Ensayos clínicos

Inclusion Criteria:

Demographic Characteristics

• Male or female participant age ≥ 18 years old.

General Criteria

• Estimated life expectancy ≥ 12 weeks. 3. ECOG performance status ≤ 1.

Sex and Contraceptive/Barrier Requirements

• Women of childbearing potential (WOCBP) must agree to abstain from sexual intercourse or to use 2 highly effective (Appendix 7) forms of contraception, at least one of which must be a barrier method, from the time of giving informed consent throughout the study, and for 5 months after the last dose of study treatment. Ivosidenib, nivolumab, and ipilimumab may have adverse effects on a fetus in utero. Furthermore, it is not known if nivolumab and ipilimumab have transient adverse effects on the composition of sperm. Subjects should be informed that taking the study medication may involve unknown risks to the fetus (unborn baby) if pregnancy were to occur during the study. Egg donation (ova, oocytes), for the purpose of reproduction, will not be allowed during the study and for 5 months after the last dose of study treatment:
  • Male subjects with WOCBP partners must use a condom during the study and until at least 3 months after the last dose of study treatment. In addition, contraception should be considered for their female partners. Contraceptive measures do not apply if the subject is sterile, vasectomized, or sexually abstinent. Sperm donation from male subjects will not be allowed during the study and for 3 months after the last dose of study treatment. Note: Please refer to Appendix 7 for further contraception considerations.

Informed Consent

• Obtained prior to any study-specific procedure as described in Section 13.3 of the protocol.

Medical and Therapeutic Criteria

• Have a histopathological diagnosis consistent with nonresectable or metastatic cholangiocarcinoma and are not eligible for curative resection, transplantation or ablative therapies.
• Have documented IDH1 gene-mutated disease based on local testing procedure (R132C/L/G/H/S mutations variants tested). Preferably using a tumor biopsy sample collected within the last 3 years.
• Have disease progression or treatment intolerance following at least 1 and no more than 2 prior systemic regimens for advanced disease (nonresectable or metastatic) with progression on the treatment that was most recently given at a minimum. including the following:
  • For Cohort 1: subjects who have not received any prior immune checkpoint inhibitor therapy but received at least 1 gemcitabine- or 5-FU-containg regimen for advanced cholangiocarcinoma;
  • For Cohort 2: subjects must have received at least two doses of anti-PD1/L1 therapy in first or second line, which may include combination with chemotherapy which should include at least 1 gemcitabine- or 5-FU-containg regimen for advanced cholangiocarcinoma. Combination therapy with other checkpoint inhibitors or investigational agents must be excluded;
  • Safety Lead-in phase: subjects eligible for either Cohort 1 or Cohort 2. Prior capecitabine or gemcitabine containing adjuvant chemotherapy will be considered a line of treatment if there is documented disease progression during or within 12 months of completing the therapy.
• Participants must have at least one measurable lesion, as defined by RECIST Version 1.1. Subjects who have received prior local therapy (including but not limited to embolization, chemoembolization, radiofrequency ablation, or radiation therapy) are eligible provided measurable disease falls outside of the treatment field or if within the field but has shown ≥ 20% growth in size post-treatment assessment.
• Adequate haematological function, defined as:
  • WBC ≥ 2 x 10^9 /L;
  • Absolute neutrophil count ≥ 1.5 x 10^9 /L;
  • Haemoglobin ≥ 9 g/dL. In case of blood transfusion, the haemoglobin assessment must be performed 2 weeks or more after the transfusion;
  • Platelet count ≥ 100 x 10^9 /L.
• Adequate coagulation function as defined by International Normalization Ratio (INR), or Prothrombin Time (PT) or Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 ULN; Any subject receiving anticoagulant therapy should have coagulation factors monitored closely throughout the study. Subjects receiving a factor Xa inhibitor who have abnormal PT/ partial thromboplastin time (PTT) may be eligible after discussion with the Sponsor.
• Adequate renal function defined as: Serum creatinine < 1.5 x ULN, unless creatinine clearance ≥ 40 mL/min (measured or calculated using the Cockcroft-Gault formula).
• Adequate hepatic function, defined as:
  • Total serum bilirubin and direct bilirubin ≤ 1.5 x ULN (total serum bilirubin ≤ 3.0 x ULN for confirmed Gilbert disease);
  • Aspartate aminotransferase and alanine aminotransferase ≤ 5 x ULN;
  • Serum albumin ≥ 2.8 g/dL.

