Tumors With Aberrations in ALK or ROS1
Conditions
Keywords
hematological malignancy, solid tumor malignancy, mutation, translocation, rearrangement, amplification, ALK, ROS1, NSCLC, B-cell lymphoma
Brief summary
The purpose of this signal seeking study was to determine whether treatment with ceritinib demonstrated sufficient efficacy in select pathway-activated solid tumors and/or hematologic malignancies to warrant further study.
Detailed description
This was an open label study to determine the efficacy and safety of treatment with ceritinib in patients with a diagnosis of solid tumors or hematological malignancies that had been pre-identified (prior to study consent) to have ALK or ROS1 positive mutations, translocations, rearrangements or amplifications and whose disease had progressed on or after standard treatment. The study consisted of a treatment phase where all patients received ceritinib capsules for a total dose of 750 mg daily for up to 8 cycles of 28 days. Disease assessments for clinical benefit were performed every 8 weeks until disease progression or end of treatment. Following discontinuation of treatment for any reason, patients were followed for safety for 30 days. Survival information was collected every 3 months until 2 years after the last patient had enrolled into the study. Study was amended to allow for discontinuation of survival period if primary endpoint was not met. Study was terminated due to low enrollment.
Interventions
DRUGCeritinib
Ceritinib was dosed on a flat scale of 750 mg (e.g., 5 x 150 mg capsules) orally,once daily, on a continuous dosing cycle. A complete treatment cycle was defined as 28 days. There were no breaks between dosing cycles.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient had a confirmed diagnosis of a select solid tumor (except ALK+ NSCLC) or hematological malignancy and was in need of treatment because of radiologic progression or relapse. * Patient must have been pre-identified as having a tumor with an ALK or ROS1 positive mutation, translocation, rearrangement or amplification. The qualifying alteration must have been assessed and reported by a CLIA-certified laboratory. ALK positivity as assessed by IHC or FISH were allowed. * Patient must have received at least one prior treatment for recurrent, metastatic and/or locally advanced disease and for whom no standard therapy options were anticipated to result in a durable remission. * Patient had progressive and measurable disease as per RECIST 1.1 or other appropriate hematological guidelines. * Patient had an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
Exclusion criteria
* Patient had received prior treatment with ceritinib. * Patients with symptomatic CNS metastases who were neurologically unstable or required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms. * Patient had received chemotherapy or anticancer therapy ≤ 4 weeks (6 weeks for nitrosourea, monoclonal antibodies or mitomycin-C) prior to starting study drug.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Overall Response Rate (ORR) and Clinical Benefit Rate (CBR) Utilizing RECIST 1.1 at Approximately 16 Weeks | Baseline up to approximately 16 weeks | Solid tumors were assessed using RECIST 1.1 criteria and included responses of complete response (CR) or partial response (PR) or stable disease (SD). For hematologic tumors, other hematological response criteria applied. CR=disappearance of all target lesions. Pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10mm. PR=at least 30% decrease in sum of diameters of target lesions from baseline sum diameters. SD=neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. Progressive disease (PD)=at least a 20% increase in sum of diameter of measured target lesions from smallest sum of diameter of all target lesions recorded at or after baseline (sum must also demonstrate an absolute increase of at least 5mm). One or more new lesions was considered PD. Overall response rate (ORR) = (CR + PR). Clinical benefit rate = (CR + PR + SD) |
| Number of Participants With Tumor Responses Utilizing RECIST 1.1 at Approximately 16 Weeks | Baseline up to approximately 16 weeks | For patients with solid tumors the assessment criteria was RECIST 1.1 and included responses of complete response (CR) or partial response (PR) or stable disease (SD). For hematologic tumors, other hematological response criteria applied. CR=disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10mm. PR=at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. SD=neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. Progressive disease (PD)=at least a 20% increase in sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline (sum must also demonstrate an absolute increase of at least 5mm). One or more new lesions was also considered progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Baseline up to approximately 27 months | Progression-free survival (PFS) was the time from the date of start of study drug to the date of event defined as the first documented progression or death due to any cause within 30 days of the last dose. If a patient has not had an event, progression-free survival was censored at the date of last adequate tumor assessment. |
