Ignite Creation Date:
2024-05-06 @ 2:37 AM
Last Modification Date:
2024-10-26 @ 11:21 AM
Study NCT ID:
NCT02086721
Status:
COMPLETED
Last Update Posted:
2017-05-31
First Post:
2013-09-03
Brief Title:
Phase I Clinical Study Combining L19-IL2 With SABR in Patients With Oligometastatic Solid Tumor
Sponsor:
Maastricht Radiation Oncology
Organization:
Maastricht Radiation Oncology
Study Overview
Official Title:
Phase I Clinical Study Combining L19-IL2 With Stereotactic Ablative Body Radiotherapy in Patients With Oligometastatic Solid Tumor
Status:
COMPLETED
Status Verified Date:
2017-05
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:
L19-IL2
Brief Summary:
The formation of metastasis is responsible for as much as 90 of cancer-associated mortality In spite of recent advances in oncologic therapy approximately 50 of the lung cancer patients have already overt disseminated cancer at diagnosis Additionally numerous patients with locoregional disease initially treated with curative intent develop oligometastases during the course of disease In both instances these stage IV patients are generally considered to be incurable and mostly treated palliatively
Oligometastases defined as 1-5 sites of active disease on whole body imaging was coined to refer to isolated sites of metastasis resembling limited tumor metastatic capacity The implication of this concept is that local cancer treatments are curative in a proportion of patients with metastases and that incorporating local therapy is a conceptually attractive approach In several but not all academic centers the standard treatment of patients with oligometastases in good general health is standard chemotherapy followed by surgery or by Stereotactic Ablative Body Radiotherapy SABR with radical dose on the macroscopic visible tumors
The widespread introduction of SABR and of minimally invasive surgery has fuelled research in treating patients with oligometastases Indeed local control of metastases can be obtained in virtually all parts of the body with a low proportion of patients experiencing severe side effects In the few prospective studies published to date approximately 20 of patients remained free of recurrence several years after treatment when all sites of disease were targeted by radiation
Along with standard anti-cancer therapeutic modalities like chemotherapy and radiotherapy RT immunotherapy has recently gained a lot of attention
Angiogenesis is one of the hallmarks of cancer and therefore considerable efforts have been made to exploit this unique target for selective drug delivery One of the appealing targets for both approaches is the splice variant of fibronectin containing extra domain B EDB which is abundantly expressed in vascular endothelial cells of a variety of primary tumors as well as metastases but virtually absent in normal tissues Recently a human recombinant scFv fragment directed against EDB designated L19 was developed and subsequently combined with the pro-inflammatory interleukin-2 IL2 resulting in the immunocytokine L19-IL2 L19-IL2 delivers high doses of IL2 to the metastatic tumor sites exploiting the selective expression of EDB on newly formed blood vessels Interleukin-2 IL2 plays an essential role in the activation phases of both specific and natural immune responses Even though it has no direct cytotoxic effects on cancer cells it can induce tumor regression by stimulating a potent cell-mediated response In summary L19-IL2 is an immunocytokine which will stimulate immune response specifically in tumors with angiogenesis and tissue remodeling
Radiotherapy is a particularly interesting partner for immunotherapy since it can be harnessed to specifically modify the immunogenicity of the primary tumors and their microenvironment in the attempt to generate an in situ immunization of the host against a patients own cancer Our hypothesis is that three independent therapeutic approaches will synergize to improve dramatically survival in patients with oligometastases of solid tumors
Oligometastases defined as 1-5 sites of active disease on whole body imaging was coined to refer to isolated sites of metastasis resembling limited tumor metastatic capacity The implication of this concept is that local cancer treatments are curative in a proportion of patients with metastases and that incorporating local therapy is a conceptually attractive approach In several but not all academic centers the standard treatment of patients with oligometastases in good general health is standard chemotherapy followed by surgery or by Stereotactic Ablative Body Radiotherapy SABR with radical dose on the macroscopic visible tumors
The widespread introduction of SABR and of minimally invasive surgery has fuelled research in treating patients with oligometastases Indeed local control of metastases can be obtained in virtually all parts of the body with a low proportion of patients experiencing severe side effects In the few prospective studies published to date approximately 20 of patients remained free of recurrence several years after treatment when all sites of disease were targeted by radiation
