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Protocol NumberBP40234
NCT Number(ClinicalTrials.gov Identfier)NCT03386721
Completed

2018-04-02 - 2023-12-06

Phase II

Terminated2

An Open-Label, Multicenter, Phase II Study to Evaluate the Therapeutic Activity of Simlukafusp Alfa (RO6874281), an Immunocytokine, Consisting of Interleukin-2 Variant (IL-2v) Targeting Fibroblast Activation Protein-Α (FAP), in Combination With Atezolizumab (Anti-PD-L1), Administered Intravenously, in Participants With Advanced and/or Metastatic Solid Tumors

  • Trial Applicant

  • Sponsor

    Hoffmann-La Roche

  • Trial scale

    Multi-Regional Multi-Center

  • Update

    2026/02/01

Investigators and Locations

Principal Investigator Wu-Chou Su Division of Hematology & Oncology
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Terminated

Audit

None

Principal Investigator James Chih-Hsin Yang Division of Hematology & Oncology
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Terminated

Audit

None

Condition/Disease

Advanced and/or Metastatic Solid Tumors

Objectives

Primary  To evaluate antitumor activity of RO6874281 in combination with atezolizumab and potentially other drugs in comparison with the SoC in participants with advanced/and or metastatic solid tumors Secondary  To further characterize the antitumor activity of RO6874281 in combination with atezolizumab and potentially other drugs in participants with advanced/and or metastatic solid tumors relative to SoC.  To evaluate the safety and tolerability of RO6874281 in combination with atezolizumab and potentially other drugs  To determine the relevance of the baseline tumor PD-L1 status for treatment benefit  To characterize in tumor samples treatment-induced PD effects of RO6874281 in combination with atezolizumab and potentially other drugs

Test Drug

RO6874281、ATEZOLIZUMAB

Active Ingredient

ATEZOLIZUMAB
RO6874281

Dosage Form

injection

Dosage

50mg/2ml
1200mg/20ml
10mg/0.4ml

Endpoints

Primary Outcome Measures :
Percentage of Participants with Objective Response of Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [ Time Frame: Baseline up to disease progression or study treatment discontinuation (assessed every 8 weeks after study treatment start, up to approximately 2 years) ]

Secondary Outcome Measures :
Percentage of Participants with Disease Control According to RECIST Version 1.1 [ Time Frame: Baseline up to disease progression or study treatment discontinuation (assessed every 8 weeks after study treatment start for the first year, and every 12 weeks thereafter, up to approximately 2 years) ]
Duration of Response (DoR) According to RECIST Version 1.1 [ Time Frame: From first occurrence of documented CR or PR up to disease progression or study treatment discontinuation (assessed every 8 weeks after study treatment start for the first year, and every 12 weeks thereafter, up to approximately 2 years) ]
Progression-Free Survival (PFS) According to RECIST Version 1.1 [ Time Frame: Baseline up to disease progression or study treatment discontinuation (assessed every 8 weeks after study treatment start for the first year, and every 12 weeks thereafter, up to approximately 2 years) ]
Overall Survival (OS) [ Time Frame: Baseline up to death due to any cause (up to approximately 2 years) ]
Percentage of Participants with Adverse Events (AEs) [ Time Frame: Baseline up to end of the study (up to approximately 2 years) ]
Percentage of Participants by Programmed Death-Ligand 1 (PD-L1) Status According to Immunohistochemical Methods [ Time Frame: Baseline, Cycle 3 Day 8, Day 1 of Cycle 9 onwards up to end of the study (up to approximately 2 years) (1 cycle = 15 days) ]
Change from Baseline in Density of Cluster of Differentiation (CD) 8 Positive (CD8+) Cells According to Immunohistochemical Methods [ Time Frame: Day1 of Cycles 1, 2, 3, 6, and 9 onwards up to end of the study (up to approximately 2 years) (1 cycle = 15 days) ]
Change from Baseline in Density of Cluster of Differentiation 3 Negative (CD3-) Perforin Positive Cells According to Immunohistochemical Methods [ Time Frame: Day1 of Cycles 1, 2, 3, 6, and 9 onwards up to end of the study (up to approximately 2 years) (1 cycle = 15 days) ]
Change from Baseline in Density of PD-L1 According to Immunohistochemical Methods [ Time Frame: Baseline, Cycle 3 Day 8, Day 1 of Cycle 9 onwards up to end of the study (up to approximately 2 years) (1 cycle = 15 days) ]

