NAPAGE: NAb-PAclitaxel and GEmcitabine in Advanced Soft Tissue Sarcoma

Study Overview
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Brief Summary
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A clinical trial with biweekly regimen of gemcitabine and nab-paclitaxel for Soft tissue sarcomas (STSs). A Promising antitumor activity in patients with metastatic STS has been reported with gemcitabine alone or in combination with taxanes including docetaxel and paclitaxel in pre-treated patients. Nab-paclitaxel is a 130-nm albumin-bound formulation of paclitaxel particles (Celgene, Summit, NJ) which was designed to eliminate the toxicities associated with Cremophor®-EL. Nab-paclitaxel at equal dose of paclitaxel showed increased antitumor activity, enhanced endothelial cell transport and 33% higher intra-tumor paclitaxel concentration in preclinical models of solid tumor xenografts promising an advantageous pharmacokinetic profile In sarcoma, nab-paclitaxel demonstrated preclinical anti-tumor activity in rhabdomyosarcoma xenograft model. Local relapsed tumors following paclitaxel treatment proved to be paclitaxel-resistant but remained responsive to nab-paclitaxel. These findings provide the rationale for further evaluation of nab-paclitaxel in combination with gemcitabine for soft tissue sarcoma treatment.

Detailed Description
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Soft tissue sarcomas (STSs) account for 1% of all human cancers and consist of at least 50 different histological subtypes which have different clinical behavior and response to chemotherapy. Patients with advanced disease (locally advanced or metastatic) have a somber prognosis with a median OS between 12 and 15 months. Palliative chemotherapy is the mainstay of treatment in the metastatic setting, although in a small subset with limited metastases local treatment may be curative. First-line treatment for advanced soft-tissue sarcoma includes doxorubicin hydrochloride, alone or in combination with other chemotherapy agents (e.g., ifosfamide), or olaratumab. Beyond first line several agents have shown activity, including gemcitabine/docetaxel, trabectedin and pazopanib, though no standard regimen has been established. Promising antitumor activity in patients with metastatic STS has been reported with gemcitabine alone or in combination with taxanes including docetaxel and paclitaxel in pre-treated patients. Nab-paclitaxel is a 130-nm albumin-bound formulation of paclitaxel particles (Abraxane®, Celgene, Summit, NJ) which was designed to eliminate the toxicities associated with Cremophor EL®. Nab-paclitaxel at equal dose of paclitaxel showed increased antitumor activity, enhanced endothelial cell transport and 33% higher intra-tumor paclitaxel concentration in preclinical models of solid tumor xenografts promising an advantageous pharmacokinetic profile In sarcoma, nab-paclitaxel demonstrated preclinical antitumor activity in rhabdomyosarcoma xenograft model. Local relapsed tumors following paclitaxel treatment proved to be paclitaxel-resistant but remained responsive to nab-paclitaxel. These findings provide the rationale for further evaluation of nab-paclitaxel in combination with gemcitabine for soft tissue sarcoma treatment. Phase Ib objective: To assess the safety and feasibility of combining nab-paclitaxel and gemcitabine Phase II objective: To determine whether or not gemcitabine/nab-paclitaxel regimen exhibits antitumor activity that is worth testing further in STS.

Official Title
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NAPAGE: NAb-PAclitaxel and GEmcitabine in Advanced Soft Tissue Sarcoma. A Multicenter Open-label Single Arm Phase Ib/IIa Trial

Conditions
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Soft Tissue Sarcoma

