Ivosidenib Plus Durvalumab and Gemcitabine/Cisplatin as First-Line Therapy in Participants with Locally Advanced or Metastatic Cholangiocarcinoma with an IDH1 Mutation

JRCT ID: jRCT2031240643

Registered date:29/01/2025

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Locally advanced, unresectable or metastatic cholangiocarcinoma with an IDH1 mutation
• Date of first enrollment: 03/02/2025
• Target sample size: 12
• Countries of recruitment: Australia,Japan,Canada,Japan,Korea,Japan,Spain,Japan,USA,Japan,Brazil,Japan,France,Japan,Germany,Japan
• Study type: Interventional

Intervention(s)

Ivosidenib will be supplied as 250 mg strength tablets to be administered QD. Participants enrolled will receive ivosidenib orally at a dose of 500 mg QD on every day of the 21-day cycle, plus gemcitabine and cisplatin (intravenous [IV] infusion of 1000 mg/m2 and 25 mg/m2, respectively) on Days 1 and 8 of each 21-day cycle plus durvalumab 1500 mg infusion every 3 weeks for up to 8 cycles (or up to 7 cycles if 1 cycle of durvalumab/gemcitabine/cisplatin was administered prior to initiation of study treatment [C1D1]), followed by ivosidenib 500 mg QD and durvalumab 1500 mg every 4 weeks.
Safety Lead-in Phase: In the Safety Lead-in Phase, ivosidenib will be administered orally at a starting dose of 500 mg QD. Depending on the DLT evaluation by the DRT, an alternative dose of 250 mg QD may be evaluated.
Expansion Phase: Participants will receive ivosidenib orally at the RCD on every day of the 21-day cycle. After the first 8 cycles, the cycle length will increase to 28 days.

Outcome(s)

Primary Outcome

[Safety Lead-in Phase]
- Dose-limiting toxicities (DLTs) associated with ivosidenib in combination with durvalumab and gemcitabine/ cisplatin as first-line therapy during the first cycle of treatment.
- Dose reductions, delays, interruptions, and discontinuation.

[Expansion Phase]
Objective response (confirmed complete response ([CR] or confirmed partial response [PR]) of anti-tumor activity of ivosidenib in combination with durvalumab and gemcitabine/cisplatin as first-line therapy using RECIST v1.1.
Estimands Attributes: The primary estimand of interest is the objective response rate (ORR). The attributes of the primary estimand are defined as follows:
- Treatment: ivosidenib plus durvalumab and gemcitabine/cisplatin.
- Population: Treated Set
- Summary measure: objective response (Yes, No)
- Intercurrent events (IE):
- Early treatment discontinuation
- Administration of further anticancer therapy

Secondary Outcome

[Safety Lead-in Phase]
Ivosidenib plasma concentrations and PK parameters including, but not limited to:
- Area under the concentration-versus-time curve (AUC) from time 0 to time of last measurable concentration (AUC0-t)
- AUC over 1 dosing interval at steady state (AUCtau,ss)
- Time to maximum concentration (Tmax)
- Maximum concentration (Cmax)
- Trough concentration (Ctrough)
- Apparent volume of distribution (Vd/F)
- Apparent clearance (CL/F)
PD parameters including plasma 2-hydroxygluturate (2-HG) concentrations
Presence of anti-drug antibodies (ADAs) for durvalumab (confirmatory results: positive or negative, titres)

[Expansion Phase]
- Incidence and severity of AEs, AESIs, and SAEs
- Dose reductions, delays, interruptions, and discontinuation
- Overall survival (OS)
- Duration of response (DOR), progression-free survival (PFS), disease control (i.e., confirmed CR, confirmed PR, or stable disease [SD]), and time to response (TTR) according to RECIST v1.1
- Ivosidenib plasma concentrations and PK parameters including, but not limited to, AUC0-t, AUCtau,ss, Tmax, Cmax, Ctrough, Vd/F, and CL/F
- Plasma 2-hydroxygluturate (2-HG) concentration
- Presence of ADAs for durvalumab (confirmatory results: positive or negative, titres)

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

Males or non-pregnant and non-lactating females aged 18 years or older.
Body weight: over 30 kg.
ECOG PS: 0-1.
Have a histopathological confirmed diagnosis consistent with locally advanced, unresectable or metastatic CCA.
Have documented IDH1 gene-mutated CCA based on local or central laboratory testing(R132C/L/G/H/S mutation variants tested).
Have at least one evaluable and measurable lesion as defined by RECIST v1.1.
Have adequate bone marrow function, hepatic function, renal function, and coagulation function.
Have recovered from any clinically relevant sequelae and toxic effects of any prior surgery, radiotherapy, or other therapy intended for the treatment of cancer.
Participants with known HBV infection must be treated with antiviral therapy per institutional practice. Following antiviral therapy initiation, participants must show adequate viral suppression as prior to study entry. Participants with a past or resolved HBV infection are eligible. Participants positive for HCV antibody are eligible only if PCR is negative for HCV RNA.

Exclude criteria

History of leptomeningeal carcinomatosis.
History of active primary immunodeficiency.
Have known symptomatic brain metastases requiring steroids (i.e., >10 mg per day of prednisone [or equivalent]).
Have a history of another concurrent primary cancer, except for curatively resected non-melanoma skin cancer or curatively treated carcinoma in situ.
Uncontrolled intercurrent illness.
Active or prior documented autoimmune or inflammatory disorders.
Have heart rate-corrected QT interval using Fridericia's formula (QTcF) of 450 msec or more, or with other factors that increase the risk of QT prolongation or arrhythmic events.
Have LVEF (echocardiogram, multiple-gated acquisition scan, or by another method according to institutional practice) < 40% by ECHO scan (or by other methods according to institutional practice) obtained within 28 days before the start of study medication.
Inability to swallow oral medication.
History of non-infectious pneumonitis that required steroids, current pneumonitis, or history of interstitial lung disease.
Any clinically significant medical condition (e.g., organ dysfunction) or laboratory abnormality likely to jeopardize the participant's safety or to interfere with the conduct of the study, in the Investigator's opinion.
Any contraindication to the use of durvalumab.
Are taking known strong cytochrome P450 (CYP) 3A4 inducers or sensitive CYP3A4 substrate medications with a narrow therapeutic window, unless they can be transferred to other medications within at least 5 half-lives prior to dosing.

Related Information

• Primary Sponsor: PANDYA SHUCHI
• Secondary ID(s): ClinicalTrials.gov ID NCT06501625