Anaplastic Large Cell Lymphoma, Glioblastoma, Inflammatory Myofibroblastic Tumor, Tumors With Aberrations in ALK
Conditions
Keywords
ALK, GBM, hematological malignancy, anaplastic lymphoma kinase, glioblastoma, anaplastic large cell lymphoma, IMT, inflammatory myofibroblastic tumor
Brief summary
This is Proof-of-Concept (POC) study to assess the preliminary antitumor activity and safety and tolerablity using ceritinib (LDK378) in the treatment of life threatening tumors that are characterized by ALK genetic alteration (and/or overexpression in some diseases).
Interventions
Ceritinib was to be administered orally once daily at a dose of 750 mg (5 capsules of 150 mg) on a continuous dosing schedule. A complete treatment cycle was defined as 28 days of once daily continuous treatment with ceritinib.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Depending on the tumor type, subjects were to be enrolled into one of the following parallel arms: ALCL (anaplastic large cell lymphoma); IMT (inflammatory myofibroblastic tumor); glioblastoma (GBM), and any other ALK+ tumor. If there were 5 or more subjects of the same tumor type in the Any other ALK+ tumor arm, then a separate arm was to be opened for that specific tumor type.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient has a histologically or cytologically confirmed diagnosis of ALK positive (ALK+) tumor other than Non-Small Cell Lung Cancer (NSCLC). * Patient must provide an archival or fresh tumor tissue before the first dose of the study drug for ALK testing at a Novartis designated central laboratory. * Patient has WHO Performance Status (PS) ≤ 2 * Patient must have received at least one line of prior systemic treatment for recurrent, locally advanced and/or metastatic disease, and may have discontinued for: * Disease progression as defined by RECIST 1.1 for solid tumors; by RANO for GBM and by Cheson assessment criteria for lymphoma, or * Intolerance described as any discontinuation due to an AE of any grade despite appropriate supportive treatment * Patient has at least one measurable lesion as defined by appropriate guidelines. A lesion at a previously irradiated site may only be counted as a target lesion if there is clear sign of progression since the irradiation. * Patient has received no chemotherapy, immunotherapy or stem cell therapy at least 4 weeks before starting ceritinib * Radiotherapy and prior ALK inhibitors must be stopped at least 1 week prior to starting ceritinib * Recovered from all toxicities related to prior anticancer therapies to grade ≤ 1 (Common Terminology Criteria for Adverse Events \[CTCAE\] v4.03).
Exclusion criteria
* Patient has ALK+lung cancer * Patient with symptomatic CNS metastases who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms. * Patient with acute or chronic GI disease that may significantly alter the absorption of ceritinib. * Patient with a history of pancreatitis or history of increased amylase or lipase that was due to pancreatic disease. * Patient has history of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis. * Patient has clinically significant, uncontrolled heart disease and/or recent cardiac event (within 6 months). * Patient has evidence of active viral hepatitis, including Hepatitis A, B or C (testing for viral hepatitis is not mandatory). * Patient has known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) Based on Investigator Assessments for Participants With at Least 16 Weeks of Treatment | Baseline up to approximately 16 weeks | The DCR is defined as the percentage of patients with complete response (CR), partial response (PR) or stable disease (SD) at 16 weeks from the start of ceritinib treatment. The assessment criteria are: Solid Tumors (RECIST 1.1., Response Evaluation Criteria in Solid Tumors); GBM (RECIST 1.1 and RANO, Response Evaluation in Neuro-Oncology); Hematologic tumors (Cheson). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) Per Investigator Assessment | Baseline, every 8 weeks until disease progression or end of treatment, whichever came first assessed up to approximately 84 weeks | ORR is defined as the percentage of patients with best overall response of complete response (CR) or partial response (PR) based on local assessment according to RECIST 1.1, RANO or Cheson hematological criteria. |
