Inclusion Criteria:
- - Subjects must have had at least one prior treatment with systemic therapy for
advanced and unresectable, or metastatic disease OR is intolerant to, has refused or
for whom there are no standard therapies that impart significant clinical benefit in
the opinion of the treating investigator.
- - An Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal
to 1 for phase 1B.
An ECOG Performance Status less than or equal to 2 for phase 2.
- - Subjects must not have more than one malignancy at the time of enrollment.
- - Adult subjects ≥ eighteen years of age.
- - A clinical diagnosis consistent with stage IV "immunogenically cold" or otherwise
incurable cancer of one of the following histologies: i) bile duct or gallbladder
cancer ii) Metastatic breast cancer, HR-negative HER2-positive, who have received at
least 3 lines of therapy for disease progression that includes: trastuzumab,
pertuzumab/trastuzumab, and ado-trastuzumab emtansine iii) neuroendocrine cancer
with the following pathological characteristics: grade 2 or 3; well- or moderately-
differentiated (Grades 1, 4, and poorly differentiated neuroendocrine pathologies
are not eligible) iv) FIGO stage IV or metastatic (using 2021 FIGO classification)
high grade serious or high grade endometrioid (based on local histopathological
findings) ovarian cancer, primary peritoneal cancer and / or fallopian-tube cancer
that is platinum resistant, with no acceptable standard of care v) pancreatic
adenocarcinoma vi) soft tissue sarcoma vii) prostate cancer subjects who are
castrate-resistant (testosterone ≤ 50 ng/dL) and have progressed on, declined, or
are intolerant to other standard of care therapies.
Subjects with prostate cancer
must have failed at least one line of treatment with an androgen inhibitor (AI)
(i.e. enzalutamide, abiraterone, etc.) or cytotoxic chemotherapy in the advanced or
metastatic setting viii) vulvar cancer.
- - Adequate hematologic and end-organ function.
- - Subjects receiving therapeutic anticoagulation must be on a stable anticoagulant
regimen for ≥ 2 weeks at start of protocol treatment.
- - Negative hepatitis B surface antigen (HBsAg) test at screening.
- - Negative HIV test at screening with the following exceptions: subjects with a
positive HIV test at screening are eligible only if they meet the following three
conditions: 1) Are stable on anti-retroviral therapy 2) Have a CD4 count ≥ 200/uL
AND 3) Have an undetectable viral load.
- - Women of childbearing potential (WOCBP) must be using an adequate method of
contraception (with a failure rate of <1% per year) to avoid pregnancy throughout
the study and for at least 160 days after the last dose of either study drug to
minimize the risk of pregnancy.
- - Males with female partners of child-bearing potential must agree to use
physician-approved contraceptive methods throughout the study and should avoid
conceiving children for 160 days following the last dose of study drug.
- - Measurable disease by RECIST criteria.
- - A life expectancy of ≥ 12 weeks.
- - Written informed consent obtained from the subject and the subject agrees to comply
with all the study-related procedures.
- - Must have formalin-fixed paraffin embedded (FFPE) tissue or 12 unstained slides
available for research purposes.
Tissue must have been obtained within the last 3
years.
- - If a new biopsy is needed for diagnostic reasons, the biopsy must be performed from
a tumor site that is not the only site of measurable disease.
- - Subject must be able to swallow capsules.
Exclusion Criteria:
- - Subjects with known MSI-H or dMMR tumor status.
- - Subjects with severe uncontrolled hypertension as defined as systolic blood pressure
> 150 mmHg or diastolic blood pressure > 100 mmHg.
- - Subjects who have had prior treatment with vascular endothelial growth factor
receptor (VEGFR) tyrosine kinase inhibitors.
- - Females or males of childbearing potential who are unwilling or unable to use an
acceptable method to avoid pregnancy for the entire study period and for at least
160 days after the last dose of study drug.
- - Females who are pregnant or breastfeeding.
- - History of leptomeningeal disease.
- - Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium >
12 mg/dL or corrected serum calcium > ULN)
- Uncontrolled tumor-related pain.
- - Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures (once monthly or more frequently, except in the case of ovarian
cancer with ascites, which may require more frequent drainage).
Subjects with
indwelling catheters are allowed.
- - 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, antiphospholipid
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré
syndrome, or multiple sclerosis, with the following exceptions:
1.
subjects with a history of autoimmune-related hypothyroidism who are on
thyroid-replacement hormone are eligible for the study.
2. subjects with controlled Type 1 diabetes mellitus who are on an insulin regimen
are eligible for the study.
3. subjects with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., subjects 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 lowpotency
topical corticosteroids.
- - There has been 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.
- - 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.
- - Significant cardiovascular disease (such as New York Heart Association Class II or
greater cardiac disease, 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.
- - History of malignancy other than the malignancies listed in the inclusion criteria
of enrollment within 5 years prior to screening, with the exception of malignancies
with a negligible risk of metastasis or death (e.g., 5-year OS rate > 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.
- - 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, or any active infection that could impact patient safety.
- - Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
of study treatment.
Note: Subjects receiving prophylactic antibiotics (e.g., to
prevent a urinary tract infection or chronic obstructive pulmonary disease
exacerbation) are eligible for the study.
- - Prior allogeneic stem cell or solid organ transplantation.
- - Current treatment with anti-viral therapy for hepatitis B virus (HBV)
- Treatment with investigational therapy within 28 days prior to initiation of study
treatment.
- - Prior treatment with CD137 agonists or immune checkpoint blockade therapies,
including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies.
- - Treatment with systemic immunostimulatory agents within 4 weeks or 5 half-lives of
the drug (whichever is longer) prior to initiation of study treatment.
- - Treatment with systemic immunosuppressive medication within 2 weeks prior to
initiation of study treatment, or anticipation of need for systemic
immunosuppressive medication during study treatment, with the following exceptions:
1.
Subjects 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.
2. Subjects who received mineralocorticoids (e.g., fludrocortisone),
corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or
low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency
are eligible for the study.
- - History of severe allergic anaphylactic reactions to chimeric or humanized
antibodies or fusion proteins.
- - Known hypersensitivity to Chinese hamster ovary cell products or to any component of
the atezolizumab formulation.
- - History of any other disease, metabolic dysfunction, physical examination finding,
or clinical laboratory finding giving reasonable suspicion of a disease or condition
that contraindicates the use of protocol therapy or that might affect the
interpretation of the results of the study or that puts the subject at high risk for
treatment complications, in the opinion of the treating physician.
- - Administration of a vaccine containing live virus within 30 days prior to the first
dose of trial treatment, during treatment with atezolizumab, and for 160 days after
the last dose of atezolizumab.
Note: Most flu vaccines are killed viruses, with the
exception of the intra-nasal vainer (Flu-Mist) which is an attenuated live virus and
therefore prohibited for 30 days prior to first dose. Subjects may receive non-live
COVID-19 vaccine.
- - Prisoners or subjects who are involuntarily incarcerated, or subjects who are
compulsorily detained for treatment of either a psychiatric or physical illness.
- - Subjects with Tumor Mutation Burden (TMB) ≥10.
- - Treatment with any cancer directed therapy (i.e. chemotherapy, radiation therapy,
Y90, microwave ablation, immunotherapy, etc.) within 28 days of study start.
- - Subjects with treated brain metastases that have remained stable for at least 90
days without steroids are allowed.
Subjects with signs of symptoms or history of
brain metastasis must have a CT or MRI of the brain within 30 days prior to the
start of protocol therapy.
- - Subjects with autoimmune diseases requiring current treatment and subjects with
history of severe autoimmune diseases, subjects with hypothyroidism, adrenal
insufficiency, or pituitary insufficiency who are stable on therapy are allowed.
- - Inability to discontinue use of medications contraindicated by the study treatment.
- - Proteinuria > 2.5 g/24 hours or 3+ with urine dipstick.
- QTc interval > 470 at screening or known cardiovascular disease defined as (a) a
clinically significant abnormal ECG at screening, or (b) myocardial infarction
within 12 weeks prior to start of protocol therapy
