Ivosidenib (AG-120) With Nivolumab in IDH1 Mutant Tumors

Inclusion Criteria:

• Be ≥18 years of age.

• Have a histopathological diagnosis (fresh or banked tumor biopsy sample, preferablycollected within the last 3 years) of an advanced solid tumor for which curativetreatment is not available and have undergone appropriate standard of care treatmentoptions (in the opinion of the treating investigator).

• Have a documented IDH1 gene-mutated disease (from a fresh tumor biopsy or the mostrecent banked tumor tissue available) based on CLIA certified sequencing (R132C/L/G/H/S mutation variants tested).

• For glioma, must have both 1) contrast enhancing disease and 2) WHO 2016 gradeII

• Have an ECOG PS score of 0 or 1 (Appendix 11.1)

• Have at least one evaluable and measurable lesion as defined by RECIST v1.1 (solidtumors) or Response Assessment in Neuro-Oncology (RANO) Criteria (glioma).

• Have recovered from toxicities associated with prior anticancer therapy to baselineor ≤ grade 1 unless stabilized under medical management per investigator.

• Have adequate bone marrow function as evidenced by:

• Absolute neutrophil count ≥ 1,500/mm3 or 1.5 × 109/L

• Hemoglobin ≥ 8 g/dL

• Platelets ≥ 100,000/mm3 or 100 × 109/L

• Have adequate hepatic function as evidenced by:

• Serum total bilirubin ≤ 2 × upper limit of normal (ULN), unless considered dueto Gilbert's disease

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 × ULNin the presence of liver metastases (or primary hepatic tumor) OR ≤ 2× ULNwithin glioma patients

• Have adequate renal function as evidenced by:

• Serum creatinine < 1.5 × ULN OR Creatinine clearance ≥ 50 mL/min based on theCockroft-Gault glomerular filtration rate (GFR) estimation: (140 - Age) x (weight inkg) x (0.85 if female)/72 x serum creatinine

• Be able to understand and willing to sign the informed consent form (or have legalrepresentation) and to comply with scheduled visits, treatment plans, procedures,and laboratory tests, including serial peripheral blood sampling, biopsies, andurine sampling, during the study. A legally authorized representative may consent onbehalf of a participant who is otherwise unable to provide informed consent ifacceptable to and approved by the IRB/Independent Ethics Committee (IEC).

• Female participants with reproductive potential must have negative serum pregnancytesting within 72 h prior to the initial administration of study drug, then every 4weeks±1 week, or a negative confirmation from an obstetrician in case of equivocalserum pregnancy results. Females of reproductive potential are defined as sexuallymature women who have not undergone a hysterectomy, bilateral oophorectomy, or tubalocclusion or who have not been naturally postmenopausal (ie, who have notmenstruated) for at least 24 consecutive months (ie, have not had menses at any timein the preceding 24 consecutive months). Men with partners who are women withreproductive potential must agree that they or their partners will use two effectiveforms of contraception (including at least one barrier form) when engaging inreproductive sexual activity.

• Women of child-bearing potential (WOCBP) receiving nivolumab will be instructed toadhere to contraception for a period of 5 months after the last dose of nivolumab.Men receiving nivolumab and who are sexually active with WOCBP will be instructed toadhere to contraception for a period of 7 months after the last dose of nivolumab.

• Effective forms of contraception are defined as hormonal oral contraceptives,injectables, patches, intrauterine devices, intrauterine hormone-releasing systems,bilateral tubal ligation, condoms with spermicide, or male partner sterilization.

Exclusion Criteria:

• Received a prior IDH inhibitor.

• Received systemic anticancer therapy or an investigational agent < 2 weeks prior toDay 1). In addition, the first dose of study treatment should not occur before aperiod ≥ 5 half-lives (t1/2)of the investigational agent has elapsed.

• For solid tumor patients: received radiotherapy to metastatic sites of disease < 2weeks prior to Day 1 and for glioma patients have received radiation within 3 monthsprior.

• For solid tumor patients, have underwent hepatic radiation, chemoembolization, andradiofrequency ablation < 4 weeks prior to Day 1.

• Participants must not have a diagnosis of immunodeficiency or is receiving systemicsteroid therapy at a dose of > 10 mg prednisone daily or equivalent at time of firstdose of study treatment.

• Participants must not have active autoimmune disease that has required systemictreatment in the past 2 years (ie, with use of disease modifying agents,corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine,insulin, or physiologic corticosteroids replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment.

• Participants must not have a known history of non-infectious pneumonitis thatrequired steroids for treatment.

• Participants must not have evidence of interstitial lung disease.

• For solid tumor patients, have known symptomatic brain metastases requiringsteroids. Participants with previously diagnosed brain metastases are eligible ifthey have completed their treatment and have recovered from the acute effects ofradiation therapy or surgery prior to study entry, have discontinued corticosteroidtreatment for these metastases for at least 1 week and have radiographically stabledisease for at least 1 month prior to study entry.

• Have a history of another primary cancer that is active requiring treatment,progressing or for which the treating investigator believes will make diseaseassessment unreliable.

• Have evidence of intracranial or intra-tumoral hemorrhage either by MRI or computedtomographic (CT) scan. Participants with resolving post-surgical changes, punctatehemorrhage, or hemosiderin are eligible.

• Underwent major surgery within 4 weeks of Day 1 or have not recovered frompost-surgery toxicities.

• Are pregnant or breastfeeding.

• Are taking known strong CYP3A4 inducers or sensitive CYP3A4 substrate medicationswith a narrow therapeutic window (Appendix 0), unless they can be transferred toother medications within ≥5 t1/2 prior to dosing.

• Are taking P-glycoprotein (P-gp) transporter-sensitive substrate medications with anarrow therapeutic window (Appendix 0), unless they can be transferred to othermedications within ≥ 5 t1/2 prior to administration of study treatment.

• Have an active infection requiring systemic anti-infective therapy or with anunexplained fever > 38.5°C within 7 days of Day 1 (at the discretion of the treatinginvestigator) participants with tumor fever may be enrolled).

• Have any known hypersensitivity to any of the components of ivosidenib or nivolumab.

• Have significant active cardiac disease within 6 months prior to the start of studytreatment, including New York Heart Association (NYHA) Class III or IV congestiveheart failure (Appendix 0); myocardial infarction; unstable angina; and/or stroke.

• Have a heart-rate corrected QT interval (using Fridericia's formula) (QTcF) (Appendix 0) ≥ 480 ms or other factors that increase the risk of QT prolongation orarrhythmic events (eg, heart failure, hypokalemia, family history of long QTinterval syndrome). Bundle branch block and prolonged QTcF interval are permittedwith approval of the Medical Monitor.

• Are taking medications that are known to prolong the QT interval (Appendix 0),unless they can be transferred to other medications within ≥ 5 t1/2 prior to dosingor unless the medications can be properly monitored during the study. (If equivalentmedication is not available, QTcF should be closely monitored.)

• Have known active hepatitis B (HBV) or hepatitis C (HCV) infections, known positivehuman immunodeficiency virus (HIV) antibody results, or acquired immunodeficiencysyndrome (AIDS) related illness. Participants with a sustained viral response to HCVtreatment or immunity to prior HBV infection will be permitted. Participants withchronic HBV that is adequately suppressed per institutional practice will bepermitted.

• Have any other acute or chronic medical or psychiatric condition, including recent (within 12 months of Day 1) or active suicidal ideation or behavior, or a laboratoryabnormality that may increase the risk associated with study participation orinvestigational product administration or may interfere with the interpretation ofstudy results and, in the judgment of the treating investigator, would make theparticipant inappropriate for entry into this study.

• Have known active inflammatory gastrointestinal disease, chronic diarrhea, previousgastric resection or lap band dysphagia, short-gut syndrome, gastroparesis, or otherconditions that limit the ingestion or gastrointestinal absorption of drugsadministered orally. Gastroesophageal reflux disease under medical treatment isallowed (assuming no drug interaction potential).

• Have been committed to an institution by an order issued either by the judicial oradministrative authorities.