Ignite Creation Date:
2024-05-06 @ 7:00 PM
Last Modification Date:
2024-10-26 @ 2:59 PM
Study NCT ID:
NCT05864742
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2024-05-10
First Post:
2023-05-01
Brief Title:
Genetically Risk-Stratified Venetoclax Ibrutinib Rituximab Navitoclax in RelapsedRefractory Mantle Cell Lymphoma
Sponsor:
Peter MacCallum Cancer Centre Australia
Organization:
Peter MacCallum Cancer Centre Australia
Study Overview
Official Title:
A Phase II Study of Genetically Risk-Stratified Combination of Venetoclax Ibrutinib and Rituximab With and Without Navitoclax in Patients With Relapsed and Refractory Mantle Cell Lymphoma AIM2
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-08
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:
This is an open label multi-centre phase II study in which RR MCL patients will be genetically risk-stratified into Standard risk no 9p211-243 loss no SMARCA2 or SMARCA4 mutdel and High risk 9p211-243 loss SMARCA2 andor SMARCA4 mutdel
Patients without the high-risk mutations will be treated with ibrutinib rituximab and venetoclax Patients with the high-risk mutations will be treated with ibrutinib rituximab venetoclax and navitoclax
Patients without the high-risk mutations will be treated with ibrutinib rituximab and venetoclax Patients with the high-risk mutations will be treated with ibrutinib rituximab venetoclax and navitoclax
Detailed Description:
The combination of ibrutinib and venetoclax in patients with RR MCL 50 TP53 aberrant was explored in the AIM1 study It demonstrated a CR rate of 71 p0001 with an estimated 15 month PFS and 18-month OS of 78 and 74 respectively Importantly using ASO-PCR with sensitivity of 1 in 104-105 56 of all patients and 82 of those who had achieved CR were MRD-negative The combination was well tolerated with generally low-grade side effects including diarrhoea 83 fatigue 75 and nausea or vomiting 71 Tumour lysis occurred in 8 n2 of the cohort These results led to the initiation of a global phase III registration study comparing ibrutinib vs ibrutinib-venetoclax in patients with RR MCL ClinicalTrials number NCT03112174
The addition of anti-CD20 monoclonal antibodies mAb has significantly improved the outcomes in indolent and aggressive B-cell lymphomas For instance in Australia the 5-year OS has improved from 534 in 1997 to 679 in 2007 largely due to incorporation of rituximab into the standard treatment regimens In a phase II study of patients with RR MCL the addition of rituximab to ibrutinib resulted in a considerably higher CR rate 44 than with ibrutinib monotherapy 21The combination of an anti-CD20 mAb with a BTK and BCL-2 inhibitor was explored in the OSASIS study which combined obinutuzumab with ibrutinib and venetoclax in RR MCL n12 Venetoclax was administered at the dose range of 200-800mgThe combination resulted in high response rates and MRD-negativity in 77 of those who had achieved CR Toxicities included haematological grade 3-4 AEs 58 no dose limiting toxicity DLT and no clinically significant non-haematological Grade 3-4 AEs However it is unknown what the CR rate and MRD-negativity rates are in genetically defined risk groups in this small study
Despite the encouraging results of AIM1 approximately 30 of patients failed to respond to the ibrutinib and venetoclax combination or relapsed whilst on study therapy after initially achieving CR Genomic analysis of these patients in comparison to those who had sustained responses identified 9p211-243 loss or mutations in the SWISNF chromatin remodelling complex SMARCA2 andor SMARCA4 mutdel as mechanisms of resistance through transcriptional upregulation of BCL-xL20 This is a BCL2 family protein not targeted by venetoclax therefore providing a selective advantage against venetoclax-based therapy