| Duration of Response (DOR) Per Investigator Assessment | Baseline, every 8 weeks until disease progression or end of treatment, whichever came first, assessed up to approximately 84 weeks | DOR is defined as the time from date of first documented CR or PR to date of first documented disease progression or death due to any cause |
| Time to Response (TTR) Per Investigator Assessment | Baseline, every 8 weeks until disease progression or end of treatment, whichever came first, assessed up to approximately 84 weeks | TTR is defined as the time from date of the first dose to date of first documented response (CR or PR) |
| Progression Free Survival (PFS) Per Investigator Assessments | Baseline, every 8 weeks until disease progression or death from any cause, assessed for up to approximately 84 weeks | PFS is defined as the time from the date of first dose of ceritinib to the date of first documented disease progression or death from any cause |
| Percent of Participant Deaths During Treatment and Follow-up | Baseline up to approximately 84 weeks | Deaths due to any cause during treatment and 30 day follow-up |
Countries
Czechia, Denmark, France, Israel, Italy, South Korea, Spain, Thailand
Participant flow
Pre-assignment details
A minimum of 10 and a maximum of 20 subjects were to be enrolled in each arm (tumor type)
Participants by arm
| Arm | Count |
|---|---|
| Anaplastic Large Cell Lymphoma (ALCL) Patients with a diagnosis of ALCL histologically or cytologically confirmed to be ALK-positive | 1 |
| Inflammatory Myofibroblastic Tumor (IMT) Patients diagnosed with IMT with a confirmed translocation involving the ALK gene | 4 |
| Glioblastoma (GBM) Patients with GBM with a translocation involving the ALK gene | 12 |
| Any Other ALK-positive Tumor Patients with any other ALK-positive tumor. Patients in this arm included adenocarcinoma (n= 2), sarcoma (1) and other (2). | 5 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 |
| Overall Study | Physician Decision | 0 | 0 | 1 | 0 |
| Overall Study | Progressive disease | 0 | 2 | 9 | 4 |
| Overall Study | Study terminated by sponsor | 1 | 2 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | Anaplastic Large Cell Lymphoma (ALCL) | Inflammatory Myofibroblastic Tumor (IMT) | Glioblastoma (GBM) | Any Other ALK-positive Tumor | Total |
|---|---|---|---|---|---|
| Age, Continuous | 36.0 years | 42.8 years STANDARD_DEVIATION 19.41 | 49.3 years STANDARD_DEVIATION 15.4 | 57.4 years STANDARD_DEVIATION 14.64 | 49.3 years STANDARD_DEVIATION 15.85 |
| Age, Customized 18 to <65 | 1 Participants | 4 Participants | 10 Participants | 3 Participants | 18 Participants |
| Age, Customized 65 to <=75 | 0 Participants | 0 Participants | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Asian | 1 participants | 1 participants | 1 participants | 3 participants | 6 participants |
| Race/Ethnicity, Customized Caucasian | 0 participants | 1 participants | 10 participants | 2 participants | 13 participants |
| Race/Ethnicity, Customized Other | 0 participants | 2 participants | 1 participants | 0 participants | 3 participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 6 Participants | 1 Participants | 11 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 6 Participants | 4 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 4 | 3 / 12 | 1 / 5 | 4 / 22 |
| other Total, other adverse events | 1 / 1 | 4 / 4 | 12 / 12 | 5 / 5 | 22 / 22 |
| serious Total, serious adverse events | 0 / 1 | 2 / 4 | 10 / 12 | 4 / 5 | 16 / 22 |
Outcome results
Primary
Disease Control Rate (DCR) Based on Investigator Assessments for Participants With at Least 16 Weeks of Treatment
The DCR is defined as the percentage of patients with complete response (CR), partial response (PR) or stable disease (SD) at 16 weeks from the start of ceritinib treatment. The assessment criteria are: Solid Tumors (RECIST 1.1., Response Evaluation Criteria in Solid Tumors); GBM (RECIST 1.1 and RANO, Response Evaluation in Neuro-Oncology); Hematologic tumors (Cheson).
