A Randomized Phase 2 Study of Combination Atezolizumab and CDX-1127 (Varlilumab) With or Without Addition of Cobimetinib in Previously Treated Unresectable Biliary Tract Cancers


About this study

The purpose of this study is to assess the response rate (ORR) of patients with unresectable, pre-treated biliary cancers treated with the combination of atezolizumab and CDX-1127 (varlilumab) with or without cobimetinib, and to assess the progression free survival (PFS) of patients with unresectable, pre-treated biliary cancers treated with the combination of atezolizumab and CDX-1127 (varlilumab) with or without cobimetinib.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria:

- Pathologically confirmed biliary tract cancer, having received at least 1 prior line
of systemic therapy, and received no more than 2 prior lines of therapy in the
metastatic setting (disease recurrence =< 6 months from the last dose of adjuvant
therapy in resected patients will be considered the first line of therapy)

- Includes intrahepatic cholangiocarcinoma (IHC), extrahepatic cholangiocarcinoma
(EHC), and gallbladder carcinoma (GBC), but not Ampulla of Vater cancers

- Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors
(RECIST) version (v)1.1

- Age >= 18 years. Because no dosing or adverse event data are currently available on
the use of atezolizumab, cobimetinib, and CDX-1127 (varlilumab) in patients < 18 years
of age, children are excluded from this study

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 80%)

- Absolute neutrophil count >= 1,500/mcL

- Hemoglobin >= 9.0 g/dl

- Platelets >= 100,000/mcL

- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (Patients with
known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =<
3 x institutional ULN

- Serum creatinine =< 1.5 x institutional ULN OR

- Creatinine clearance > 30 mL/min/1.73 m^2 (calculated by Cockcroft-Gault method) for
patients with creatinine levels above institutional normal

- Albumin >= 3.0 g/dL

- Prothrombin time (PT)/activated partial thromboplastin time (aPTT) =< 1.5 x ULN (This
applies only to patients who do not receive therapeutic anticoagulation; patients
receiving therapeutic anticoagulation, such as low-molecular-weight heparin or
warfarin, should be on a stable dose)

- Creatine kinase (CK)/creatine phosphokinase (CPK) < 5 x ULN

- Oxygen saturation >= 92% on room air

- Left ventricular ejection fraction > 50%

- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial

- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable on suppressive therapy, if indicated

- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load

- Patients must be willing to undergo 2 sets of core needle biopsies. If possible,
biopsied sites should be different than those used for measurable disease/RECIST
measurements, but this is not mandatory

- Patients must have an estimated life expectancy of greater than 3 months

- Patients must be able to swallow pills

- Patients should not have evidence of retinal pathology on ophthalmologic examination;
or neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular
macular degeneration

- The effects of atezolizumab, cobimetinib, and CDX-1127 (varlilumab) on the developing
human fetus are unknown. For this reason, women of child-bearing potential and men
must agree to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry, for the duration of study participation, and 5
months after the last dose of atezolizumab. Should a woman become pregnant or suspect
she is pregnant while she or her partner is participating in this study, she should
inform her treating physician immediately. Men treated or enrolled on this protocol
must also agree to use adequate contraception prior to the study, for the duration of
study participation, and 5 months (150 days) after completion of atezolizumab,
cobimetinib, and CDX-1127 (varlilumab) administration

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients with prior allogeneic bone marrow transplantation within the past 5 years or
prior solid organ transplantation at any point

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events (other than alopecia or neuropathy) due to agents
administered more than 4 weeks earlier. However, the following therapies are allowed:

- Hormone-replacement therapy or oral contraceptives

- Herbal therapy > 1 week prior to randomization (herbal therapy intended as
anticancer therapy must be discontinued at least 1 week prior to randomization)

- Palliative radiotherapy for bone metastases > 2 weeks prior to randomization

- Prior treatment with anti-CTLA-4, anti-PD-1, or anti-PD-L1or other immune checkpoint
inhibitor therapeutic antibodies or pathway-targeting agents. Patients who have only
received previous durvalumab (anti-PD-L1) as part of first line in combination with
gemcitabine and cisplatin (TOPAZ-1 regimen [NCT03875235]) are eligible

- Prior treatment with MEK or ERK inhibitors

- Treatment with any other investigational agent within 4 weeks prior to randomization

- Treatment with systemic immunostimulatory agents (including, but not limited to,
interferon [IFN]-alpha or interleukin [IL]-2) within 6 weeks prior to randomization

- Treatment with systemic immunosuppressive medications (including, but not limited to,
prednisone (> 10 mg), cyclophosphamide, tacrolimus, sirolimus, azathioprine,
methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2
weeks prior to randomization.

- Patients who have received acute, low dose, systemic immunosuppressant
medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled.

- The use of physiologic doses of systemic corticosteroids and mineralocorticoids
(e.g., fludrocortisone) for patients with orthostatic hypotension or
adrenocortical insufficiency is allowed.

