IRB Study Number 24-386
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
To assess the efficacy of ivosidenib treatment based on tumor assessments by a BICR in Grade 1 and Grade 2 participants
Secondary Objectives
To assess the efficacy of ivosidenib treatment based on tumor assessments by a BICR in all randomized participants
To assess the efficacy of ivosidenib treatment based on OS
To assess the additional efficacy of ivosidenib treatment in Grade 1 and Grade 2 participants and all randomized participants
To assess the safety and tolerability of treatment with ivosidenib
To assess the impact of treatment on HRQoL and health economic outcomes assessments
To evaluate the PK and PD of ivosidenib
Inclusion Criteria
Demographic characteristics
- Male or female participant aged ≥18 years old.
General criteria
ECOG PS of 0 to 1. Participants with an ECOG PS of 2 due to functional limitations as a result of prior surgical resections or due to the anatomical location of the tumor will be permitted.
Be willing to complete HRQoL (EORTC-QLQ-C30, EQ-5D-5L, and PROMIS) assessments during study treatment.
Sex and contraceptive/barrier requirements
- Women of childbearing potential must agree to undergo medically supervised pregnancy blood tests prior to starting the IMP. The first pregnancy test will be performed at Screening (within 7 days prior to the first IMP administration) and another on the day of the first IMP administration, the result of which must be confirmed negative prior to dosing. Women of childbearing potential must agree to abstain from sexual intercourse or use 2 effective methods of birth control (a highly effective method and a barrier method; both described in Appendix 7) from the time of giving informed consent and during study treatment until at least 90 days after the last dose of IMP. Hormonal contraception alone is not considered an acceptable method of contraception and should be combined with a barrier method. Women of childbearing potential, as well as fertile men with partners who are female with reproductive potential, must agree to use 2 effective forms of contraception (one of them a highly effective method and the other one a barrier method) from the time of giving informed consent throughout the study and for 90 days (both females and males) following the last dose of IMP. Sperm donation will not be allowed during the study and for 90 days after the last dose of IMP. 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. Participants will sign a prescreening and/or main consent form depending on when their IDH1 mutation testing is performed.
Medical and therapeutic criteria
Histopathological diagnosis (fresh or banked tumor biopsy sample, collected within the last 3 years) consistent with locally advanced or metastatic conventional chondrosarcoma Grades 1, 2, or 3 and not eligible for curative resection.
At least one BICR-confirmed measurable lesion as defined by RECIST v1.1. Participants who have received prior radiation therapy are eligible provided measurable disease falls outside of the treatment field or within the field and has shown ≥20% growth in size since post-treatment assessment.
Received 0 to 1 prior systemic treatment regimen in the advanced/metastatic setting (adjuvant/maintenance/consolidation treatment during which metastatic disease recurrence/progression occurred will be considered as prior systemic treatment) for chondrosarcoma.
Participants must have radiographic progression/recurrence of disease according to RECIST v1.1 defined as:
• Radiographic progression of disease (local and/or distant) documented by 2 imaging assessments performed no more than 6 months (±2 weeks) apart within 12 months before randomization. OR
• Any recurrence of disease (local and/or distant) after complete surgical resection and documented by imaging within 6 months (±2 weeks) before randomization.
Documented IDH1 gene-mutated disease (from a fresh tumor biopsy or the most recent banked tumor tissue available that was sourced from either a primary or metastatic tumor lesion) based on central laboratory testing (R132C/L/G/H/S mutation variants tested; see Section 9.1).
Adequate renal function defined as:
• Creatinine clearance ≥30 mL/min, based on using the Cockcroft & Gault formula (Appendix 4)
- Adequate hepatic function defined as:
• Total serum bilirubin ≤1.5 × ULN (unless considered due to Gilbert disease where it must be ≤ 3.0 × ULN.)
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤2.5 × ULN. For participants with bone metastases and/or disease-related hepatic involvement, ALP must be ≤5 × ULN.
- Adequate bone marrow function without transfusions or growth factors for at least 2 weeks prior to the blood test.
• Absolute neutrophil count ≥1,500/mm3 or 1.5 × 109/L
• Hemoglobin ≥8 g/dL
• Platelets ≥75,000/mm3 or 75 × 109/L
- Recovered from any clinically relevant sequelae and toxic effects of any prior surgery, radiotherapy, or other therapy intended for the treatment of cancer.
Exclusion Criteria
General criteria
Unable to swallow oral medication.
Pregnant or lactating women.
Unlikely to cooperate in the study.
Participating in another interventional study at the same time; participation in noninterventional registries or epidemiological studies is allowed.
Participant already enrolled in the study (informed consent signed) and had received at least one dose of IMP.
Medical and therapeutic criteria
Prior therapy with an IDH1 inhibitor.
Received systemic anticancer therapy <2 weeks prior to randomization (washout from prior investigational or immune-based anticancer therapy is 4 weeks).
Received radiotherapy <2 weeks prior to randomization.
Have known symptomatic brain metastases requiring steroids >10 mg per day prednisone (or equivalent). 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 randomization, have discontinued or reduced corticosteroid treatment to ≤10 mg per day for these metastases for at least 4 weeks and have radiographically stable disease of brain lesions for at least 3 months prior to randomization.
Have a history of another primary cancer, with the exception of: a) curatively resected non-melanoma skin cancer; b) curatively treated carcinoma in situ; or c) pT1-2 prostatic cancer Gleason score <6 or d) participant is free of other primary solid or liquid tumor for ≥1 year prior to the start of study treatment and, in the opinion of the Investigator, the disease will not affect participant’s outcome in the setting of current chondrosarcoma diagnosis.
Major surgery within 4 weeks prior to randomization.
Are taking known strong cytochrome P450 (CYP) 3A4 inducers or sensitive CYP3A4 substrate medications with a narrow therapeutic window, unless (after at least 5 half-lives have elapsed) they can be transferred to other medications prior to randomization.
Have an active infection requiring systemic anti-infective therapy or with an unexplained fever >38.5°C within 7 days prior to randomization (at the discretion of the Investigator, participants with tumor fever may be enrolled).
Have any known hypersensitivity to any of the components of ivosidenib or the matched placebo.
Have significant active cardiac disease within 6 months prior to randomization, including New York Heart Association (NYHA) Class III or IV congestive heart failure; myocardial infarction; unstable angina; and/or stroke.
Have LVEF <40% by ECHO scan (or by other methods according to institutional practice) obtained within 28 days prior to randomization.
Have a heart-rate corrected QT interval (using Fridericia’s formula) (QTcF) ≥ 450 msec or other factors that increase the risk of QT prolongation or arrhythmic events (eg, heart failure, hypokalemia, family history of long QT interval syndrome). Participants with a bundle branch block combined with a prolonged QTcF interval may be permitted based on local cardiology assessment.
Are taking medications that are known to prolong the QT interval unless (after at least 5 half-lives have elapsed) they can be transferred to other medications prior to randomization 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 HIV antibody results, or 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 or HIV that are adequately suppressed per institutional practice will be permitted.
Have any other acute or chronic medical or psychiatric condition, including recent (within last 12 months) or active suicidal ideation or behavior, or a laboratory abnormality that may increase the risk associated with study participation or IMP administration or may interfere with the interpretation of study results and, in the judgment of the 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 known medical history of progressive multifocal leukoencephalopathy (PML).
Prior/Concomitant therapy
For prior and prohibited concomitant medication, refer to Section 6.3.