Time frame: Baseline up to approximately 16 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anaplastic Large Cell Lymphoma (ALCL) | Disease Control Rate (DCR) Based on Investigator Assessments for Participants With at Least 16 Weeks of Treatment | 100.00 percentage of participants |
| Inflammatory Myofibroblastic Tumor (IMT) | Disease Control Rate (DCR) Based on Investigator Assessments for Participants With at Least 16 Weeks of Treatment | 75.00 percentage of participants |
| Glioblastoma (GBM) | Disease Control Rate (DCR) Based on Investigator Assessments for Participants With at Least 16 Weeks of Treatment | 0.0 percentage of participants |
| Any Other ALK-positive Tumor | Disease Control Rate (DCR) Based on Investigator Assessments for Participants With at Least 16 Weeks of Treatment | 40.0 percentage of participants |
Secondary
Duration of Response (DOR) Per Investigator Assessment
DOR is defined as the time from date of first documented CR or PR to date of first documented disease progression or death due to any cause
Time frame: Baseline, every 8 weeks until disease progression or end of treatment, whichever came first, assessed up to approximately 84 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anaplastic Large Cell Lymphoma (ALCL) | Duration of Response (DOR) Per Investigator Assessment | NA weeks |
| Inflammatory Myofibroblastic Tumor (IMT) | Duration of Response (DOR) Per Investigator Assessment | NA weeks |
| Glioblastoma (GBM) | Duration of Response (DOR) Per Investigator Assessment | NA weeks |
| Any Other ALK-positive Tumor | Duration of Response (DOR) Per Investigator Assessment | NA weeks |
Secondary
Overall Response Rate (ORR) Per Investigator Assessment
ORR is defined as the percentage of patients with best overall response of complete response (CR) or partial response (PR) based on local assessment according to RECIST 1.1, RANO or Cheson hematological criteria.
Time frame: Baseline, every 8 weeks until disease progression or end of treatment, whichever came first assessed up to approximately 84 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anaplastic Large Cell Lymphoma (ALCL) | Overall Response Rate (ORR) Per Investigator Assessment | 100.0 percentage of participants |
| Inflammatory Myofibroblastic Tumor (IMT) | Overall Response Rate (ORR) Per Investigator Assessment | 75.0 percentage of participants |
| Glioblastoma (GBM) | Overall Response Rate (ORR) Per Investigator Assessment | 0.0 percentage of participants |
| Any Other ALK-positive Tumor | Overall Response Rate (ORR) Per Investigator Assessment | 0.0 percentage of participants |
Secondary
Percent of Participant Deaths During Treatment and Follow-up
Deaths due to any cause during treatment and 30 day follow-up
Time frame: Baseline up to approximately 84 weeks
Population: There were no deaths in the ALCL and IMT arms
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anaplastic Large Cell Lymphoma (ALCL) | Percent of Participant Deaths During Treatment and Follow-up | 0.0 percent of participants |
| Inflammatory Myofibroblastic Tumor (IMT) | Percent of Participant Deaths During Treatment and Follow-up | 0.0 percent of participants |
| Glioblastoma (GBM) | Percent of Participant Deaths During Treatment and Follow-up | 25.0 percent of participants |
| Any Other ALK-positive Tumor | Percent of Participant Deaths During Treatment and Follow-up | 20.0 percent of participants |
Secondary
Progression Free Survival (PFS) Per Investigator Assessments
PFS is defined as the time from the date of first dose of ceritinib to the date of first documented disease progression or death from any cause
Time frame: Baseline, every 8 weeks until disease progression or death from any cause, assessed for up to approximately 84 weeks
Population: no participants met definition of PFS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Inflammatory Myofibroblastic Tumor (IMT) | Progression Free Survival (PFS) Per Investigator Assessments | NA weeks |
| Glioblastoma (GBM) | Progression Free Survival (PFS) Per Investigator Assessments | 1.7 weeks |
| Any Other ALK-positive Tumor | Progression Free Survival (PFS) Per Investigator Assessments | 1.7 weeks |
Secondary
Time to Response (TTR) Per Investigator Assessment
TTR is defined as the time from date of the first dose to date of first documented response (CR or PR)
Time frame: Baseline, every 8 weeks until disease progression or end of treatment, whichever came first, assessed up to approximately 84 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anaplastic Large Cell Lymphoma (ALCL) | Time to Response (TTR) Per Investigator Assessment | 7.1 weeks |
| Inflammatory Myofibroblastic Tumor (IMT) | Time to Response (TTR) Per Investigator Assessment | 16.4 weeks |
| Glioblastoma (GBM) | Time to Response (TTR) Per Investigator Assessment | NA weeks |
| Any Other ALK-positive Tumor | Time to Response (TTR) Per Investigator Assessment | NA weeks |