Along with standard anti-cancer therapeutic modalities like chemotherapy and radiotherapy RT immunotherapy has recently gained a lot of attention
Angiogenesis is one of the hallmarks of cancer and therefore considerable efforts have been made to exploit this unique target for selective drug delivery One of the appealing targets for both approaches is the splice variant of fibronectin containing extra domain B EDB which is abundantly expressed in vascular endothelial cells of a variety of primary tumors as well as metastases but virtually absent in normal tissues Recently a human recombinant scFv fragment directed against EDB designated L19 was developed and subsequently combined with the pro-inflammatory interleukin-2 IL2 resulting in the immunocytokine L19-IL2 L19-IL2 delivers high doses of IL2 to the metastatic tumor sites exploiting the selective expression of EDB on newly formed blood vessels Interleukin-2 IL2 plays an essential role in the activation phases of both specific and natural immune responses Even though it has no direct cytotoxic effects on cancer cells it can induce tumor regression by stimulating a potent cell-mediated response In summary L19-IL2 is an immunocytokine which will stimulate immune response specifically in tumors with angiogenesis and tissue remodeling
Radiotherapy is a particularly interesting partner for immunotherapy since it can be harnessed to specifically modify the immunogenicity of the primary tumors and their microenvironment in the attempt to generate an in situ immunization of the host against a patients own cancer Our hypothesis is that three independent therapeutic approaches will synergize to improve dramatically survival in patients with oligometastases of solid tumors
Detailed Description:
1 Tumor vasculature Profound differences exist between vascular endothelium and surrounding stroma of normal tissues and tumors Tumor vasculature is extremely disorganized and tortuous Vascular shunts are frequent and distinguishing arterioles from venules can be challenging Apart from the architecture the blood flow itself is strikingly altered it can be sluggish sometimes stationary or even reverse The endothelium in tumors proliferates rapidly and contributes to active angiogenesis The direct contact of the tumor endothelium with the hosts blood pool makes this site a unique target for selective drug delivery
2 L19 Fibronectin FN is a broadly present soluble constituent of plasma and other body fluids FN usually exists as a dimer formed by two nearly identical approximately 250 kDa subunits covalently linked near their C-terminus by a pair of disulfide bonds Even though FN molecules are the product of a single gene the resulting protein can exist in multiple forms that arise from alternative spicing of pre-mRNA that can generate up to 20 variants in humans Splicing occurs in 3 regions of the FN gene leading to inclusion or exclusion of either one of the two type III repeats named EDB and EDA The 91 amino acid sequence of EDB is identical in mice rats rabbits dogs and humans EDB-containing FN is dispensable during embryogenesis but is thought to play a modulating role in the growth of connective tissues In adults EDB-FN is highly expressed in normal tissues during angiogenesis but not in mature vessels Furthermore EDB-containing FN is abundantly found in solid tumors It is mainly produced by tumor cells and deposited in the subendothelial extracellular matrix of solid tumors and hematological malignancies
L19 is the single chain scFv human antibody that specifically targets EDB-FN Antibody fragments in small scFv formats are useful and versatile tools with various advantages including rapid blood clearance and easy manipulation for antibody engineering The L19 antibody has been shown to recognize and target EDB-FN in vivo both in animal models and patients In past years the L19 antibody has been conjugated with numerous agents including therapeutic radionuclides and cytokines
3 Interleukin-2 Cytokines are a heterogeneous group of soluble small polypeptides or glycoproteins exerting pleiotropic or redundant effects promoting growth differentiation and activation of normal cells Cytokines produced by immune cells may have pro- or anti-inflammatory and immune-modulatory activities In malignant diseases cytokine production and release can be affected by the tumor itself andor therapeutic interventions Cytokines may also display potent anticancer activities but are frequently hampered by treatment-related toxicities prohibiting dose-escalation to therapeutically effective concentrations
