Durvalumab and Tremelimumab With or Without High or Low-Dose Radiation Therapy in Treating Patients With Metastatic Colorectal or Non-small Cell Lung Cancer

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed non-small cell lungcancer (cohort 1) or colorectal cancer (cohort 2)

• Patients must have measurable disease, defined as at least one lesion that can beaccurately measured in at least one dimension (longest diameter to be recorded fornon-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) withconventional techniques or as >= 10 mm (>= 1.5 cm) with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam

• Patients in both cohorts must have progressive disease following prior therapy;specifically:

• Cohort 1 (NSCLC): Patients must have evidence of radiologic or clinical diseaseprogression during previous treatment with systemic PD-1 directed therapyand/or have been deemed not to derive clinical benefit from PD-1 directedtreatment; this includes patients who demonstrated an initial response andsubsequent progression; no prior treatment with chemotherapy or targeted agentsare required; intervening therapy is allowed between previous PD-1 directedtreatment and there is no required interval from prior PD-1 treatment required;PD-1 directed treatment includes treatment with antibodies targeting the PD-1receptor such as pembrolizumab or nivolumab, as well as PD-L1 targetedantibodies such as MEDI4736 (durvalumab), atezolizumab and avelumab; theseagents may have been administered as part of a clinical trial

• Cohort 2 (colorectal cancer): Patients must have progressed on >= one-linechemotherapy

• At least 21 days must have elapsed from prior systemic therapy (chemotherapy orradiation)

• Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 60%)and life expectancy greater than 6 months; furthermore, enrollment of patients withgreater than 10 measurable lesions is discouraged

• Patients must have normal organ and marrow function independent of transfusion forat least 7 days prior to screening and independent of growth factor support for atleast 14 days prior to screening

• Hemoglobin (Hgb) >= 9 g/dl

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 100,000/mcL

• Total bilirubin =< 1.5 x normal institutional limits; this will not apply topatients with confirmed Gilbert's syndrome (persistent or recurrenthyperbilirubinemia [predominantly unconjugated bilirubin] in the absence of evidenceof hemolysis or hepatic pathology), who will be allowed in consultation with theirphysician

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) = < 2.5 x institutional upper limit of normal; for patients with hepaticmetastases, ALT and AST =< 5 x ULT

• Measured creatinine clearance (CL) > 40 mL/min OR calculated creatinine clearance (CL) > 40 mL/min as determined by Cockcroft-Gault (using actual body weight)

• Patients must have at least one lesion that has not previously been irradiated (andis not within a previously radiated field) and for which palliative radiation ispotentially indicated and could be safely delivered at the radiation doses specifiedin this protocol; this lesion must not be the only measurable lesion so that it isstill possible to determine the response rate outside of the radiation treatmentfield; this lesion must not be within the central nervous system (CNS) (brain orspinal cord) or requiring urgent or emergent palliative radiation given the timingof radiation specified on this protocol; furthermore, this lesion:

• For cohort 1 (NSCLC cohort) - the lesion to be irradiated must be in the lung,lymph nodes, adrenal gland or liver

• For cohort 2 (colorectal cohort) - the lesion to be irradiated must be in theliver

• The effects of MEDI4736 and tremelimumab on the developing human fetus are unknown;for this reason and because radiation is known to be teratogenic, evidence ofpost-menopausal status or negative urinary or serum pregnancy test for femalepre-menopausal patients is required; women will be considered post-menopausal ifthey have 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 have beenamenorrheic 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 or underwentsurgical sterilization (bilateral oophorectomy or hysterectomy)

• Women >= 50 years of age would be considered post-menopausal if they have beenamenorrheic for 12 months or more following cessation of all exogenous hormonaltreatments, had radiation-induced oophorectomy with last menses > 1 year ago,had chemotherapy-induced menopause with > 1 year interval since last menses, orunderwent surgical sterilization (bilateral oophorectomy or hysterectomy)

• Females of childbearing potential who are sexually active with a non sterilized malepartner must use at least 1 highly effective method of contraception from the timeof screening and must agree to continue using such precautions for 180 days afterthe last dose of durvalumab + tremelimumab combination therapy or 90 days after thelast dose of durvalumab monotherapy; non-sterilized male partners of a femalepatient must use male condom plus spermicide throughout this period; cessation ofbirth control after this point should be discussed with a responsible physician; notengaging in sexual activity for the total duration of the drug treatment and thedrug washout period is an acceptable practice; however, periodic abstinence, therhythm method, and the withdrawal method are not acceptable methods of birthcontrol; female patients should also refrain from breastfeeding throughout thisperiod

• Non-sterilized males who are sexually active with a female partner of childbearingpotential must use a male condom plus spermicide from screening through 180 daysafter receipt of the final dose of durvalumab + tremelimumab combination therapy or 90 days after receipt of the final dose of durvalumab monotherapy; not engaging insexual activity is an acceptable practice; however, occasional abstinence, therhythm method, and the withdrawal method are not acceptable methods ofcontraception; male patients should refrain from sperm donation throughout thisperiod

• Female partners (of childbearing potential) of male patients must also use a highlyeffective method of contraception throughout this period

• Highly effective methods of contraception, defined as one that results in a lowfailure rate (ie, less than 1% per year) when used consistently and correctly aredescribed in the table below; note that some contraception methods are notconsidered highly effective (e.g. male or female condom with or without spermicide;female cap, diaphragm, or sponge with or without spermicide; non-copper containingintrauterine device; progestogen-only oral hormonal contraceptive pills whereinhibition of ovulation is not the primary mode of action [excludingCerazette/desogestrel which is considered highly effective]; and triphasic combinedoral contraceptive pills)

• Should a woman become pregnant or suspect she is pregnant while she or herpartner is participating in this study, she should inform her treatingphysician immediately

• Ability of a patient or a Legally Authorized Representative (LAR) to understand andthe willingness to sign a written informed consent document

• Body weight > 30 kg

• Must have a life expectancy of at least 12 weeks

• Cohort 1 (NSCLC cohort)

• Ability to undergo a fresh tumor biopsy for the purpose of screening for thisclinical trial (including able and willing to give valid written consent) toability or to provide an available archival tumor sample taken less than 3months prior to study enrollment (and not obtained prior to progression on aPD-1/PD-L1 inhibitor) if a fresh tumor biopsy is not feasible with anacceptable clinical risk; tumor lesions used for fresh biopsies should be thesame lesions to be irradiated when possible and should not be the same lesionsused as Response Evaluation Criteria in Solid Tumors (RECIST) target lesions,unless there are no other lesions accessible; additional, optional archivaltumor tissue is also requested from before the prior PD-1 directed therapy

• Cohort 2 (colorectal cohort)

• Ability to undergo a fresh tumor biopsy for the purpose of screening for thisclinical trial (including able and willing to give valid written consent) toability or to provide an available archival tumor sample taken less than 3months prior to study enrollment if a fresh tumor biopsy is not feasible withan acceptable clinical risk; tumor lesions used for fresh biopsies should bethe same lesions to be irradiated when possible and should not be the samelesions used as RECIST target lesions, unless there are no other lesionsaccessible

• Microsatellite stable (MSS) tumor as documented by either:

• Immunohistochemistry (IHC) testing that does not suggest loss of MLH-1,MSH-2, PMS2 or MSH6

• Polymerase chain reaction (PCR) testing that does not suggestmicrosatellite instability (MSI)

Exclusion Criteria:

• Patients who have had systemic (chemotherapy, biologic therapy or radiotherapy)within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study

• Receipt of prior radiotherapy or condition for any reason that would contributeradiation dose that would exceed tolerance of normal tissues, at the discretion ofthe treating physician

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1)

• Patients who are receiving any other investigational agents

• Patients with untreated brain metastases, spinal cord compression, or leptomeningealcarcinomatosis should be excluded from this clinical trial; patients whose brainmetastases have been treated may participate provided they show radiographicstability (defined as 2 brain images, both of which are obtained after treatment tothe brain metastases; these imaging scans should both be obtained at least fourweeks apart and show no evidence of intracranial progression); in addition, anyneurologic symptoms that developed either as a result of the brain metastases ortheir treatment must have resolved or be stable either, without the use of steroids,or are stable on a steroid dose of =< 10 mg/day of prednisone or its equivalent (andanti-convulsants) for at least 14 days prior to the start of treatment

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to tremelimumab and MEDI4736 or previous toxicity attributed toMEDI4736 or other PD-1 or PD-L1 directed therapy that led to drug discontinuation

• Prior exposure to immune-mediated therapy, including durvalumab and tremelimumab,except for anti-PD-1 or anti-PD-L1 therapy (including durvalumab) in NSCLC patients;this includes anti-CTLA-4 agents (prior treatment with these agents is NOT allowedin either cohort) and, excludes therapeutic anticancer vaccines, excludingtherapeutic anticancer vaccines; exposure to other investigational agents may bepermitted after discussion with the study principal investigator (PI)

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith study requirements

• Pregnant women are excluded from this study because MEDI4736 (durvalumab),tremelimumab are immune checkpoint inhibitors with the potential for teratogenic orabortifacient effects, as is radiation therapy; because there is an unknown butpotential risk for adverse events in nursing infants secondary to treatment of themother with MEDI4736(durvalumab), tremelimumab and radiation, breastfeeding shouldbe discontinued if the mother is treated with MEDI4736(durvalumab), tremelimumab andradiation

