Metastatic Melanoma, Brain Metastases
Conditions
Keywords
metastases, melanoma, encorafenib, binimetinib
Brief summary
Phase II clinical trial, with two cohorts of patients included in parallel, all with melanoma BRAF mutated and brain metastases without previous local treatment in the brain. Cohort 1 will include patients with asymptomatic brain metastases and cohort 2 will include patients with symptomatic brain metastasis.
Interventions
DRUGencorafenib
Encorafenib 75mg and 50mg (capsules) for a 450mg daily for oral administration during 56 days and after local radiation treatment. If no progression of disease progression (PD) is reported, treatment will continue until PD, unacceptable toxicity or death.
DRUGbinimetinib
Binimetinib 15mg (tablets) for a 45mg/12 hours for oral administration during 56 days and after local radiation treatment.
RADIATIONWhole brain radiation therapy
The whole brain planning target volume (PTV) will receive 30 Gy in 10 fractions. Treatment will be delivered once daily, 5 fractions per week, over 2 to 2.5 weeks.
RADIATIONRadiosurgery/stereotactic radiosurgery
Dose selection must be based on previously published Radiation Therapy Oncology Group (RTOG) data, with dose modification left up to the treating physician. The total dose will depend on the size of the metastatic lesion(s) and proximity to critical structures. Suggested doses are as follow: 1 fraction x 15-25 Gy; 3 fractions x 9-11 Gy; 5 fractions x 6-7 Gy; or 6 fractions x 5-6 Gy. For GTV \> 20 mm hypofractionated stereotactic radiotherapy could be preferred. Treatment will be delivered once daily, alternate-day, 3 fractions per week.
Sponsors
Pierre Fabre Medicament
MFAR
Grupo Español Multidisciplinar de Melanoma
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Cohort 1 will include patients with asymptomatic brain metastases and without previous local treatment in the brain (N=48), while cohort 2 will include patients with symptomatic brain metastasis and without previous local treatment in the brain (N=15).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent of approved by the investigator's Institutional Review Board (IRB)/Independent Ethics Committee (IEC), prior to the performance of any trial activities. * Histologically confirmed diagnosis of unresectable metastatic cutaneous melanoma, or unknown primary melanoma with one or more brain metastasis with a diameter of 10 to 50 mm, measured by contrast enhanced MRI. * Presence of a BRAF V600E or V600K mutation, or both, in their tumour tissue. * Barthel Index of Activities of Daily Living \> 10. * Subjects aged ≥ 18 years. * ECOG 0-1 in asymptomatic patients (cohort 1), 0-2 in symptomatic patients (cohort 2). * Adequate haematological function (Haemoglobin ≥ 9 g/dL, may have been transfused; Platelet count ≥ 100 × 109/L; Absolute neutrophil count (ANC) ≥ 1.5 × 109/L.) * Adequate hepatic function defined by a total bilirubin level ≤ 2.0 × the upper limit of normality (ULN) and AST and ALT levels ≤ 2.5 × ULN or AST and ALT levels ≤ 5 x ULN (for subjects with documented metastatic disease to the liver). * Serum Creatinine ≤ 2.0 x ULN or estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method). * Evidence of at least one measurable lesion as detected by radiological or photographic methods according to guidelines based on Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. * Naïve untreated patients or patients who have progressed on or after prior first line immunotherapy for unresectable locally advanced or metastatic melanoma, but it must have ended at least 6 weeks prior to randomization; prior adjuvant therapy is permitted (e.g. IFN, IL-2 therapy, any other immunotherapy, radiotherapy or chemotherapy), BRAF or MEK inhibitors can be used in the adjuvant setting, providing the relapse does not occur during the adjuvant treatment or within 12 months after the end of it, and providing the adjuvant treatment with targeted therapy did not cause in the patient any grade 3-4 toxicity not including medically serious and reversible/controlled toxicities (ex: GGT elevation, CPK elevation, vomiting). * Steroids or anticonvulsants are allowed if clinically needed and are not being administered in an increasing dose. * Female subjects must either be of non-reproductive potential (ie, post-menopausal by history: ≥60 years old and no menses for ≥1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry. * Normal functioning of daily living activities. * Willingness and ability to attend scheduled visits, follow the treatment schedule and undergo clinical tests and other study procedures.