Interleukin-2 IL2 plays an essential role in the activation phases of both specific and natural immune responses Even though it has no direct cytotoxic effects on cancer cells it can induce tumor regression by stimulating a potent cell-mediated response As such IL2 is one of the treatment options in metastatic renal cell carcinoma patients
4 L19-IL2 In order to overcome toxicity while simultaneously delivering therapeutic doses of IL2 to the tumor issue the elegant option of combining the anti-EDB scFv L19 antibody with IL2 was pursued It has been shown that the L19-IL2 conjugate mediates the selective delivery and accumulation of IL2 at tumor endothelial cells where the EDB antigen is expressed during angiogenesis leading to a dramatic increase of the therapeutic efficacy of IL2 In the first preclinical study 80 of the xenograft tumors including teratocarcinoma and small cell lung cancer tackled with L19-IL2 were subsequently composed of connective and necrotic tissue At the same time an increase in the levels of interferon-gamma and of cytotoxic lymphocytes macrophages and natural killer cells was found These histological and therapeutic effects were underlined in a orthotopic pancreatic cancer model treated with the antibody-cytokine conjugate One year later this response percentage was repeated in Ramos lymphoma xenografts treated with L19-IL2 and the anti-CD20 antibody rituximab whereby a complete remission lasting for more than one year was found in 4 of the 5 mice treated
In a recent phase III clinical trial the use of L19-IL2 was proven safe in a variety of stage IV malignancies with a recommended dose of 225 Mio IU Furthermore it was safely combined with dacarbazine in stage IV melanoma patients maintaining the same recommended dose level In the first study the overall objective response rate was reported to be 51 after two cycles and in the second this rate was 28 with one complete response still ongoing 21 months after treatment initiation
At present three phase III clinical trials on L19-IL2 alone or in combination with chemotherapy for patients with metastatic melanoma ClinicalTrialsgov numbers NCT01055522 and NCT01253096 and pancreatic cancer ClinicalTrialsgov number NCT01198522 are ongoing
Summary Study Design
Details on SABR
Prescribed dose is risk adapted to the metastatic localization and closeness to organs at risk in accordance with local protocol of MAASTRO clinic Patients will receive a dose schedule of 1 x 30 Gy 3 x 15-20 Gy 5 x 12 Gy 8 x 75 Gy to the 80 or 100 isodose which should encompass the periphery of the PTV as closely as possible Maximum dose is not restricted but volumes with a dose higher than 105 must be located within the gross tumor The minimum dose allowed is EQD2αẞ10 60 Gy an ablative dose with EQD2iso 875Gy10 should always be the objective Treatment will be delivered with intensity modulated arcs treatments
Step -1 Assessment of the toxicity of 10 Mio IU of L19-IL2 n3-6 this step is only chosen when dose-limiting toxicity occurs in Step 1
Administration of 10 Mio IU of L19-IL2 given on day 1 3 and 5 of each 21-day cycle max 6 cycles via iv bolus injection starting within one week after completion of SABR
Toxicity will be scored at every intravenous iv drug administration and on day 7 14 and 21 of the cycle according to the CTCAE40 scoring system Hematology liver and kidney function will be controlled on day 1 3 and 5 prior to L19-IL2 administration and on day 7 14 and 21
When in 03 patients a toxicity of grade 2 or more has occurred step 1 is considered safe If in 13 or more patients a grade 2 or more toxicity has occurred 3 more patients will be included in this step If another grade 2 or more toxicity occurs in 13 or more patients the study will be stopped When at maximum 16 patients experience grade 2 toxicity this step will be considered safe When step 1 is considered safe step 2 will be initiated
Step 1 Assessment of the toxicity of 15 Mio IU of L19-IL2 n3-6 Administration of 15 Mio IU of L19-IL2 given on day 1 3 and 5 of each 21-day cycle max 6 cycles via iv bolus injection starting within one week after completion of SABR
Toxicity will be scored at every iv drug administration and on day 7 14 and 21 of the cycle according to the CTCAE40 scoring system Hematology liver and kidney function will be controlled on day 1 3 and 5 prior to L19-IL2 administration and on day 7 14 and 21
When in 03 patients a toxicity of grade 2 or more has occurred step 1 is considered safe If in 13 or more patients a grade 2 or more toxicity has occurred 3 more patients will be included in this step If another grade 2 or more toxicity occurs in 13 or more patients the study will be stopped When at maximum 16 patients experience grade 2 toxicity this step will be considered safe When step 1 is considered safe step 2 will be initiated
Step 2 Assessment of the toxicity of 225 Mio IU of L19-IL2 n3-6 Administration of 225 Mio IU of L19-IL2 given on day 1 3 and 5 of each 21-day cycle max 6 cycles via iv bolus injection starting within one week after completion of SABR
