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

Specific somatic cancer mutations in IDH1 were originally identified in 2008.
Cancers with high frequency of IDH1 mutation include: gliomas, cancers of the
brain which impact ~ 28,000 patients a year with significant clinical morbidity
and mortality; cholangiocarinoma, a cancer of the biliary tract with very poor
prognosis that is increasing in incidence; and AML, an aggressive leukemia from
which 10,000 patients die each year. Additionally, IDH1 mutations have been
identified at high frequency in chondrosarcoma, a rare cancer, and in low
frequency in several common cancers including MDS, melanoma, breast, colon, and
prostate cancers.

Since the initial identification of IDH1 mutations, studies have revealed the
importance of mutant IDH1 (and subsequently analogous mutants of IDH2) as a
cancer driver. Mutation of IDH1 at 132nd amino acid residue (R132*) alters its
normal function. When mutated at this position, IDH1 no longer converts *-
ketoglutarate to isocitrate, but rather to the metabolite 2-HG. Pre-clinical
studies have established that the introduction of mutant IDH and the resultant
accumulation of 2-HG levels can block normal cellular differentiation and
contribute to tumorigenesis. The clinical relevance of these data has been
recently established. Preliminary clinical data was recently reported from a
Phase I clinical study of an inhibitor of IDH2, which is a paralog of IDH1 that
also initiates cancer via the production of 2-HG. Of 24 evaluable patients with
pre-treated IDH2 mutant AML, 14 clinical responses were observed, including 6
complete responses and 3 complete responses with incomplete recoveries. These
data emphasize the clinical potential for targeting mutant IDH1-dependent
production of 2-HG in advanced malignancies.

IDH305 is an orally available, brain-penetrant, mutant-selective allosteric
IDH1 inhibitor that blocks mutant IDH1-dependent production of the
*oncometabolite* 2-HG, and inhibits the proliferation of IDH1 mutant
preclinical models. The primary purpose of this study is to evaluate the
clinical safety profile and PK characteristics of IDH305 in cancer patients. In
addition, based on the rationale that the inhibition of IDH1R132 and the
subsequent reduction of 2-HG will have anti-proliferative effect, the potential
for anti-tumor activity of IDH305 in a patients with IDH1 mutant malignancies
will be explored. Results from this study will inform the clinical development
of IDH305 in patients with IDH1 mutant cancer.

The main objective is to estimate the MTD(s) and/or RDE(s) of IDH305 in
patients with IDH1R132 mutant malignancies, as measured by the incidence of
dose-limiting toxicities.
Secondary objectives are characterization of the safety, tolerability, PK
profile, PD profile of IDH305 and to assess any preliminary anti-tumor activity
of IDH305 in patients with glioma, cholangiocarcinoma/other solid tumors and
AML/MDS.

This is an open-label, multi-center Phase I dose escalation followed by a dose
expansion in disease-specific cohorts.

Treatment with IDH305.

Pre-screening:
Blood collection and/or tumor biopsy/bone marrow aspirate (if an archival tumor
sample is not available)

Study:
- Possible toxicity derived from the study treatment. The known adverse events
are documented in the informed consent form.
-The study assessments are used in routine practice: blood collection, imaging
assessments (CT/MRI and X-ray), ECG, bone marrow aspirates, tumor biopsies. A
flowchart with all these assessments can be found in the informed consent form.
-Adequate contraception
-Frequent (and possibly longer) study visits