Exclusion criteria
* Uveal or mucosal melanoma. * History of leptomeningeal metastases, with the exception that they are only seen in brain MRI and the patient has ECOG 0-1 and no neurological symptoms (except for cohort 2, where symptomatic patients will be allowed if ECOG is 0-2). * Another cancer in the last five years, except for in situ carcinoma of the cervix or squamous cell carcinoma of the skin adequately treated or limited basal cell skin cancer adequately controlled. * History of or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO) or history of retinal degenerative disease (RDD). * Any previous systemic chemotherapy treatment, extensive brain radiotherapy, targeted therapy for locally advanced unresectable or metastatic melanoma; Immunotherapy treatment is allowed but must have ended at least 6 weeks prior to randomization. * History of Gilbert's syndrome. * Previous treatment with a BRAF or MEK inhibitor in metastatic setting. This treatment will be allowed in the adjuvant setting (see above). Previous treatments with immunotherapy will be allowed in both the metastatic and adjuvant setting. * Known positive serology for human immunodeficiency virus, or an active hepatitis B or hepatitis C infection, or both. * Impaired cardiovascular function or clinically significant cardiovascular diseases Clinically significant (i.e., active) cardiovascular disease: cerebrovascular accident/stroke (\< 6 months prior to enrolment), myocardial infarction (\< 6 months prior to enrolment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), a LVEF \< 50% evaluated by MUGA or echocardiography, or serious cardiac arrhythmia requiring medication or a triplicate average baseline QTc interval \> 500 ms. * Uncontrolled arterial hypertension despite medical treatment. * Moderate (Child Pugh Class B) or severe (Child Pugh Class C) hepatic impairment. * Impairment of gastrointestinal function. * Neuromuscular disorders associated with high concentrations of creatine kinase. * Pregnant or nursing (lactating) women. * Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study. * Known hypersensitivity to encorafenib, binimetinib or their components. * Persisting toxicity related to prior therapy of Grade \>1 NCI-CTCAE v 4.03; however, alopecia and sensory neuropathy Grade ≤ 2 is acceptable. * Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ highly effective birth control from screening to 180 days after the last dose of study treatment. * Known alcohol or drug abuse. * Inability to swallow tablets or capsules. * Total lactase deficiency or glucose-galactose malabsorption.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Intracranial Objective Response (iORR) by Modified RECIST 1.1 Before Local Radiotherapy Treatment in Full Dataset | 24 months after start of treatment | iORR calculated as the proportion of patient with a best overall intracranial response of complete response (CR) or partial response (PR) before local treatment according to modified RECIST 1.1. Modified RECIST 1.1 consists of: Up to 5 intracranial lesions could be selected as target lesions Target lesions might have a longest diameter ≥ 5 mm when evaluated by contrast-enhanced MRI This endpoint was also independently reported in patients with symptomatic and asymptomatic brain metastasis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Intracranial Progression-free Survival (iPFS) by RECIST 1.1 | Throughout the study period, up to approximately 24 months | Defined as the time from the date of inclusion to the date of the first documented intracranial disease progression or death due to any cause, whichever occurs first. PFS was determined based on tumor assessment (modified RECIST version 1.1 criteria). The local Investigator's assessments was used for analyses. Those patients who were alive and had not progressed at the last follow-up, date of progression was censored at the date of the last follow-up. Patients with no additional image test other than baseline were censored the day after inclusion. |
| Extracranial Progression-free Survival (ePFS) in Both Cohorts | Throughout the study period, up to approximately 24 months | Defined as the time from the date of inclusion to the date of the first documented extracranial disease progression or death due to any cause, whichever occurs first. PFS was determined based on tumor assessment (RECIST version 1.1 criteria). The local Investigator's assessments was used for analyses. Those patients who were alive and had not progressed at the last follow-up, date of progression was censored at the date of the last follow-up. Patients with no additional image test other than baseline were censored the day after inclusion. |
