Agios Presents Phase 1 Data from Dose-Escalation and Expansion Cohorts of AG-120 (Ivosidenib) in Patients with Previously Treated IDH1 Mutant Positive Cholangiocarcinoma
Durable Disease Control with Six Month PFS rate of 38.5% and 12 Month PFS Rate of 20.7%; Median PFS of 3.8 Months
Stable Disease Observed in 56% of Patients; 5% of Patients Achieved a Partial Response
AG-120 (Ivosidenib) Well-tolerated in Heavily Pre-Treated Cholangiocarcinoma Population
“The durable disease control signal seen with the Phase 1 data, combined with AG-120’s favorable safety profile, are encouraging for patients with advanced IDH1 mutant cholangiocarcinoma who have received multiple prior therapies,” said
“Consistent with AG-120’s unique mechanism of action and in the context of this heavily pre-treated patient population, we believe durable stable disease is a meaningful measure of clinical benefit,” said
The ongoing Phase 1 trial is assessing the safety and tolerability of AG-120 in advanced solid tumors, including glioma, cholangiocarcinoma and chondrosarcomas with an IDH1 mutation. Enrollment is now complete for the dose-escalation and expansion cohorts. As of
A safety analysis conducted for all 73 treated patients as of the data cut-off demonstrated that AG-120 was well-tolerated with a favorable safety profile in IDH1 mutant positive cholangiocarcinoma patients.
- No dose limiting toxicities or treatment-related deaths have been observed.
- The majority of adverse events (AEs) reported were mild to moderate, with the most common regardless of causality being fatigue, nausea, diarrhea and decreased appetite.
- Four patients experienced drug-related AEs ≥ grade 3: two at the 500 mg dose level, fatigue (n=1) and blood alkaline phosphatase increases (n=1) and two at the 1200 mg dose level, fatigue (n=1) and blood phosphorous decreases (n=1).
- One patient had a dose reduction for a grade 2 AE of worsening leg cramps that was considered to be possibly drug-related.
Efficacy data from all 73 treated patients as of the data cut-off showed:
- Four patients (5%) experienced a confirmed partial response (one at 300 mg QD and three at 500 mg QD). A partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
- Forty-one patients (56%) experienced stable disease.
- Landmark analyses of progression free survival at six (PFS6) and 12 months (PFS12) were 38.5% and 20.7% respectively. The median progression free survival (PFS) was 3.8 months (95% CI 3.6, 7.3).
- AG-120 treatment inhibited plasma 2-hydroxyglutarate (2-HG) to within levels found in healthy volunteers, and also reduced 2-HG in tumor biopsies, with 2-HG levels in plasma and tumor biopsies showing a positive correlation.
- Pathology review of on-study tumor biopsies were conducted in a patient achieving a partial response, which showed morphologic changes suggestive of cellular differentiation which is consistent with the proposed mechanism of action of AG-120.
ClarIDHy Phase 3 Trial
AG-120 (ivosidenib) is currently being evaluated in an ongoing, global, registration-enabling randomized Phase 3 trial known as ClarIDHy, enrolling 186 previously treated IDH1m positive cholangiocarcinoma patients who have documented disease progression following one or two systemic therapies in the advanced setting.
- Patients will be randomized 2:1 to receive either single-agent AG-120 500 mg once daily or placebo with crossover to AG-120 permitted at the time of progression.
- The primary endpoint of the trial is PFS with secondary endpoints including safety and tolerability, overall response rate, overall survival, duration of response, PK/PD and quality of life assessments.
- Assuming a median PFS of 3 months for the control group, the study was designed with 96% power to detect a hazard ratio of 0.5 for PFS (AG-120 vs placebo), with a one-sided alpha of 0.025.
Thermo Fisher Scientificis providing next-generation sequencing to detect IDH1m for all tumor samples as inclusion criteria for enrollment in the study and will develop and commercialize the validated companion diagnostic.
Cholangiocarcinoma (CC) is a rare cancer of the bile ducts within and outside of the liver. Cases that occur within the liver are known as intrahepatic cholangiocarcinoma (IHCC) and those that occur outside the liver are considered extrahepatic. Mutations in IDH1 occur in 13–15% of CC cases overall and in up to 25% of IHCC cases. Current treatment options for localized disease include surgery, radiation and/or other ablative treatments. There are no approved systemic therapies for cholangiocarcinoma and limited chemotherapy options are available in the advanced setting. Gemcitabine-based chemotherapy is often recommended for newly diagnosed metastatic disease. Progression-free survival (PFS) in patients with advanced biliary cancer receiving second-line chemotherapy is 2–3 months.
Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding the potential of IDH1 as a therapeutic targets; the potential benefits of Agios' product candidates targeting IDH1, including ivosidenib (AG-120); and the potential benefit of its strategic plans and focus. The words “believe,” “aim” “will” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from Agios' current expectations and beliefs. For example, there can be no guarantee that any product candidate Agios is developing will successfully commence or complete necessary preclinical and clinical development phases, or that development of any of Agios' product candidates will successfully continue. There can be no guarantee that any positive developments in Agios' business will result in stock price appreciation. Management's expectations and, therefore, any forward-looking statements in this press release could also be affected by risks and uncertainties relating to a number of other important factors, including: Agios' results of clinical trials and preclinical studies, including subsequent analysis of existing data and new data received from ongoing and future studies; the content and timing of decisions made by the U.S.
Kendra Adams, 617-844-6407 Senior Director, Investor & Public Relations Kendra.Adams@agios.com Renee Leck, 617-649-8299 Senior Manager, Investor & Public Relations Renee.Leck@agios.com Media: Holly Manning, 617-844-6630 Associate Director, Corporate Communications Holly.Manning@agios.com