Inclution Criteria

INCLUSION CRITERIA
5.1.1 General Inclusion Criteria for all Participants
Participants are eligible to be included in the study only if all of the following criteria
apply:
Informed Consent
1. Signed informed consent.
Age
2. Age  18 years.
Type of Participants and Disease Characteristics
3. Participants who have progressed on at least one previous regimen of anticancer
therapy (ie, chemotherapy, mutation targeted therapy, and/or CPI therapy.)
4. Measurable disease, as defined by Response Evaluation Criteria in Solid Tumors
(RECIST) v1.1.
5. ECOG Performance Status 0 or 1 or Karnofsky Performance Score  70.
6. Life expectancy of  12 weeks.
7. Confirmed at least one tumor lesion with location accessible to safely biopsy per
clinical judgment of the treating physician (not applicable to Part I Cohort A).
8. Consent to provide an archival tumor tissue sample (if available, applicable to all
participants)
9. Willingness to undergo baseline and on-treatment tumor biopsies for PD biomarker
analysis (not applicable to Part I Cohort A).
10. Adequate cardiovascular function:
New York Heart Association (NYHA) Heart Failure Stage  2.
a. Left ventricular ejection fraction  50%, as determined by multiple-gated
acquisition scan or transthoracic echocardiogram.
b. Baseline-corrected QT (QTcF) interval  470 milliseconds.
c. Resting systolic blood pressure  150 mm Hg and diastolic blood pressure 100
mm Hg (average of  3 readings on  2 sessions).
d. Resting heart rate between 45 to 100 bpm.
11. Adverse events related to any previous radiotherapy, chemotherapy, or surgical
procedure must have resolved to Grade ≤ 1, except alopecia (any grade) and
Grade 2 peripheral neuropathy.
12. Adequate hematological function: neutrophil count of  1.5  109
cells/L, platelet
count of  100,000/L, hemoglobin  9 g/dL (5.6 mmol/L), lymphocytes  0.8  109
cells/L.
13. Adequate liver function, including total bilirubin  1.5  upper limit of normal (ULN)
(excluding Gilbert’s syndrome; see below), aspartate aminotransferase (AST), and
alanine aminotransferase (ALT)  3  ULN (in case of liver metastases: ≤ 5  ULN).
Gamma-glutamyl transferase > 2.5  ULN should be discussed and agreed with the
Sponsor.
14. Adequate renal function: serum creatinine  1.5  ULN or creatinine clearance by
Cockcroft-Gault formula 50 mL/min for participants in whom, in the Investigator‘s
judgment, serum creatinine levels do not adequately reflect renal function.
15. Participants with unilateral pleural effusion are eligible if they fulfill both of the
following:
a. NYHA Class 1.
b. Global initiative for obstructive lung disease test level 1 (forced expiratory volume
1 / forced vital capacity < 0.7 and forced expiratory volume  80% predicted).
Sex
16. Male and female participants
The contraception and abstinence requirements are intended to prevent exposure of an
embryo to the study treatment. The reliability of sexual abstinence for male and/or
female enrollment eligibility needs to be evaluated in relation to the duration of the
clinical study and the preferred and usual lifestyle of the participant. Periodic abstinence
(eg, calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are
not acceptable methods of contraception.
a) Female participants
A female participant is eligible to participate if she is not pregnant (see Appendix 5),
not breastfeeding, and at least one of the following conditions applies:
 Not a woman of childbearing potential (WOCBP, as defined in Section 1 of
Appendix 5).
OR
 WOCBP, who:
– Agree to remain abstinent (refrain from heterosexual intercourse) or use
