Ignite Creation Date:
2024-05-06 @ 8:11 AM
Last Modification Date:
2024-10-26 @ 11:57 AM
Study NCT ID:
NCT02687958
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2023-05-30
First Post:
2016-02-17
Brief Title:
Study of Everolimus as Maintenance Therapy for Metastatic NEC With Pulmonary or Gastroenteropancreatic Origin
Sponsor:
Gruppo Oncologico Italiano di Ricerca Clinica
Organization:
Gruppo Oncologico Italiano di Ricerca Clinica
Study Overview
Official Title:
Phase II Randomized Multicenter Study of Everolimus as Maintenance Therapy for Metastatic Neuroendocrine Carcinoma With Pulmonary or Gastroenteropancreatic Origin
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2023-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Cisplatin and Etoposide is the standard of care in NEC originating from the gastro-intestinal tract and lung based on retrospective studies
Nevertheless the prognosis of this group of patients is still poor with median survival of less than 20 months
Everolimus is an mammilian target of rapamycin mTOR inhibitor that has been demonstrated to be active in patients with well and moderately differentiated primitive neuroectodermal tumor pNET
Recently the Investigators demonstrated that the mammilian target of rapamycin mTOR pathway is overexpressed in NEC
Based on the activity of Everolimus in the treatment of patients with well and moderately differentiated p-NET and on the evidence that even poorly differentiated forms express the pathway of m-TOR is conceivable that Everolimus could be active even in NEC
Nevertheless the prognosis of this group of patients is still poor with median survival of less than 20 months
Everolimus is an mammilian target of rapamycin mTOR inhibitor that has been demonstrated to be active in patients with well and moderately differentiated primitive neuroectodermal tumor pNET
Recently the Investigators demonstrated that the mammilian target of rapamycin mTOR pathway is overexpressed in NEC
Based on the activity of Everolimus in the treatment of patients with well and moderately differentiated p-NET and on the evidence that even poorly differentiated forms express the pathway of m-TOR is conceivable that Everolimus could be active even in NEC
Detailed Description:
A platinum based chemotherapy Cisplatin or Carboplatin plus Etoposide is the standard of care in NEC originating from the gastro-intestinal tract and lung based on retrospective studies In these clinical studies and in clinical practice the median number of cycle administered is six due to dose depending toxicity of platinum and to the concept of maximum response
The expression of mTOR pathways was evaluated in gastroenteropancreatic - Neuroendocrine tumor GEP-NEC
The Investigator found that 69 67 of poorly differentiated GEP-NEC evaluated expressed p mTOR Interestingly this expression was not observed in small cell carcinoma 10
Recently was demonstrated that the mTOR pathway is overexpressed in NEC 11 Based on the activity of Everolimus in the treatment of patients with well and moderately differentiated p-NET and on the evidence that even poorly differentiated forms express the pathway of m-TOR is conceivable that Everolimus could be active even in NEC In particular we want to test the hypothesis that a maintenance therapy or an early second line with Everolimus 10 mgdaily in non progressive patients after first line chemotherapy could improve outcome prolonging progression free survival PFS
The NORDIC NEC study recently published retrospectively analyzed 305 patients with metastatic GI NEC or unknown primary predominantly with GI metastases
In this large retrospective study patients with Ki-67 55 are less responsive to platinum based chemotherapy but have a longer survival than patients with Ki-67 55 then Ki-67 55 is a positive prognostic factor and a negative predictive factor to platinum based chemotherapy 7
These data indicate that GI-NEC might be not consider as a unique entity even if they are all classified as G3 according to WHO 2010 classification
In this randomized Phase 2 trial the investigator want to evaluate the activity of Everolimus 10 mgdaily as maintenance therapy in patients with NEC and Ki-67 55
In fact this subgroup of NEC patients could benefit mostly from a maintenance treatment with Everolimus 10 mgdaily since they are less chemo responder and they show better prognosis as G1-G2 NET
There is not a standard second line therapy for NEC patients treated with platinum based doublet nevertheless Temozolamide and Capecitabine TX represent a regimen used in this setting based on small and retrospective series 8 Therefore in our study we recommend that all patients at first progression even if out of the study will receive TX Capecitabine 750 mgm2 po BID days 1-14 plus Temozolomide 200 mgm2 po quaque die QD days 10-14 q28 in order to homogenize second line treatment However second line treatment is chosen by single investigators
The aim of this study is to evaluate the activity of a maintenance therapy or early second line with Everolimus 10 mg daily in patients with stable disease partial response or complete response after 6 cycles of induction chemotherapy with Cisplatin or Carboplatin plus Etoposide or alternative first line chemotherapy administered according to clinical practice
The primary endpoint is progression free survival PFS defined as the time between randomization and the first evidence of progressive disease or date of death whichever occurs first Documentation of disease progression will be defined as per Response Evaluation Criteria in Solid Tumors RECIST 11 criteria based on investigator assessment The censoring date for a patient who is known to be progression-free would be the date of the last tumor assessment
Secondary objectives are
Overall survival OS defined as the time from randomization to death from any cause
