Ignite Creation Date:
2024-05-06 @ 3:47 PM
Last Modification Date:
2024-10-26 @ 1:56 PM
Study NCT ID:
NCT04750928
Status:
RECRUITING
Last Update Posted:
2024-07-15
First Post:
2021-02-10
Brief Title:
Cyclin-Dependent Kinase CDK46 Inhibitor Abemaciclib for Neurofibromatosis Type I NF1 Related Atypical Neurofibromas
Sponsor:
National Cancer Institute NCI
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
A Phase 0III Study of the Cyclin-Dependent KinaseCDK46 Inhibitor Abemaciclib for Neurofibromatosis Type 1 NF1 Related Atypical Neurofibromas
Status:
RECRUITING
Status Verified Date:
2024-10-16
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:
Background
NF1 is a genetic disease that causes tumors called atypical neurofibromas These tumors which arise from nerves can cause serious medical problems The only treatment is surgery Researchers want to see if a drug called abemaciclib can help
Objective
To find a safe tolerable dose of abemaciclib for treating atypical neurofibromas
Eligibility
People ages 12 and older who have NF1 and have one or more atypical neurofibromas that cannot or will not be removed with surgery
Design
Participants will be screened with
Medical history and physical exam
Blood urine and heart tests
MRI Participants will lie in a machine that takes pictures of the body A padding or coil will be placed around their head They may have a contrast agent injected into a vein
Biopsy sample A small piece of tumor will be removed using a large needle
Participants will have frequent visits during the study These will include repeats of the screening tests as well as the following
PET scan Participants will lie in a machine that takes pictures of the body They will have a contrast agent injected into their arm
Questionnaires about the effects of abemaciclib on pain and quality of life
Possible photographs of tumors
Participants will take abemaciclib capsules orally twice daily in 28-day cycles They will take the drug for up to 2 years Some may be able to take it for longer
Participants will have a follow-up visit about 30 days after their last dose of the study drug Then they will have visits every 3 months for 1 year
NF1 is a genetic disease that causes tumors called atypical neurofibromas These tumors which arise from nerves can cause serious medical problems The only treatment is surgery Researchers want to see if a drug called abemaciclib can help
Objective
To find a safe tolerable dose of abemaciclib for treating atypical neurofibromas
Eligibility
People ages 12 and older who have NF1 and have one or more atypical neurofibromas that cannot or will not be removed with surgery
Design
Participants will be screened with
Medical history and physical exam
Blood urine and heart tests
MRI Participants will lie in a machine that takes pictures of the body A padding or coil will be placed around their head They may have a contrast agent injected into a vein
Biopsy sample A small piece of tumor will be removed using a large needle
Participants will have frequent visits during the study These will include repeats of the screening tests as well as the following
PET scan Participants will lie in a machine that takes pictures of the body They will have a contrast agent injected into their arm
Questionnaires about the effects of abemaciclib on pain and quality of life
Possible photographs of tumors
Participants will take abemaciclib capsules orally twice daily in 28-day cycles They will take the drug for up to 2 years Some may be able to take it for longer
Participants will have a follow-up visit about 30 days after their last dose of the study drug Then they will have visits every 3 months for 1 year
Detailed Description:
Background
Neurofibromatosis type 1 NF1 is a genetic tumor predisposition syndrome incidence of 13000 which results in the development of progressive tumor and non-tumor manifestations the majority of which have no effective medical therapies 25-50 of individuals with neurofibromatosis type 1 NF1 develop histologically benign plexiform neurofibromas PN which can cause substantial morbidity Recently the POB identified that MEK inhibitors cause shrinkage of the majority of PN and that PN shrinkage is associated with clinical benefit
A natural history study of NF1 at the NCI has gathered comprehensive imaging information using longitudinal whole-body MRI with volumetric measurements By this approach distinct nodular lesions DNL were identified many of which are atypical neurofibromas ANF based on pathology review
The NCI POB and others have described ANF as precursor lesions for aggressive soft tissue sarcomas called malignant peripheral nerve sheath tumors MPNST which show poor response to chemotherapy and have poor survival Of note ANF appear to be less responsive to treatment with MEK inhibitors indicating a different biology
Exome sequencing of 16 ANF resected at the National Cancer Institute Pediatric Oncology Branch NCI POB and Belgium revealed that 90 of the cases had heterozygous loss of CDKN2AB as the only new somatic change in addition to biallelic NF1 deletion consistent with prior reports These results demonstrate that transformation of NF1 nerve tumors may genetically proceed through the premalignant ANF by a common mechanism that might be a point of intervention
CDKN2A is the primary inhibitory brake on CDK46 driven signaling and is commonly deleted in glioblastoma pancreas bladder breast and prostate cancer The specific CDK46 inhibitor abemaciclib has FDA approval for the treatment of metastatic breast cancer
ANF is a prototypic premalignant lesion for testing experimental intervention as these lesions are at risk for transformation and share a common potentially druggable genomic alteration CDKN2AB deletion We propose a clinical trial of abemaciclib in children and adults with NF1 and unresectable ANF
