cycle 1 and 8
10. Apparent volume of distribution at steady state (Vss) of vanucizumab measured from serum samples taken at predose on day 1 of cycle 1, 2, 4, 6, 8, and every 2 cycles thereafter until disease progression and/or 45 days after last dose, predose and at end of infusion on day 15 of each cycle until disease progression and/or 45 days after last dose, and 6 and 24 h postdose on day 15 of cycle 1 and 8.
11. Apparent Terminal Half-Life (t1/2) of vanucizumab measured from serum samples taken at predose on day 1 of cycle 1, 2, 4, 6, 8, and every 2 cycles thereafter until disease progression and/or 45 days after last dose, predose and at end of infusion on day 15 of each cycle until disease progression and/or 45 days after last dose, and 6 and 24 h postdose on day 15 of cycle 1 and 8.

Parts I (dose escalation) and II (expansion):
1. AUClast of selicrelumab following subcutaneous (SC) administration measured from serum samples taken at -1, 4, 8, 24, 48, and 72 h of cycle 1 and taken at -1 and 8 h of cycle 3, 4, 5, 7 and every 3 cycles thereafter until disease progression and/or 45 days after the last dose (up to approximately 42 months)
2. AUCinf of selicrelumab following subcutaneous (SC) administration measured from serum samples taken at -1, 4, 8, 24, 48, and 72 h of cycle 1 and taken at -1 and 8 h of cycle 3, 4, 5, 7 and every 3 cycles thereafter until disease progression and/or 45 days after the last dose (up to approximately 42 months)
3. Maximum Concentration (Cmax) of selicrelumab following SC administration measured from serum samples taken at -1, 4, 8, 24, 48, and 72 h of cycle 1 and taken at -1 and 8 h of cycle 3, 4, 5, 7 and every 3 cycles thereafter until disease progression and/or 45 days after the last dose (up to approximately 42 months)
4. Time to Maximum Concentration (Tmax) of selicrelumab Following SC administration measured from serum samples taken at -1, 4, 8, 24, 48, and 72 h of cycle 1 and taken at -1 and 8 h of cycle 3, 4, 5, 7 and every 3 cycles thereafter until disease progression and/or 45 days after the last dose (up to approximately 42 months)
5. Apparent Clearance (CL/F) of selicrelumab following SC administration measured from serum samples taken at -1, 4, 8, 24, 48, and 72 h of cycle 1 and taken at -1 and 8 h of cycle 3, 4, 5, 7 and every 3 cycles thereafter until disease progression and/or 45 days after the last dose (up to approximately 42 months)
6. Apparent Volume of distribution (Vd/F) of selicrelumab following SC administration measured from serum samples taken at -1, 4, 8, 24, 48, and 72 h of cycle 1 and taken at -1 and 8 h of cycle 3, 4, 5, 7 and every 3 cycles thereafter until disease progression and/or 45 days after the last dose (up to approximately 42 months)
7. Apparent terminal half-life (t1/2) of selicrelumab following SC administration measured from serum samples taken at -1, 4, 8, 24, 48, and 72 h of cycle 1 and taken at -1 and 8 h of cycle 3, 4, 5, 7 and every 3 cycles thereafter until disease progression and/or 45 days after the last dose (up to approximately 42 months)
6. Trough Concentration (Ctrough) of selicrelumab following SC administration for cycle 1 measured from serum samples taken at -1, 4, 8, 24, 48, and 72 h on day 2 of cycle 1 during Part 1; or taken at -1, 24, 48, and 72 h on day 1 and day 8, and -10 min on day 15, of cycle 1 during Part II
7. Trough Concentration (Ctrough) of selicrelumab following SC administration for cycle 3 measured from serum samples taken at -1 and 8 h on day 2 of cycle 3 during Part I; or taken at -1 h on day 1 of cycle 3 during Part II
8. Time taken to achieve the first quantifiable plasma concentration of selicrelumab following SC administration measured from serum samples taken at -1, 4, 8, 24, 48, and 72 h on day 2 of cycle 1, and -1 and 8 h on day 2 of cycle 3, during Part I; or taken at -1, 24, 48, and 72 h on day 1 and day 8, and -10 min on day 15, of cycle 1, and -1 h on day 1 of cycle 3, during Part II
9. Blood and tumor tissue immune cell subpopulations measured from serum samples taken pre-dose of vanicizumab on day 1, 4, and 9 of cycle 1 (as well as pre-dose and 6 h post-dose on day 15 for cohort 8), day 1 and 9 of cycle 2, 4, 7, and 10, during Part I; or pre-dose on day 1, 3, 8 and 15 of cycle 1 and day 1 and 8 of cycles 2, 4, 7, and 10, during Part II
10. Peripheral blood level of cytokines measured from serum samples taken pre-dose of vanicizumab on day 1 of cycles 1 and 2, or pre-dose and 3 h post-dose of selicrelumab on day 2 of cycle 1, 2, and 4
11. Blood soluble proteins measured from serum samples taken on day 1, 2, 3, 9, and 15 of cycle 1, day 1, 3, 9, and 15 of cycle 2, day 1 of cycle 4 and 5, day 1 and 15 of cycle 7, and day 1 of cycle 10
12. Best overall response assessed by unidimensional Immune-Related Response Criteria (irRC) during tumor assessments at baseline and on day 1 of cycle 3, 5, and 7, and every 12 weeks thereafter, until disease progression until the first documentation of a complete or partial response, or participant's discontinuation or death, whichever occurs first (up to approximately 42 months)
13. Duration of objective response assessed by irRC during tumor assessments at baseline and on day 1 of cycle 3, 5, and 7, and every 12 weeks thereafter, until disease progression until the first documentation of a complete or partial response, or participant's discontinuation or death, whichever occurs first (up to approximately 42 months)
14. Disease control assessed by irRC during tumor assessments at baseline and on day 1 of cycle 3, 5, and 7, and every 12 weeks thereafter, until disease progression until the first documentation of a complete or partial response, or participant's discontinuation or death, whichever occurs first (up to approximately 42 months)
15. PFS assessed by irRC during tumor assessments at baseline and on day 1 of cycle 3, 5, and 7, and every 12 weeks thereafter, until disease progression until the first documentation of a complete or partial response, or participant's discontinuation or death, whichever occurs first (up to approximately 42 months)
16. Clinical activity of SC selicrelumab in combination with bevacizumab as assessed by unidimensional Immune-Related Response Criteria (irRC) from day 1 of cycle 1 to safety follow up visit (45 days post final dose)
17. Overall Survival (OS) measured from patient records from baseline until participant's discontinuation or death, whichever occurs first (up to approximately 42 months)
18. Concentration at the end of Infusion (Cend) of Bevacizumab measured from serum samples taken at day 1 of every cycle until cycle 7 and at day 15 of cycle 1, at radiographical disease progression/tumor regression, and at safety follow up visit (45 days post final dose)
19. Minimum Concentration (Cmin) of bevacizumab after infusion measured from serum samples taken at day 1 of every cycle until cycle 7 and at day 15 of cycle 1, at radiographical disease progression/tumor regression, and at safety follow up visit (45 days post final dose)