METASTATIC PANCREATIC DUCTAL ADENOCARCINOMA

Study WO39850 is a Phase Ib/III, open-label, multicohort, multicenter, randomized, global clinical study in patients with metastatic PDAC. The study is composed of two parts: Part 1 of the study (Phase Ib) includes Cohorts 1, 2, and 3, and Part 2 of the study (Phase III) consists of a single gated cohort (Cohort 4). Primary Efficacy Objective  Cohort 1: To evaluate the preliminary efficacy of RO6958688 plus atezolizumab and nab-paclitaxel plus gemcitabine relative to SOC  Cohort 2: To evaluate the preliminary efficacy of RO6958688 plus atezolizumab relative to SOC  Cohort 3: To evaluate the preliminary efficacy of RO6958688 plus atezolizumab in patients with high CEA-expressing tumors  Cohort 4: To determine if RO6958688 plus atezolizumab results in improved OS relative to nal-IRI plus 5-FU/LV

RO6958688、Tecentriq、Onivyde、Leucovorin、Abraxane、Fluorouracil (5-FU)、Gemcitabine

Atezolizumab
Fluorouracil
Gemcitabine
Leucovorin
Nab-paclitaxel
Nanoliposomal Irinotecan
RO6958688

Concentrate for solution for IV infusion Concentrate for solution for IV infusion. Solution for IV infusion Solution for IV infusion Solution for IV infusion Powder for solution for injection Powder for suspension for infusion

100mg/2ml 1200mg/20ml 300mg/30ml 5000mg/100ml 50mg/10ml 1000mg 100mg

Part 1, Cohort 1 (First-Line): Overview
Treatment-naive patients with metastatic PDAC will be enrolled in Cohort 1. The cohort
will consist of a safety run-in phase followed by a randomized phase with two arms.

Safety Run-In Phase
The safety run-in phase will allow evaluation of the preliminary safety profile of
RO6958688 and atezolizumab in combination with nab-paclitaxel and gemcitabine prior
to initiating the randomized phase of the study for Cohort 1.
Enrollment in the randomized phase of the study will be initiated after review of the
safety run-in data by the IMC (refer to Section 3.1.1.1 for a detailed description of the
safety run-in phase). In the randomized phase, patients will be randomized to receive
RO6958688 in combination with atezolizumab and nab-paclitaxel plus gemcitabine or
nab-paclitaxel plus gemcitabine to assess the preliminary efficacy and safety for
RO6958688 in combination with atezolizumab and nab-paclitaxel plus gemcitabine by
means of randomized comparison with SOC (nab-paclitaxel in combination with
gemcitabine).

Part 1, Cohort 2 (Second Line): Overview
Cohort 2 will consist of a single randomized phase with two arms. Patients with
metastatic PDAC whose disease progressed during or following a gemcitabine-based
first-line therapy will be randomized to RO6958699 plus atezolizumab or nal-IRI plus
5-FU/LV to assess the preliminary efficacy and safety of RO6958699 in combination with
atezolizumab by means of a randomized comparison with SOC (nal-IRI in combination
with 5-FU/LV).

Part 1, Cohort 3 (Third Line): Overview
Cohort 3 will consist of a single non-randomized arm enrolling patients with metastatic
PDAC whose disease has progressed during or following a gemcitabine-based therapy
and a fluoropyrimidine-based therapy.

