Clinical trial NCT02665416: Study Evaluating the Safety, Pharmacokinetics (PK), Pharmacodynamics (PD), and Therapeutic Activity of Selicrelumab (RO7009789) With Vanucizumab or Bevacizumab in Participants With Metastatic Solid Tumors
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced/Metastatic Solid Tumors
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2016-01-27
Enrollment: 94
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Participants With Dose-Limiting Toxicities (DLTs)
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: MTD of Selicrelumab in Combination With Vanucizumab
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Recommended Phase II Dose of Selicrelumab in Combination With Vanucizumab
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Percentage of Participants With Adverse Events (AEs)
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: 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)
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Part II: Percentage of Participants With Best Overall Response per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Criteria
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Part II: Duration of Objective Response per RECIST v1.1 Criteria
timeFrame: TBaseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Part II: Percentage of Participants With Disease Control per RECIST v1.1 Criteria
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Part II: Progression-free Survival (PFS) per RECIST v1.1 Criteria
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Secondary outcomes:
measure: Percentage of Participants With Anti-Drug Antibodies (ADAs) to Selicrelumab
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Percentage of Participants with ADAs to Vanucizumab
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Area Under the Concentration-Time Curve From Time 0 to Last Measureable Concentration (AUClast) of Selicrelumab Following Subcutaneous (SC) Administration
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Area Under the Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Selicrelumab Following SC Administration
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Maximum Concentration (Cmax) of Selicrelumab Following SC Administration
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Time to Maximum Concentration (Tmax) of Selicrelumab Following SC Administration
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Apparent Clearance (CL/F) of Selicrelumab Following SC Administration
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Apparent Volume of Distribution (Vd/F) of Selicrelumab Following SC Administration
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Apparent Terminal Half-Life (t1/2) of Selicrelumab Following SC Administration
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Part I: AUClast of Vanucizumab
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Part I: AUCinf of Vanucizumab
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Part I: Concentration at the End of Infusion (Cend) of Vanucizumab
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Part I: CL of Vanucizumab
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Part I: Vss of Vanucizumab
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Part I: t1/2 of Vanucizumab
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Part I: Percentage of Participants With Best Overall Response per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Criteria
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Part I: Duration of Objective Response per RECIST v1.1 Criteria
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Part I: Percentage of Participants With Disease Control per RECIST v1.1 Criteria
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Part I: Progression-free Survival (PFS) per RECIST v1.1 Criteria
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: 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)
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Change in Blood and Tumor Tissue Immune Cell Subpopulations
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Change in Peripheral Blood Level of Cytokines
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Change in Blood Soluble Proteins
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Percentage of Participants With Best overall Response Immune-Related Response Criteria (irRC)
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Duration of Objective Response per irRC
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Percentage of Participants With Disease Control per irRC
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: PFS per irRC
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Clinical Activity of SC Selicrelumab in Combination with Bevacizumab as Assessed by Unidimensional Immune-Related Response Criteria (irRC)
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Overall Survival (OS)
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first (up to approximately 42 months)
measure: Concentration at the end of Infusion (Cend) of Bevacizumab
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
measure: Minimum Concentration (Cmin) of Bevacizumab after Infusion
timeFrame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars Sinai Medical Center
state: California
city: Denver
country: United States
facility: Univ of CO Health Science Ctr
state: Colorado
city: New Haven
country: United States
facility: Yale Cancer Center; Medical Oncology
state: Connecticut
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires St-Luc
city: Toronto
country: Canada
facility: University Health Network; Princess Margaret Hospital; Medical Oncology Dept
state: Ontario
city: København Ø
country: Denmark
facility: Rigshospitalet; Onkologisk Klinik
city: Milano
country: Italy
facility: Irccs Ospedale San Raffaele;Oncologia Medica
state: Lombardia
city: Amsterdam
country: Netherlands
facility: Antoni van Leeuwenhoek Ziekenhuis
city: Rotterdam
country: Netherlands
facility: Erasmus Medisch Centrum
city: L Hospitalet De Llobregat
country: Spain
facility: ICO L'Hospitalet; Servicio de oncologia medica
state: Barcelona
city: Barcelona
country: Spain
facility: Hospital del Mar; Servicio de Oncologia
city: Barcelona
country: Spain
facility: Hospital Univ Vall d'Hebron; Servicio de Oncologia
city: Madrid
country: Spain
facility: START Madrid. Centro Integral Oncologico Clara Campal; CIOCC
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: