Gemcitabine and docetaxel combination chemotherapy for advanced bone and soft tissue sarcomas: protocol for an open-label, non-randomised, Phase 2 study

Background The prognosis of patients with metastatic or advanced sarcomas is poor and there are few options for treatment. Several studies have shown that gemcitabine and docetaxel (GD) combination chemotherapy has antitumor activity against various subtypes of sarcoma. Recently, some studies have shown a favourable outcome for GD combination chemotherapy for relapsed high-grade osteosarcoma and spindle cell sarcoma of bone. If the effectiveness of GD is proven, this will result in new treatment options for advanced bone and soft tissue sarcomas (STS). The aim of this prospective Phase 2 study is to evaluate the efficacy and toxicity of the GD combination in patients with advanced bone sarcomas and STS. Methods This is a Phase 2, single-arm, open-label study to investigate the efficacy and safety of combination chemotherapy with GD for advanced bone sarcomas and STS and will enrol 20 patients. The patients will receive gemcitabine 900 mg/m2 on Days 1 and 8, and docetaxel 70 mg/m2 on Day 8 in 3-week cycles until disease progression or other evidence of treatment failure. The primary aim of this study is to analyse GD’s effect on progression-free survival (PFS). The secondary objectives are to analyse treatment efficacy and safety in terms of response rate, tumour control rate, overall survival, and adverse event rate. The length of follow-up will be 5 years. Discussion This study will evaluate the efficacy and safety of combination therapy with gemcitabine and docetaxel for bone sarcomas and STS. If this combination proves to be acceptable, it could be used for as second, third, or later line therapy for patients with sarcomas (especially bone sarcomas). In the future, the role of various treatments, including GD therapy, will be clarified for specific subtypes of sarcoma. Trial registration This study was registered as UMIN000031004 (University Hospital Medical Information Network-Clinical Trial Registry: UMIN-CTR) on 1 March 1 2018 and with the Japan Registry of Clinical Trials (jRCT) as jRCTs051180042 on 30 January 2019. The posted information will be updated as needed to reflect protocol amendments and study progress. Electronic supplementary material The online version of this article (10.1186/s12885-019-5923-7) contains supplementary material, which is available to authorized users.


Background
Sarcomas are a heterogeneous group of rare mesenchymal malignant tumours. Chemotherapy has a proven role in the treatment of primary bone sarcomas, including osteosarcoma and Ewing sarcoma. Small round-cell soft tissue sarcomas (STS) such as rhabdomyosarcoma and Ewing sarcoma, which usually occur in children and young adults, are sensitive to chemotherapy. Osteosarcoma and small round-cell sarcomas are therefore treated with chemotherapy in combination with surgery or radiation therapy. The therapy for high-risk patients with high-grade large non-small round-cell STS, which usually occurs in older adults, is usually surgery and chemotherapy. There is no established chemotherapy for bone sarcomas other than osteosarcoma and Ewing sarcoma.
A combination chemotherapy regimen comprising methotrexate, doxorubicin, and cisplatin (MAP) is used for osteosarcoma, whereas regimens including vincristine, doxorubicin, ifosfamide, and actinomycin D (VAIA) or vincristine, doxorubicin, and cyclophosphamide plus ifosfamide and etoposide (VDC-IE) are used for Ewing sarcoma. Vincristine, doxorubicin, and cyclophosphamide (VAC) is used for rhabdomyosarcoma and doxorubicin plus ifosfamide for non-round cell STS. Because no standard chemotherapy for bone sarcomas other than osteosarcoma and Ewing sarcoma has yet been established, combination chemotherapy based on cisplatin, doxorubicin, and ifosfamide is mainly used; however, the efficacy is still uncertain. Prognosis of patients with advanced soft tissue and bone sarcomas is poor. Adriamycin-based combination chemotherapy results in a higher response rate than other combinations, ranging from 25 to 40%, but median overall survival (OS) is only 8-12 months [1,2]. Similarly, adult patients with metastatic bone sarcomas have a 5-year overall survival of less than 25% [3,4].
The anticancer agents gemcitabine and docetaxel are used to treat various malignant tumours, including nonsmall cell lung cancer and breast cancer. Combination chemotherapy with gemcitabine and docetaxel (GD) has been shown to be effective for metastatic leiomyosarcoma and other STS [5][6][7][8][9][10]. Recently, GD has been used for recurrent or refractory osteosarcoma and other bone sarcomas because several studies showed that this combination is effective [10][11][12]. Chemotherapeutic options for advanced sarcomas are limited. Recent options used in patients with advanced STS have included pazopanib, trabectedin, and eribulin. There are few options for second-or third-line therapy for refractory or metastatic bone sarcomas that has previously been treated with standard chemotherapy. If the effectiveness of GD is proven, it has the potential to result in new treatment options for advanced bone sarcomas and STS. Subtypes of sarcoma also respond differently to various chemotherapy drugs and treatment regimens. Future studies should analyse the response pattern of patients with different histologic subtypes of bone and soft tissue sarcoma. The aim of this Phase 2 study is to evaluate the efficacy and toxicity of GD in patients with advanced bone sarcomas and STS.

Study objectives
The primary aim of this study is to analyse the GD therapy effect on progression-free survival (PFS). The secondary objectives are to analyse treatment efficacy and safety by assessing response rate, tumour control rate, overall survival and adverse event rate.
The target sample size is based on expected response rate; however, the primary endpoint is defined as PFS because prolonging time to disease progression is important even if the response rate is less than expected.

