Ignite Creation Date:
2024-05-06 @ 2:34 AM
Last Modification Date:
2024-10-26 @ 11:20 AM
Study NCT ID:
NCT02076243
Status:
TERMINATED
Last Update Posted:
2017-10-25
First Post:
2014-02-26
Brief Title:
Treatment With Nab-paclitaxel in Cutaneous SCC
Sponsor:
Icahn School of Medicine at Mount Sinai
Organization:
Icahn School of Medicine at Mount Sinai
Study Overview
Official Title:
Phase II Trial of Nab-Paclitaxel as First Line Cytotoxic Chemotherapy in Patients With Unresectable and Metastatic Cutaneous Squamous Cell Carcinoma
Status:
TERMINATED
Status Verified Date:
2017-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Closed by sponsor
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This is an investigator initiated phase II study to assess the efficacy of a chemotherapy called nab-paclitaxel as first line cytotoxic chemotherapy in subjects with unresectable locally advanced or metastatic cutaneous squamous cell carcinoma SCC All subjects receive the treatment by vein weekly and receive the same dose of the treatment
The risk of developing cutaneous SCC is approximately 10 in a lifetime The vast majority are treated surgically and do not recur However a small percentage become unresectable over time or metastasize distantly in the body Unresectable and metastatic cutaneous SCC has a poor prognosis and oncologists often choose a whole body therapy without the benefit of prospective efficacy data Very little prospective investigation into the efficacy of specific chemotherapy regimens as a function of line of therapy has been performed in this patient population Nab-paclitaxel is type of chemotherapy that has demonstrated activity in other types of cancer such as lung and head and neck cancers The primary objective of this study is to determine the response rate percentage of subjects with tumor shrinkage to nab-paclitaxel treatment in subjects with cutaneous SCC who have not received cytotoxic chemotherapy in the unresectable or the metastatic settings Secondary objectives are the progression free survival time until tumor starts to grow safety assessment of the percentage of subjects whose tumor expresses a protein called SPARC and correlating the expression of SPARC with response to treatment To determine if the tumor expresses SPARC part of a prior standard biopsy such as that performed to establish the diagnosis of SCC will be used SPARC is a protein that is overexpressed in a range of different cancer types and may alter the environment around the tumor possibly in a way that may make the SCC more responsive to treatment with nab-paclitaxel
The risk of developing cutaneous SCC is approximately 10 in a lifetime The vast majority are treated surgically and do not recur However a small percentage become unresectable over time or metastasize distantly in the body Unresectable and metastatic cutaneous SCC has a poor prognosis and oncologists often choose a whole body therapy without the benefit of prospective efficacy data Very little prospective investigation into the efficacy of specific chemotherapy regimens as a function of line of therapy has been performed in this patient population Nab-paclitaxel is type of chemotherapy that has demonstrated activity in other types of cancer such as lung and head and neck cancers The primary objective of this study is to determine the response rate percentage of subjects with tumor shrinkage to nab-paclitaxel treatment in subjects with cutaneous SCC who have not received cytotoxic chemotherapy in the unresectable or the metastatic settings Secondary objectives are the progression free survival time until tumor starts to grow safety assessment of the percentage of subjects whose tumor expresses a protein called SPARC and correlating the expression of SPARC with response to treatment To determine if the tumor expresses SPARC part of a prior standard biopsy such as that performed to establish the diagnosis of SCC will be used SPARC is a protein that is overexpressed in a range of different cancer types and may alter the environment around the tumor possibly in a way that may make the SCC more responsive to treatment with nab-paclitaxel
Detailed Description:
Non-melanoma skin cancers represent the most common type of cancer in the United States with cutaneous SCC comprising 20 of these malignancies The risk of developing cutaneous SCC is approximately 10 in a lifetime This risk increases with age and varies according to the latitude in which one lives The incidence rate in the United States is increasing as a result of multiple factors including altered sun exposure patterns and population aging Early detection is critical as the vast majority are cured by definitive localized therapy with an overall 5-year cure rate of greater than 90
Although the vast majority of cutaneous SCCs are treated surgically with curative intent the estimated case fatality rate ranges from 1-5 depending on reported study If regional lymph nodes are involved a standard treatment approach is lymphadenectomy followed by the consideration of adjuvant therapy radiation - chemotherapy However a subset of these patients ultimately will develop unresectable or distantly metastatic recurrences
Unresectable SCC is treated using systemic approaches usually encompassing cytotoxic chemotherapy However clinical investigation to determine efficacy of specific agents has been very limited and not studied in a rigorous fashion Efficacy data stems largely from case reports and limited case series and from a very small number of phase II trials As for targeted therapies treatment with cetuximab demonstrated limited activity RR 11 in a 36 patient phase II trial Many oncologists tend to treat with platinum agents taxanes and 5-FU based regimens However no standard exists As such there is a need to explore more systematically the efficacy of specific chemotherapeutic agents with the goal of developing a standard treatment approach
