This open-label, two-part study is designed to assess the safety, PK, PD, and therapeutic activity of Selicrelumab in combination with vanucizumab or bevacizumab in participants with metastatic solid tumors not amenable to standard treatment. Part I (dose escalation) is designed to establish the maximum tolerated dose (MTD) of Selicrelumab in this combination. Part II (expansion) is intended to characterize the safety and tolerability of Selicrelumab in combination with bevacizumab among indication-specific cohorts and to confirm the recommended dose.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
94
Selicrelumab will be provided as concentrate for solution to be administered via SC injection
Vanucizumab will be provided as solution to be administered via IV infusion.
Bevacizumab will be administered via IV infusion.
Cedars Sinai Medical Center
Los Angeles, California, United States
Univ of CO Health Science Ctr
Denver, Colorado, United States
Yale Cancer Center; Medical Oncology
New Haven, Connecticut, United States
Dana Farber Cancer Institute
Boston, Massachusetts, United States
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States
Cliniques Universitaires St-Luc
Brussels, Belgium
University Health Network; Princess Margaret Hospital; Medical Oncology Dept
Toronto, Ontario, Canada
Rigshospitalet; Onkologisk Klinik
København Ø, Denmark
Irccs Ospedale San Raffaele;Oncologia Medica
Milan, Lombardy, Italy
Antoni van Leeuwenhoek Ziekenhuis
Amsterdam, Netherlands
...and 6 more locations
Percentage of Participants With Dose-Limiting Toxicities (DLTs)
From Day (D) 1 until D28 of Cycle (C)1 (cycle length=28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
MTD of Selicrelumab in Combination With Vanucizumab
From D1 until D28 of C1 (cycle length=28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Recommended Phase II Dose of Selicrelumab in Combination With Vanucizumab
From D1 until D28 of C1 (cycle length=28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Percentage of Participants With Adverse Events (AEs)
From D1 of C1 until treatment discontinuation and approximately 45 days after last dose (cycle length=28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Part II: Clinical Activity of SC Selicrelumab in Combination with Bevacizumab as Assessed by Response Evaluation in Solid Tumors, Version 1.1 (RECIST v1.1)
From D1 of C1 through safety follow up visit (45 days post final dose; Cycle = 28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Part II: Percentage of Participants With Best Overall Response per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Criteria
Tumor assessments at Screening and on D1 of C3, C5, C7; and every 12 weeks thereafter until disease progression (cycle length=28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Part II: Duration of Objective Response per RECIST v1.1 Criteria
Tumor assessments at Screening and on D1 of C3, C5, C7; and every 12 weeks thereafter until disease progression (cycle length=28 days)
Time frame: TBaseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Part II: Percentage of Participants With Disease Control per RECIST v1.1 Criteria
Tumor assessments at Screening and on D1 of C3, C5, C7; and every 12 weeks thereafter until disease progression (cycle length=28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Part II: Progression-free Survival (PFS) per RECIST v1.1 Criteria
Tumor assessments at Screening and on D1 of C3, C5, C7; and every 12 weeks thereafter until disease progression (cycle length=28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Percentage of Participants With Anti-Drug Antibodies (ADAs) to Selicrelumab
Predose (-1 hour \[h\]) on D2 of C1, C2, C3, C4, C7, and every 3 cycles until/at disease progression and/or 45 days after last dose (cycle length=28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Percentage of Participants with ADAs to Vanucizumab
Predose (within 10 minutes \[min\] before infusion) on D1 of C1, C2, C4, and every 2 cycles until/at disease progression and/or 45 days after last dose (cycle length=28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Area Under the Concentration-Time Curve From Time 0 to Last Measureable Concentration (AUClast) of Selicrelumab Following Subcutaneous (SC) Administration