Inclusion Criteria for All Cohorts
Patients must meet the following criteria for entry into any cohort of this study:
 Signed Informed Consent Form
 Age  18 years at time of signing Informed Consent Form
 Ability to comply with the study protocol, in the investigator’s judgment
 ECOG Performance Status of 0 or 1 (see Appendix 6)
 Life expectancy  3 months, as determined by the investigator
 Histologically or cytologically confirmed metastatic PDAC
The definitive diagnosis of metastatic PDAC will be made by integrating the
histopathologic data within the context of clinical and radiographic data.
Patients with endocrine or acinar pancreatic carcinoma are not eligible for
the study.
 Measurable disease (at least one target lesion) according to RECIST v1.1 (see
Appendix 4)
Previously irradiated lesions can be considered as measurable disease only if
progressive disease has been unequivocally documented at that site since
radiation.
 Availability of a representative tumor specimen that is suitable for determination of
PD-L1 and CEA status by means of central testing
Tumor tissue samples will be collected from all patients at baseline, preferably by
means of a biopsy performed at study entry. If a biopsy is not deemed feasible
by the investigator, archival tumor tissue may be submitted.
A formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a paraffin block
(preferred) or at least 10 slides (15 slides preferred) containing unstained, freshly
cut, serial sections must be submitted along with an associated pathology report
prior to study enrollment.
 Adequate hematologic and end-organ function, defined using the following
laboratory test results, obtained within 14 days prior to initiation of study treatment:
– ANC  1.5109
/L (1500/L) without granulocyte colony-stimulating factor
support
– WBC count  2.5109
/L (2500/L)
– Lymphocyte count  0.8109
/L (800/L)
– Platelet count  100 109
/L (100,000/L) without transfusion
– Hemoglobin  90 g/L (9.0 g/dL)
Patients may be transfused to meet this criterion.
– AST, ALT, and ALP  2.5 upper limit of normal (ULN), with the
following exceptions:
Patients with documented liver metastases: AST and ALT  5 ULN
Patients with documented liver or bone metastases: ALP  5 ULN
– Serum bilirubin  1.5 ULN with the following exception:
Patients with known Gilbert disease: serum bilirubin level  3  ULN
– Serum creatinine 1.5 ULN
– Serum albumin  30 g/L (3.0 g/dL)
– For patients not receiving therapeutic anticoagulation: INR and aPTT
 1.5 ULN
 Negative HIV test at screening, unless not permitted per local regulations
 Negative hepatitis B surface antigen (HBsAg) test at screening
 Negative total hepatitis B core antibody (HBcAb) test at screening, or positive
HBcAb test followed by a negative HBV DNA test at screening
The HBV DNA test will be performed only for patients who have a positive
HBcAb test.
 Negative hepatitis C virus (HCV) antibody test at screening or positive HCV
antibody test followed by a negative HCV RNA test at screening
The HCV RNA test will be performed only for patients who have a positive
HCV antibody test.
 For patients receiving therapeutic anticoagulation: stable anticoagulant regimen
 For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive methods with a failure rate of
1% per year during the treatment period and for 5 months after the last dose of
atezolizumab, for 4 months after the last dose of RO6958688, for 1 month after the
last dose of nal-IRI, and for 6 months after the last dose of 5-FU/LV of nab-paclitaxel,
and 6 months after the last dose of gemcitabine, whichever is later
A woman is considered to be of childbearing potential if she is postmenarcheal,
has not reached a postmenopausal state (12 continuous months of amenorrhea with no identified cause other than menopause), and has not
undergone surgical sterilization (removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year include
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit
ovulation, hormone-releasing intrauterine devices, and copper intrauterine
devices.
The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the patient.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation
methods) and withdrawal are not acceptable methods of contraception.
 For men: agreement to remain abstinent (refrain from heterosexual intercourse) or
use contraceptive measures, and agreement to refrain from donating sperm, as
defined below:
With female partners of childbearing potential, men must remain abstinent or
use a condom plus an additional contraceptive method that together result in a
failure rate of 1% per year during the treatment period and for 90 days after the
last administration of RO6958688 and up to 4 months after the last dose of
nal-IRI and up to 6 months after the last dose of 5-FU, nab-paclitaxel, and
gemcitabine. Men must refrain from donating sperm during this same period.
With pregnant female partners, men must remain abstinent or use a condom
during the treatment period and for 90 days after the last dose of study
treatment to avoid exposing the embryo.
The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the patient.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation
methods) and withdrawal are not acceptable methods of contraception.
Advice on conservation of sperm should be sought prior to treatment with 5-FU
because of the possibility of irreversible infertility due to therapy with fluorouracil.
Male patients who receive atezolizumab only (only if RO6958688 is
discontinued 90 days and treatment with atezolizumab is continued) are not
required to use contraception during atezolizumab treatment; pregnancies in
female partners of male patients receiving atezolizumab monotherapy are not
required to be reported.