Navitoclax a BCL2BCL-XLBCL-W inhibitor was demonstrated by our in-vitro data to be able to overcome the resistance in SWISNF mutant cells resensitising them to the ibrutinib-venetoclax combinationThe combination of navitoclax and venetoclax has been recently explored in RR acute lymphoblastic leukaemia ALL and lymphoblastic lymphoma Venetoclax was administered at 200mg on day 1 followed by 400mg daily thereafter Navitoclax was administered at 3 dose levels 25mg 50mg and if 45kg also 100mg Common non-haematological AEs included diarrhoea 47 nausea 47 hypokalaemia 45 and abdominal pain 43 while Grade 3-4 haematologic AEs included febrile neutropenia 47 thrombocytopenia 26 and anaemia 17 The incidence of grade 3-4 thrombocytopenia in this study is consistent with existing data on navitoclax toxicity profile It is caused by navitoclax-mediated inhibition of Bcl-XL leading to accelerated platelet apoptosis Combination with venetoclax allows for lower doses of navitoclax which can mitigate the effect on platelets
Although there is no published data on the combination of navitoclax and rituximab the safety and synergy of rituximab and navitoclax in CLL and indolent lymphoma has been reported with better response rates than in Phase I studies with either agent alone
The AIM1 study demonstrated ibrutinib and venetoclax to be a highly effective treatment strategy for patients with RR MCL Ancillary questions that we will address include
1 Can addition of rituximab to the venetoclax and ibrutinib combination increase the depth and durability of response RR MCL
2 Can addition of navitoclax in high-risk RR MCL improve rates of CR
3 What is the safety and tolerability of these combinations
The rationale for the staggered drug introduction and dose titration
1 Ibrutinib and rituximab lead-in before venetoclax and navitoclax in high-risk group
Ibrutinib lead-in is expected to sensitise the lymphoma cells to venetoclax
Rituximab-induced rapid cytoreduction in order to reduce the tumour cell numbers and therefore the risk of patients harbouring MCL cells capable of adaption to the BH3-mimetics
Maintaining the same dosing schedule of ibrutinib and venetoclax as AIM1 in the standard-risk cohort would allow direct comparison with AIM1
2 Navitoclax dosing
Given the ability of BCL-xL to be rapidly up-regulated in response to venetoclax and ibrutinib co-administration of navitoclax and venetoclax is crucial Navitoclax will therefore be introduced in week 4 ie after 3 weeks
We acknowledge that recovery of the platelet count whilst on navitoclax relies on compensatory mechanisms by the bone marrow which may be suppressed by venetoclax however in order to effectively inhibit BCL-XL we propose a target dose of 200mg with careful up-titration from an initial dose of 50mg as guided by the platelet count
Furthermore recovery of navitoclax-induced thrombocytopenia would partially depend on the bone marrow reserve Bone marrow involvement in MCL has been reported in 5029-6330 of cases which is significantly lower than in CLL or ALL We therefore anticipate that the impact of navitoclax on platelet count would be better compensated in MCL than in diseases with greater degree of bone marrow infiltration Importantly only 2 out of 24 patients 8 on AIM1 study had a platelet count of 75 x 109L at screening Throughout the first 16 weeks the platelet count remained 75 x 109L in 92 and 50 x 109L in 96 of patients unpublished data
Additionally in order to mitigate the risk of ibrutinib-related bleeding exacerbated by Grade 3-4 thrombocytopenia ibrutinib and navitoclax will be withheld until platelet count is 25 x 109L and there is no further bleeding
The addition of anti-CD20 monoclonal antibodies mAb has significantly improved the outcomes in indolent and aggressive B-cell lymphomas For instance in Australia the 5-year OS has improved from 534 in 1997 to 679 in 2007 largely due to incorporation of rituximab into the standard treatment regimens In a phase II study of patients with RR MCL the addition of rituximab to ibrutinib resulted in a considerably higher CR rate 44 than with ibrutinib monotherapy 21The combination of an anti-CD20 mAb with a BTK and BCL-2 inhibitor was explored in the OSASIS study which combined obinutuzumab with ibrutinib and venetoclax in RR MCL n12 Venetoclax was administered at the dose range of 200-800mgThe combination resulted in high response rates and MRD-negativity in 77 of those who had achieved CR Toxicities included haematological grade 3-4 AEs 58 no dose limiting toxicity DLT and no clinically significant non-haematological Grade 3-4 AEs However it is unknown what the CR rate and MRD-negativity rates are in genetically defined risk groups in this small study