Predose (-1 h) and 3 (only C2), 4, 8, 24, 48, 72 h postdose on C1 and C2; predose (-1 h) and 8 h postdose on C3, C4, C7, and every 3 cycles until/at disease progression and/or 45 days after last dose (up to 24 months in Part I and 18 months in Part II; cycle length=28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Area Under the Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Selicrelumab Following SC Administration
Predose (-1 h) and 3 (only C2), 4, 8, 24, 48, 72 h postdose on C1 and C2; predose (-1 h) and 8 h postdose on C3, C4, C7, and every 3 cycles until/at disease progression and/or 45 days after last dose (cycle length=28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Maximum Concentration (Cmax) of Selicrelumab Following SC Administration
Predose (-1 h) and 3 (only C2), 4, 8, 24, 48, 72 h postdose on C1 and C2; predose (-1 h) and 8 h postdose on C3, C4, C7, and every 3 cycles until/at disease progression and/or 45 days after last dose (cycle length=28 days)
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Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Time to Maximum Concentration (Tmax) of Selicrelumab Following SC Administration
Predose (-1 h) and 3 (only C2), 4, 8, 24, 48, 72 h postdose on C1 and C2; predose (-1 h) and 8 h postdose on C3, C4, C7, and every 3 cycles until/at disease progression and/or 45 days after last dose (cycle length=28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Apparent Clearance (CL/F) of Selicrelumab Following SC Administration
Predose (-1 h) and 3 (only C2), 4, 8, 24, 48, 72 h postdose on C1 and C2; predose (-1 h) and 8 h postdose on C3, C4, C7, and every 3 cycles until/at disease progression and/or 45 days after last dose (cycle length=28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Apparent Volume of Distribution (Vd/F) of Selicrelumab Following SC Administration
Predose (-1 h) and 3 (only C2), 4, 8, 24, 48, 72 h postdose on C1 and C2; predose (-1 h) and 8 h postdose on C3, C4, C7, and every 3 cycles until/at disease progression and/or 45 days after last dose (cycle length=28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Apparent Terminal Half-Life (t1/2) of Selicrelumab Following SC Administration
Predose (-1 h) and 3 (only C2), 4, 8, 24, 48, 72 h postdose on C1 and C2; predose (-1 h) and 8 h postdose on C3, C4, C7, and every 3 cycles until/at disease progression and/or 45 days after last dose (cycle length=28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Part I: AUClast of Vanucizumab
Predose (within 10 min) on D1 of C1, C2, C4, C6, C8, every 2 cycles thereafter disease progression and/or 45 days after last dose; predose (within 10 min), end of infusion (infusion duration=60-90 min) on D15 of C1 to C9 and each cycle thereafter until disease progression and/or 45 days after last dose; 6 and 24 h postdose on D15 of C1 and C8 (cycle length = 28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Part I: AUCinf of Vanucizumab
Predose (within 10 min) on D1 of C1, C2, C4, C6, C8, every 2 cycles thereafter disease progression and/or 45 days after last dose; predose (within 10 min), end of infusion (infusion duration=60-90 min) on D15 of C1 to C9 and each cycle thereafter until disease progression and/or 45 days after last dose; 6 and 24 h postdose on D15 of C1 and C8 (cycle length = 28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Part I: Concentration at the End of Infusion (Cend) of Vanucizumab
Predose (within 10 min) on D1 of C1, C2, C4, C6, C8, every 2 cycles thereafter disease progression and/or 45 days after last dose; predose (within 10 min), end of infusion (infusion duration=60-90 min) on D15 of C1 to C9 and each cycle thereafter until disease progression and/or 45 days after last dose; 6 and 24 h postdose on D15 of C1 and C8 (cycle length = 28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Part I: CL of Vanucizumab
Predose (within 10 min) on D1 of C1, C2, C4, C6, C8, every 2 cycles thereafter disease progression and/or 45 days after last dose; predose (within 10 min), end of infusion (infusion duration=60-90 min) on D15 of C1 to C9 and each cycle thereafter until disease progression and/or 45 days after last dose; 6 and 24 h postdose on D15 of C1 and C8 (cycle length = 28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Part I: Vss of Vanucizumab
Predose (within 10 min) on D1 of C1, C2, C4, C6, C8, every 2 cycles thereafter disease progression and/or 45 days after last dose; predose (within 10 min), end of infusion (infusion duration=60-90 min) on D15 of C1 to C9 and each cycle thereafter until disease progression and/or 45 days after last dose; 6 and 24 h postdose on D15 of C1 and C8 (cycle length = 28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Part I: t1/2 of Vanucizumab