Exclusion Criteria

General Criteria

• Inability to swallow oral medication.
• Pregnant and lactating women.
• WOCBP who tested positive in a serum pregnancy test within 24 hours prior to the first day of IMP administration. An extension up to 72 hours prior to the start of study treatment is permissible in situations where the results cannot be obtained within the standard 24-hour window.
• Unlikely to cooperate in the study.
• Participation in another interventional study at the same time or within 2 weeks prior to the first IMP administration. Participation in non-interventional registries or epidemiological studies is allowed. In addition, the first dose of ivosidenib should not occur before a period greater than or equal to 5 half-lives or 28 days, whichever is shorter, of the last dose of the investigational molecule.

Medical and Therapeutic Criteria

• Subjects who received prior treatment with an IDH inhibitor or prior treatment with an immune checkpoint inhibitor other than anti-PD1/L1.
• Have a history of another primary cancer, with the exception of: a) curatively resected nonmelanoma skin cancer; b) curatively treated cervical carcinoma in situ; or c) other primary solid or liquid tumor within 2 years prior (i.e., participants with a history of prior malignancy are eligible if treatment was completed at least 2 years before and the subject has no evidence of disease), with no known active disease present that, in the opinion of the Investigator, will not affect subject outcome in the setting of current cholangiocarcinoma diagnosis.
• Subjects with prior Grade ≥ 3 immune-related AE (irAE) resulting from ICI therapy or have history of life-threatening toxicity related to prior immune therapy (ICI or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (e.g., hypothyroidism).
• Subjects with active autoimmune disease or any condition requiring systemic treatment with either corticosteroids (> 10 mg daily of prednisone equivalents) or other immunesuppressive medications within 14 days of study treatment. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Known prior severe hypersensitivity to investigational products or any component in their formulations.
• Participants who have not recovered from toxicity of previous anticancer therapy, including Grade ≥ 1 non-hematologic toxicity, according to the NCI CTCAE v5.0, prior to the first IMP administration. Residual Grade ≤ 2 toxicity from chemotherapy (e.g., alopecia, neuropathy) may be allowed.
• Major surgery within 4 weeks prior to the first IMP administration or participants who have not recovered from side effects of the surgery.
• Have LVEF (ECHO, MUGA scan, or by other method according to institutional practice) < 40% by ECHO scan (or by other methods according to institutional practice) obtained within 28 days prior to the start of study treatment.
• Subjects who have heart rate-corrected QT interval using Fridericia’s formula (QTcF) of ≥ 450 msec or with other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome). Subjects with bundle branch block and prolonged QTcF should be reviewed by the Sponsor for potential inclusion.
• History of motor neuropathy considered to be of autoimmune origin (e.g., Guillain-Barre syndrome, myasthenia gravis).
• Known immunodeficiency or HIV, hepatitis B, or hepatitis C infection. Antibody to hepatitis B or C without evidence of active infection may be allowed. Subjects with chronic hepatitis B virus that is adequately controlled per institutional guideline will be permitted.
• Severe or uncontrolled active acute or chronic infection.
• Have known symptomatic brain metastases requiring steroids. Subjects 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 4 weeks, and have radiographically stable disease for at least 3 months prior to study entry:
  • Note: Up to 10 mg per day of prednisone equivalent will be allowed.
• Subjects who have received systemic anti-cancer treatment or palliative radiotherapy to bone metastases or other non-liver lesions less than 2 weeks before the first dose of ivosidenib. Arterial therapies and radiation to liver lesions less than 4 weeks before the first dose of ivosidenib.
• Treatment with a live/attenuated vaccine withing 30 days of first study treatment.
• Any clinically significant medical condition (e.g., organ dysfunction) or laboratory abnormality likely to jeopardize the participant’s safety or to interfere with the conduct of the study, in the Investigator’s opinion.
• Any contraindication to the use of nivolumab or ipilimumab as per standard labelling and local guidance.
• Are taking known strong cytochrome P450 (CYP) 3A4 inducers or sensitive CYP3A4 substrate medications with a narrow therapeutic window, unless they can be transferred to other medications within ≥ 5 half-lives prior to dosing. Note: Please refer to Appendix 10, Table 2 and Table 5, for further drug-drug interaction considerations.

Prior/Concomitant Therapy

• For prior and forbidden concomitant medication, refer to Section 6.3.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 5/2/23. Questions regarding updates should be directed to the study team contact.