| Intracranial Progression-free Rates | at 6 months (week 24), 12 months (week 48) and 24-month (week 96) | Proportion of patients free of intracranial progression assessed by modified RECIST at 6 months (week 24), 12 months (week 48) and 24-month (week 96) considering date of inclusion estimated through Kaplan-Meier method |
| Overall Survival | Throughout the study period, up to approximately 24 months | Calculated as the time from date of inclusion to date of death due to any cause. |
| Duration of Intracranial Response | Throughout the study period, up to approximately 24 months | Calculated as the time from the date of first documented CR or PR to the first documented intracranial progression or death due to underlying cancer accoridng to modified RECIST 1.1, in patients with documented intracranial CR or PR before local treatment. |
| Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | Throughout the study period, up to approximately 24 months | Number of patients experiencing treatment related adverse events. These events were graded accrding to CTCAE, a scale that ranges from 0 (less intense; no event) to 5 (death) . Here we report the number of patients experiencing any grade toxicities and the number of patients experiencing high grade (grade 3-5) toxicities. |
| Change on Quality of Life at Week 8 in Both Cohorts Based on the EORTC QLQ 30 Scale | 8 weeks | The EORTC QLQ-C30 questionnaire is validated for cancer. It is composed of 30 questions or items that assess QoL. The questionnaire is structured in 5 functional scales physical functioning, daily activities, emotional functioning, cognitive functioning and social functioning), 3 symptom scales (fatigue, pain and nausea, vomiting), 1 global health status scale, and 6 independent items (dyspnea, insomnia, anorexia, constipation, diarrhea and economic impact). Values between 1 and 4 (1: not at all, 2: a little, 3: quite, 4: a lot) are assigned according to the patient's responses to the item, only in items 29 and 30 are they evaluated with a score of 1 to 7 (1: dreadful, 7: excellent). The scores obtained are standardized and a score between 0 and 100 is obtained, which determines the level of impact of the cancer on the patient on each of the scales. Higher values indicate better performance |
| Change on Quality of Life at Week 24 in Both Cohorts Based on the EORTC QLQ 30 Scale | 24 weeks | The EORTC QLQ-C30 questionnaire is validated for cancer. It is composed of 30 questions or items that assess QoL. The questionnaire is structured in 5 functional scales physical functioning, daily activities, emotional functioning, cognitive functioning and social functioning), 3 symptom scales (fatigue, pain and nausea, vomiting), 1 global health status scale, and 6 independent items (dyspnea, insomnia, anorexia, constipation, diarrhea and economic impact). Values between 1 and 4 (1: not at all, 2: a little, 3: quite, 4: a lot) are assigned according to the patient's responses to the item, only in items 29 and 30 are they evaluated with a score of 1 to 7 (1: dreadful, 7: excellent). The scores obtained are standardized and a score between 0 and 100 is obtained, which determines the level of impact of the cancer on the patient on each of the scales. Higher values indicate better performance |
| Extracranial Progression-free Rates | at 6 months (week 24), 12 months (week 48) and 24-month (week 96) | Proportion of patients free of extracranial progression assessed by modified RECIST at 6 months (week 24), 12 months (week 48) and 24-month (week 96) considering date of inclusion estimated through Kaplan-Meier method |
| Overall Survival Rates | at 6 months, 12 month and 24-month | Proportion of of patients alive at 6 months, 12 month and 24-month considering date of inclusion estimated using Kaplan-Meier. Patients alive at the moment of the analysis were censored on the date of their last follow-up. |
Countries
Spain
Participant flow
Recruitment details
the initial sample size was set at 48 patients, to ensure obtaining 38 evaluable patients. The cohort of symptomatic patients was exploratory and no formal sample calculation was performed, anticipating the inclusion of up to 15 patients.The trial was amended and patients were included irrespective of symptomatology.