| Percentage of Participants With Progression-Free Survival (PFS) - Kaplan-Meier Estimates | Basleline up to approximately 27 months | Progression-free survival (PFS) was the time from the date of start of study drug to the date of event defined as the first documented progression or death due to any cause within 30 days of the last dose. If a patient has not had an event, progression-free survival was censored at the date of last adequate tumor assessment. |
| Overall Survival (OS) - Number of Participant Deaths | Baseline up to approximately 27 months | Overall survival (OS) is defined as the time from the date of first dose to the date of death due to any cause |
| Duration of Response (DOR) | baseline up to approximately 30 months | Duration of response (DOR) is defined as time from the first documented response (CR or PR) to the date first documented disease progression or relapse or death due to any cause |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ceritinib 750 mg Ceritinib was dosed on a flat scale of 750 mg (e.g., 5 x 150 mg capsules) orally, once daily, on a continuous dosing cycle. A complete treatment cycle was defined as 28 days with no breaks between dosing cycles. | 47 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 9 |
| Overall Study | Death | 2 |
| Overall Study | Disease progression | 32 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Study terminated by sponsor | 2 |
Baseline characteristics
| Characteristic | Ceritinib 750 mg |
|---|---|
| Age, Customized <65 | 27 Participants |
| Age, Customized ≥65 - < 75 | 15 Participants |
| Age, Customized ≥75 | 5 Participants |
| Participants with primary tumor type (sponsor adjudicated) Ampullary adenocarcinoma | 1 Participants |
| Participants with primary tumor type (sponsor adjudicated) Appendix | 1 Participants |
| Participants with primary tumor type (sponsor adjudicated) Breast | 2 Participants |
| Participants with primary tumor type (sponsor adjudicated) Central nervous system | 1 Participants |
| Participants with primary tumor type (sponsor adjudicated) Cervix | 1 Participants |
| Participants with primary tumor type (sponsor adjudicated) Colorectal cancer | 10 Participants |
| Participants with primary tumor type (sponsor adjudicated) Gastroesophageal junction | 1 Participants |
| Participants with primary tumor type (sponsor adjudicated) Head and neck squamous cell carcinoma | 1 Participants |
| Participants with primary tumor type (sponsor adjudicated) Liver | 1 Participants |
| Participants with primary tumor type (sponsor adjudicated) Lung non-small cell adenocarcinoma | 7 Participants |
| Participants with primary tumor type (sponsor adjudicated) Lymphoma | 1 Participants |
| Participants with primary tumor type (sponsor adjudicated) Neuroendocrine | 1 Participants |
| Participants with primary tumor type (sponsor adjudicated) Ovarian | 5 Participants |
| Participants with primary tumor type (sponsor adjudicated) Pancreas | 1 Participants |
| Participants with primary tumor type (sponsor adjudicated) Prostate | 1 Participants |
| Participants with primary tumor type (sponsor adjudicated) Sarcoma | 7 Participants |
| Participants with primary tumor type (sponsor adjudicated) Skin non-melanoma | 1 Participants |
| Participants with primary tumor type (sponsor adjudicated) Uterus | 2 Participants |
| Participants with primary tumor type (sponsor adjudicated) Uveal Melanoma | 2 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants |
| Race/Ethnicity, Customized Black | 2 Participants |
| Race/Ethnicity, Customized Caucasian | 38 Participants |
| Race/Ethnicity, Customized Native American | 1 Participants |
| Race/Ethnicity, Customized Other | 3 Participants |
| Sex/Gender, Customized Female Able to bear children | 2 Participants |
| Sex/Gender, Customized Female Postmenopausal | 14 Participants |
| Sex/Gender, Customized Female Premenarche | 0 Participants |
| Sex/Gender, Customized Female Sterile of child bearing age | 6 Participants |
| Sex/Gender, Customized Male | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 5 / 47 |
| other Total, other adverse events | 46 / 47 |
| serious Total, serious adverse events | 16 / 47 |
Outcome results
Primary
Number of Participants With Tumor Responses Utilizing RECIST 1.1 at Approximately 16 Weeks
For patients with solid tumors the assessment criteria was RECIST 1.1 and included responses of complete response (CR) or partial response (PR) or stable disease (SD). For hematologic tumors, other hematological response criteria applied. CR=disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10mm. PR=at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. SD=neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. Progressive disease (PD)=at least a 20% increase in sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline (sum must also demonstrate an absolute increase of at least 5mm). One or more new lesions was also considered progression.