Despite the encouraging results of AIM1 approximately 30 of patients failed to respond to the ibrutinib and venetoclax combination or relapsed whilst on study therapy after initially achieving CR Genomic analysis of these patients in comparison to those who had sustained responses identified 9p211-243 loss or mutations in the SWISNF chromatin remodelling complex SMARCA2 andor SMARCA4 mutdel as mechanisms of resistance through transcriptional upregulation of BCL-xL20 This is a BCL2 family protein not targeted by venetoclax therefore providing a selective advantage against venetoclax-based therapy
Navitoclax a BCL2BCL-XLBCL-W inhibitor was demonstrated by our in-vitro data to be able to overcome the resistance in SWISNF mutant cells resensitising them to the ibrutinib-venetoclax combinationThe combination of navitoclax and venetoclax has been recently explored in RR acute lymphoblastic leukaemia ALL and lymphoblastic lymphoma Venetoclax was administered at 200mg on day 1 followed by 400mg daily thereafter Navitoclax was administered at 3 dose levels 25mg 50mg and if 45kg also 100mg Common non-haematological AEs included diarrhoea 47 nausea 47 hypokalaemia 45 and abdominal pain 43 while Grade 3-4 haematologic AEs included febrile neutropenia 47 thrombocytopenia 26 and anaemia 17 The incidence of grade 3-4 thrombocytopenia in this study is consistent with existing data on navitoclax toxicity profile It is caused by navitoclax-mediated inhibition of Bcl-XL leading to accelerated platelet apoptosis Combination with venetoclax allows for lower doses of navitoclax which can mitigate the effect on platelets
Although there is no published data on the combination of navitoclax and rituximab the safety and synergy of rituximab and navitoclax in CLL and indolent lymphoma has been reported with better response rates than in Phase I studies with either agent alone
The AIM1 study demonstrated ibrutinib and venetoclax to be a highly effective treatment strategy for patients with RR MCL Ancillary questions that we will address include
1 Can addition of rituximab to the venetoclax and ibrutinib combination increase the depth and durability of response RR MCL
2 Can addition of navitoclax in high-risk RR MCL improve rates of CR
3 What is the safety and tolerability of these combinations
The rationale for the staggered drug introduction and dose titration
1 Ibrutinib and rituximab lead-in before venetoclax and navitoclax in high-risk group
Ibrutinib lead-in is expected to sensitise the lymphoma cells to venetoclax
Rituximab-induced rapid cytoreduction in order to reduce the tumour cell numbers and therefore the risk of patients harbouring MCL cells capable of adaption to the BH3-mimetics
Maintaining the same dosing schedule of ibrutinib and venetoclax as AIM1 in the standard-risk cohort would allow direct comparison with AIM1
2 Navitoclax dosing
Given the ability of BCL-xL to be rapidly up-regulated in response to venetoclax and ibrutinib co-administration of navitoclax and venetoclax is crucial Navitoclax will therefore be introduced in week 4 ie after 3 weeks
We acknowledge that recovery of the platelet count whilst on navitoclax relies on compensatory mechanisms by the bone marrow which may be suppressed by venetoclax however in order to effectively inhibit BCL-XL we propose a target dose of 200mg with careful up-titration from an initial dose of 50mg as guided by the platelet count
Furthermore recovery of navitoclax-induced thrombocytopenia would partially depend on the bone marrow reserve Bone marrow involvement in MCL has been reported in 5029-6330 of cases which is significantly lower than in CLL or ALL We therefore anticipate that the impact of navitoclax on platelet count would be better compensated in MCL than in diseases with greater degree of bone marrow infiltration Importantly only 2 out of 24 patients 8 on AIM1 study had a platelet count of 75 x 109L at screening Throughout the first 16 weeks the platelet count remained 75 x 109L in 92 and 50 x 109L in 96 of patients unpublished data
Additionally in order to mitigate the risk of ibrutinib-related bleeding exacerbated by Grade 3-4 thrombocytopenia ibrutinib and navitoclax will be withheld until platelet count is 25 x 109L and there is no further bleeding
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
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