Predose (within 10 min) on D1 of C1, C2, C4, C6, C8, every 2 cycles thereafter disease progression and/or 45 days after last dose; predose (within 10 min), end of infusion (infusion duration=60-90 min) on D15 of C1 to C9 and each cycle thereafter until disease progression and/or 45 days after last dose; 6 and 24 h postdose on D15 of C1 and C8 (cycle length = 28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Part I: Percentage of Participants With Best Overall Response per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Criteria
Tumor assessments at Screening and on D1 of C3, C5, C7; and every 12 weeks thereafter until disease progression (cycle length=28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Part I: Duration of Objective Response per RECIST v1.1 Criteria
Tumor assessments at Screening and on D1 of C3, C5, C7; and every 12 weeks thereafter until disease progression (cycle length=28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Part I: Percentage of Participants With Disease Control per RECIST v1.1 Criteria
Tumor assessments at Screening and on D1 of C3, C5, C7; and every 12 weeks thereafter until disease progression (cycle length=28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Part I: Progression-free Survival (PFS) per RECIST v1.1 Criteria
Tumor assessments at Screening and on D1 of C3, C5, C7; and every 12 weeks thereafter until disease progression (cycle length=28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Part I: Clinical Activity of SC Selicrelumab in Combination with Bevacizumab as Assessed by Response Evaluation in Solid Tumors, Version 1.1 (RECIST v1.1)
From D1 of C1 through safety follow up visit (45 days post final dose; cycle length = 28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Change in Blood and Tumor Tissue Immune Cell Subpopulations
Part I: C1 at D1 pre-dose Vanicizumab, D4, D9 (D15 pre and 6h post for cohorts 8 onwards); C2 at D1 and D9; C4,7,10 at D1 and D9; PD Part II: C1 D1(pre), D3,D8,D15; C2,4,7,10 D1,D8; PD
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Change in Peripheral Blood Level of Cytokines
C1D1 pre-dose Vanicizumab, C1 D2 pre-dose Selicrelumab and 3h post-dose Selicrelumab, C2D1 pre-dose Vanicizumab, C2D2 pre-dose Selicrelumab and 3h post-dose Selicrelumab, C4 D2 pre-dose Selicrelumab and 3h post-dose, PD
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Change in Blood Soluble Proteins
D1, 2, 3, 9, 15 of C1; D1, 3, 9, 15 of C2; D1 of C 4,5; D1, 15 of C7, D1 of C10, PD
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Percentage of Participants With Best overall Response Immune-Related Response Criteria (irRC)
Tumor assessments at Screening and on D1 of C3, C5, C7; and every 12 weeks thereafter until disease progression (cycle length=28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Duration of Objective Response per irRC
Tumor assessments at Screening and on D1 of C3, C5, C7; and every 12 weeks thereafter until disease progression (cycle length=28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Percentage of Participants With Disease Control per irRC
Tumor assessments at Screening and on D1 of C3, C5, C7; and every 12 weeks thereafter until disease progression (cycle length=28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
PFS per irRC
Tumor assessments at Screening and on D1 of C3, C5, C7; and every 12 weeks thereafter until disease progression (cycle length=28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Clinical Activity of SC Selicrelumab in Combination with Bevacizumab as Assessed by Unidimensional Immune-Related Response Criteria (irRC)
From D1 of C1 through safety follow up visit (45 days post final dose; cycle length = 28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Overall Survival (OS)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first (up to approximately 42 months)
Concentration at the end of Infusion (Cend) of Bevacizumab
D1 and D15 of C1, then D1 of every cycle until C7; at radiographical disease progression/tumor regression; at safety follow up visit (45 days post final dose; Cycle = 28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Minimum Concentration (Cmin) of Bevacizumab after Infusion
D1 and D15 of C1, then D1 of every cycle until C7; at radiographical disease progression/tumor regression; at safety follow up visit (45 days post final dose; Cycle = 28 days)
Time frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)