Time frame: Baseline up to approximately 16 weeks
Population: tumor response was reported for all patients and for a subgroup of patients with colorectal cancer
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ceritinib 750 mg | Number of Participants With Tumor Responses Utilizing RECIST 1.1 at Approximately 16 Weeks | Complete response - all patients | 0 Participants |
| Ceritinib 750 mg | Number of Participants With Tumor Responses Utilizing RECIST 1.1 at Approximately 16 Weeks | Partial response - all patients | 3 Participants |
| Ceritinib 750 mg | Number of Participants With Tumor Responses Utilizing RECIST 1.1 at Approximately 16 Weeks | Stable disease- all patients | 6 Participants |
| Ceritinib 750 mg | Number of Participants With Tumor Responses Utilizing RECIST 1.1 at Approximately 16 Weeks | Progressive disease - all patients | 32 Participants |
| Ceritinib 750 mg | Number of Participants With Tumor Responses Utilizing RECIST 1.1 at Approximately 16 Weeks | Non-evaluable - all patients | 6 Participants |
| Ceritinib 750 mg | Number of Participants With Tumor Responses Utilizing RECIST 1.1 at Approximately 16 Weeks | Stable disease - Colorectal cancer patients | 1 Participants |
| Ceritinib 750 mg | Number of Participants With Tumor Responses Utilizing RECIST 1.1 at Approximately 16 Weeks | PD - Colorectal cancer patients | 8 Participants |
| Ceritinib 750 mg | Number of Participants With Tumor Responses Utilizing RECIST 1.1 at Approximately 16 Weeks | Non-evaluable - Colorectal cancer patients | 1 Participants |
Primary
Percentage of Participants Overall Response Rate (ORR) and Clinical Benefit Rate (CBR) Utilizing RECIST 1.1 at Approximately 16 Weeks
Solid tumors were assessed using RECIST 1.1 criteria and included responses of complete response (CR) or partial response (PR) or stable disease (SD). For hematologic tumors, other hematological response criteria applied. CR=disappearance of all target lesions. Pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10mm. PR=at least 30% decrease in sum of diameters of target lesions from baseline sum diameters. SD=neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. Progressive disease (PD)=at least a 20% increase in sum of diameter of measured target lesions from smallest sum of diameter of all target lesions recorded at or after baseline (sum must also demonstrate an absolute increase of at least 5mm). One or more new lesions was considered PD. Overall response rate (ORR) = (CR + PR). Clinical benefit rate = (CR + PR + SD)
Time frame: Baseline up to approximately 16 weeks
Population: ORR and CBR was reported for all patients and for a subgroup of patients with colorectal cancer
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ceritinib 750 mg | Percentage of Participants Overall Response Rate (ORR) and Clinical Benefit Rate (CBR) Utilizing RECIST 1.1 at Approximately 16 Weeks | ORR (CR + PR) for all patients | 6.4 percentage of paarticipants |
| Ceritinib 750 mg | Percentage of Participants Overall Response Rate (ORR) and Clinical Benefit Rate (CBR) Utilizing RECIST 1.1 at Approximately 16 Weeks | CBR (CR + PR + SD) for all patients | 19.1 percentage of paarticipants |
| Ceritinib 750 mg | Percentage of Participants Overall Response Rate (ORR) and Clinical Benefit Rate (CBR) Utilizing RECIST 1.1 at Approximately 16 Weeks | ORR (CR + PR) for colorectal cancer patients | 0.0 percentage of paarticipants |
| Ceritinib 750 mg | Percentage of Participants Overall Response Rate (ORR) and Clinical Benefit Rate (CBR) Utilizing RECIST 1.1 at Approximately 16 Weeks | CBR (CR + PR + SD) for colorectal cancer | 10.0 percentage of paarticipants |
Secondary
Duration of Response (DOR)
Duration of response (DOR) is defined as time from the first documented response (CR or PR) to the date first documented disease progression or relapse or death due to any cause
Time frame: baseline up to approximately 30 months
Population: only 2 patients met criteria for duration of response
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ceritinib 750 mg | Duration of Response (DOR) | One Patient with PR | 132 days |
| Ceritinib 750 mg | Duration of Response (DOR) | Second Patient with PR | 113 days |
Secondary
Overall Survival (OS) - Number of Participant Deaths
Overall survival (OS) is defined as the time from the date of first dose to the date of death due to any cause
Time frame: Baseline up to approximately 27 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ceritinib 750 mg | Overall Survival (OS) - Number of Participant Deaths | Deaths due to study indication | 14 Participants |
| Ceritinib 750 mg | Overall Survival (OS) - Number of Participant Deaths | Deaths due to study indication while on treatment | 5 Participants |
Secondary
Percentage of Participants With Progression-Free Survival (PFS) - Kaplan-Meier Estimates
Progression-free survival (PFS) was the time from the date of start of study drug to the date of event defined as the first documented progression or death due to any cause within 30 days of the last dose. If a patient has not had an event, progression-free survival was censored at the date of last adequate tumor assessment.
