A Phase I study of IDH305 in patients with advanced malignancies that harbor IDH1R132 mutations (CIDH305X2101)

Recruitment & Eligibility

Status: Completed

Sex: Not specified

Target Recruitment: 17

Inclusion Criteria

Patients eligible for inclusion in this study have to meet all of the following criteria:
* Subject must be *18 years of age
* Patients with advanced malignancies whose tumors harbor IDHR132 mutations and for whom there are no curative therapy options who have progressed despite standard treatment.
* Availability of a representative tumor specimen (primary or metastatic, archival or newly obtained) for predictive and exploratory biomarker testing (eligibility will not be affected if a sample is not available or medically feasible to obtain).
* ECOG performance
* ECOG performance status * 2
* Measurable disease as per RECIST v1.1 (cholangiocarcinoma/other solid tumors), RANO criteria (glioma), IWG criteria (AML/MDS) in the dose expansion

Exclusion Criteria

Exclusion Criteria for Patients with cholangiocarcinoma or other solid tumors and gliomas:
Patients eligible for this study must not meet any of the following criteria prior to the first treatment.
* Prior treatment with a mutant-specific IDH1 inhibitor (with the exception of glioma patients)
* Major surgery within the 2 weeks preceding the first dose IDH305
* Patients who require medications that are narrow therapeutic index substrates of CYP3A, CYP2C9, CYP2C19, and CYP2C8 or strong inhibitors and strong inducers of CYP3A
* Rapidly progressing neurological symptoms related to underlying disease requiring increasing doses of corticosteroids. Steroid use for management of gliomas or brain metastases is allowed but the dose must be stable for at least 1 week preceding the baseline MRI/CT. If the corticosteroid dose is increased between the date of imaging and the initiation of study treatment, a new baseline MRI/CT is required.
* Malignant disease, other than that being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within the prior 2 years; completely resected basal cell and squamous cell skin cancers; any malignancy considered to be indolent and that has never required therapy; and completely resected carcinoma in situ of any type
* Patients with corrected QT using the Fridericia correction (QTcF) > 470 msec, or other clinically significant, uncontrolled heart disease, including acute myocardial infarction or unstable angina < 3 months prior to the first dose of IDH305
* Any other medical condition that would, in the investigator*s judgment, prevent the patient*s participation in the clinical study due to safety concerns or compliance with clinical study procedures such as the presence of other clinically significant cardiac, respiratory, gastrointestinal, renal, hepatic or neurological disease
* Patient*s with Gilbert*s syndrome or other heritable disorders of bile processing
* Patients with Acute Promyelocytic Leukemia
* Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of study treatment
* Sexually active males must use a condom during intercourse while taking the drug and for 70 days after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Incidence rate of dose limiting toxicities (DLTs) during the first cycle of<br /><br>IDH305 treatment.</p><br>

Secondary Outcome Measures

Name	Time	Method
<p>-Safety: Incidence and severity of AEs and SAEs, including changes in<br /><br>laboratory values, vital signs and ECGs.<br /><br>-Tolerability: Dose interruptions and reductions.<br /><br>-Plasma concentration versus time of IDH305 and PK parameters.<br /><br>-Changes of 2-hydroxyglutarate concentration between pre and post-treatment<br /><br>tumors and blood samples.<br /><br>-Overall response rate (ORR) assessed by investigators per RANO for patients<br /><br>with glioma, per RECIST version 1.1 for patients with cholangiocarcinoma/other<br /><br>solid tumors, per IWG for patients with AML/MDS along with time-related<br /><br>efficacy endpoints by disease area (PFS [progression-free survival] or EFS<br /><br>[event-free survival], TTR [time to response] and DOR [duration of response])</p><br>