contraceptive methods that result in a failure rate of 1% per year during the
treatment period and for at least 4 months after the last dose of study drug for
RO6874281 and for at least 5 months after the last dose of atezolizumab.
Examples of contraceptive methods with a failure rate of  1% per year include
bilateral tubal occlusion, male sterilization, established proper use of hormonal
contraceptives that inhibit ovulation, and hormone-releasing intrauterine devices
(see Appendix 5).
– Have a negative pregnancy test (serum) within the 7 days before the first study
treatment administration.
 Male Participants
During the treatment period and for at least 2 months after the last dose of
RO6874281, agreement to:
– Remain abstinent (refrain from heterosexual intercourse) or use contraceptive
measures such as a condom plus an additional contraceptive method that
together result in a failure rate of  1% per year, with partners who are WOCBP
(as defined in Section 1 of Appendix 5).
– With pregnant female partners, remain abstinent (refrain from heterosexual
intercourse) or use contraceptive measures such as a condom to avoid
exposing the embryo.
– Refrain from donating sperm.
Gilbert’s Syndrome:
Participants with Gilbert’s syndrome will be eligible for the study. The diagnosis of
Gilbert's syndrome is suspected in people who have persistent, slightly elevated levels of
unconjugated bilirubin ( 3.0  ULN) without any other apparent cause. A diagnosis of
Gilbert’s syndrome will be based on the exclusion of other diseases on the basis of the
following criteria:
a. Unconjugated hyperbilirubinemia noted on several occasions.
b. No evidence of hemolysis (normal hemoglobin, normal haptoglobin levels,
reticulocyte count), and lactate dehydrogenase.
c. Normal liver function tests.
d. Absence of other diseases associated with unconjugated hyperbilirubinemia.
5.1.2 Specific Inclusion Criteria for Participants with NSCLC
Checkpoint Inhibitor Naïve Participants (Part I Cohort A)
a) Participants must not have received CPI therapy (eg, anti-CTLA-4, anti-PD-1/L1)
before study enrollment.
b) Participant must have progressed on at least one previous systemic therapy for
advanced or metastatic disease.
c) Participants may be enrolled if they are ineligible for SoC therapy or if they are not
willing to receive conventional therapy.
d) Participants whose tumors have a known sensitizing mutation (eg, EGFR, ALK, etc.)
must have experienced disease progression (during or after treatment) or
intolerance to treatment with a respective targeted therapy.
Checkpoint Inhibitor Experienced Participants (Part I Cohort B)
e) Participants must have experienced documented disease progression on or after
CPI therapy (investigational or approved).
f) The CPI may have been administered as monotherapy or as part of a combination
regimen at any time during the anti-cancer treatment before study enrollment.
g) Participants with suspected or documented disease progression within the first
12 weeks of CPI therapy may not be eligible and require discussion with the
Sponsor. Screening tumor assessment should confirm previous progression.
h) No history of severe immune-related adverse effects from CPI treatment (National
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]
Grade 3 and 4).
Checkpoint Inhibitor Naïve Participants (Part I Cohort C)
i) Participants in this mandatory biopsy cohort must meet the specific inclusion criteria
for CPI-naïve participants (see Part I Cohort A above) as well as having accessible
tumor lesions that can be safely biopsied.

