Clinical Trials /

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

NCT02665416

Description:

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.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
  • Malignant Solid Tumor
  • Non-Small Cell Lung Carcinoma
  • Ovarian Carcinoma
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: BP29889
  • SECONDARY ID: 2015-003480-11
  • SECONDARY ID: RG7876
  • NCT ID: NCT02665416

Conditions

  • Advanced/Metastatic Solid Tumors

Interventions

DrugSynonymsArms
SelicrelumabRO7009789Part I (Dose Escalation): Selicrelumab, Vanucizumab
VanucizumabPart I (Dose Escalation): Selicrelumab, Vanucizumab
BevacizumabPart II (Expansion): Selicrelumab, Bevacizumab

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Part I (Dose Escalation): Selicrelumab, VanucizumabExperimentalParticipants will receive a fixed dose of vanucizumab, 2 grams via IV infusion on Days 1 and 15 of every 28-day cycle. Selicrelumab will be given SC, or potentially IV, in ascending dose levels on Day 2 of Cycles 1 to 4 and every third cycle thereafter. Treatment will continue as long as the participant experiences clinical benefit or until unacceptable toxicity, withdrawal of consent, or the end of Part I of the study (expected 9 months).
  • Selicrelumab
  • Vanucizumab
Part II (Expansion): Selicrelumab, BevacizumabExperimentalBevacizumab will be administered via IV infusion on days 1 and 15 of every 28-day cycle. Selicrelumab will be given SC after the Bevacizumab infusion at the dose determined in the Part I of the study on Day 2 of Cycles 1 to 4 and every third cycle thereafter. Treatment will continue as long as the participant experiences clinical benefit or until unacceptable toxicity, withdrawal of consent, or the end of Part II of the study (expected 15 months).
  • Selicrelumab
  • Bevacizumab