Objectives
Phase 0 To determine the pharmacodynamic effect of 7-10 days of abemaciclib treatment prior to tumor resection on levels of phosphorylated Retinoblastoma pRb
Phase I To determine the recommended Phase II dose RP2D of abemaciclib in participants with NF1 and a measurable ANF
Phase II To determine the objective response rate ORR in the target ANF complete and partial response CR PR response determined by volumetric MRI analysis 20 volume reduction compared to baseline
Eligibility
Participants must be at least 12 years of age with a diagnosis of NF1 with associated agerelated requirements as follows
Willingness of participants 12 years old and 18 years old to undergo pretreatment percutaneous biopsy of ANF if deemed feasible with minimal morbidity
Willingness of participants 18 years old to undergo pre-treatment and ontreatment percutaneous biopsy of ANF if deemed feasible with minimal morbidity
Phase 0 Only
Age 18 years old
Presence of 1 measurable ANF biopsy confirmed for which surgical removal at the NIH would not likely cause significant morbidity and is clinically indicated
Phase III Only
--Presence of 1 measurable ANF biopsy confirmed for which surgical removal could cause significant morbidity OR for which participant is unwilling to undergo surgical resection OR the presence of more than one distinct nodular lesion DNL including at least 1 biopsy proven ANF
For participants of all ages with ANF who cannot be safely biopsied with minimal morbidity biopsy requirement to be performed at NIH Clinical Center will be waived from eligibility criteria In this case review of available archival tissue by NIH Pathology will be necessary to confirm diagnosis of ANF which is mandatory for eligibility
Design
This is a Phase 0III non-randomized open label single institution study of the CDK46 inhibitor abemaciclib in children and adults with NF1 and a measurable ANF or with multiple ANFDNL
The accrual ceiling will be set at 55 eligible participants to include participants who are screened but found to not be eligible to undergo treatment
Phase 0 For participants with a biopsy-proven ANF that can be removed without significant anticipated clinical morbidity and where resection of the ANF is clinically indicated
Participants will receive abemaciclib at the same dose level and schedule as the Phase III portion at the time of enrollment for at least 7 days and no more than 10 days immediately prior to tumor resection
Tumor will be fully resected as per clinical care and participants will discontinue study drug
Participants will be followed for 30 days post-treatment or until resolution to grade 1 of any abemaciclib-related adverse events
The phase 0 study will have a 2-stage design with 3 participants in the first stage and an expansion to a total of 5 participants if at least one of the initial 3 participants achieves a pharmacodynamic response
Phase III For participants with a biopsy-proven ANF for which surgical removal could cause significant morbidity OR for which participant is unwilling to undergo surgical resection OR the presence of more than one distinct nodular lesion DNL
Primarily because the tolerability of investigational agents may differ between the NF1 population and non-NF1 population and secondarily because abemaciclib has not been evaluated in children to date there will be a limited dose finding phase
During the Phase 1 portion of the trial the first 6 participants enrolled will be treated at 75 of the adult recommended Phase II dose ARP2D 150mg PO BID of abemaciclib used in participants with malignancies in a 28-day cycle For participants 18 years of age dosing will be based on body surface area BSA
Cohorts of up to 6 participants will be enrolled with dose adjustment depending on dose-limiting toxicities DLT until the maximum tolerated dose MTD recommended Phase II dose RP2D is established
The Phase II trial is a Simon minimax two-stage trial design An observed response rate of approximately 30 or greater would be considered desirable The first stage of the Phase II portion of the trial will enroll 15 evaluable participants if 0 to 2 of the 15 have a PR or CR then no further participants will be accrued If 3 or more of the 15 participants have a PR or CR then accrual would continue until a total of 21 evaluable participants have been enrolled in phase II
All participants will undergo careful toxicity monitoring Restaging MRI for response will be performed pre-cycles 3 and 5 and then every 4 cycles for remainder of the first year
Neurofibromatosis type 1 NF1 is a genetic tumor predisposition syndrome incidence of 13000 which results in the development of progressive tumor and non-tumor manifestations the majority of which have no effective medical therapies 25-50 of individuals with neurofibromatosis type 1 NF1 develop histologically benign plexiform neurofibromas PN which can cause substantial morbidity Recently the POB identified that MEK inhibitors cause shrinkage of the majority of PN and that PN shrinkage is associated with clinical benefit
A natural history study of NF1 at the NCI has gathered comprehensive imaging information using longitudinal whole-body MRI with volumetric measurements By this approach distinct nodular lesions DNL were identified many of which are atypical neurofibromas ANF based on pathology review
The NCI POB and others have described ANF as precursor lesions for aggressive soft tissue sarcomas called malignant peripheral nerve sheath tumors MPNST which show poor response to chemotherapy and have poor survival Of note ANF appear to be less responsive to treatment with MEK inhibitors indicating a different biology
