Ignite Creation Date:
2024-05-06 @ 11:41 AM
Last Modification Date:
2024-10-26 @ 12:48 PM
Study NCT ID:
NCT03576378
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2024-02-26
First Post:
2018-04-26
Brief Title:
BrEPEM-LH-22017 for Older Patients With Untreated Hodgkin Lymphoma HL
Sponsor:
Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea
Organization:
Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea
Study Overview
Official Title:
A Phase IbII Trial of Combined SGN-35 BrentuximabVedotin Therapy With Cyclophosphamide Procarbazine Prednisone Etoposide and Mitoxantrone BrEPEM for Older Patients With Untreated Hodgkin Lymphoma HL
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-02
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 the phase Ib of the study is to identify the maximum tolerated dose MTD of Brentuximab Vedotin BV in combination with EPEM and to assess the toxicity of the combination of BV with EPEM In the phase II efficacy will be evaluatedBesides progression-free survival PFS event-free survival EFS overall survival OS the duration of response the overall response rate ORR based on best response will be evaluated
Detailed Description:
Hodgkin lymphoma HL is a lymphoid neoplasm characterized by the presence of CD30-positive Hodgkin Reed-Sternberg cells in a background of inflammatory cells The majority of patients with HL have a good outcome with first-line chemotherapy such as ABVD doxorubicin bleomycin vinblastine and dacarbazine or BEACOPP bleomycin etoposide doxorubicin cyclophosphamide vincristineprocarbazine and prednisone sometimes combined with radiation therapy However the same lymphoma has different results in the older than 60 years-old patients This population of 60 years of age or older accounts for 20 of all HL cases Age at diagnosis is an independent adverse prognostic factor for HL The poor outcome in this group is due to both toxicity of chemo and radiotherapy resulting in higher treatment-related mortality and insufficient dosing of the applied treatment
Most clinical trials exclude older patients with HL because older patients have more unfavorable risk profiles and the approaches to treat older patients with HL with intensive regimens resulted in treatment associated mortality of up to 21 More effective treatments to get better results in this patient population are required
In 2001 the problem about the need for effective treatments with acceptable toxicity for the older patients with HL was discussed After that different international groups accepted the challenge of trial organization for older patients with HL
Two phase 2 studies were developed with modified chemotherapy regimens The first BACOPP Bleomycin doxorubicin Cyclophosphamide vincristine prednisolone and procarbazine was a BEACOPP regimen modified used in younger patients In this study 65 patients with early unfavorable or advanced stage HL aged between 60 and 75 years were included
Eighty-five percent of patients achieved complete remission 3 achieved partial remission and 7 developed progressive disease Eighteen patients died 30 including 7 treatment-associated deaths This chemotherapy regimen although was effective had an important toxicity in this older HL patient population The second trial was PVAG regimen composed of gemcitabine prednisone vincristine and adriamycin The treatment was used in elderly HL patients in early unfavorable and advanced stages Fifty-nine patients were enrolled in this study 78 of patients achieved complete remission CR o CR uncertain 34 responded with partial response 25 didnt achieve a response or relapsed Seventeen deaths were observed but only 1 of them was secondary to treatment-related toxicity
The VEPEMB phase II study vinblastine cyclophosphamide prednisolone procarbazine etoposide mitoxantrone and bleomycin was also developed For VEPEMB study 105 HL patients over 65 years of age were treated of which 48 were early stage IA-IIA HL patients and 57 were advanced stage IIB-IV HL patients CR was achieved in 98 of early stage and 58 of advanced stage HL patients Five-year actuarial OS rate was 94 in early stage and 32 in advanced stage HL patients Two patients died during the treatment induction but not related to treatment toxicity In the United Kingdom the VEPEMB treatment was adopted in the new SHIELD Study of Hodgkin in the Elderly Database program that was a prospective study made up of two components I a phase II trial with VEPEMB treatment and II a prospective registration study of patients no treated as part of the VEPEMB study One hundred and seventy-five patients were enrolled in this program 103 patients received VEPEMB treatment and 72 patients received other therapies ABVD regimen CHOP CLVPP regimen etc In this study 74 of CR in early stage and 61 of CR in advanced stage in older HL patients were observed with the VEPEMB treatment Three-year overall survival OS and progression-free survival PFS were 81 and 74 respectively Of patients achieving CR 13 with early-stage and 5 with advanced-stage disease progressed The overall treatment-related mortality was 7 VEPEMB has demonstrated minimal pulmonary toxicity in this study only 1 patient This therapeutic regimen provides adequate disease control in elderly patients with HL with acceptable toxicity and sustained remission in those who have a complete response
