Study of AG-120 in Previously Treated Advanced Cholangiocarcinoma With IDH1 Mutations (ClarIDHy)

Servier

Status and phase: Completed; Phase 3

Conditions: Advanced Cholangiocarcinoma; Metastatic Cholangiocarcinoma

Treatments: Drug: AG-120; Drug: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT02989857

AG120-C-005

Details and patient eligibility

About

Study AG120-C-005 is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study of orally administered AG-120. Participants, all personnel involved in the evaluation of participants' response to treatment (e.g., Investigators, study coordinators, study pharmacists), and designated Sponsor team members will be blinded to study treatment. Participants are required to have a histologically-confirmed diagnosis of isocitrate dehydrogenase-1 (IDH1) gene-mutated cholangiocarcinoma that is not eligible for curative resection, transplantation, or ablative therapies prior to enrollment. IDH1 mutation testing will be performed at participating investigative sites. Participants must have progression of disease and have received at least 1 but not more than 2 prior treatment regimens for advanced disease (nonresectable or metastatic). All participants must have received either a gemcitabine or a 5 fluorouracil (5-FU) based chemotherapy regimen.

Enrollment: 187 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Be ≥18 years of age.
2. Have a histopathological diagnosis (fresh or banked tumor biopsy sample, preferably collected within the last 3 years) of nonresectable or metastatic cholangiocarcinoma and are not eligible for curative resection, transplantation, or ablative therapies.
3. Have documented IDH1 gene-mutated disease (from a fresh tumor biopsy or the most recent banked tumor tissue available) based on central laboratory testing (R132C/L/G/H/S mutation variants tested).
4. Have an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1
5. Have an expected survival of ≥3 months.
6. Have at least one evaluable and measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Participants 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 within the field and has shown ≥20% growth in size since post-treatment assessment.
7. Have documented disease progression following at least 1 and no more than 2 prior systemic regimens for advanced disease (nonresectable or metastatic). Participants must have received at least 1 gemcitabine- or 5-FU-containing regimen for advanced cholangiocarcinoma. Participants who have received systemic adjuvant chemotherapy will be permitted provided there is documented disease progression during or within 6 months of completing the therapy.

Exclusion criteria

1. Received a prior IDH inhibitor.
2. Received systemic anticancer therapy or an investigational agent <2 weeks prior to Day 1 (washout from prior immune based anticancer therapy is 4 weeks). In addition, the first dose of study treatment should not occur before a period ≥5 half-lives of the investigational agent has elapsed.
3. Received radiotherapy to metastatic sites of disease <2 weeks prior to Day 1.
4. Underwent hepatic radiation, chemoembolization, and radiofrequency ablation <4 weeks prior to Day 1.
5. Have known symptomatic brain metastases requiring steroids. 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 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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187 participants in 3 patient groups, including a placebo group

AG-120

Active Comparator group

Description:

Participants received AG-120 500 mg, tablet, orally, once a day (QD) in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.

Treatment:

Drug: AG-120

Placebo

Placebo Comparator group

Description:

Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.

Treatment:

Drug: Placebo

After Cross over to AG-120

Experimental group

Description:

Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.

Treatment:

Drug: AG-120