• Female patients who are pregnant or breastfeeding or male or female patients ofreproductive potential who are not willing to employ effective birth control fromscreening to 90 days after the last dose of durvalumab monotherapy or 180 days afterthe last dose of durvalumab + tremelimumab combination therapy, whichever is later

• Human immunodeficiency virus (HIV)-positive patients are ineligible; appropriatestudies will be undertaken in patients receiving combination antiretroviral therapywhen indicated

• Any concurrent chemotherapy, immune therapy, biologic, hormonal therapy for cancertreatment

• Current or prior use of immunosuppressive medication within 14 days before the firstdose of their assigned IP; 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 its equivalent

• Steroids as pre-medication for hypersensitivity reactions (e.g., CT scanpre-medication)

• Major surgical procedure (as defined by the investigator) within 28 days prior tothe first dose of IP; Note: local surgery of isolated lesions for palliative intentis acceptable

• History of allogeneic organ transplantation

• Active or prior documented autoimmune or inflammatory disorders (includinginflammatory bowel disease, diverticulitis [with the exception of diverticulosis];sarcoidosis syndrome, or other serious gastrointestinal [GI] chronic conditionsassociated with diarrhea; systemic lupus erythematosus; Wegener syndrome [granulomatosis with polyangiitis]; myasthenia gravis; Graves disease; rheumatoidarthritis; hypophysitis; uveitis, sarcoidosis syndrome, etc.) within the past 3years prior to the start of treatment; the following are exceptions to thiscriterion:

• Patients with vitiligo or alopecia

• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable onhormone replacement or psoriasis not requiring systemic treatment

• Any chronic skin condition that does not require systemic therapy

• Patients without active disease in the last 5 years may be included but onlyafter consultation with the study physician

• Patients with celiac disease controlled by diet alone

• History of another primary malignancy except for

• Malignancy treated with curative intent and with no known active disease >= 5years before the first dose of study drug and of low potential risk forrecurrence

• Adequately treated non-melanoma skin cancer or lentigo maligna without evidenceof disease

• Adequately treated carcinoma in situ without evidence of disease (e.g.,cervical cancer in situ)

• Mean QT interval corrected for heart rate (QTc) >= 470 ms calculated fromelectrocardiograms (ECGs) using Fridericia's correction; abnormal ECGs should berepeated

• History of active primary immunodeficiency

• Known history of previous clinical diagnosis of tuberculosis

• Active infection including hepatitis B (known positive hepatitis B virus [HBV]surface antigen [HBsAg]) result or, hepatitis C; patients with a past or resolvedHBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] andabsence of HBsAg) are eligible; patients positive for hepatitis C (HCV) antibody areeligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA); negative serologies documented over the past year are sufficient evidence ofthis

• Receipt of live, attenuated vaccine within 30 days prior to the first dose ofinvestigational treatment; Note: patients, if enrolled, should not receive livevaccine during the study and up to 30 days after the last dose of investigationaltreatment

• Any condition that, in the opinion of the investigator, would interfere withevaluation of the investigational treatment or interpretation of patient safety orstudy results

• Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteriafor Adverse Events (CTCAE) grade >= 2 from previous anticancer therapy with theexception of alopecia, vitiligo, and the laboratory values defined in the inclusioncriteria

• Patients with grade >= 2 neuropathy will be evaluated on a case-by-case basisafter consultation with the study physician; patients with irreversibletoxicity not reasonably expected to be exacerbated by treatment with durvalumabor tremelimumab may be included only after consultation with the studyphysician

• Cohort 1 (NSCLC cohort)

• In regards to administration of prior anti-PD-1 or anti PD-L1 antibodies, apatients:

• Must not have experienced a toxicity that led to permanent discontinuationof prior immunotherapy

• All adverse events (AEs) while receiving prior immunotherapy must havecompletely resolved or resolved to baseline prior to screening for thisstudy

• Must not have experienced a >= grade 3 immune related AE or an immunerelated neurologic or ocular AE of any grade while receiving priorimmunotherapy; NOTE: subjects with endocrine AE of =< grade 2 arepermitted to enroll if they are stably maintained on appropriatereplacement therapy and are asymptomatic

• Must not have required the use of additional immunosuppression other thancorticosteroids for the management of an AE, not have experiencedrecurrence of an AE if re-challenged, and not currently requiremaintenance doses of > 10 mg prednisone or equivalent per day

• Eligibility for Food and Drug Administration (FDA)-approved agents targetingthe EGFR, ROS1 or ALK pathway, which should be evaluated as per standard ofcare; exceptions to this requirement may be considered on a case-by-case basisby the principal investigator if the patient was previously treated withanother targeted agent