Exclusion Criteria

EXCLUSION CRITERIA
5.2.1 General Exclusion Criteria for all Participants
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Symptomatic or untreated CNS metastases.
2. History of treated asymptomatic CNS metastases with any of the following criteria:
a. Metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 10 mm
of the optic apparatus (optic nerves and chiasm).
b. History of intracranial hemorrhage or spinal cord hemorrhage.
c. Lacking radiographic demonstration of improvement upon the completion of
CNS-directed therapy and evidence of interim progression between the
completion of CNS-directed therapy and the baseline radiographic study.
d. Ongoing requirement for dexamethasone as therapy for CNS disease;
anticonvulsants at a stable dosage are allowed.
e. Stereotactic radiation or whole-brain radiation within 28 days before study
treatment administration.
f. Last CNS radiographic study < 4 weeks since completion of radiotherapy and
< 2 weeks since discontinuation of corticosteroids.
g. CNS metastases treated by neurosurgical resection or brain biopsy performed
within 28 days before study treatment administration.
3. Spinal cord compression not definitively treated with surgery and/or radiation or
previously diagnosed and treated spinal cord compression without evidence that
disease has been clinically stable for  2 weeks before enrollment.
4. Leptomeningeal disease.
5. An active second malignancy (exceptions are non-melanoma skin cancer, cervical
carcinoma in situ, or prostate carcinoma that is in remission under androgen
deprivation therapy for  2 years, or participants who have a history of malignancy
and have been treated with curative intent and the participant is expected to be
cured as per Investigator’s assessment). Other exceptions may apply and require
discussion between the Investigator and the Sponsor.
6. Evidence of significant, uncontrolled concomitant diseases that could affect
compliance with the protocol or interpretation of results, including diabetes mellitus,
history of relevant pulmonary disorders, and known autoimmune diseases or other
disease with ongoing fibrosis (such as scleroderma, pulmonary fibrosis, and
emphysema).
7. Episode of significant cardiovascular/cerebrovascular acute disease within 6 months
before study treatment administration, including any of the following: hypertensive
crisis/encephalopathy, uncontrolled hypertension (systolic blood
pressure  150 mmHg and/or diastolic blood pressure  100 mm Hg), unstable
angina, transient ischemic attack/stroke, congestive heart failure of any NYHA
classification (for NYHA classification, refer to inclusion criteria), serious cardiac
arrhythmia requiring treatment (exceptions are atrial fibrillation, paroxysmal
supraventricular tachycardia), history of thromboembolic events (such as myocardial
infarction, stroke or pulmonary embolism), hypertensive encephalopathy.
8. History of significant vascular disease (eg, aortic aneurysm, aortic dissection).
9. Peripheral arterial thrombosis within 6 months before study treatment administration.
10. Active or uncontrolled infections.
11. Human immunodeficiency virus or hepatitis B or hepatitis C virus infection.
12. Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection
(excluding fungal infections of nail beds) or any major episode of infection requiring
treatment with IV antibiotics or hospitalization (relating to the completion of the
course of antibiotics, except if for tumor fever) within 4 weeks before study treatment
administration.
13. History of chronic liver disease or evidence of hepatic cirrhosis.
14. Serious, non-healing wound; active ulcer; or untreated bone fracture.
15. Dementia or altered mental status that would prohibit informed consent.
16. History of, active or suspicion of autoimmune disease, including but not limited to
systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease,
vascular thrombosis associated with anti-phospholipid syndrome, Wegener’s
granulomatosis, Sjögren’s syndrome, Bell’s palsy, Guillain-Barré syndrome, multiple
sclerosis, vasculitis, or glomerulonephritis.
Participants with a history of autoimmune hypothyroidism on a stable dosage of
thyroid replacement hormone may be eligible with approval by the Medical Monitor.
Participants with controlled type 1 diabetes mellitus on a stable insulin regimen may
be eligible for this study with approval by the Medical Monitor.
17. History of idiopathic pulmonary fibrosis, pneumonitis (including drug-induced),
organizing pneumonia (ie, bronchiolitis obliterans, cryptogenic organizing
pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis)
is permitted.
18. Bilateral pleural effusion confirmed by x-ray.
19. Any other diseases, metabolic dysfunction, physical examination finding, or clinical
laboratory finding that give reasonable suspicion of a disease or condition that
would contraindicate the use of an investigational drug.
Previous/Concomitant Therapy
20. Concurrent therapy with any other investigational drug (defined as a treatment for
which there is currently no regulatory authority-approved indication).
21. Immunomodulating agents:
a. Last dose with any of the following agents, for example, etanercept, infliximab,
tacrolimus, cyclosporine, mycophenolic acid, alefacept, or efalizumab (or similar
agents)  28 days before study treatment administration.
b. Previous immunotherapies including but not limited to any cytokine therapies,
particularly IL-2 and IL-2 conjugates, IFN-, IFN-.
c. Regular immunosuppressive therapy (ie, for organ transplantation, chronic
rheumatologic disease).
22. Chronic use of steroids (including inhaled).
23. Radiotherapy within the last 4 weeks before start of study treatment administration,
with the exception of limited field palliative radiotherapy.
24. Administration of a live, attenuated vaccine within 4 weeks before Cycle 1 Day 1 or
at any time during the study and 5 months after the last dose of atezolizumab.
Other Exclusions
25. Major surgery or significant traumatic injury  28 days before study treatment
administration (excluding fine needle biopsies) or anticipation of the need for major
surgery during study treatment.
26. Known hypersensitivity to any of the components of the RO6874281 drug product or
atezolizumab drug product, including but not limited to hypersensitivity to Chinese
Hamster Ovary cell products or other recombinant human or humanized antibodies.
27. Severe dyspnea at rest or requiring supplementary oxygen therapy.

The Estimated Number of Participants

  • Taiwan

    29 participants

  • Global

    460 participants

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