Toxicity will be scored at every iv drug administration and on day 7 14 and 21 of the cycle according to the CTCAE40 scoring system Hematology liver and kidney function will be controlled on day 1 3 and 5 prior to L19-IL2 administration and on day 7 14 and 21
When in 03 patients a toxicity of grade 2 or more has occurred step 1 is considered safe If in 13 or more patients a grade 2 or more toxicity has occurred 3 more patients will be included in this step If another grade 2 or more toxicity occurs in 13 or more patients the study will be stopped When at maximum 16 patients experience grade 2 toxicity this step will be considered safe When step 1 is considered safe step 2 will be initiated
Step 3 Expansion cohort of the maximally tolerable dose n10 Administration of the maximally tolerable dose of L19-IL2 given on day 1 3 and 5 of each 21-day cycle max 6 cycles via iv bolus injection starting within one week after completion of SABR
Toxicity will be scored at every iv drug administration and on day 7 14 and 21 of the cycle according to the CTCAE40 scoring system Hematology liver and kidney function will be controlled on day 1 3 and 5 prior to L19-IL2 administration and on day 7 14 and 21
2 L19 Fibronectin FN is a broadly present soluble constituent of plasma and other body fluids FN usually exists as a dimer formed by two nearly identical approximately 250 kDa subunits covalently linked near their C-terminus by a pair of disulfide bonds Even though FN molecules are the product of a single gene the resulting protein can exist in multiple forms that arise from alternative spicing of pre-mRNA that can generate up to 20 variants in humans Splicing occurs in 3 regions of the FN gene leading to inclusion or exclusion of either one of the two type III repeats named EDB and EDA The 91 amino acid sequence of EDB is identical in mice rats rabbits dogs and humans EDB-containing FN is dispensable during embryogenesis but is thought to play a modulating role in the growth of connective tissues In adults EDB-FN is highly expressed in normal tissues during angiogenesis but not in mature vessels Furthermore EDB-containing FN is abundantly found in solid tumors It is mainly produced by tumor cells and deposited in the subendothelial extracellular matrix of solid tumors and hematological malignancies
L19 is the single chain scFv human antibody that specifically targets EDB-FN Antibody fragments in small scFv formats are useful and versatile tools with various advantages including rapid blood clearance and easy manipulation for antibody engineering The L19 antibody has been shown to recognize and target EDB-FN in vivo both in animal models and patients In past years the L19 antibody has been conjugated with numerous agents including therapeutic radionuclides and cytokines
3 Interleukin-2 Cytokines are a heterogeneous group of soluble small polypeptides or glycoproteins exerting pleiotropic or redundant effects promoting growth differentiation and activation of normal cells Cytokines produced by immune cells may have pro- or anti-inflammatory and immune-modulatory activities In malignant diseases cytokine production and release can be affected by the tumor itself andor therapeutic interventions Cytokines may also display potent anticancer activities but are frequently hampered by treatment-related toxicities prohibiting dose-escalation to therapeutically effective concentrations
Interleukin-2 IL2 plays an essential role in the activation phases of both specific and natural immune responses Even though it has no direct cytotoxic effects on cancer cells it can induce tumor regression by stimulating a potent cell-mediated response As such IL2 is one of the treatment options in metastatic renal cell carcinoma patients
4 L19-IL2 In order to overcome toxicity while simultaneously delivering therapeutic doses of IL2 to the tumor issue the elegant option of combining the anti-EDB scFv L19 antibody with IL2 was pursued It has been shown that the L19-IL2 conjugate mediates the selective delivery and accumulation of IL2 at tumor endothelial cells where the EDB antigen is expressed during angiogenesis leading to a dramatic increase of the therapeutic efficacy of IL2 In the first preclinical study 80 of the xenograft tumors including teratocarcinoma and small cell lung cancer tackled with L19-IL2 were subsequently composed of connective and necrotic tissue At the same time an increase in the levels of interferon-gamma and of cytotoxic lymphocytes macrophages and natural killer cells was found These histological and therapeutic effects were underlined in a orthotopic pancreatic cancer model treated with the antibody-cytokine conjugate One year later this response percentage was repeated in Ramos lymphoma xenografts treated with L19-IL2 and the anti-CD20 antibody rituximab whereby a complete remission lasting for more than one year was found in 4 of the 5 mice treated