Brentuximab vedotin BV is an antibody-drug conjugate ADC consisting of three components a the chimeric anti-CD30 antibody cAC10 b Monomethylauristatin E MMAE and c a protease-cleavable linker that attaches MMAE to cAC10 Binding of BV to cells is followed by internalization of the ADC and cleavage of the peptide linker by lysosomal enzymes and subsequent release of MMAE an antimitotic agent blocks the polymerization of tubulin resulting in G2M phase growth arrest and apoptotic death in a way similar to taxanes
Moreover due to membrane permeability of MMAE a possible cytotoxic effect on bystander malignant cells and surrounding stroma may occur In vivo BV inhibits proliferation induces apoptosis and complete tumor regression in mouse xenograft models of both HL and anaplastic large cell lymphoma ALCL with improved efficacy relative to the unconjugated antibody
First Phase I trial was made in patients with relapsedrefractory CD30 positive lymphomas Brentuximab vedotin was administered every 3 weeks at doses escalating from 01 to 36 mgkg Forty-five patients were treated in this study Ninety-three percent of the patients had classical Hodgkin lymphoma
The maximum tolerated dose MTD for doses every 3 weeks was defined as 18mgkg and the dose-limiting toxicities were febrile neutropenia prostatitis Objective responses were observed in 17 patients including 11 CR
A pivotal open-label single arm Phase II trial studied the efficacy and safety of BV in patients with relapse or refractory HL after autologous stem-cell transplantation ASCT The used dose was 18mgkg intravenously every 3 weeks for a maximum of 16 infusions One hundred two patients were enrolled with a median age of 31 years The ORR was 75 and 34 of patients achieved a CR The median duration of response was 67months and it increased up 205 months for patients who achieved a CR
The most common treatment-related adverse events AEs occurring in 10 of all patients were peripheral neuropathy PN 42 nausea 35 fatigue 34 neutropenia 19 diarrhea 18 pyrexia 14 vomiting 13 arthralgia 12 pruritus 12 myalgia 11 peripheral motor neuropathy 11 and alopecia 10
The combination of BV with ABVD and AVD chemotherapeutic regimens was investigated in a phase I study in 51 untreated patients with HL The maximum tolerated dose of BV combined with ABVD or AVD was not reached and no DLT was observed up to 12 mgkg every 2 weeks
However an increased incidence of pulmonary toxicity was observed with the association with bleomycin Ninety-two percent of patients achieved CR which compares favorably with historical controls A phase 3 study comparing BV combined with AVD versus ABVD alone is ongoing
Based on the previous phase I study of Younes of the combination of BV with ABVD or AVD therapy no dose-limiting toxicity were observed with 12 mgKg of BV and the maximum tolerated dose was not exceeded at 12 mgKg of BV combined with ABVD or AVD Since the combination of BV and EPEM has not been tested before a safety run in stage phase is added to the protocol
Most clinical trials exclude older patients with HL because older patients have more unfavorable risk profiles and the approaches to treat older patients with HL with intensive regimens resulted in treatment associated mortality of up to 21 More effective treatments to get better results in this patient population are required
In 2001 the problem about the need for effective treatments with acceptable toxicity for the older patients with HL was discussed After that different international groups accepted the challenge of trial organization for older patients with HL
Two phase 2 studies were developed with modified chemotherapy regimens The first BACOPP Bleomycin doxorubicin Cyclophosphamide vincristine prednisolone and procarbazine was a BEACOPP regimen modified used in younger patients In this study 65 patients with early unfavorable or advanced stage HL aged between 60 and 75 years were included
Eighty-five percent of patients achieved complete remission 3 achieved partial remission and 7 developed progressive disease Eighteen patients died 30 including 7 treatment-associated deaths This chemotherapy regimen although was effective had an important toxicity in this older HL patient population The second trial was PVAG regimen composed of gemcitabine prednisone vincristine and adriamycin The treatment was used in elderly HL patients in early unfavorable and advanced stages Fifty-nine patients were enrolled in this study 78 of patients achieved complete remission CR o CR uncertain 34 responded with partial response 25 didnt achieve a response or relapsed Seventeen deaths were observed but only 1 of them was secondary to treatment-related toxicity