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

          -  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

          -  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 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of Participants With Dose-Limiting Toxicities (DLTs)
Time Frame:From Day (D) 1 until D28 of Cycle (C)1
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Percentage of Participants With Anti-Drug Antibodies (ADAs) to Selicrelumab
Time Frame: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 (up to 9 months in Part I and 15 months in Part II; cycle length=28 days)
Safety Issue:
Description:
Measure:Percentage of Participants with ADAs to Vanucizumab
Time Frame: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 (up to 9 months in Part I and 15 months in Part II; cycle length=28 days)
Safety Issue:
Description:
Measure:Area Under the Concentration-Time Curve From Time 0 to Last Measureable Concentration (AUClast) of Selicrelumab Following Subcutaneous (SC) Administration
Time Frame: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 9 months in Part I and 15 months in Part II)
Safety Issue:
Description:Each cycle will be 28 days in duration.
Measure:Area Under the Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Selicrelumab Following SC Administration
Time Frame: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 9 months in Part I and 15 months in Part II)
Safety Issue:
Description:Each cycle will be 28 days in duration.
Measure:Maximum Concentration (Cmax) of Selicrelumab Following SC Administration
Time Frame: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 9 months in Part I and 15 months in Part II)
Safety Issue:
Description:Each cycle will be 28 days in duration.
Measure:Time to Maximum Concentration (Tmax) of Selicrelumab Following SC Administration
Time Frame: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 9 months in Part I and 15 months in Part II)
Safety Issue:
Description:Each cycle will be 28 days in duration.
Measure:Apparent Clearance (CL/F) of Selicrelumab Following SC Administration
Time Frame: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 9 months in Part I and 15 months in Part II)
Safety Issue:
Description:Each cycle will be 28 days in duration.
Measure:Apparent Volume of Distribution (Vd/F) of Selicrelumab Following SC Administration
Time Frame: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 9 months in Part I and 15 months in Part II)
Safety Issue:
Description:Each cycle will be 28 days in duration.
Measure:Apparent Terminal Half-Life (t1/2) of Selicrelumab Following SC Administration
Time Frame: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 9 months in Part I and 15 months in Part II)
Safety Issue:
Description:Each cycle will be 28 days in duration.
Measure:AUClast of Selicrelumab Following Intravenous (IV) Administration
Time Frame:D2 of C1 up to 9 months in Part I and 15 months in Part II (detailed timeframe is provided in outcome description)
Safety Issue:
Description:Predose (-1 h) and 15 min, at the end of infusion (infusion duration=30 min), 2, 4, 6, 8, 10, 24, 30-36, 48, 72, 168 h postdose on C1 and C2; predose (-1 h), at the end of infusion, 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 9 months in Part I and 15 months in Part II; cycle length=28 days)
Measure:AUCinf of Selicrelumab Following IV Administration
Time Frame:D2 of C1 up to 9 months in Part I and 15 months in Part II (detailed timeframe is provided in outcome description)
Safety Issue:
Description:Predose (-1 h) and 15 min, at the end of infusion (infusion duration=30 min), 2, 4, 6, 8, 10, 24, 30-36, 48, 72, 168 h postdose on C1 and C2; predose (-1 h), at the end of infusion, 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 9 months in Part I and 15 months in Part II; cycle length=28 days)
Measure:Cmax of Selicrelumab Following IV Administration
Time Frame:D2 of C1 up to 9 months in Part I and 15 months in Part II (detailed timeframe is provided in outcome description)
Safety Issue:
Description:Predose (-1 h) and 15 min, at the end of infusion (infusion duration=30 min), 2, 4, 6, 8, 10, 24, 30-36, 48, 72, 168 h postdose on C1 and C2; predose (-1 h), at the end of infusion, 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 9 months in Part I and 15 months in Part II; cycle length=28 days)
Measure:Minimum Concentration (Cmin) of Selicrelumab Following IV Administration
Time Frame:D2 of C1 up to 9 months in Part I and 15 months in Part II (detailed timeframe is provided in outcome description)
Safety Issue:
Description:Predose (-1 h) and 15 min, at the end of infusion (infusion duration=30 min), 2, 4, 6, 8, 10, 24, 30-36, 48, 72, 168 h postdose on C1 and C2; predose (-1 h), at the end of infusion, 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 9 months in Part I and 15 months in Part II; cycle length=28 days)
Measure:CL of Selicrelumab Following IV Administration
Time Frame:D2 of C1 up to 9 months in Part I and 15 months in Part II (detailed timeframe is provided in outcome description)
Safety Issue:
Description:Predose (-1 h) and 15 min, at the end of infusion (infusion duration=30 min), 2, 4, 6, 8, 10, 24, 30-36, 48, 72, 168 h postdose on C1 and C2; predose (-1 h), at the end of infusion, 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 9 months in Part I and 15 months in Part II; cycle length=28 days)
Measure:Volume of Distribution at Steady-State (Vss) of Selicrelumab Following IV Administration
Time Frame:D2 of C1 up to 9 months in Part I and 15 months in Part II (detailed timeframe is provided in outcome description)
Safety Issue:
Description:Predose (-1 h) and 15 min, at the end of infusion (infusion duration=30 min), 2, 4, 6, 8, 10, 24, 30-36, 48, 72, 168 h postdose on C1 and C2; predose (-1 h), at the end of infusion, 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 9 months in Part I and 15 months in Part II; cycle length=28 days)
Measure:t1/2 of Selicrelumab Following IV Administration
Time Frame:D2 of C1 up to 9 months in Part I and 15 months in Part II (detailed timeframe is provided in outcome description)
Safety Issue:
Description:Predose (-1 h) and 15 min, at the end of infusion (infusion duration=30 min), 2, 4, 6, 8, 10, 24, 30-36, 48, 72, 168 h postdose on C1 and C2; predose (-1 h), at the end of infusion, 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 9 months in Part I and 15 months in Part II; cycle length=28 days)
