Ignite Creation Date:
2024-05-06 @ 3:56 AM
Last Modification Date:
2024-10-26 @ 11:41 AM
Study NCT ID:
NCT02419287
Status:
COMPLETED
Last Update Posted:
2023-03-06
First Post:
2015-04-03
Brief Title:
Pilot Study of Crizotinib in Relapsed ALK Lymphomas
Sponsor:
University of Milano Bicocca
Organization:
University of Milano Bicocca
Study Overview
Official Title:
Pilot Study of Crizotinib in Relapsed ALK Lymphomas
Status:
COMPLETED
Status Verified Date:
2023-03
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:
The purpose of this study is to determine the response and the duration of it in patients affected by ALK lymphoma that are resistant or refractory to standard cytotoxic treatment that will be treated with crizotinib
Detailed Description:
Study Rationale
Crizotinib is a selective ATP-competitive small-molecule inhibitor of the c-MetHGFR and ALK receptor tyrosine kinases and their oncogenic variants eg c-MetHGFR mutations or NPM-ALK fusion protein Consistent with this mechanism of action Crizotinib inhibited phosphorylation of c-MetHGFR and NPM-ALK and their kinase target dependent functions in tumour cells both in vitro and in vivo This compound will be clinically evaluated in oncology indications in which c-MetHGFR or NPM-ALK are dysregulated including but not limited to renal lung gastric brain prostate head and neck cancers multiple myeloma and selected lymphomas Crizotinib demonstrated preclinical antitumour activity including marked cytoreduction in several tumour models that expressed activated c-MetHGFR or NPM-ALK supporting the rationale for study in clinical trials Collective PKPD modelling and efficacy data demonstrated that
1 near complete inhibition free plasma IC90 of c-MetHGFR activity during the entire dosing interval was necessary to achieve robust antitumour effect as it was demonstrated several years ago for imatinib
2 the target efficacious free plasma concentration range was determined to be 81 to 128 nM 37 to 58 ngmL The projected efficacious dose in humans is estimated to be 70 to 100 mg once daily
Additional safety and efficacy data presented at the 2010 ASCO meeting Tan et al Bang et al confirmed these data plasma concentrations exceeding efficacious levels were obtained in patients receiving at least 100 mgday of crizotinib in addition objective tumour regressions were observed in 50 of 82 advanced lung cancer patients whose tumours were positive for the EML4ALK fusion Therefore the treatment of ALK lymphomas with crizotinib represents a rational attempt at treating a human cancer through the inactivation of its oncogenic mechanism
When administered to 11 patients affected by relapsed resistant ALK lymphomas crizotinib obtained an Overall Response Rate ORR of 1011 91 which included 9 Complete Responses CR 82 and 1 Partial Response Disease status at the latest follow-up June 2013 is as follows 4 CR months 17 26 31 36 and 3 deaths due to progression 1 patient in CR after crizotinib who received alloBMT and 2 patients treated post alloBMT are still in CR but they stopped crizotinib 1 patient is in CR under brentuximab Progression Free Survival PSF and Overall Survival rates at 3 years are 636 and 727 Crizotinib exerted a potent antitumor activity in advanced ALK lymphoma and produced durable responses in this population of heavily pre-treated patients In addition this study demonstrated that PCR-based detection of the NPM-ALK fusion in the peripheral blood may be an effective method to monitor disease response and progression
Although crizotinib shows activity relapses occur typically within 5 months after starting treatment and were supported by mutations like I1171N
Objectives Primary Define the objective response rates ORR and duration of it in subjects with ALK lymphomas resistant or refractory to standard cytotoxic treatment according to RECIST 11 criteria
Secondary
Define progression free survival PFS and overall survival OS in ALK lymphoma patients treated with crizotinib that are resistant or refractory to standard cytotoxic treatment Determine the toxicity profile of crizotinib in ALK lymphoma patients resistant or refractory to standard cytotoxic treatment
Determine the Quality of Life QoL in this population of patients using the the EORTC - C30 Quality of Life questionnaire
Study the molecular mechanism of resistance to crizotinib
Study design This is a phase II study open to 12 eligible patients with anaplastic large cell lymphoma with a confirmed ALK rearrangement Enrollment will start in February 2015 and it will last 24 months
All patients must have been pretreated with at least one line of standard cytotoxic chemotherapy and they must have demonstrated progression regardless of initial response on the last treatment
Subject selection Before any clinical procedure patients will sign the Informed Consent Every patients included in this protocols will have to respect all inclusionexclusion criteria
Study procedure The study begins with a screening period to assess eligibility up to and including 28 days prior to the first dose of crizotinib The treatment period begins on Day 1 of Cycle 1 Assessments of tumor response will be performed after 1 month 2 months only Q-RT-PCR for NPMALK 3 months and then every 12 weeks starting from the first day of treatment with crizotinib After 1 year of treatment assessments will be collected every six months From the beginning of the third year assessments will be performed yearly till the end of the study Clinical laboratory assessments Quantitative Real-Time PCR Q-RT-PCR and tumor imaging will be performed as described in Appendix 1
Treatment will continue until patient experiences unacceptable toxicity or progressive disease PD starts a new anti-cancer therapy or dies
When the patient discontinues from study treatment an EOT visit must be performed within 7 days of the last dose of crizotinib Patients will be contacted for the safety with a follow-up 30 days after their last dose of crizotinib
During the follow up phase patients will be contacted once a year to obtain information pertaining to survival status until death loss to follow-up withdrawal of consent to survival follow-up or the end of the study Patients do not need to visit the clinic during the survival follow-up
Study Treatment Patients will receive crizotinib at the dose of 250 mg BID administered orally Crizotinib will be taken at approximately the same time each day
In case of toxicity it is possible to proceed to a dose reduction or a temporary interruption of crizotinib according with the attached table Appendix 2
