Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as Ceritinib, Zykadia
LDK378 · 16 trials · 16 indications
PFS is defined as the time from the date of randomization to the date of the first radiologically documented disease progression (as assessed by BIRC per RECIST 1.1) or death due to any cause. A patient who had not progressed or died at the date of the analysis cut-off or had received another anticancer therapy had their PFS censored at the time of the last adequate tumor evaluation before the earlier of the cut-off date or the anticancer therapy date. The distribution of PFS was estimated using the Kaplan-Meier (KM) method.
PFS was defined as the time from the date of randomization to the date of the first radiologically documented disease progression or death due to any cause.
ORR, defined as the percentage of participants with a best overall confirmed response of complete response (CR) or partial response (PR) in the whole body as assessed per RECIST 1.1 by the investigator. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Overall response rate (ORR) is defined as the percentage of participants with a best overall confirmed response of complete response (CR) or partial response (PR) in the whole body as assessed per RECIST 1.1 by the investigator. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed \& non-target lesions are not in progression or in complete response.
ORR per RECIST 1.1 calculated as the percentage of participants with a best overall response (OR) defined as complete response (CR) or partial response (PR) as assessed by the investigator. CR:Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
ORR per RECIST 1.1 calculated as the percentage of patients with a best overall confirmed response defined as complete response or partial response (CR+PR) as assessed by investigator. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm 1. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
ORR (complete response (CR)+ partial response (PR)) per RECIST 1.1 as assessed by investigator
Pharmacokinetics (PK) parameters, including but not limited to AUClast, AUC0-24h, Cmax, Tmax, Tlast, Racc, and CLss/F
Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version (v) 4.0. The frequency of toxicities will be tabulated for the dose estimated to be the MTD.
Graded according to NCI CTCAE v4.0. The frequency of toxicities will be tabulated for the dose estimated to be the MTD.
Graded according to NCI CTCAE v4.0. The frequency of toxicities will be tabulated for the dose estimated to be the MTD.
AUClast: The area under the concentration-time curve from time zero to the last measurable concentration time. AUC0-24h: The area under the plasma concentration-time curve calculated from time zero to 24 hours. AUCinf: Area under the plasma (serum, or blood) concentration versus time curve from time zero to infinity
AUC0-24h: The area under the plasma concentration-time curve calculated from time zero to 24 hours.
Cmax is the maximum (peak) concentration of drug in plasma
Tmax is the time to reach maximum plasma concentration.
Safety and tolerability of LDK378 at 750 mg once daily dose in Chinese adult patients with ALK-rearranged locally advanced or metastatic NSCLC
Evaluate the pharmacokinetics of a single dose of LDK378 in subjects with impaired hepatic function as compared to healthy subjects
Evaluate the pharmacokinetics of a single dose of LDK378 in subjects with impaired hepatic function as compared to healthy subjects
Evaluate the pharmacokinetics of a single dose of LDK378 in subjects with impaired hepatic function as compared to healthy subjects
Evaluate the pharmacokinetics of a single dose of LDK378 in subjects with impaired hepatic function as compared to healthy subjects
Evaluate the pharmacokinetics of a single dose of LDK378 in subjects with impaired hepatic function as compared to healthy subjects
Evaluate the pharmacokinetics of a single dose of LDK378 in subjects with impaired hepatic function as compared to healthy subjects
Evaluate the pharmacokinetics of a single dose of LDK378 in subjects with impaired hepatic function as compared to healthy subjects
A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant therapies that occurs within the first 21 days of treatment with LDK378 and meets a specified defined criteria. A participant with multiple occurrences of DLTs under one treatment is counted only once in the Adverse Event category for that treatment. A participant with multiple DLTs within a primary system organ class is counted only once in the total row.
cycle = within the first 28 days of patient's first dose
As a single agent when administered orally to Japanese patients with tumors characterized by genetic alterations in ALK. The number of patients and category of Dose Limiting Toxicities (DLTs)
The maximum tolerated dose (MTD) was defined as the highest dose for a given schedule that was expected to cause DLTs in no more than 33% of patients during the first cycle of treatment. A patient with multiple occurrences of a DLT under one treatment is counted only once in the AE category for that treatment. MTD was determined at 750mg.