Participants by arm
| Arm | Count |
|---|---|
| COMBO450 Encorafenib - Orally, 75 mg and 50 mg capsules Binimetinib - Orally, 15 mg tablets
In each cohort, patients will be treated with encorafenib 450 mg once daily and binimetinib 45 mg twice daily until PD or death.
encorafenib: Encorafenib 75mg and 50mg (capsules) for a 450mg daily for oral administration during 56 days and after local radiation treatment.
If no progression of disease progression (PD) is reported, treatment will continue until PD, unacceptable toxicity or death.
binimetinib: Binimetinib 15mg (tablets) for a 45mg/12 hours for oral administration during 56 days and after local radiation treatment.
Whole brain radiation therapy: The whole brain planning target volume (PTV) will receive 30 Gy in 10 fractions.
Treatment will be delivered once daily, 5 fractions per week, over 2 to 2.5 weeks.
Radiosurgery/stereotactic radiosurgery: Dose selection must be based on previously published Radiation Therapy Oncology Group (RTOG) data, with dose modification left up to the treating physician. The total dose will depend on the size of the metastatic lesion(s) and proximity to critical structures.
Suggested doses are as follow: 1 fraction x 15-25 Gy; 3 fractions x 9-11 Gy; 5 fractions x 6-7 Gy; or 6 fractions x 5-6 Gy.
For GTV \> 20 mm hypofractionated stereotactic radiotherapy could be preferred. Treatment will be delivered once daily, alternate-day, 3 fractions per week. | 48 |
| Total | 48 |
Baseline characteristics
| Characteristic | COMBO450 | — |
|---|---|---|
| Age, Continuous | 54 years | — |
| Barthel Index Moderate dependent (13-18) | 6 Participants | — |
| Barthel Index NA | 2 Participants | — |
| Barthel Index Severe dependent (5-12) | 4 Participants | — |
| Barthel Index Slight dependent (19-20) | 33 Participants | — |
| Barthel Index Total dependent (0-4) | 3 Participants | — |
| BRAF genotype V600E Mutated | 41 Participants | — |
| BRAF genotype V600E Not mutated | 7 Participants | — |
| BRAF genotype V600K Mutated | 11 Participants | — |
| BRAF genotype V600K Not mutated | 37 Participants | — |
| BRAF genotype V600 other Mutated | 25 Participants | — |
| BRAF genotype V600 other Not mutated | 23 Participants | — |
| BRAF genotype V600R Mutated | 6 Participants | — |
| BRAF genotype V600R Not mutated | 42 Participants | — |
| Brain symptoms Asymptomatic | 25 Participants | — |
| Brain symptoms Symptomatic | 23 Participants | — |
| Corticosteroid dose | 8 milligram per day | — |
| Corticosteroids use at baseline No | 15 Participants | — |
| Corticosteroids use at baseline Yes | 33 Participants | — |
| Eastern cooperative oncology group (ECOG) performance status (PS) at baseline Score 0 | 26 Participants | — |
| Eastern cooperative oncology group (ECOG) performance status (PS) at baseline Score 1 | 20 Participants | — |
| Eastern cooperative oncology group (ECOG) performance status (PS) at baseline Score 2 | 2 Participants | — |
| Extracranial metastases No | 7 Participants | — |
| Extracranial metastases Yes | 41 Participants | — |
| Lactate dehydrogenase (LDH) levels > ULN | 21 Participants | — |
| Lactate dehydrogenase (LDH) levels Unknown | 1 Participants | — |
| Lactate dehydrogenase (LDH) levels ≤ upper limit normal (ULN) | 26 Participants | — |
| Number of brain target lesion 1 intracranial lesion | 21 Participants | — |
| Number of brain target lesion 2 intracranial lesions | 15 Participants | — |
| Number of brain target lesion 3 or more intracranial lesions | 12 Participants | — |
| Previous anti-PD-1 based immunotherapy Anti PD-1 | 11 Participants | — |
| Previous anti-PD-1 based immunotherapy Anti PD-1 / anti CTLA-4 | 5 Participants | — |
| Previous anti-PD-1 based immunotherapy No previous PD-L1 | 32 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Radiotherapy received in the EBRAIN trial Fractioned stereotactic radiotherapy (FSRT) | 6 Participants | — |
| Radiotherapy received in the EBRAIN trial None | 17 Participants | — |
| Radiotherapy received in the EBRAIN trial Radiosurgery (RS) | 10 Participants | — |
| Radiotherapy received in the EBRAIN trial Whole brain radiotherapy (WBRT) | 15 Participants | — |
| Region of Enrollment Spain | 48 participants | — |
| Sex: Female, Male Female | 24 Participants | — |
| Sex: Female, Male Male | 24 Participants | — |
| Sum of longest diameters of intracranial target lesions | 26.5 millimeters | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 33 / 48 |
| other Total, other adverse events | 48 / 48 |
| serious Total, serious adverse events | 22 / 48 |
Outcome results
Primary
Intracranial Objective Response (iORR) by Modified RECIST 1.1 Before Local Radiotherapy Treatment in Full Dataset
iORR calculated as the proportion of patient with a best overall intracranial response of complete response (CR) or partial response (PR) before local treatment according to modified RECIST 1.1. Modified RECIST 1.1 consists of: Up to 5 intracranial lesions could be selected as target lesions Target lesions might have a longest diameter ≥ 5 mm when evaluated by contrast-enhanced MRI This endpoint was also independently reported in patients with symptomatic and asymptomatic brain metastasis.
Time frame: 24 months after start of treatment
Population: The endpoint is calculated for the full dataset and also in two subgroups with symptomatic or asymptomatic brain metastasis, respectively.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| COMBO450 | Intracranial Objective Response (iORR) by Modified RECIST 1.1 Before Local Radiotherapy Treatment in Full Dataset | Full analysis set | Patients with intracranial response | 34 Participants |
| COMBO450 | Intracranial Objective Response (iORR) by Modified RECIST 1.1 Before Local Radiotherapy Treatment in Full Dataset | Full analysis set | Patients with NO intracranial response | 13 Participants |
| COMBO450 | Intracranial Objective Response (iORR) by Modified RECIST 1.1 Before Local Radiotherapy Treatment in Full Dataset | Full analysis set | Not evaluable | 1 Participants |
| COMBO450 | Intracranial Objective Response (iORR) by Modified RECIST 1.1 Before Local Radiotherapy Treatment in Full Dataset | Asymptomatic brain metastasis | Patients with intracranial response | 20 Participants |
| COMBO450 | Intracranial Objective Response (iORR) by Modified RECIST 1.1 Before Local Radiotherapy Treatment in Full Dataset | Asymptomatic brain metastasis | Patients with NO intracranial response | 5 Participants |
| COMBO450 | Intracranial Objective Response (iORR) by Modified RECIST 1.1 Before Local Radiotherapy Treatment in Full Dataset | Asymptomatic brain metastasis | Not evaluable | 0 Participants |
| COMBO450 | Intracranial Objective Response (iORR) by Modified RECIST 1.1 Before Local Radiotherapy Treatment in Full Dataset | Symptomatic brain metastasis | Patients with intracranial response | 14 Participants |
| COMBO450 | Intracranial Objective Response (iORR) by Modified RECIST 1.1 Before Local Radiotherapy Treatment in Full Dataset | Symptomatic brain metastasis | Patients with NO intracranial response | 8 Participants |