Exclusion Criteria for All Patients
Patients who meet any of the following criteria will be excluded from study entry:
 Prior treatment with any of the protocol-specified study treatments, with the
exception of chemotherapy (for Cohorts 2, 3, and 4 only)
 Treatment with investigational therapy within 28 days prior to initiation of
study treatment
 Systemic treatment for PDAC within 2 weeks or 5 half-lives of the drug (whichever is
longer) prior to initiation of study treatment
 Patients with paraspinal, paratracheal, and mediastinal pathological lesions larger
than 2 cm unless they have been previously irradiated
Irradiation must be completed at least 7 days prior to randomization.
 Patients with bilateral lung lesions or patients with lobectomy or pneumonectomy with lung metastases in the remaining lung and either dyspnea or SaO2 92% (at
rest and on room air) at baseline
 Adverse events from prior anti-cancer therapy that have not resolved to Grade 1 or
better with the exception of alopecia of any grade and Grade  2 peripheral
neuropathy
 Uncontrolled tumor-related pain
Patients requiring pain medication must be on a stable regimen at study entry.
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases
or metastases causing nerve impingement) should be treated prior to enrollment.
Patients should be recovered from the effects of radiation. There is no required
minimum recovery period.
Asymptomatic metastatic lesions that would likely cause functional deficits or
intractable pain with further growth (e.g., epidural metastasis that is not currently
associated with spinal cord compression) should be considered for loco-regional
therapy if appropriate prior to enrollment.
 Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures (procedures expected to occur once monthly or more
frequently)
Patients with indwelling catheters (e.g., PleurX®
) are allowed.
 Uncontrolled or symptomatic hypercalcemia ( 1.5 mmol/L ionized calcium or
calcium 12 mg/dL or corrected serum calcium greater than ULN)
Patients who are receiving denosumab prior to randomization must be willing
and eligible to discontinue its use and replace it with a bisphosphonate instead
while in the study.
 Known primary central nervous system (CNS) malignancy or untreated or actively
progressing CNS metastases
Patients with a history of treated CNS metastases are eligible, provided that all of
the following criteria are met:
– Measurable disease per RECIST v1.1 must be present outside the CNS.
– The patient has no history of intracranial hemorrhage or spinal cord
hemorrhage.
– Metastases are limited to the cerebellum or the supratentorial region (i.e., no
metastases to the midbrain, pons, medulla, or spinal cord).
– There is no evidence of interim progression between completion of
CNS-directed therapy and the screening brain scan.
– The patient has not received stereotactic radiotherapy within 7 days prior to
initiation of study treatment or whole-brain radiotherapy within 14 days prior
to initiation of study treatment.
– The patient has no ongoing requirement for corticosteroids as therapy for
CNS disease. Anticonvulsant therapy at a stable dose is permitted.
Asymptomatic patients with CNS metastases newly detected at screening
are eligible for the study after receiving radiotherapy or surgery, with no
need to repeat the screening brain scan.
 History of leptomeningeal disease
 History of severe allergic, anaphylactic reactions to chimeric or humanized
antibodies or fusion proteins
 Known hypersensitivity to Chinese hamster ovary cell products
 Known allergy or hypersensitivity to any of the study drugs or any of their excipients
 Active or history of autoimmune disease or immune deficiency, including, but not
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré
syndrome, or multiple sclerosis (for a more comprehensive list of autoimmune
diseases and immune deficiencies; see Appendix 7), with the following exceptions:
Patients with a history of autoimmune-related hypothyroidism who are on
thyroid-replacement hormone are eligible for the study.
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen
are eligible for the study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis are
excluded) are eligible for the study provided all of following conditions are met:
– Rash must cover 10% of body surface area.
– Disease is well controlled at baseline and requires only low-potency topical
corticosteroids.
– There is no occurrence of acute exacerbations of the underlying condition
requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic
agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within
the previous 12 months.
 For patients with positive serology of auto-antibody panel (anti-nuclear antibody,
antidouble-stranded DNA, cytoplasmic antineutrophil cytoplasmic antibody, and
perinuclear antineutrophil cytoplasmic antibody) at screening, referral to a
specialist (i.e., rheumatologist) for further assessments if the investigator, after
discussion with the Medical Monitor, considers the results to be clinically significant
 Prior allogeneic stem cell or solid organ transplantation
 History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of
active pneumonitis on screening chest computed tomography (CT) scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
 Active tuberculosis
 Current treatment with anti-viral therapy for HBV
 Known clinically significant liver disease, including alcoholic hepatitis, cirrhosis, fatty
liver disease, and inherited liver disease
 Severe infection within 4 weeks prior to initiation of study treatment, including, but
not limited to, hospitalization for complications of infection, bacteremia, or
severe pneumonia
 Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of
study treatment
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection
or chronic obstructive pulmonary disease [COPD] exacerbation) or infection due
to biliary stent (re)placement are eligible for the study.
 Significant cardiovascular disease, such as New York Heart Association cardiac
disease (Class II or greater), myocardial infarction, or cerebrovascular accident
within 3 months prior to initiation of study treatment, unstable arrhythmia, or
unstable angina
 Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of
study treatment, or anticipation of need for a major surgical procedure during
the study
Placement of a central venous access catheter (e.g., port or similar) or biliary
stent is not considered a major surgical procedure and is therefore permitted.
 Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study
treatment, or anticipation of need for such a vaccine during the study
 History of malignancy other than pancreatic carcinoma within 5 years prior to
screening, with the exception of those patients with a negligible risk of metastasis or
death (e.g., 5-year OS of  90%), such as adequately treated carcinoma in situ of
the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal
carcinoma in situ, or Stage I uterine cancer
 Any other disease, metabolic dysfunction, physical examination finding, or clinical
laboratory finding that contraindicates the use of an investigational drug, may affect
the interpretation of the results, or may render the patient at high risk from treatment
complications
 Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies,
including antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies
 Treatment with systemic immunostimulatory agents (including, but not limited to,
interferons and IL-2) within 4 weeks or 5 half-lives of the drug (whichever is longer),
prior to initiation of study treatment
 Treatment with systemic immunosuppressive medication (including, but not limited
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
antiTNF- agents) within 2 weeks prior to initiation of study treatment, or
anticipation of need for systemic immunosuppressive medication during the study,
with the following exceptions:
– Patients who received acute, low-dose systemic immunosuppressant medication
or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study
after discussion with and approval by the Medical Monitor.
– Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids
for COPD or asthma, or low-dose corticosteroids for orthostatic hypotension or
adrenal insufficiency are eligible for the study.
 Pregnancy or breastfeeding, or intention to become pregnant during the study
Women of childbearing potential must have a negative serum pregnancy test
result within 14 days prior to initiation of study treatment.