Time frame: Basleline up to approximately 27 months
Population: reported for all patients and for a subgroup of patients with colorectal cancer
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ceritinib 750 mg | Percentage of Participants With Progression-Free Survival (PFS) - Kaplan-Meier Estimates | 1 Month | 81.0 Percentage of participants |
| Ceritinib 750 mg | Percentage of Participants With Progression-Free Survival (PFS) - Kaplan-Meier Estimates | 2 Month | 34.8 Percentage of participants |
| Ceritinib 750 mg | Percentage of Participants With Progression-Free Survival (PFS) - Kaplan-Meier Estimates | 3 Month | 34.8 Percentage of participants |
| Ceritinib 750 mg | Percentage of Participants With Progression-Free Survival (PFS) - Kaplan-Meier Estimates | 4 Month | 24.1 Percentage of participants |
| Ceritinib 750 mg | Percentage of Participants With Progression-Free Survival (PFS) - Kaplan-Meier Estimates | 5 Month | 21.4 Percentage of participants |
| Ceritinib 750 mg | Percentage of Participants With Progression-Free Survival (PFS) - Kaplan-Meier Estimates | 6 Month | 15.3 Percentage of participants |
| Ceritinib 750 mg | Percentage of Participants With Progression-Free Survival (PFS) - Kaplan-Meier Estimates | 9 Month | 11.5 Percentage of participants |
| Ceritinib 750 mg | Percentage of Participants With Progression-Free Survival (PFS) - Kaplan-Meier Estimates | 12 Month | 7.7 Percentage of participants |
| Ceritinib 750 mg | Percentage of Participants With Progression-Free Survival (PFS) - Kaplan-Meier Estimates | 18 Month | 7.7 Percentage of participants |
| Ceritinib 750 mg | Percentage of Participants With Progression-Free Survival (PFS) - Kaplan-Meier Estimates | 24 Month | 7.7 Percentage of participants |
| Ceritinib 750 mg | Percentage of Participants With Progression-Free Survival (PFS) - Kaplan-Meier Estimates | 30 Month | 7.7 Percentage of participants |
| Ceritinib 750 mg | Percentage of Participants With Progression-Free Survival (PFS) - Kaplan-Meier Estimates | 1 Month Colorectal cancer patients | 90.0 Percentage of participants |
| Ceritinib 750 mg | Percentage of Participants With Progression-Free Survival (PFS) - Kaplan-Meier Estimates | 2 Month Colorectal cancer patients | 12.5 Percentage of participants |
| Ceritinib 750 mg | Percentage of Participants With Progression-Free Survival (PFS) - Kaplan-Meier Estimates | 3 Month Colorectal cancer patients | 12.5 Percentage of participants |
| Ceritinib 750 mg | Percentage of Participants With Progression-Free Survival (PFS) - Kaplan-Meier Estimates | 4 Mongth Colorectal cancer patients | 12.5 Percentage of participants |
| Ceritinib 750 mg | Percentage of Participants With Progression-Free Survival (PFS) - Kaplan-Meier Estimates | 5 Month Colorectal cancer patients | 12.5 Percentage of participants |
| Ceritinib 750 mg | Percentage of Participants With Progression-Free Survival (PFS) - Kaplan-Meier Estimates | 6 Month Colorectal cancer patients | 12.5 Percentage of participants |
| Ceritinib 750 mg | Percentage of Participants With Progression-Free Survival (PFS) - Kaplan-Meier Estimates | 9 Month Colorectal cancer patients | 12.5 Percentage of participants |
Secondary
Progression-Free Survival (PFS)
Progression-free survival (PFS) was the time from the date of start of study drug to the date of event defined as the first documented progression or death due to any cause within 30 days of the last dose. If a patient has not had an event, progression-free survival was censored at the date of last adequate tumor assessment.
Time frame: Baseline up to approximately 27 months
Population: reported for all patients and for a subgroup of patients with colorectal cancer
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ceritinib 750 mg | Progression-Free Survival (PFS) | All patients | 1.8 months |
| Ceritinib 750 mg | Progression-Free Survival (PFS) | Colorectal cancer patients | 1.8 months |
Post Hoc
All Collected Deaths
On treatment deaths were collected from FPFT up to 30 days after study drug discontinuation, for a maximum duration of 27 months (treatment duration ranged from 0.2 to 25.9 months). Deaths post treatment survival follow up were collected after the on treatment period, up to approximately 39 months.
Time frame: approx. 26 months, approx. 39 months
Population: Clinical Database Population: All treated patients
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ceritinib 750 mg | All Collected Deaths | Total deaths | 14 Participants |
| Ceritinib 750 mg | All Collected Deaths | Deaths on treatment | 5 Participants |