Clinical trial NCT03524898: NAPAGE: NAb-PAclitaxel and GEmcitabine in Advanced Soft Tissue Sarcoma
Official title: NAPAGE: NAb-PAclitaxel and GEmcitabine in Advanced Soft Tissue Sarcoma. A Multicenter Open-label Single Arm Phase Ib/IIa Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Soft Tissue Sarcoma
Keywords: Nab-Paclitaxel
Gemcitabine
Advanced soft tissue sarcoma
Cancer
Sarcoma
Abraxane®
Lead sponsor: Swiss Group for Clinical Cancer Research
Sponsor class: OTHER
First posted: 2018-05-15
Enrollment: 39
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Phase I: Dose-limiting toxicity (DLT)
timeFrame: during the first cycle of treatment (28 days)
measure: Phase II: Progression-free rate (PFR)
timeFrame: at 12 weeks after registration
Secondary outcomes:
measure: Phase I: PFR 12 weeks
timeFrame: at 12 weeks after registration
measure: Phase I: Best response assessed according to RECIST v1.1
timeFrame: assessed for up to 5 years after patient registration
measure: Phase I: Adverse events (AEs), assessed according to NCI CTCAE v4.03
timeFrame: assessed for up to 5 years after patient registration
measure: Phase II: Progression-free survival (PFS)
timeFrame: assessed for up to 5 years after patient registration
measure: Phase II: Overall Survival (OS)
timeFrame: assessed for up to 5 years after patient registration
measure: Phase II: Best response assessed according to RECIST v1.1
timeFrame: assessed for up to 5 years after patient registration
measure: Phase II: AEs, assessed according to NCI CTCAE v4.03
timeFrame: from registration until 28 days after administration of the last dose of trial treatment
measure: Phase II: Symptom-related quality of life assessed by questionnaires
timeFrame: assessed for up to 5 years after patient registration
measure: Phase II: Nab-paclitaxel related sensory neuropathy assessed by questionnaires
timeFrame: assessed for up to 5 years after patient registration
Other outcomes:
Locations:
city: Basel
country: Switzerland
facility: Universitaetsspital Basel
city: Bellinzona
country: Switzerland
facility: Istituto Oncologico della Svizzera Italiana
city: Bern
country: Switzerland
facility: Inselspital, Bern
city: Chur
country: Switzerland
facility: Kantonsspital Graubünden
city: Geneva
country: Switzerland
facility: Hopital Cantonal Universitaire de Geneve
city: Lausanne
country: Switzerland
facility: CHUV - Swiss Cancer Center Lausanne
city: St. Gallen
country: Switzerland
facility: Kantonsspital St. Gallen
city: Zürich
country: Switzerland
facility: UniversitätsSpital Zürich
Study officials:
affiliation: Département d'Oncologie CHUV , Lausanne
name: Antonia Digklia, MD
role: STUDY_CHAIR
affiliation: Cantonal Hospital of St. Gallen
name: Christian Rothermundt, MD
role: STUDY_CHAIR
References: