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

This study will describe the safety, response rate, progression free and overall survival, and summarize safety events of ivosidenib in combination with nivolumab in participants with advanced solid tumors (nonresectable or metastatic) or enhancing gliomas. Participants are required to have a histologically consistent diagnosis of IDH1 gene mutated tumor that is not eligible for curative therapy. Enrolled subjects will receive orally administered ivosidenib dosed daily on 28-day cycles and nivolumab will be infused every 28 days. Participants will be assessed at every visit for adverse events starting from the first dose of study treatment. Assessment (CT or MRI) for evaluation of disease response will be conducted every 8 weeks (±7 days) from the first day of treatment cycle 1 and/or at any time when progression of disease is suspected. A Post-Treatment Follow-Up Visit for safety will occur 28 (+/- 5) days after the last dose of study drug.

Inclusion criteria

• Be ≥18 years of age.
• Have a histopathological diagnosis (fresh or banked tumor biopsy sample, preferably collected within the last 3 years) of an advanced solid tumor for which curative treatment is not available and have undergone appropriate standard of care treatment options (in the opinion of the treating investigator).
• Have a documented IDH1 gene-mutated disease (from a fresh tumor biopsy or the most recent 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 grade II
• 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 (solid tumors) or Response Assessment in Neuro-Oncology (RANO) Criteria (glioma).
• Have recovered from toxicities associated with prior anticancer therapy to baseline or ≤ 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 due to Gilbert's disease
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 × ULN in the presence of liver metastases (or primary hepatic tumor) OR ≤ 2× ULN within glioma patients
• Have adequate renal function as evidenced by:

• Serum creatinine < 1.5 × ULN OR Creatinine clearance ≥ 50 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR) estimation: (140 - Age) x (weight in kg) x (0.85 if female)/72 x serum creatinine
• Be able to understand and willing to sign the informed consent form (or have legal representation) and to comply with scheduled visits, treatment plans, procedures, and laboratory tests, including serial peripheral blood sampling, biopsies, and urine sampling, during the study. A legally authorized representative may consent on behalf of a participant who is otherwise unable to provide informed consent if acceptable to and approved by the IRB/Independent Ethics Committee (IEC).
• Female participants with reproductive potential must have negative serum pregnancy testing within 72 h prior to the initial administration of study drug, then every 4 weeks±1 week, or a negative confirmation from an obstetrician in case of equivocal serum pregnancy results. Females of reproductive potential are defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy, or tubal occlusion or who have not been naturally postmenopausal (ie, who have not menstruated) for at least 24 consecutive months (ie, have not had menses at any time in the preceding 24 consecutive months). Men with partners who are women with reproductive potential must agree that they or their partners will use two effective forms of contraception (including at least one barrier form) when engaging in reproductive sexual activity.
• Women of child-bearing potential (WOCBP) receiving nivolumab will be instructed to adhere 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 to adhere 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 to Day 1). In addition, the first dose of study treatment should not occur before a period ≥ 5 half-lives (t1/2)of the investigational agent has elapsed.
• For solid tumor patients: received radiotherapy to metastatic sites of disease < 2 weeks prior to Day 1 and for glioma patients have received radiation within 3 months prior.
• For solid tumor patients, have underwent hepatic radiation, chemoembolization, and radiofrequency ablation < 4 weeks prior to Day 1.
• Participants must not have a diagnosis of immunodeficiency or is receiving systemic steroid therapy at a dose of > 10 mg prednisone daily or equivalent at time of first dose of study treatment.
• Participants must not have active autoimmune disease that has required systemic treatment 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 pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Participants must not have a known history of non-infectious pneumonitis that required steroids for treatment.
• Participants must not have evidence of interstitial lung disease.
• For solid tumor patients, have known symptomatic brain metastases requiring steroids. Participants with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry, have discontinued corticosteroid treatment for these metastases for at least 1 week and have radiographically stable disease 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 disease assessment unreliable.
• Have evidence of intracranial or intra-tumoral hemorrhage either by MRI or computed tomographic (CT) scan. Participants with resolving post-surgical changes, punctate hemorrhage, or hemosiderin are eligible.
• Underwent major surgery within 4 weeks of Day 1 or have not recovered from post-surgery toxicities.
• Are pregnant or breastfeeding.
• Are taking known strong CYP3A4 inducers or sensitive CYP3A4 substrate medications with a narrow therapeutic window (Appendix 0), unless they can be transferred to other medications within ≥5 t1/2 prior to dosing.
• Are taking P-glycoprotein (P-gp) transporter-sensitive substrate medications with a narrow therapeutic window (Appendix 0), unless they can be transferred to other medications within ≥ 5 t1/2 prior to administration of study treatment.
• Have an active infection requiring systemic anti-infective therapy or with an unexplained fever > 38.5°C within 7 days of Day 1 (at the discretion of the treating investigator) 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 study treatment, including New York Heart Association (NYHA) Class III or IV congestive heart 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 or arrhythmic events (eg, heart failure, hypokalemia, family history of long QT interval syndrome). Bundle branch block and prolonged QTcF interval are permitted with 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 dosing or unless the medications can be properly monitored during the study. (If equivalent medication is not available, QTcF should be closely monitored.)
• Have known active hepatitis B (HBV) or hepatitis C (HCV) infections, known positive human immunodeficiency virus (HIV) antibody results, or acquired immunodeficiency syndrome (AIDS) related illness. Participants with a sustained viral response to HCV treatment or immunity to prior HBV infection will be permitted. Participants with chronic HBV that is adequately suppressed per institutional practice will be permitted.
• 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 laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the treating investigator, would make the participant inappropriate for entry into this study.
• Have known active inflammatory gastrointestinal disease, chronic diarrhea, previous gastric resection or lap band dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally. Gastroesophageal reflux disease under medical treatment is allowed (assuming no drug interaction potential).
• Have been committed to an institution by an order issued either by the judicial or administrative authorities.