Measure:AUClast of Vanucizumab
Time Frame:Day 1 up to 9 months in Part I and 15 months in Part II (detailed timeframe is provided in outcome description)
Safety Issue:
Description: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 (up to 9 months in Part I and 15 months in Part II; cycle length=28 days); 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 (up to 9 months in Part I and 15 months in Part II); 6 and 24 h postdose on D15 of C1
Measure:AUCinf of Vanucizumab
Time Frame:Day 1 up to 9 months in Part I and 15 months in Part II (detailed timeframe is provided in outcome description)
Safety Issue:
Description: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 (up to 9 months in Part I and 15 months in Part II; cycle length=28 days); 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 (up to 9 months in Part I and 15 months in Part II); 6 and 24 h postdose on D15 of C1
Measure:Concentration at the End of Infusion (Cend) of Vanucizumab
Time Frame:Day 1 up to 9 months in Part I and 15 months in Part II (detailed timeframe is provided in outcome description)
Safety Issue:
Description: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 (up to 9 months in Part I and 15 months in Part II; cycle length=28 days); 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 (up to 9 months in Part I and 15 months in Part II); 6 and 24 h postdose on D15 of C1
Measure:CL of Vanucizumab
Time Frame:Day 1 up to 9 months in Part I and 15 months in Part II (detailed timeframe is provided in outcome description)
Safety Issue:
Description: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 (up to 9 months in Part I and 15 months in Part II; cycle length=28 days); 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 (up to 9 months in Part I and 15 months in Part II); 6 and 24 h postdose on D15 of C1
Measure:Vss of Vanucizumab
Time Frame:Day 1 up to 9 months in Part I and 15 months in Part II (detailed timeframe is provided in outcome description)
Safety Issue:
Description: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 (up to 9 months in Part I and 15 months in Part II; cycle length=28 days); 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 (up to 9 months in Part I and 15 months in Part II); 6 and 24 h postdose on D15 of C1
Measure:t1/2 of Vanucizumab
Time Frame:Day 1 up to 9 months in Part I and 15 months in Part II (detailed timeframe is provided in outcome description)
Safety Issue:
Description: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 (up to 9 months in Part I and 15 months in Part II; cycle length=28 days); 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 (up to 9 months in Part I and 15 months in Part II); 6 and 24 h postdose on D15 of C1
Measure:Change in Blood and Tumor Tissue Immune Cell Subpopulations
Time Frame:From D1 of C1 until D9 of C10 or disease progression, whichever occurs first (up to 9 months in Part I and 15 months in Part II; cycle length=28 days)
Safety Issue:
Description:
Measure:Change in Peripheral Blood Level of Cytokines
Time Frame:From D1 of C1 to 3 h postdose on D2 of C4 or disease progression, whichever occurs first (up to 9 months in Part I and 15 months in Part II; cycle length=28 days)
Safety Issue:
Description:
Measure:Change in Blood Soluble Proteins
Time Frame:From D1 of C1 until D15 of C7 or disease progression, whichever occurs first (up to 9 months in Part I and 15 months in Part II; cycle length=28 days)
Safety Issue:
Description:
Measure:Percentage of Participants With Best Overall Response per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Criteria
Time Frame:Tumor assessments at Screening and on D1 of C3, C5, C7; and every 12 weeks thereafter until disease progression (up to 9 months in Part I and 15 months in Part II; cycle length=28 days)
Safety Issue:
Description:
Measure:Percentage of Participants With Best overall Response Immune-Related Response Criteria (irRC)
Time Frame:Tumor assessments at Screening and on D1 of C3, C5, C7; and every 12 weeks thereafter until disease progression (up to 9 months in Part I and 15 months in Part II; cycle length=28 days)
Safety Issue:
Description:
Measure:Duration of Objective Response per RECIST v1.1 Criteria
Time Frame:Tumor assessments at Screening and on D1 of C3, C5, C7; and every 12 weeks thereafter until disease progression (up to 9 months in Part I and 15 months in Part II; cycle length=28 days)
Safety Issue:
Description:
Measure:Duration of Objective Response per irRC
Time Frame:Tumor assessments at Screening and on D1 of C3, C5, C7; and every 12 weeks thereafter until disease progression (up to 9 months in Part I and 15 months in Part II; cycle length=28 days)
Safety Issue:
Description:
Measure:Percentage of Participants With Disease Control per RECIST v1.1 Criteria
Time Frame:Tumor assessments at Screening and on D1 of C3, C5, C7; and every 12 weeks thereafter until disease progression (up to 9 months in Part I and 15 months in Part II; cycle length=28 days)
Safety Issue:
Description:
Measure:Percentage of Participants With Disease Control per irRC
Time Frame:Tumor assessments at Screening and on D1 of C3, C5, C7; and every 12 weeks thereafter until disease progression (up to 9 months in Part I and 15 months in Part II; cycle length=28 days)
Safety Issue:
Description:
Measure:Progression-free Survival (PFS) per RECIST v1.1 Criteria
Time Frame:Tumor assessments at Screening and on D1 of C3, C5, C7; and every 12 weeks thereafter until disease progression (up to 9 months in Part I and 15 months in Part II; cycle length=28 days)
Safety Issue:
Description:
Measure:PFS per irRC
Time Frame:Tumor assessments at Screening and on D1 of C3, C5, C7; and every 12 weeks thereafter until disease progression (up to 9 months in Part I and 15 months in Part II; cycle length=28 days)
Safety Issue:
Description:
Measure:Overall Survival (OS)
Time Frame:Baseline until death (up to 9 months in Part I and 15 months in Part II)
Safety Issue:
Description:
Measure:Concentration at the end of Infusion (Cend) of Bevacizumab
Time Frame: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)
Safety Issue:
Description:
Measure:Minimum Concentration (Cmin) of Bevacizumab after Infusion
Time Frame: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)
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hoffmann-La Roche

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