Exome sequencing of 16 ANF resected at the National Cancer Institute Pediatric Oncology Branch NCI POB and Belgium revealed that 90 of the cases had heterozygous loss of CDKN2AB as the only new somatic change in addition to biallelic NF1 deletion consistent with prior reports These results demonstrate that transformation of NF1 nerve tumors may genetically proceed through the premalignant ANF by a common mechanism that might be a point of intervention
CDKN2A is the primary inhibitory brake on CDK46 driven signaling and is commonly deleted in glioblastoma pancreas bladder breast and prostate cancer The specific CDK46 inhibitor abemaciclib has FDA approval for the treatment of metastatic breast cancer
ANF is a prototypic premalignant lesion for testing experimental intervention as these lesions are at risk for transformation and share a common potentially druggable genomic alteration CDKN2AB deletion We propose a clinical trial of abemaciclib in children and adults with NF1 and unresectable ANF
Objectives
Phase 0 To determine the pharmacodynamic effect of 7-10 days of abemaciclib treatment prior to tumor resection on levels of phosphorylated Retinoblastoma pRb
Phase I To determine the recommended Phase II dose RP2D of abemaciclib in participants with NF1 and a measurable ANF
Phase II To determine the objective response rate ORR in the target ANF complete and partial response CR PR response determined by volumetric MRI analysis 20 volume reduction compared to baseline
Eligibility
Participants must be at least 12 years of age with a diagnosis of NF1 with associated agerelated requirements as follows
Willingness of participants 12 years old and 18 years old to undergo pretreatment percutaneous biopsy of ANF if deemed feasible with minimal morbidity
Willingness of participants 18 years old to undergo pre-treatment and ontreatment percutaneous biopsy of ANF if deemed feasible with minimal morbidity
Phase 0 Only
Age 18 years old
Presence of 1 measurable ANF biopsy confirmed for which surgical removal at the NIH would not likely cause significant morbidity and is clinically indicated
Phase III Only
--Presence of 1 measurable ANF biopsy confirmed for which surgical removal could cause significant morbidity OR for which participant is unwilling to undergo surgical resection OR the presence of more than one distinct nodular lesion DNL including at least 1 biopsy proven ANF
For participants of all ages with ANF who cannot be safely biopsied with minimal morbidity biopsy requirement to be performed at NIH Clinical Center will be waived from eligibility criteria In this case review of available archival tissue by NIH Pathology will be necessary to confirm diagnosis of ANF which is mandatory for eligibility
Design
This is a Phase 0III non-randomized open label single institution study of the CDK46 inhibitor abemaciclib in children and adults with NF1 and a measurable ANF or with multiple ANFDNL
The accrual ceiling will be set at 55 eligible participants to include participants who are screened but found to not be eligible to undergo treatment
Phase 0 For participants with a biopsy-proven ANF that can be removed without significant anticipated clinical morbidity and where resection of the ANF is clinically indicated
Participants will receive abemaciclib at the same dose level and schedule as the Phase III portion at the time of enrollment for at least 7 days and no more than 10 days immediately prior to tumor resection
Tumor will be fully resected as per clinical care and participants will discontinue study drug
Participants will be followed for 30 days post-treatment or until resolution to grade 1 of any abemaciclib-related adverse events
The phase 0 study will have a 2-stage design with 3 participants in the first stage and an expansion to a total of 5 participants if at least one of the initial 3 participants achieves a pharmacodynamic response
Phase III For participants with a biopsy-proven ANF for which surgical removal could cause significant morbidity OR for which participant is unwilling to undergo surgical resection OR the presence of more than one distinct nodular lesion DNL
Primarily because the tolerability of investigational agents may differ between the NF1 population and non-NF1 population and secondarily because abemaciclib has not been evaluated in children to date there will be a limited dose finding phase
During the Phase 1 portion of the trial the first 6 participants enrolled will be treated at 75 of the adult recommended Phase II dose ARP2D 150mg PO BID of abemaciclib used in participants with malignancies in a 28-day cycle For participants 18 years of age dosing will be based on body surface area BSA
Cohorts of up to 6 participants will be enrolled with dose adjustment depending on dose-limiting toxicities DLT until the maximum tolerated dose MTD recommended Phase II dose RP2D is established
The Phase II trial is a Simon minimax two-stage trial design An observed response rate of approximately 30 or greater would be considered desirable The first stage of the Phase II portion of the trial will enroll 15 evaluable participants if 0 to 2 of the 15 have a PR or CR then no further participants will be accrued If 3 or more of the 15 participants have a PR or CR then accrual would continue until a total of 21 evaluable participants have been enrolled in phase II
All participants will undergo careful toxicity monitoring Restaging MRI for response will be performed pre-cycles 3 and 5 and then every 4 cycles for remainder of the first year
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 21-C-0011 | None | None | None |