No dose escalation is scheduled The metabolism of crizotinib is predominantly mediated by the CYP3A isozymes in human liver microsomes and hepatocytes Co-administration with drugs that are CYP3A inhibitors and inducers may change plasma concentration of crizotinib in humans Concomitant use of potent CYP3A inhibitors or inducers are not allowed
Crizotinib is a selective ATP-competitive small-molecule inhibitor of the c-MetHGFR and ALK receptor tyrosine kinases and their oncogenic variants eg c-MetHGFR mutations or NPM-ALK fusion protein Consistent with this mechanism of action Crizotinib inhibited phosphorylation of c-MetHGFR and NPM-ALK and their kinase target dependent functions in tumour cells both in vitro and in vivo This compound will be clinically evaluated in oncology indications in which c-MetHGFR or NPM-ALK are dysregulated including but not limited to renal lung gastric brain prostate head and neck cancers multiple myeloma and selected lymphomas Crizotinib demonstrated preclinical antitumour activity including marked cytoreduction in several tumour models that expressed activated c-MetHGFR or NPM-ALK supporting the rationale for study in clinical trials Collective PKPD modelling and efficacy data demonstrated that
1 near complete inhibition free plasma IC90 of c-MetHGFR activity during the entire dosing interval was necessary to achieve robust antitumour effect as it was demonstrated several years ago for imatinib
2 the target efficacious free plasma concentration range was determined to be 81 to 128 nM 37 to 58 ngmL The projected efficacious dose in humans is estimated to be 70 to 100 mg once daily
Additional safety and efficacy data presented at the 2010 ASCO meeting Tan et al Bang et al confirmed these data plasma concentrations exceeding efficacious levels were obtained in patients receiving at least 100 mgday of crizotinib in addition objective tumour regressions were observed in 50 of 82 advanced lung cancer patients whose tumours were positive for the EML4ALK fusion Therefore the treatment of ALK lymphomas with crizotinib represents a rational attempt at treating a human cancer through the inactivation of its oncogenic mechanism
When administered to 11 patients affected by relapsed resistant ALK lymphomas crizotinib obtained an Overall Response Rate ORR of 1011 91 which included 9 Complete Responses CR 82 and 1 Partial Response Disease status at the latest follow-up June 2013 is as follows 4 CR months 17 26 31 36 and 3 deaths due to progression 1 patient in CR after crizotinib who received alloBMT and 2 patients treated post alloBMT are still in CR but they stopped crizotinib 1 patient is in CR under brentuximab Progression Free Survival PSF and Overall Survival rates at 3 years are 636 and 727 Crizotinib exerted a potent antitumor activity in advanced ALK lymphoma and produced durable responses in this population of heavily pre-treated patients In addition this study demonstrated that PCR-based detection of the NPM-ALK fusion in the peripheral blood may be an effective method to monitor disease response and progression
Although crizotinib shows activity relapses occur typically within 5 months after starting treatment and were supported by mutations like I1171N
Objectives Primary Define the objective response rates ORR and duration of it in subjects with ALK lymphomas resistant or refractory to standard cytotoxic treatment according to RECIST 11 criteria
Secondary
Define progression free survival PFS and overall survival OS in ALK lymphoma patients treated with crizotinib that are resistant or refractory to standard cytotoxic treatment Determine the toxicity profile of crizotinib in ALK lymphoma patients resistant or refractory to standard cytotoxic treatment
Determine the Quality of Life QoL in this population of patients using the the EORTC - C30 Quality of Life questionnaire
Study the molecular mechanism of resistance to crizotinib
Study design This is a phase II study open to 12 eligible patients with anaplastic large cell lymphoma with a confirmed ALK rearrangement Enrollment will start in February 2015 and it will last 24 months
All patients must have been pretreated with at least one line of standard cytotoxic chemotherapy and they must have demonstrated progression regardless of initial response on the last treatment
Subject selection Before any clinical procedure patients will sign the Informed Consent Every patients included in this protocols will have to respect all inclusionexclusion criteria
Study procedure The study begins with a screening period to assess eligibility up to and including 28 days prior to the first dose of crizotinib The treatment period begins on Day 1 of Cycle 1 Assessments of tumor response will be performed after 1 month 2 months only Q-RT-PCR for NPMALK 3 months and then every 12 weeks starting from the first day of treatment with crizotinib After 1 year of treatment assessments will be collected every six months From the beginning of the third year assessments will be performed yearly till the end of the study Clinical laboratory assessments Quantitative Real-Time PCR Q-RT-PCR and tumor imaging will be performed as described in Appendix 1
Treatment will continue until patient experiences unacceptable toxicity or progressive disease PD starts a new anti-cancer therapy or dies
When the patient discontinues from study treatment an EOT visit must be performed within 7 days of the last dose of crizotinib Patients will be contacted for the safety with a follow-up 30 days after their last dose of crizotinib
During the follow up phase patients will be contacted once a year to obtain information pertaining to survival status until death loss to follow-up withdrawal of consent to survival follow-up or the end of the study Patients do not need to visit the clinic during the survival follow-up
Study Treatment Patients will receive crizotinib at the dose of 250 mg BID administered orally Crizotinib will be taken at approximately the same time each day
In case of toxicity it is possible to proceed to a dose reduction or a temporary interruption of crizotinib according with the attached table Appendix 2
No dose escalation is scheduled The metabolism of crizotinib is predominantly mediated by the CYP3A isozymes in human liver microsomes and hepatocytes Co-administration with drugs that are CYP3A inhibitors and inducers may change plasma concentration of crizotinib in humans Concomitant use of potent CYP3A inhibitors or inducers are not allowed
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