| COMBO450 | Intracranial Objective Response (iORR) by Modified RECIST 1.1 Before Local Radiotherapy Treatment in Full Dataset | Symptomatic brain metastasis | Not evaluable | 1 Participants |
Secondary
Change on Quality of Life at Week 24 in Both Cohorts Based on the EORTC QLQ 30 Scale
The EORTC QLQ-C30 questionnaire is validated for cancer. It is composed of 30 questions or items that assess QoL. The questionnaire is structured in 5 functional scales physical functioning, daily activities, emotional functioning, cognitive functioning and social functioning), 3 symptom scales (fatigue, pain and nausea, vomiting), 1 global health status scale, and 6 independent items (dyspnea, insomnia, anorexia, constipation, diarrhea and economic impact). Values between 1 and 4 (1: not at all, 2: a little, 3: quite, 4: a lot) are assigned according to the patient's responses to the item, only in items 29 and 30 are they evaluated with a score of 1 to 7 (1: dreadful, 7: excellent). The scores obtained are standardized and a score between 0 and 100 is obtained, which determines the level of impact of the cancer on the patient on each of the scales. Higher values indicate better performance
Time frame: 24 weeks
Population: Only patients who completed the quality of life questionnaires
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| COMBO450 | Change on Quality of Life at Week 24 in Both Cohorts Based on the EORTC QLQ 30 Scale | Week 24 | 74.9 Score |
| COMBO450 | Change on Quality of Life at Week 24 in Both Cohorts Based on the EORTC QLQ 30 Scale | Baseline | 78.4 Score |
Comparison: Comparison between baseline and W24p-value: 0.754Wilcoxon (Mann-Whitney)
Secondary
Change on Quality of Life at Week 8 in Both Cohorts Based on the EORTC QLQ 30 Scale
The EORTC QLQ-C30 questionnaire is validated for cancer. It is composed of 30 questions or items that assess QoL. The questionnaire is structured in 5 functional scales physical functioning, daily activities, emotional functioning, cognitive functioning and social functioning), 3 symptom scales (fatigue, pain and nausea, vomiting), 1 global health status scale, and 6 independent items (dyspnea, insomnia, anorexia, constipation, diarrhea and economic impact). Values between 1 and 4 (1: not at all, 2: a little, 3: quite, 4: a lot) are assigned according to the patient's responses to the item, only in items 29 and 30 are they evaluated with a score of 1 to 7 (1: dreadful, 7: excellent). The scores obtained are standardized and a score between 0 and 100 is obtained, which determines the level of impact of the cancer on the patient on each of the scales. Higher values indicate better performance
Time frame: 8 weeks
Population: Only patients who completed the quality of life questionnaires
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| COMBO450 | Change on Quality of Life at Week 8 in Both Cohorts Based on the EORTC QLQ 30 Scale | Week 8 | 85.5 Score |
| COMBO450 | Change on Quality of Life at Week 8 in Both Cohorts Based on the EORTC QLQ 30 Scale | Baseline | 78.4 Score |
Comparison: Comparison between baseline and Week 8p-value: 0.015Wilcoxon (Mann-Whitney)
Secondary
Duration of Intracranial Response
Calculated as the time from the date of first documented CR or PR to the first documented intracranial progression or death due to underlying cancer accoridng to modified RECIST 1.1, in patients with documented intracranial CR or PR before local treatment.