Safety profile Safety of the treatment will be evaluated by serious and non serious adverse events AEs AEs will be graded according to the Common Toxicity Criteria for Adverse Effects CTCAE v403
Evaluation of prognosticpredictive factors on tumoral tissue of patients treated with maintenance everolimus 10 mgdaily The expression of mTOR and kinases involved in its pathway will be assessed by immunohistochemistry IHC
Detection and count of circulating tumor cells CTCs from peripheral blood samples by VERIDEX and correlation between CTCs number and outcome of patients in terms of PFS and OS
Detection of circulating tumor DNA ctDNA and correlation between ctDNA levels and and outcome of patients in terms of PFS and OS Evaluation of mTOR pathway genes mutations on ctDNA
This study population will comprise subjects diagnosed with GEP-NEC or large-cells neuroendocrine carcinoma of the Lung with Ki67 55 with stable disease partial of complete response after 6 cycles of first line chemotherapy
Adverse Event An AE is any noxious unintended or untoward medical occurrence that may appear or worsen in a subject during the course of a study It may be a new intercurrent illness a worsening concomitant illness an injury or any concomitant impairment of the subjects health including laboratory test values as specified by the criteria below regardless of etiology Any worsening ie any clinically significant adverse change in the frequency or intensity of a preexisting condition should be considered an AE A diagnosis or syndrome should be recorded on the AE page of the case report form CRF rather than the individual signs or symptoms of the diagnosis or syndrome
Disease progression is not to be reported as an AE An overdose accidental or intentional whether or not it is associated with an AE or abuse withdrawal sensitivity or toxicity to an investigational product should be reported as an AE If an overdose is associated with an AE the overdose and adverse event should be reported as separate terms
All subjects will be monitored for AEs during the study Assessments may include monitoring of any or all of the following parameters the subjects clinical symptoms laboratory pathological radiological or surgical findings physical examination findings or other appropriate tests and procedures
All AEs will be recorded by the Investigator from the time the subject signs informed consent to at least 30 days after the last dose of CT or until the last study visit whichever period is longer Adverse Events and serious adverse events SAEs will be recorded on the AE page of the CRF and in the subjects source documents All SAEs must be reported to PIs within 24 hours of the Investigators knowledge of the event by facsimile or other appropriate method using the SAE Report Form or approved equivalent form All SAEs will be also reported to Novartis safety desk within 15 days of learning
Serious adverse events will be summarized
Safety analyses All pats who receive at least 1 dose of study drug will be evaluated for safety and toxicity Adverse event AE terms and severity grades will be assigned by the investigator using CTCAE v 403
Safety analyses will include listings andor summaries of the following
Treatment emergent adverse events TEAEs including seriousness severity and possible relationship to study drug
Dose adjustments
CTCAE grades for laboratory and non laboratory parameters
Number of Patients Thirty pts 20 in experimental arm and 10 in the control arm will be randomized
Statistical method This is an open-label study Patients who meet all inclusionexclusion criteria for enrollment will be allowed to enroll in the study Those patients entering the study during all the trial will be allocated to arm A or arm B Assignment to treatment will be determined prior to Cycle 1 d1 using an interactive response system by mail at a central location Patients will be sequentially allocated to arm A or arm B with a 12 ratio
This is a phase II study not powered for statistical comparison between arm A and B The number of patients is sufficient for an exploratory analysis of the activity of Everolimus as maintenance therapy in this setting of patients Only if the results in this analysis will be encouraging a second step of the study will be powered for a comparison between arm A and B
The expression of mTOR pathways was evaluated in gastroenteropancreatic - Neuroendocrine tumor GEP-NEC
The Investigator found that 69 67 of poorly differentiated GEP-NEC evaluated expressed p mTOR Interestingly this expression was not observed in small cell carcinoma 10
Recently was demonstrated that the mTOR pathway is overexpressed in NEC 11 Based on the activity of Everolimus in the treatment of patients with well and moderately differentiated p-NET and on the evidence that even poorly differentiated forms express the pathway of m-TOR is conceivable that Everolimus could be active even in NEC In particular we want to test the hypothesis that a maintenance therapy or an early second line with Everolimus 10 mgdaily in non progressive patients after first line chemotherapy could improve outcome prolonging progression free survival PFS
The NORDIC NEC study recently published retrospectively analyzed 305 patients with metastatic GI NEC or unknown primary predominantly with GI metastases
In this large retrospective study patients with Ki-67 55 are less responsive to platinum based chemotherapy but have a longer survival than patients with Ki-67 55 then Ki-67 55 is a positive prognostic factor and a negative predictive factor to platinum based chemotherapy 7
These data indicate that GI-NEC might be not consider as a unique entity even if they are all classified as G3 according to WHO 2010 classification
In this randomized Phase 2 trial the investigator want to evaluate the activity of Everolimus 10 mgdaily as maintenance therapy in patients with NEC and Ki-67 55
In fact this subgroup of NEC patients could benefit mostly from a maintenance treatment with Everolimus 10 mgdaily since they are less chemo responder and they show better prognosis as G1-G2 NET