Nab-paclitaxel is an intriguing option to use for treatment given demonstrated efficacy in other malignancies with SCC histology In clinical practice many oncologists use paclitaxel despite the lack of rigorous clinical investigation The use of paclitaxel is limited by toxicities associated with the solvent Cermaphor EL
Nab-paclitaxel is an albumin bound form of paclitaxel In other malignancies such as breast cancer nab-paclitaxel is associated with improved response rates and time to progression relative to paclitaxel Nab-paclitaxel based chemotherapy has demonstrated efficacy in other malignancies with SCC histology including head and neck carcinoma and NSCLC
SPARC secreted protein acidic and rich in cysteine also known as osteonectin and BM-40 is a 43kD secreted extracellular matrix glycoprotein first identified in 1984 and noted to have high binding affinity for albumin SPARC further affects angiogenesis by interacting with growth factors such as VEGF and basic fibroblast growth factor bFGF It binds with platelet derived growth factor PDGF inhibiting binding to its receptors SPARC interacts with bFGF and inhibits the migration of endothelial cells
Overexpression of SPARC has been found in many tumor types including breast melanoma brain colon skin and several others and is associated with increased tumor invasion and metastasis For example in melanoma SPARC expression is clinically correlated with aggressiveness and metastatic phenotypes In melanoma models SPARC is associated with decreased E-cadherin and increased N-cadherin expression suggesting that it may regulate epithelial-mesenchymal transition in the earlier stages of malignant transformation SPARC expression has also been associated with increased breast cancer cell invasiveness The absence of SPARC has been shown to suppress the development of UV-induced squamous cell carcinoma in a mouse model
Another tumor promoting mechanism of SPARC is in its interaction with inflammation There is evidence that SPARC may play a role in dampening the immune response to tumor cells Melanoma cells lacking SPARC expression induced neutrophil recruitment increased chemotactic factors such as IL-8 GRO and leukotrienes and resulted in tumor cell rejection This observation decreased neutrophil recruitment in the presence of SPARC has also been noted in other models including SPARC null versus wild type mice SPARC may regulate the apoptotic pathway of neutrophils involving Fas ligand
SPARC is able to affect tumor progression at several levels It plays a role in epithelial-mesenchymal transformation It promotes tumor growth and metastasis by inhibiting immune surveillance and promoting angiogenesis and it is correlated with metastatic cell aggressiveness
The overexpression of SPARC in many tumors and the tumor microenvironment and its high binding affinity for albumin make an albumin-bound drug delivery attractive Via the gp60 and caveolae-mediated albumin transport pathway albumin is transported from the blood vessel into the tumor Albumin-bound paclitaxel nab-paclitaxel was approved by the FDA in January 2005 for the treatment of metastatic breast cancer Nab-paclitaxel takes advantage of this transport carrying paclitaxel into tumor cells There it may be preferentially retained in tissues overexpressing SPARC SPARC has been shown to be overexpressed in squamous cell carcinomas of the head and neck 61 versus 0 in normal head and neck tissue
The use of intra-arterial nab-paclitaxel has been examined in locally advanced squamous cell carcinoma of the head and neck with response rates of 75-78 A retrospective analysis showed that SPARC upregulation in the tumor tissue was associated with increased response in 16 patients with squamous cell carcinoma of the head and neck who received intra-arterial nab-paclitaxel
This is a single arm phase II study assessing the efficacy of treatment with nab-paclitaxel abraxane administered weekly days 18 and 15 of 28 day cycle to patients with unresectable locoregional or distantly metastatic cutaneous squamous cell carcinoma SCC A Simon 2 stage design will be used If no responses are seen in the first 12 patients it will be concluded that the response rate is no greater than 3 and the trial will be stopped for futility at the end of stage one Otherwise the trial will enroll 9 more patients for a total of 21
In summary the development of unresectable locally advanced or distantly metastatic cutaneous SCC confers a very poor prognosis While various types of systemic therapy are used by oncologists choices are based on anecdotal experiences and a limited number of case series and small phase II studies Nab-paclitaxel has demonstrated significant anti-tumor activity in several malignancies of SCC morphology Taxanes are often used as systemic treatment for unresectable cutaneous SCC This study will allow for prospective evaluation of the activity of abraxane as first line systemic cytotoxic chemotherapy a defined line of cytotoxic therapy in the treatment of advanced SCC The hypothesis of this phase II study is that abraxane will demonstrate significant anti-tumor activity a defined by a primary endpoint of best overall response rate It is hypothesized that increased SPARC expression will correlate with response to nab-paclitaxel treatment and serve as a biomarker for treatment response
Although the vast majority of cutaneous SCCs are treated surgically with curative intent the estimated case fatality rate ranges from 1-5 depending on reported study If regional lymph nodes are involved a standard treatment approach is lymphadenectomy followed by the consideration of adjuvant therapy radiation - chemotherapy However a subset of these patients ultimately will develop unresectable or distantly metastatic recurrences
