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 prior checkpoint therapy (anti-PD1/L1 or anti-CTLA4 antibody)
- 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.