Intervention / Treatment
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* Drug: Nab-Paclitaxel
* Drug: gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed minimum grade 2, locally advanced or metastatic STS refractory to chemotherapy and not suitable for local treatment. Minimum one line and maximum 2 lines of previous chemotherapy for advanced/metastatic STS Measurable disease according to RECIST v1.1 Age ≥ 18 years WHO performance status 0-2 Adequate hematological, hepatic and renal function Negative pregnancy test Effective method of birth control Peripheral neuropathy at enrolment must be ≤ grade 1 Exclusion Criteria: Uncontrolled CNS metastases Previous or concomitant malignancy diagnosed within 3 years More than 2 lines of previous systemic treatment for STS Previous sarcoma treatment with gemcitabine and/or nab-paclitaxel or other taxanes Radiotherapy within 4 weeks prior to registration Concurrent or recent treatment with any other experimental drug Concomitant use of other anti-cancer drugs Severe or uncontrolled cardiovascular disease History of cerebrovascular accident or intracranial hemorrhage within 2 months prior to registration Evidence of active, noninfectious pneumonitis or history of interstitial lung disease Known history of human immunodeficiency virus (HIV) or active chronic Hepatitis C or Hepatitis B Virus infection or any uncontrolled active systemic infection Any concomitant drugs contraindicated for use with the trial drugs according to the approved product information Known hypersensitivity to the trial drug(s)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a single-arm phase Ib/IIa multi-center study in patients with locally advanced or metastatic soft tissue sarcoma who have received first line or second line chemotherapy with no response or with evidence of disease progression.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: nab-paclitaxel and gemcitabine<br>Treatment consists of the combination treatment of nab-paclitaxel and gemcitabine, which is given every 2 weeks during 28-day cycle intervals until disease progression. | Drug: Nab-Paclitaxel<br>* 150 mg/m2 / 125 mg/m2<br>* Other names: Abraxane;Drug: gemcitabine<br>* 1000 mg/m2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Dose-limiting toxicity (DLT) | DLT is defined as any of the following adverse events (AEs) occurring during the first cycle of treatment and regarded by the investigators and/or the Sponsor to be related to nab-paclitaxel and/or gemcitabine (AEs not related to the IMPs are not regarded as DLT) | during the first cycle of treatment (28 days) | 
| Phase II: Progression-free rate (PFR) | PFR at 12 weeks after registration determined by the percentage of progression-free patients at 12 weeks. Progression is defined as one of the following events (whichever occurs first): Progressive disease (PD) assessed according to the RECIST v1.1 before week 13 (allowed is a 1 week delay in the tumor assessment at week 12). Death due to any cause up to week 12. Start of second line treatment before week 12. No tumor assessment after week 11 without subsequent treatment which shows stabilization or response. | at 12 weeks after registration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: PFR 12 weeks |  | at 12 weeks after registration | 
| Phase I: Best response assessed according to RECIST v1.1 |  | assessed for up to 5 years after patient registration | 
| Phase I: Adverse events (AEs), assessed according to NCI CTCAE v4.03 |  | assessed for up to 5 years after patient registration | 
| Phase II: Progression-free survival (PFS) | PFS defined as the time from registration until progression according to RECIST v1.1 or death from any cause, whichever occurs first. Patients without an event at the time of analysis and patients starting a new anticancer therapy in the absence of an event will be censored at the date of the last tumor assessment before the start of the new therapy, if any. | assessed for up to 5 years after patient registration | 
| Phase II: Overall Survival (OS) | OS defined as the time from registration until death from any cause. Patients without an event at the time of analysis will be censored at the date they were last known to be alive. | assessed for up to 5 years after patient registration | 
| Phase II: Best response assessed according to RECIST v1.1 |  | assessed for up to 5 years after patient registration | 
| Phase II: AEs, assessed according to NCI CTCAE v4.03 |  | from registration until 28 days after administration of the last dose of trial treatment | 
| Phase II: Symptom-related quality of life assessed by questionnaires | Symptom-related quality of life will be assessed with the M.D. Anderson Symptom Inventory (MDASI), which measures the severity of 13 cancer-related symptoms and their impact on six dimensions of daily life at their worst in the last 24 hours on a 0-10 numerical rating scale, with 0 being not present and 10 being as bad as you can imagine. | assessed for up to 5 years after patient registration | 
| Phase II: Nab-paclitaxel related sensory neuropathy assessed by questionnaires | To address an important side-effect of nab-paclitaxel, sensory neuropathy will be assessed by the 4-item subscale of the FACT/GOG-Ntx (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity), which measures the severity of sensory neuropathy in the last 7 days on a 0-4 numerical rating scale, with 0 being not at all and 4 being very much. | assessed for up to 5 years after patient registration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nab-Paclitaxel, Gemcitabine, Advanced soft tissue sarcoma, Cancer, Sarcoma, Abraxane®