Unresectable SCC is treated using systemic approaches usually encompassing cytotoxic chemotherapy However clinical investigation to determine efficacy of specific agents has been very limited and not studied in a rigorous fashion Efficacy data stems largely from case reports and limited case series and from a very small number of phase II trials As for targeted therapies treatment with cetuximab demonstrated limited activity RR 11 in a 36 patient phase II trial Many oncologists tend to treat with platinum agents taxanes and 5-FU based regimens However no standard exists As such there is a need to explore more systematically the efficacy of specific chemotherapeutic agents with the goal of developing a standard treatment approach
Nab-paclitaxel is an intriguing option to use for treatment given demonstrated efficacy in other malignancies with SCC histology In clinical practice many oncologists use paclitaxel despite the lack of rigorous clinical investigation The use of paclitaxel is limited by toxicities associated with the solvent Cermaphor EL
Nab-paclitaxel is an albumin bound form of paclitaxel In other malignancies such as breast cancer nab-paclitaxel is associated with improved response rates and time to progression relative to paclitaxel Nab-paclitaxel based chemotherapy has demonstrated efficacy in other malignancies with SCC histology including head and neck carcinoma and NSCLC
SPARC secreted protein acidic and rich in cysteine also known as osteonectin and BM-40 is a 43kD secreted extracellular matrix glycoprotein first identified in 1984 and noted to have high binding affinity for albumin SPARC further affects angiogenesis by interacting with growth factors such as VEGF and basic fibroblast growth factor bFGF It binds with platelet derived growth factor PDGF inhibiting binding to its receptors SPARC interacts with bFGF and inhibits the migration of endothelial cells
Overexpression of SPARC has been found in many tumor types including breast melanoma brain colon skin and several others and is associated with increased tumor invasion and metastasis For example in melanoma SPARC expression is clinically correlated with aggressiveness and metastatic phenotypes In melanoma models SPARC is associated with decreased E-cadherin and increased N-cadherin expression suggesting that it may regulate epithelial-mesenchymal transition in the earlier stages of malignant transformation SPARC expression has also been associated with increased breast cancer cell invasiveness The absence of SPARC has been shown to suppress the development of UV-induced squamous cell carcinoma in a mouse model
Another tumor promoting mechanism of SPARC is in its interaction with inflammation There is evidence that SPARC may play a role in dampening the immune response to tumor cells Melanoma cells lacking SPARC expression induced neutrophil recruitment increased chemotactic factors such as IL-8 GRO and leukotrienes and resulted in tumor cell rejection This observation decreased neutrophil recruitment in the presence of SPARC has also been noted in other models including SPARC null versus wild type mice SPARC may regulate the apoptotic pathway of neutrophils involving Fas ligand
SPARC is able to affect tumor progression at several levels It plays a role in epithelial-mesenchymal transformation It promotes tumor growth and metastasis by inhibiting immune surveillance and promoting angiogenesis and it is correlated with metastatic cell aggressiveness
The overexpression of SPARC in many tumors and the tumor microenvironment and its high binding affinity for albumin make an albumin-bound drug delivery attractive Via the gp60 and caveolae-mediated albumin transport pathway albumin is transported from the blood vessel into the tumor Albumin-bound paclitaxel nab-paclitaxel was approved by the FDA in January 2005 for the treatment of metastatic breast cancer Nab-paclitaxel takes advantage of this transport carrying paclitaxel into tumor cells There it may be preferentially retained in tissues overexpressing SPARC SPARC has been shown to be overexpressed in squamous cell carcinomas of the head and neck 61 versus 0 in normal head and neck tissue
The use of intra-arterial nab-paclitaxel has been examined in locally advanced squamous cell carcinoma of the head and neck with response rates of 75-78 A retrospective analysis showed that SPARC upregulation in the tumor tissue was associated with increased response in 16 patients with squamous cell carcinoma of the head and neck who received intra-arterial nab-paclitaxel
This is a single arm phase II study assessing the efficacy of treatment with nab-paclitaxel abraxane administered weekly days 18 and 15 of 28 day cycle to patients with unresectable locoregional or distantly metastatic cutaneous squamous cell carcinoma SCC A Simon 2 stage design will be used If no responses are seen in the first 12 patients it will be concluded that the response rate is no greater than 3 and the trial will be stopped for futility at the end of stage one Otherwise the trial will enroll 9 more patients for a total of 21
In summary the development of unresectable locally advanced or distantly metastatic cutaneous SCC confers a very poor prognosis While various types of systemic therapy are used by oncologists choices are based on anecdotal experiences and a limited number of case series and small phase II studies Nab-paclitaxel has demonstrated significant anti-tumor activity in several malignancies of SCC morphology Taxanes are often used as systemic treatment for unresectable cutaneous SCC This study will allow for prospective evaluation of the activity of abraxane as first line systemic cytotoxic chemotherapy a defined line of cytotoxic therapy in the treatment of advanced SCC The hypothesis of this phase II study is that abraxane will demonstrate significant anti-tumor activity a defined by a primary endpoint of best overall response rate It is hypothesized that increased SPARC expression will correlate with response to nab-paclitaxel treatment and serve as a biomarker for treatment response
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