The VEPEMB phase II study vinblastine cyclophosphamide prednisolone procarbazine etoposide mitoxantrone and bleomycin was also developed For VEPEMB study 105 HL patients over 65 years of age were treated of which 48 were early stage IA-IIA HL patients and 57 were advanced stage IIB-IV HL patients CR was achieved in 98 of early stage and 58 of advanced stage HL patients Five-year actuarial OS rate was 94 in early stage and 32 in advanced stage HL patients Two patients died during the treatment induction but not related to treatment toxicity In the United Kingdom the VEPEMB treatment was adopted in the new SHIELD Study of Hodgkin in the Elderly Database program that was a prospective study made up of two components I a phase II trial with VEPEMB treatment and II a prospective registration study of patients no treated as part of the VEPEMB study One hundred and seventy-five patients were enrolled in this program 103 patients received VEPEMB treatment and 72 patients received other therapies ABVD regimen CHOP CLVPP regimen etc In this study 74 of CR in early stage and 61 of CR in advanced stage in older HL patients were observed with the VEPEMB treatment Three-year overall survival OS and progression-free survival PFS were 81 and 74 respectively Of patients achieving CR 13 with early-stage and 5 with advanced-stage disease progressed The overall treatment-related mortality was 7 VEPEMB has demonstrated minimal pulmonary toxicity in this study only 1 patient This therapeutic regimen provides adequate disease control in elderly patients with HL with acceptable toxicity and sustained remission in those who have a complete response
Brentuximab vedotin BV is an antibody-drug conjugate ADC consisting of three components a the chimeric anti-CD30 antibody cAC10 b Monomethylauristatin E MMAE and c a protease-cleavable linker that attaches MMAE to cAC10 Binding of BV to cells is followed by internalization of the ADC and cleavage of the peptide linker by lysosomal enzymes and subsequent release of MMAE an antimitotic agent blocks the polymerization of tubulin resulting in G2M phase growth arrest and apoptotic death in a way similar to taxanes
Moreover due to membrane permeability of MMAE a possible cytotoxic effect on bystander malignant cells and surrounding stroma may occur In vivo BV inhibits proliferation induces apoptosis and complete tumor regression in mouse xenograft models of both HL and anaplastic large cell lymphoma ALCL with improved efficacy relative to the unconjugated antibody
First Phase I trial was made in patients with relapsedrefractory CD30 positive lymphomas Brentuximab vedotin was administered every 3 weeks at doses escalating from 01 to 36 mgkg Forty-five patients were treated in this study Ninety-three percent of the patients had classical Hodgkin lymphoma
The maximum tolerated dose MTD for doses every 3 weeks was defined as 18mgkg and the dose-limiting toxicities were febrile neutropenia prostatitis Objective responses were observed in 17 patients including 11 CR
A pivotal open-label single arm Phase II trial studied the efficacy and safety of BV in patients with relapse or refractory HL after autologous stem-cell transplantation ASCT The used dose was 18mgkg intravenously every 3 weeks for a maximum of 16 infusions One hundred two patients were enrolled with a median age of 31 years The ORR was 75 and 34 of patients achieved a CR The median duration of response was 67months and it increased up 205 months for patients who achieved a CR
The most common treatment-related adverse events AEs occurring in 10 of all patients were peripheral neuropathy PN 42 nausea 35 fatigue 34 neutropenia 19 diarrhea 18 pyrexia 14 vomiting 13 arthralgia 12 pruritus 12 myalgia 11 peripheral motor neuropathy 11 and alopecia 10
The combination of BV with ABVD and AVD chemotherapeutic regimens was investigated in a phase I study in 51 untreated patients with HL The maximum tolerated dose of BV combined with ABVD or AVD was not reached and no DLT was observed up to 12 mgkg every 2 weeks
However an increased incidence of pulmonary toxicity was observed with the association with bleomycin Ninety-two percent of patients achieved CR which compares favorably with historical controls A phase 3 study comparing BV combined with AVD versus ABVD alone is ongoing
Based on the previous phase I study of Younes of the combination of BV with ABVD or AVD therapy no dose-limiting toxicity were observed with 12 mgKg of BV and the maximum tolerated dose was not exceeded at 12 mgKg of BV combined with ABVD or AVD Since the combination of BV and EPEM has not been tested before a safety run in stage phase is added to the protocol
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