- The use of topical and inhaled corticosteroids are allowed due to low systemic

- Patients taking bisphosphonate therapy for symptomatic hypercalcemia. Use of
bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is

- Presence of therapeutically actionable mutation with approved targeted therapy (e.g.
FGFR fusion patients are eligible for study therapy in the 3rd line setting). Patient
must have received somatic mutation testing (tissue or liquid) prior to enrollment

- Clinically significant ascites (palpable on exam, paracentesis in last 3 months,
and/or symptomatic)

- Patients with known primary central nervous system (CNS) malignancy or symptomatic CNS
metastases are excluded, with the following exceptions:

- Patients with asymptomatic treated CNS metastases may be enrolled, provided all
the criteria listed above are met as well as the following:

- Radiographic demonstration of improvement upon the completion of CNS
directed therapy and no evidence of interim progression between the
completion of CNS directed therapy and the screening radiographic study

- No stereotactic radiation or whole-brain radiation within 28 days prior to

- Screening CNS radiographic study >= 4 weeks from completion of radiotherapy
and >= 2 weeks from discontinuation of corticosteroids

- Follow-up brain imaging 3 months after central nervous system (CNS)-directed
therapy shows no evidence of progression

- History of malignant bowel obstruction

- History of severe allergic, anaphylactic, or other hypersensitivity reactions to
Chinese hamster ovary cell products, chimeric, humanized, or other recombinant human
antibodies or fusion proteins

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to atezolizumab, cobimetinib, or CDX-1127 (varlilumab)

- Patients receiving any medications or substances that are considered moderate to
strong inhibitors or inducers of CYP3A and are not able to switch to an alternative
that minimizes interaction potential will ineligible. Coadministration of cobimetinib
with a strong CYP3A4 inhibitor can increase cobimetinib systemic exposure
significantly (e.g. itraconazole increased serum systemic cobimetinib exposure by 6.7
fold). On the other end, coadministration of cobimetinib with a strong CYP3A inducer
may decrease cobimetinib systemic exposure by more than 80% thus reducing its
efficacy. Because the lists of these agents are constantly changing, it is important
to regularly consult a frequently-updated list such as
http://medicine.iupui.edu/clinpharm/ddis/; medical reference texts such as the
Physicians' Desk Reference may also provide this information. As part of the
enrollment/informed consent procedures, the patient will be counseled on the risk of
interactions with other agents, and what to do if new medications need to be
prescribed or if the patient is considering a new over-the-counter medicine or herbal

- Patients on mild inhibitors or inducers of CYP3A are allowed

- Patients with a known clinically significant liver disease, including active viral,
alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease.

- Patients with past or resolved hepatitis B infection (defined as having a
negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc
[antibody to hepatitis B core antigen] antibody test) are eligible.

- Patients positive for hepatitis C virus (HCV) antibody are eligible only if
polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)

- Patients who have received immunosuppressive treatment for systemic autoimmune
disease, including, but not limited to, systemic lupus erythematosus, rheumatoid
arthritis, inflammatory bowel disease, vascular thrombosis associated with
antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, multiple
sclerosis, vasculitis, or glomerulonephritis within the last 2 years.

- Patients with a history autoimmune endocrine disorders on stable doses of
physiologic hormone replacement may be eligible.

- Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may
be eligible.

- Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis would
be excluded) are permitted provided that they meet the following conditions:

- Patients with psoriasis must have a baseline ophthalmologic exam to rule out
ocular manifestations

- Rash must cover less than 10% of body surface area (BSA)

- Disease is well controlled at baseline and only requiring low potency
topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%,
fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)

- No acute exacerbations of underlying condition within the last 12 months
(not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate,
retinoids, biologic agents, oral calcineurin inhibitors; high potency or
oral steroids)

- Patients with history Guillain-Barre syndrome or myasthenia gravis at any point
will not be eligible

- History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
organizing pneumonia (i.e., 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

- Patients with active tuberculosis (TB) are excluded

- Severe infections within 4 weeks prior to randomization, including, but not limited
to, hospitalization for complications of infection, bacteremia, or severe pneumonia

- Signs or symptoms of infection within 2 weeks prior to randomization

- Received oral or intravenous (IV) antibiotics within 2 weeks prior to randomization

- Patients receiving prophylactic/suppressive antibiotics will not be eligible

- Major surgical procedure within 28 days prior to randomization or anticipation of need
for a major surgical procedure during the course of the study

- Administration of a live, attenuated vaccine within 4 weeks before randomization or
anticipation that such a live, attenuated vaccine will be required during the study
and up to 5 months after the last dose of atezolizumab.

- Influenza vaccination should be given during influenza season only (approximately
October to March). Patients must not receive live, attenuated influenza vaccine
within 4 weeks prior to Randomization or at any time during the study.

- Coronavirus disease 2019 (COVID-19) vaccination is not exclusionary but should be
administered at least 7 days before study start

- Patients with psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study because one or more study agents have the
potential for teratogenic or abortifacient effects. Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with atezolizumab, cobimetinib, and CDX-1127 (varlilumab), breastfeeding should
be discontinued if the mother is treated with atezolizumab, cobimetinib, and CDX-1127

- Patients who are using ethinyl estradiol containing oral contraceptives when
administered concomitantly with cobimetinib, are excluded due to increased risk of
venous thromboembolism

- Patients with a history of clinically significant cardiac dysfunction, including the

- Left ventricular ejection fraction (LVEF) below institutional lower limit of
normal (LLN) or below 50%, whichever is lower

- Current unstable angina

- Current symptomatic congestive heart failure (CHF) of New York Heart Association
class 2 or higher

- Uncontrolled hypertension >= grade 2 (patients with a history hypertension
controlled with anti-hypertensives to =< grade 1 are eligible).

- Uncontrolled arrhythmias

- Myocardial infarction, severe/unstable angina, symptomatic chronic heart failure
(CHF), cerebrovascular accident or transient ischemic attack within the previous
6 months

- History of treatment with cardiotoxic agents

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 9/20/22. Questions regarding updates should be directed to the study team contact.

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Rochester, Minn.

Mayo Clinic principal investigator

Lionel Aurelien Kankeu Fonkoua, M.D.

Closed for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

Scottsdale/Phoenix, Ariz.

Mayo Clinic principal investigator

Mitesh Borad, M.D.

Closed for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

More information


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