In a recent phase III clinical trial the use of L19-IL2 was proven safe in a variety of stage IV malignancies with a recommended dose of 225 Mio IU Furthermore it was safely combined with dacarbazine in stage IV melanoma patients maintaining the same recommended dose level In the first study the overall objective response rate was reported to be 51 after two cycles and in the second this rate was 28 with one complete response still ongoing 21 months after treatment initiation
At present three phase III clinical trials on L19-IL2 alone or in combination with chemotherapy for patients with metastatic melanoma ClinicalTrialsgov numbers NCT01055522 and NCT01253096 and pancreatic cancer ClinicalTrialsgov number NCT01198522 are ongoing
Summary Study Design
Details on SABR
Prescribed dose is risk adapted to the metastatic localization and closeness to organs at risk in accordance with local protocol of MAASTRO clinic Patients will receive a dose schedule of 1 x 30 Gy 3 x 15-20 Gy 5 x 12 Gy 8 x 75 Gy to the 80 or 100 isodose which should encompass the periphery of the PTV as closely as possible Maximum dose is not restricted but volumes with a dose higher than 105 must be located within the gross tumor The minimum dose allowed is EQD2αẞ10 60 Gy an ablative dose with EQD2iso 875Gy10 should always be the objective Treatment will be delivered with intensity modulated arcs treatments
Step -1 Assessment of the toxicity of 10 Mio IU of L19-IL2 n3-6 this step is only chosen when dose-limiting toxicity occurs in Step 1
Administration of 10 Mio IU of L19-IL2 given on day 1 3 and 5 of each 21-day cycle max 6 cycles via iv bolus injection starting within one week after completion of SABR
Toxicity will be scored at every intravenous iv drug administration and on day 7 14 and 21 of the cycle according to the CTCAE40 scoring system Hematology liver and kidney function will be controlled on day 1 3 and 5 prior to L19-IL2 administration and on day 7 14 and 21
When in 03 patients a toxicity of grade 2 or more has occurred step 1 is considered safe If in 13 or more patients a grade 2 or more toxicity has occurred 3 more patients will be included in this step If another grade 2 or more toxicity occurs in 13 or more patients the study will be stopped When at maximum 16 patients experience grade 2 toxicity this step will be considered safe When step 1 is considered safe step 2 will be initiated
Step 1 Assessment of the toxicity of 15 Mio IU of L19-IL2 n3-6 Administration of 15 Mio IU of L19-IL2 given on day 1 3 and 5 of each 21-day cycle max 6 cycles via iv bolus injection starting within one week after completion of SABR
Toxicity will be scored at every iv drug administration and on day 7 14 and 21 of the cycle according to the CTCAE40 scoring system Hematology liver and kidney function will be controlled on day 1 3 and 5 prior to L19-IL2 administration and on day 7 14 and 21
When in 03 patients a toxicity of grade 2 or more has occurred step 1 is considered safe If in 13 or more patients a grade 2 or more toxicity has occurred 3 more patients will be included in this step If another grade 2 or more toxicity occurs in 13 or more patients the study will be stopped When at maximum 16 patients experience grade 2 toxicity this step will be considered safe When step 1 is considered safe step 2 will be initiated
Step 2 Assessment of the toxicity of 225 Mio IU of L19-IL2 n3-6 Administration of 225 Mio IU of L19-IL2 given on day 1 3 and 5 of each 21-day cycle max 6 cycles via iv bolus injection starting within one week after completion of SABR
Toxicity will be scored at every iv drug administration and on day 7 14 and 21 of the cycle according to the CTCAE40 scoring system Hematology liver and kidney function will be controlled on day 1 3 and 5 prior to L19-IL2 administration and on day 7 14 and 21
When in 03 patients a toxicity of grade 2 or more has occurred step 1 is considered safe If in 13 or more patients a grade 2 or more toxicity has occurred 3 more patients will be included in this step If another grade 2 or more toxicity occurs in 13 or more patients the study will be stopped When at maximum 16 patients experience grade 2 toxicity this step will be considered safe When step 1 is considered safe step 2 will be initiated
Step 3 Expansion cohort of the maximally tolerable dose n10 Administration of the maximally tolerable dose of L19-IL2 given on day 1 3 and 5 of each 21-day cycle max 6 cycles via iv bolus injection starting within one week after completion of SABR
Toxicity will be scored at every iv drug administration and on day 7 14 and 21 of the cycle according to the CTCAE40 scoring system Hematology liver and kidney function will be controlled on day 1 3 and 5 prior to L19-IL2 administration and on day 7 14 and 21
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