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

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

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.

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.

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)