Oleclumab and Durvalumab for the Treatment of Recurrent, Refractory, or Metastatic Sarcoma

Inclusion Criteria:

• Age: 18 years of age or older (cohort 1 and cohort 2); 12 years of age or older (cohort 3)

• Histologically or cytologically confirmed sarcoma that fall into one of thefollowing categories. Patients with low-grade tumors are eligible if there isdefinite evidence of metastasis or progression

• Angiosarcoma

• Dedifferentiated liposarcoma

• Osteosarcoma

• Must have received and have progressed, are refractory or intolerant to standardtherapy appropriate for the specific sarcoma subtype, if there is a standard therapyfor the subtype

• Subjects must have at least 1 lesion that is measurable by RECIST

• A previously irradiated lesion can be considered a target lesion if the lesionis well defined, measurable per RECIST, and has clearly progressed sinceradiation

• Subjects undergoing fresh tumor biopsies must have additional non-targetlesions that can be biopsied at acceptable risk as judged by the investigatoror if no other lesions suitable for biopsy, then a RECIST target lesion usedfor biopsy must be >= 2 cm in longest diameter

• Subjected must consent to provide archived tumor specimens for correlative biomarkerstudies. Tumor tissue must be identified and availability confirmed prior toinitiation of study therapy. In the setting where archival material is unavailableor unsuitable for use, or there have been multiple intervening therapies subjectsmust consent and undergo fresh tumor biopsy. A tumor lesion planned for biopsy mustnot have a RECIST target lesion unless there are no other lesions suitable forbiopsy and lesions used for biopsy is >= 2 cm in longest diameter

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (useKarnofsky for patients > 16 years and Lansky for patients =< 16)

• Absolute neutrophil count >= 1.5 x 10^9/L (1,500/mm^3) (without growth factor within 28 days of first dose or transfusion within 14 days of first dose support)

• Platelet count >= 100 x 10^9/L (100,000/mm^3) (without growth factor within 28 daysof first dose or transfusion within 14 days of first dose support)

• Hemoglobin >= 9.0 g/dL (without growth factor within 28 days of first dose ortransfusion within 14 days of first dose support)

• Calculated creatinine clearance (CrCl) or 24-hour urine CrCl > 40 mL/minCockcroft-Gault formula (using actual body weight) will be used to calculate CrCl

• Total bilirubin =< 1.5 x upper limit of normal (ULN); for subjects withdocumented/suspected Gilbert's disease or liver metastases, bilirubin =< 3 x ULN

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN;for subjects with hepatic metastases, ALT and AST =< 5 x ULN

• Female patients of childbearing potential who are not abstinent and intend to besexually active with a non-sterilized male partner must use at least 1 highlyeffective method of contraception (defined below) from the time of screeningthroughout the total duration of the drug treatment and the drug washout period (90days after the last dose of durvalumab monotherapy). Non-sterilized male partners ofa female patient of childbearing potential must use male condom plus spermicidethroughout this period. Cessation of birth control after this point should bediscussed with a responsible physician. Periodic abstinence, the rhythm method, andthe withdrawal method are not acceptable methods of birth control. Female patientsshould also refrain from breastfeeding throughout this period.

• Non-sterilized male patients who are not abstinent and intend to be sexually activewith a female partner of childbearing potential must use a male condom plusspermicide from the time of screening throughout the total duration of the drugtreatment and drug washout period (90 days after the last dose of durvalumabmonotherapy). However, periodic abstinence, the rhythm method, and the withdrawalmethod are not acceptable methods of contraception. Male patients should refrainfrom sperm donation throughout this period

• Female partners (of childbearing potential) of male patients must also use a highlyeffective method of contraception throughout this period as defined below. Notes:Females of childbearing potential are defined as those who are not surgicallysterile (i.e., bilateral salpingectomy, bilateral oophorectomy, or completehysterectomy) or post-menopausal. Women will be considered post-menopausal if theyhave been amenorrheic for 12 months without an alternative medical cause. Thefollowing age-specific requirements apply:

• Women < 50 years of age would be considered post-menopausal if they haveamenorrheic for 12 months or more following cessation of exogenous hormonaltreatments and if they have luteinizing hormone and follicle-stimulatinghormone levels in the post-menopausal range for the institution.

• Women >= 50 years of age would be considered post-menopausal if they haveamenorrheic for 12 months or more following cessation of all exogenous hormonaltreatment, had radiation-induced menopause with last menses > 1 year ago, hadchemotherapy-induced menopause with last menses > 1 year ago.