| Arm | Type | Description |
|---|---|---|
| Ceritinib | EXPERIMENTAL | Ceritinib administered continuously through oral dosing at a dosage of 750 mg once daily in fasted state. |
| Chemotherapy | ACTIVE_COMPARATOR | Pemetrexed plus cisplatin or carboplatin (based on Investigator's choice) for 4 cycles (Induction) followed by pemetrexed as single agent (Maintenance) |
| LDK378 (Ceritinib) | EXPERIMENTAL | Participants who received LDK378 750mg once daily on a 28 day cycle. |
| Arm 1 (PrALKi=Y, PrBRad=Y) | EXPERIMENTAL | Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation). |
| Arm 2 (PrALKi=Y, PrBRad=N) | EXPERIMENTAL | Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation). |
| Arm 3 (PrALKi=N, PrBRad=Y) | EXPERIMENTAL | Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation). |
| Arm 4 (PrALKi=N, PrBRad=N) | EXPERIMENTAL | Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation). |
| Arm 5 (LepDis) | EXPERIMENTAL | Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3. |
| LDK378 | EXPERIMENTAL | Patients treated with ceritinib/LDK378 750 mg once-daily, fasted |
| Dose Escalation | EXPERIMENTAL | - |
| Dose Expansion | EXPERIMENTAL | - |
| ceritinib 450 mg with a low-fat meal | EXPERIMENTAL | Oral ceritinib QD (21 days/ cycle) at a dose of 450 mg (3×150 mg/capsule) administered in the morning immediately (within 30 minutes)following a low-fat meal. |
| ceritinib 600 mg with a low-fat meal | EXPERIMENTAL | Oral ceritinib QD (21 days/ cycle) at a dose of 600 mg (4×150 mg/capsule) administered in the morning immediately (within 30 minutes) following a low-fat meal. |
| ceritinib 750 mg on an empty stomach | ACTIVE_COMPARATOR | Oral ceritinib QD (21 days/ cycle) at a dose of 750 mg (5×150 mg/capsule) administered in the morning on an empty stomach (i.e., fasted from food and drink except water) |
| Arm 1 (ceritinib MTD then with gemcitabine alone) | EXPERIMENTAL | Dose Escalation Cohort 1: Patients with advanced solid tumors for whom gemcitabine hydrochloride-based therapy is clinically appropriate receive ceritinib PO (QD on days 1-28 and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Expansion Cohort 1E: Once the MTD of ceritinib has been determined, an additional 10 patients with ALK-positive advanced solid tumors who previously progressed on gemcitabine hydrochloride-based therapy receive ceritinib and gemcitabine hydrochloride as in the dose escalation cohort 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. |
| Arm 2 (ceritinib MTD then with gemcitabine and nab-paclitaxel) | EXPERIMENTAL | Dose Escalation Cohort 2: Patients with advanced pancreatic cancer receive ceritinib PO QD on days 1-28, gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15, and paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Expansion Cohort 2E: Once the MTD of ceritinib has been determined, patients with ALK-positive advanced solid tumors receive ceritinib, gemcitabine hydrochloride, and paclitaxel albumin-stabilized nanoparticle formulation as in the dose escalation cohort 2. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. |
| Arm 3 (ceritinib MTD then with gemcitabine and cisplatin) | EXPERIMENTAL | Dose Escalation Cohort 3: Patients with advanced solid tumors for whom gemcitabine hydrochloride and cisplatin-based therapy is clinically appropriate receive ceritinib PO QD on days 1-28, gemcitabine hydrochloride IV over 30 minutes on days 1 and 8, and cisplatin IV on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Expansion Cohort 3E: Once the MTD of ceritinib has been determined, an additional 10 patients with ALK-positive advanced solid tumors receive ceritinib, gemcitabine hydrochloride, and cisplatin as in the dose escalation cohort 3. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. |
| Normal Hepatic Function | EXPERIMENTAL | Subjects with normal hepatic function |
| Mild Hepatic Impairment | EXPERIMENTAL | Subjects with mild hepatic impairment |
| Moderate Hepatic Impairment | EXPERIMENTAL | Subjects with moderate hepatic impairment |
| Severe Hepatic Impairment | EXPERIMENTAL | Subjects with severe hepatic impairment |
