Study Evaluating the Safety, Pharmacokinetics (PK), Pharmacodynamics (PD), and Therapeutic Activity of Selicrelumab (RO7009789) With Vanucizumab or Bevacizumab in Participants With Metastatic Solid Tumors

Advanced/Metastatic Solid Tumors Clinical Trial

Official title:

An Open-Label, Multicenter, Dose Escalation Phase Ib Study With Expansion Cohorts to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Therapeutic Activity of RO7009789 (CD40 Agonistic Monoclonal Antibody) in Combination With Vanucizumab (Anti-Ang2 and Anti-VEGF Bi-Specific Monoclonal Antibody, Part I) or Bevacizumab (Anti-VEGF Monoclonal Antibody, Part II) in Patients With Metastatic Solid Tumors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02665416
• Other study ID #: BP29889
• Secondary ID: 2015-003480-11RG
• Status: Completed
• Phase: Phase 1
• Start date: January 25, 2016
• Est. completion date: October 30, 2019

Study information

• Verified date: April 2020
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 94
• Est. completion date: October 30, 2019
• Est. primary completion date: October 30, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Part I: Histologically confirmed advanced/metastatic solid tumor (except prostate cancer and squamous non-small cell lung cancer [NSCLC])

• Part II: Histologically confirmed advanced/metastatic platinum-resistant ovarian carcinoma (aPROC), head and neck squamous cell carcinoma (HNSCC), or non-squamous NSCLC previously treated with anti-PD-L1/PD-1 inhibitor alone or in combination (e.g. atezolizumab, nivolumab, pembrolizumab, durvalumab, avelumab)

• Checkpoint inhibitor (CPI)- experienced patients must have experienced documented disease progression on or after PD-L1/PD-1 inhibitor therapy

• In CPI-experienced patients, the PD-L1/PD-1 inhibitor must have been part of the most recent systemic anticancer therapy administered prior to study enrollment

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

• Life expectancy >/= 16 weeks

• Adequate hematologic, renal, hepatic, and cardiovascular function

• Measurable disease per Response Evaluation Criteria in Solid Tumors, v 1.1 (RECIST v1.1)

• Tumors must be acceptable for biopsy. Participants in Part II may be enrolled without a biopsy if the collection is not clinically feasible.

• Agreement to use adequate contraceptive measures among men or among women of childbearing potential

Exclusion Criteria:

• Prostate cancer or squamous NSCLC

• Recent systemic anti-cancer treatment

• Prior treatment with anti-programmed death (PD) 1 or anti-programmed death ligand (PD-L) 1 therapeutic antibody, vanucizumab, or compounds targeting cluster of differentiation (CD) 40 less than 4 weeks or 5xt1/2 (whichever is shorter) prior to enrollment

• Part II: Treatment targeting vascular endothelial growth factor (VEGF) or receptor within 12 months prior to enrollment

• Systemic immunosuppressive medication within 2 weeks prior to day 1 of cycle 1

• Chronic daily treatment with non-steroidal anti-inflammatory drugs

• Unacceptable/unresolved toxicity from prior anti-cancer therapy

• Patients who have had a surgical procedure or significant traumatic injury within 28 days prior to initiation of study treatment, or a core biopsy or other minor surgical procedure within 7 days prior to initiation of study treatment

• Bisphosphonate therapy for symptomatic hypercalcemia

• Significant vascular disease

• History of hypertensive crisis or hypertensive encephalopathy

• Current or recent use of aspirin (>325 mg/day) or clopidogrel (>75 mg/day)

• History of vein thrombosis/thromboembolism, or use of anticoagulants within 7 days prior to study drug

• Primary tumor in place in participants with colorectal cancer, or evidence of bowel involvement (metastasis, direct tumor invasion) in participants with other non-gastrointestinal cancer

• Significant cardiovascular or cerebrovascular disease within 6 months prior to D1 of C1

• History of fistula, bowel obstruction, perforation, or abscess

• Prior radiotherapy to pelvis or abdomen, recto-sigmoid involvement, or bowel involvement among participants with aPROC

• Severe non-healing wound, active ulcer or untreated bone fracture

• Pregnant or lactating women

• History of autoimmune disease

• Human immunodeficiency virus (HIV) or hepatitis B or C

• Severe infection or receipt of a live/attenuated vaccine within 4 weeks prior to D1 of C1

• Other significant malignancies within 3 years prior to D1 of C1

• Allergy/hypersensitivity to study drug

• Prior allogeneic bone marrow or solid organ transplant

• Other conditions/findings that may contraindicate use of study drug

• Major surgery within 4 weeks prior to study drug

• Known clinically significant liver disease

• History of hemoptysis or bleeding diathesis, or known coagulopathies

• Known symptomatic or untreated central nervous system (CNS) malignancy

Related Conditions & MeSH terms

• Advanced/Metastatic Solid Tumors
• Neoplasms

Intervention

Drug:
• Selicrelumab
Selicrelumab will be provided as concentrate for solution to be administered via SC injection
• Vanucizumab
Vanucizumab will be provided as solution to be administered via IV infusion.
• Bevacizumab
Bevacizumab will be administered via IV infusion.

Locations

Country	Name	City	State
Belgium	Cliniques Universitaires St-Luc	Bruxelles
Canada	University Health Network; Princess Margaret Hospital; Medical Oncology Dept	Toronto	Ontario
Denmark	Rigshospitalet; Onkologisk Klinik	København Ø
Italy	Irccs Ospedale San Raffaele;Oncologia Medica	Milano	Lombardia
Netherlands	Antoni van Leeuwenhoek Ziekenhuis	Amsterdam
Netherlands	Erasmus Medisch Centrum	Rotterdam
Spain	Hospital del Mar; Servicio de Oncologia	Barcelona
Spain	Hospital Univ Vall d'Hebron; Servicio de Oncologia	Barcelona
Spain	ICO L'Hospitalet; Servicio de oncologia medica	L Hospitalet De Llobregat	Barcelona
Spain	START Madrid. Centro Integral Oncologico Clara Campal; CIOCC	Madrid
Spain	Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia	Valencia
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Univ of CO Health Science Ctr	Denver	Colorado
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Yale Cancer Center; Medical Oncology	New Haven	Connecticut

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Denmark,  Italy,  Netherlands,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Dose-Limiting Toxicities (DLTs)	From Day (D) 1 until D28 of Cycle (C)1 (cycle length=28 days)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Primary	MTD of Selicrelumab in Combination With Vanucizumab	From D1 until D28 of C1 (cycle length=28 days)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Primary	Recommended Phase II Dose of Selicrelumab in Combination With Vanucizumab	From D1 until D28 of C1 (cycle length=28 days)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Primary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Primary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Primary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Primary	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)	TBaseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Primary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Primary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	Overall Survival (OS)		Baseline until Participant's discontinuation or death, whichever occurs first (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary	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)	Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)