There is not a standard second line therapy for NEC patients treated with platinum based doublet nevertheless Temozolamide and Capecitabine TX represent a regimen used in this setting based on small and retrospective series 8 Therefore in our study we recommend that all patients at first progression even if out of the study will receive TX Capecitabine 750 mgm2 po BID days 1-14 plus Temozolomide 200 mgm2 po quaque die QD days 10-14 q28 in order to homogenize second line treatment However second line treatment is chosen by single investigators
The aim of this study is to evaluate the activity of a maintenance therapy or early second line with Everolimus 10 mg daily in patients with stable disease partial response or complete response after 6 cycles of induction chemotherapy with Cisplatin or Carboplatin plus Etoposide or alternative first line chemotherapy administered according to clinical practice
The primary endpoint is progression free survival PFS defined as the time between randomization and the first evidence of progressive disease or date of death whichever occurs first Documentation of disease progression will be defined as per Response Evaluation Criteria in Solid Tumors RECIST 11 criteria based on investigator assessment The censoring date for a patient who is known to be progression-free would be the date of the last tumor assessment
Secondary objectives are
Overall survival OS defined as the time from randomization to death from any cause
Safety profile Safety of the treatment will be evaluated by serious and non serious adverse events AEs AEs will be graded according to the Common Toxicity Criteria for Adverse Effects CTCAE v403
Evaluation of prognosticpredictive factors on tumoral tissue of patients treated with maintenance everolimus 10 mgdaily The expression of mTOR and kinases involved in its pathway will be assessed by immunohistochemistry IHC
Detection and count of circulating tumor cells CTCs from peripheral blood samples by VERIDEX and correlation between CTCs number and outcome of patients in terms of PFS and OS
Detection of circulating tumor DNA ctDNA and correlation between ctDNA levels and and outcome of patients in terms of PFS and OS Evaluation of mTOR pathway genes mutations on ctDNA
This study population will comprise subjects diagnosed with GEP-NEC or large-cells neuroendocrine carcinoma of the Lung with Ki67 55 with stable disease partial of complete response after 6 cycles of first line chemotherapy
Adverse Event An AE is any noxious unintended or untoward medical occurrence that may appear or worsen in a subject during the course of a study It may be a new intercurrent illness a worsening concomitant illness an injury or any concomitant impairment of the subjects health including laboratory test values as specified by the criteria below regardless of etiology Any worsening ie any clinically significant adverse change in the frequency or intensity of a preexisting condition should be considered an AE A diagnosis or syndrome should be recorded on the AE page of the case report form CRF rather than the individual signs or symptoms of the diagnosis or syndrome
Disease progression is not to be reported as an AE An overdose accidental or intentional whether or not it is associated with an AE or abuse withdrawal sensitivity or toxicity to an investigational product should be reported as an AE If an overdose is associated with an AE the overdose and adverse event should be reported as separate terms
All subjects will be monitored for AEs during the study Assessments may include monitoring of any or all of the following parameters the subjects clinical symptoms laboratory pathological radiological or surgical findings physical examination findings or other appropriate tests and procedures
All AEs will be recorded by the Investigator from the time the subject signs informed consent to at least 30 days after the last dose of CT or until the last study visit whichever period is longer Adverse Events and serious adverse events SAEs will be recorded on the AE page of the CRF and in the subjects source documents All SAEs must be reported to PIs within 24 hours of the Investigators knowledge of the event by facsimile or other appropriate method using the SAE Report Form or approved equivalent form All SAEs will be also reported to Novartis safety desk within 15 days of learning
Serious adverse events will be summarized
Safety analyses All pats who receive at least 1 dose of study drug will be evaluated for safety and toxicity Adverse event AE terms and severity grades will be assigned by the investigator using CTCAE v 403
Safety analyses will include listings andor summaries of the following
Treatment emergent adverse events TEAEs including seriousness severity and possible relationship to study drug
Dose adjustments
CTCAE grades for laboratory and non laboratory parameters
Number of Patients Thirty pts 20 in experimental arm and 10 in the control arm will be randomized
Statistical method This is an open-label study Patients who meet all inclusionexclusion criteria for enrollment will be allowed to enroll in the study Those patients entering the study during all the trial will be allocated to arm A or arm B Assignment to treatment will be determined prior to Cycle 1 d1 using an interactive response system by mail at a central location Patients will be sequentially allocated to arm A or arm B with a 12 ratio
This is a phase II study not powered for statistical comparison between arm A and B The number of patients is sufficient for an exploratory analysis of the activity of Everolimus as maintenance therapy in this setting of patients Only if the results in this analysis will be encouraging a second step of the study will be powered for a comparison between arm A and B
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None