Time frame: Throughout the study period, up to approximately 24 months
Population: Only patients who have an intracranial responses were analyzed for its duration.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| COMBO450 | Duration of Intracranial Response | 5.6 months |
Secondary
Extracranial Progression-free Rates
Proportion of patients free of extracranial progression assessed by modified RECIST at 6 months (week 24), 12 months (week 48) and 24-month (week 96) considering date of inclusion estimated through Kaplan-Meier method
Time frame: at 6 months (week 24), 12 months (week 48) and 24-month (week 96)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| COMBO450 | Extracranial Progression-free Rates | 6 months | 64.1 Percentage of patients free of PD |
| COMBO450 | Extracranial Progression-free Rates | 12 months | 31.2 Percentage of patients free of PD |
| COMBO450 | Extracranial Progression-free Rates | 24 months | 5.8 Percentage of patients free of PD |
Secondary
Extracranial Progression-free Survival (ePFS) in Both Cohorts
Defined as the time from the date of inclusion to the date of the first documented extracranial disease progression or death due to any cause, whichever occurs first. PFS was determined based on tumor assessment (RECIST version 1.1 criteria). The local Investigator's assessments was used for analyses. Those patients who were alive and had not progressed at the last follow-up, date of progression was censored at the date of the last follow-up. Patients with no additional image test other than baseline were censored the day after inclusion.
Time frame: Throughout the study period, up to approximately 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| COMBO450 | Extracranial Progression-free Survival (ePFS) in Both Cohorts | 7.7 months |
Secondary
Intracranial Progression-free Rates
Proportion of patients free of intracranial progression assessed by modified RECIST at 6 months (week 24), 12 months (week 48) and 24-month (week 96) considering date of inclusion estimated through Kaplan-Meier method
Time frame: at 6 months (week 24), 12 months (week 48) and 24-month (week 96)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| COMBO450 | Intracranial Progression-free Rates | 12 months | 29.5 Percentage of patients free of PD |
| COMBO450 | Intracranial Progression-free Rates | 24 months | 5.5 Percentage of patients free of PD |
| COMBO450 | Intracranial Progression-free Rates | 6 months | 66.8 Percentage of patients free of PD |
Secondary
Intracranial Progression-free Survival (iPFS) by RECIST 1.1
Defined as the time from the date of inclusion to the date of the first documented intracranial disease progression or death due to any cause, whichever occurs first. PFS was determined based on tumor assessment (modified RECIST version 1.1 criteria). The local Investigator's assessments was used for analyses. Those patients who were alive and had not progressed at the last follow-up, date of progression was censored at the date of the last follow-up. Patients with no additional image test other than baseline were censored the day after inclusion.
Time frame: Throughout the study period, up to approximately 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| COMBO450 | Intracranial Progression-free Survival (iPFS) by RECIST 1.1 | 8.5 months |
Secondary
Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0
Number of patients experiencing treatment related adverse events. These events were graded accrding to CTCAE, a scale that ranges from 0 (less intense; no event) to 5 (death) . Here we report the number of patients experiencing any grade toxicities and the number of patients experiencing high grade (grade 3-5) toxicities.
Time frame: Throughout the study period, up to approximately 24 months
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| COMBO450 | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | Any grade toxicities | Experienced Toxicity | 40 Participants |
| COMBO450 | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | Any grade toxicities | Do NOT experienced toxicity | 8 Participants |
| COMBO450 | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | Grade 3-5 toxicities | Experienced Toxicity | 12 Participants |
| COMBO450 | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | Grade 3-5 toxicities | Do NOT experienced toxicity | 36 Participants |
Secondary
Overall Survival
Calculated as the time from date of inclusion to date of death due to any cause.
Time frame: Throughout the study period, up to approximately 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| COMBO450 | Overall Survival | 15.9 months |
Secondary
Overall Survival Rates
Proportion of of patients alive at 6 months, 12 month and 24-month considering date of inclusion estimated using Kaplan-Meier. Patients alive at the moment of the analysis were censored on the date of their last follow-up.
Time frame: at 6 months, 12 month and 24-month
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| COMBO450 | Overall Survival Rates | 6 months | 91.6 Percentage of patients alive |
| COMBO450 | Overall Survival Rates | 12 months | 59.2 Percentage of patients alive |
| COMBO450 | Overall Survival Rates | 24 months | 15.5 Percentage of patients alive |