| LDK378 and AUY922 | EXPERIMENTAL | - |
| Dose-escalation | EXPERIMENTAL | Open-label dose escalation study of LDK378, administered orally in Japanese patients with tumors characterized by genetic alterations in anaplastic lymphoma kinase (ALK) |
| Dose-expansion | EXPERIMENTAL | Open-label study of LDK378, administered orally in Japanese patients with tumors characterized by genetic alterations in ALK to see further safety, anti-tumor activity, and PK data in patients who has progressed since prior therapy with alectinib |
| LDK378 750 mg: Arm 1A and Arm 1B | EXPERIMENTAL | NSCLC patients previously treated with an ALK inhibitor |
| LDK378 750 mg: Arm 2 | EXPERIMENTAL | NSCLC patients not previously treated with an ALK inhibitor |
| LDK378 750 mg: Arm 3 | EXPERIMENTAL | Patients with other tumors that are ALK positive other than NSCLC |
| Name | Type | Description |
|---|---|---|
| Ceritinib | DRUG | Ceritinib was administered orally once-daily fasted at a dose of 750 mg capsules on a continuous dosing schedule. |
| Pemetrexed | DRUG | Pemetrexed was administered at a dose of 500 mg/m\^2 as an intravenous (iv) infusion on Day 1 of each 21-day cycle |
| Cisplatin | DRUG | Cisplatin was administered by iv infusion at a dose of 75 mg/m\^2 every 21 days for up to 4 cycles. |
| Carboplatin | DRUG | Carboplatin was administered as iv infusion (AUC 5-6) every 21 days up to 4 cycles |
| Docetaxel | DRUG | Docetaxel was one of the chemotherapy treatments. Docetaxel, a reconstituted solution, was intravenously administered over 1 hour, at 75 mg/m\^2 every 21 days. |
| LDK378 | DRUG | Oral LDK378 750mg once daily |
| warfarin | DRUG | - |
| midazolam | DRUG | - |
| Ceritinib (LDK378) | DRUG | - |
| Nivolumab | DRUG | - |
| Gemcitabine Hydrochloride | DRUG | Given IV |
| Laboratory Biomarker Analysis | OTHER | Correlative studies |
| Paclitaxel Albumin-Stabilized Nanoparticle Formulation | DRUG | Given IV |
| Pharmacological Study | OTHER | Correlative studies |
| AUY922 | DRUG | AUY922 is an intravenous infusion that will be administered by the investigative site to the patient on a weekly basis. |
Key Inclusion Criteria: 1. The patient had a histologically or cytologically confirmed diagnosis of non-squamous Non-small cell lung cancer (NSCLC) that was Anaplastic lymphoma kinase (ALK) positive as assessed by the Ventana Immunohistochemistry (IHC) test. The test was performed at Novartis desig...
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LDK378 is an investigational small molecule studied in oncology for cancers driven by abnormalities in the anaplastic lymphoma kinase (ALK) gene. Its clinical trials have focused on ALK-positive non-small cell lung cancer (NSCLC), including patients previously treated with other ALK inhibitors such as crizotinib and alectinib.
LDK378 targets anaplastic lymphoma kinase (ALK), a protein whose genetic alterations drive certain cancers. By inhibiting ALK, LDK378 is designed to interfere with signaling that promotes tumor growth in ALK-rearranged or ALK-positive malignancies, particularly non-small cell lung cancer.
LDK378 is being developed by Novartis AG, which trades under the ticker NVS. Novartis has sponsored the clinical trials evaluating LDK378 in ALK-positive non-small cell lung cancer and related conditions.
LDK378 is in clinical development, with trials conducted across Phase 1 and Phase 2. The program includes four completed trials, and no active trials are currently listed. LDK378 is investigational and has not been approved by the FDA for any indication.
LDK378 has been evaluated in four completed trials: NCT02450903 in ALK-positive NSCLC previously treated with alectinib, NCT02040870 in Chinese patients with ALK-rearranged NSCLC previously treated with crizotinib, NCT01950481 on hepatic impairment pharmacokinetics, and NCT01772797 combining LDK378 with AUY922 in ALK-rearranged NSCLC.
Yes, LDK378 is also known as ceritinib. Both names refer to the same Novartis ALK inhibitor studied in ALK-positive non-small cell lung cancer and other ALK-driven tumors.