Treatment With Nab-paclitaxel in Cutaneous SCC
Treatment With Nab-paclitaxel in Cutaneous SCC
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.
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 1,8, 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.
Inclusion Criteria:

 -  Histologically confirmed unresectable locoregional or distantly metastatic squamous
 cell carcinoma arising from a cutaneous surface, lip, or ear. Basosquamous histology
 is eligible.

 -  ECOG PS 0 or 1

 -  Life expectancy of more than 4 months

 -  Adequate renal, hepatic, and bone marrow function:

 -  Patients must have adequate liver function: AST and ALT < 2.5 X upper limit of normal,
 alkaline phosphatase < 2.5 X upper limit of normal, unless bone metastasis is present
 in the absence of liver metastasis, Bilirubin < 1.5 mg/dL

 -  Patients must have adequate bone marrow function: Platelets >100,000 cells/mm3,
 Hemoglobin > 9.0g/dL, WBC > 3,000 cells/mm3, and ANC > 1,500 cells/mm3

 -  Patients must have adequate renal function: creatinine <1.5 mg/dL

 -  Age > 18 years old

 -  Women of childbearing potential and sexually active males must agree to use effective
 contraception during treatment and for three months after completing treatment

 -  Negative serum or urine B-hCG pregnancy test at screening for patients of childbearing
 potential

 -  No previous or concurrent malignancy except inactive nonmelanoma skin cancer, in situ
 carcinoma of the cervix, treated grade 1 papillary bladder cancer, localized prostate
 cancer detected via biopsy only and being treated with "watchful waiting", or other
 cancers where the patient has no evidence of recurrence for more than 5 years

 -  Must be at least 28 days since surgical procedure and/or radiation therapy and at
 least 4 weeks since last treatment with targeted therapies such as cetuximab or
 immunotherapy.

 -  No significant inter-current illness such as serious infection requiring intravenous
 antibiotics.

 -  Patients must have < Grade 2 pre-existing peripheral neuropathy (per CTCAE v4.0)

 -  Ability to provide informed consent

 Exclusion Criteria:

 -  Prior systemic cytotoxic chemotherapy for unresectable SCC. Prior adjuvant or
 neoadjuvant cytotoxic chemotherapy provided not within prior 28 days is allowed. Prior
 systemic therapies with a targeted agent (cetuximab) or immunotherapy in the setting
 of unresectable SCC (is allowed).

 -  Prior taxane based chemotherapy

 -  The presence of any CNS tumor that has not been stable for at least 3 months off of
 corticosteroids and confirmed by imaging.

 -  Prior major organ transplant or autoimmune disease requiring chronic immunosuppression

 -  Psychiatric illness or social situation that would preclude compliance.

 -  Active or chronic infection with HIV, hepatitis B or hepatitis C. Formal testing
 should be performed if clinical suspicion.

 -  Patients with New York Heart Association class II, III, or IV disease or arrhythmia
 requiring treatment (rate controlled Atrial fibrillation is allowed)

 -  Lack of measurable disease on imaging studies as defined by RECIST 1.

 -  Any condition that in the opinion of the treating physician is likely to prevent the
 patient from complying with any aspect of the protocol or that may put the patient at
 unacceptable risk

 -  Known allergy to treatment medication