Highly effective methods of contraception, defined as one that results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly are described below. Note that some contraception methods are not considered highly effective (e.g. male or female condom with or without spermicide; female cap, diaphragm, or sponge with or without spermicide; non-copper containing intrauterine device; progesterone-only oral hormonal contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral contraceptive pills.

• Copper T intrauterine device

• Levonorgestrel-releasing intrauterine system: e.g., Mirena

• Implants: Etonogestrel-releasing implants: e.g. Implanon or Norplant

• Injection: Medroxyprogesterone injection: e.g., Depo-Provera

• Combined pill: Normal and low dose combined oral contraceptive pill

• Patch: Norelgestromin/ethinylestradiol-releasing transdermal system: e.g., OrthoEvra

• Minipill: Progesterone based oral contraceptive pill using desogestrel: Cerazette iscurrently the only highly effective progesterone-based

• Life expectancy of at least 6 months

• Ability to understand the purposes and risk of the study and has signed awritten consent form approved by the investigator's Institutional Review Board (IRB)/Ethics Committee

• Weight >= 35 kg

Exclusion Criteria:

• Prior therapy with anti-PD1, anti-PD-L1 (including durvalumab) or anti-CD73

• Active or prior documented autoimmune disease (including inflammatory bowel disease,celiac disease, Wegener syndrome) within the past 2 years. Subjects with childhoodatopy or asthma, vitiligo, alopecia, Hashimoto syndrome, Grave's disease, orpsoriasis not requiring systemic treatment (within the past 2 years) are notexcluded

• Untreated central nervous system metastatic disease, leptomeningeal disease, or cordcompression. Subjects previously treated central nervous system metastases that areradiographically and neurologically stable for at least 28 days and do not requirecorticosteroids (or any dose) for symptomatic management for at least 14 days priorto first dose of durvalumab and oleclumab are permitted to enroll

• Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventionalstudy

• Receipt of any conventional or investigational anticancer therapy within 21 daysprior to the first dose of study drug

• Any concurrent chemotherapy, immunotherapy, or biologic or hormonal therapy forcancer treatment. Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable. Inaddition, local treatment (e.g., by local surgery or radiotherapy) of isolatedlesions for palliative intent is acceptable beyond the first cycle with priorconsultation and in agreement with the principal investigator (PI)

• Unresolved toxicities from prior anticancer therapy, defined as having not resolvedto National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 grade 0 or 1 with the exception of alopecia and laboratoryvalues listed per the inclusion criteria. Subjects with irreversible toxicity thatis not reasonably expected to be exacerbated by any of the investigational productsmay be included (e.g., hearing loss) after consultation with the medical monitor

• Current or prior use of immunosuppressive medication within 14 days prior to thefirst of durvalumab or oleclumab. The following are exceptions to this criterion:

• Intranasal, inhaled, topical steroids, or local steroid injections (e.g.,intra-articular injection)

• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day ofprednisone or equivalent

• Steroids as premedication for hypersensitivity reactions (e.g., computedtomography [CT] scan premedication)

• History of primary immunodeficiency, solid organ transplantation, or previousclinical diagnosis of tuberculosis

• True positive test results for human immunodeficiency virus (HIV) or hepatitis B orhepatitis C

• Receipt of live, attenuated vaccine within 30 days prior to the first dose ofinvestigational products (NOTE: Subjects, if enrolled, should not receive livevaccine during the study and 180 days after the last dose of investigationalproducts)

• Major surgery (as defined by the investigator) within 4 weeks or thoracotomy forpulmonary metastases within 2 weeks prior to first dose of treatment or if stillrecovering from prior surgery. Local surgery of isolated lesions for palliativeintent is acceptable

• Other invasive malignancy, within 2 years except for noninvasive malignancies suchas cervical carcinoma in situ, non-melanomatous carcinoma of the skin or ductalcarcinoma in situ of the breast that has/have been surgically cured

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension, unstableangina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, orpsychiatric illness/social situations that would limit compliance with studyrequirement, substantially increase risk of incurring adverse events (AEs) fromdurvalumab or oleclumab, or compromise the ability of the subject to give writteninformed consent

• Any condition that, in the opinion of the investigator or sponsor, would interferewith evaluation of the investigational product or interpretation of subject safetyor study results

• Patients with a history of pneumonitis (active within past 6 months) or interstitiallung disease

• Subjects with a history of venous thrombosis within the past 3 months

• Subjects prior history of myocardial infarction, transient ischemic attack, orstroke in the last 3 months