Design
This is a Phase 2, single-arm, open-label study to investigate the efficacy and safety of combination chemotherapy with gemcitabine and docetaxel (GD) for advanced bone sarcomas and STS. Patients will receive gemcitabine 900 mg/m 2 on Days 1 and 8, and docetaxel 70 mg/ m 2 on Day 8, repeated at 21 days intervals until disease progression or other evidence of treatment failure. Patients will undergo computed tomography or magnetic resonance imaging and be evaluated for response after every second cycle using Response Evaluation Criteria in Solid Tumours (RECIST). The total duration of the study will be 5 years; all participants will attend for follow-up every 4-8 weeks after progression or treatment failure. A flowchart of the study design is presented in Fig. 1.

Patient cohort
The participants in this study will be recruited at Kobe University Hospital.

Target sample size and rationale
A sample size of 16 will be required for a threshold response rate of 6% (based on the results of previous studies) and an expected response rate of 25%, with a one-sided α of 0.1 and a β of approximately 0.2. To allow for four dropouts, the target sample size of this study has been set to 20. Assuming that four patients will be enrolled per year, the enrolment period has been set to 5 years.

Study treatment Drugs used
The drugs will be administered in accordance with instructions in the package inserts.
Gemcitabine (Gemzar®, Eli Lilly Oncology, Indianapolis IN, USA), Docetaxel (Taxotere®, Sanofi-Aventis, Paris, France) The study patients will receive the marketed drugs that are available at the medical institution.

Protocol treatment
Protocol treatment should be started within 14 days after enrolment (day of enrolment counted as day zero; thus, up to the same day of the week after the next one is acceptable), and repeated in 3-week cycles until the criteria for treatment withdrawal (below) have been met. The drugs may be administered only after the participant has been confirmed to fulfil the following criteria within 3 days before Day 1 of each cycle: haemoglobin ≥8.0 g/dL, neutrophil count ≥1,000/mm 3 , platelet count ≥50,000/ mm 3 , AST (GOT) ≤ 90 IU/L, ALT (GPT) ≤ 125 IU/L for male and ≤ 69 IU/L for female participants, creatinine ≤1.605 mg/dL for male and ≤ 1.185 mg/dL for female participants, grade 0-2 fatigue, grade 0-2 oedema limbs, grade 0-1 diarrhoea, grade 0-1 haematuria, grade 0-1 mucositis oral, grade 0-1 supraventricular tachycardia, grade 0-1 ventricular arrhythmia, grade 0-1 pneumonitis, and grade 0-1 infection. The drugs may be administered only after the participant has been confirmed to fulfil the following criteria within 3 days before Day 8: haemoglobin ≥8.0 g/dL, neutrophil count ≥1,000/mm 3 , platelet count ≥50,000/mm 3 , AST (GOT) ≤ 90 IU/L, ALT (GPT) ≤ 125 IU/L for male and ≤ 69 IU/L for female participants. The drugs should not be administered on Day 8 if the participant has Grade 2 or worse pneumonitis. If the above criteria are not fulfilled, protocol treatment should be withheld until they are met. If initiation of Fig. 1 Flowchart of Phase 2 study of gemcitabine and docetaxel combination chemotherapy for sarcomas treatment is still considered contraindicated 15 days after Day 1 of that cycle, the patient will be classified as a "protocol treatment withdrawal".

Criteria for dose reduction
Doses will be reduced in participants with any toxicity meeting the criteria listed in Table 1 (adverse events for which a causal relationship to the protocol treatment cannot be ruled out). A 20% reduction in doses of gemcitabine and docetaxel is suggested. Dose modifications are allowed once, the dosage cannot be re-escalated. If toxicity does not abate during the monitoring period, administration of gemcitabine or docetaxel will be interrupted and/or the dose further reduced. The protocol treatment should be permanently discontinued for any haematological or non-haematological toxicity requiring an interruption of ≥14 days.

Primary endpoint
The primary endpoint is progression-free survival (PFS), calculated as time from enrolment until first objective documentation of disease progression, treatment failure, or death from any cause.

Secondary endpoints
Secondary endpoints are objective tumour response, calculated as overall response rate and disease control rate, along with time to onset of response. Assessment of response and progression is based on RECIST version 1.1 [13]. Overall survival (OS) will be calculated as time from enrolment until death from any cause. Safety and tolerability will be assessed continuously throughout the study. Adverse events will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) [14]. The worst grade of an event during the observation period will be used to denote the severity of that adverse event. Primary and secondary prophylaxis of neutropenia will be routinely assessed and documented in each cycle. Repeated physical examinations will be conducted throughout the study period (consisting of the treatment and post-treatment follow-up periods), including assessment of vital signs and haematological and chemical laboratory tests.

Statistical analysis
The per protocol set (PPS) will consist of the full analysis of subjects enrolled in this study, excluding those lacking baseline data or with any significant protocol violations involving the study method or concomitant therapy. The safety analysis set will consist of all patients enrolled in this study who received at least one dose of the study drugs. The primary analysis of PFS will be performed on the PPS 1 year after the end of the enrolment period. A confirmatory analysis of all secondary endpoints will be performed at the end of the follow-up period. Kaplan-Meier curves will be used to analyse PFS, OS, and median survival time and 95% confidence intervals for point estimates will be calculated using Greenwood's formula. The safety endpoint of this study is the frequency of adverse events. No interim analysis is planned.

Discussion
Bone sarcomas and STS are rare and heterogeneous malignant tumours that account for approximately 1% of all malignant tumours. Osteosarcoma, the most common primary malignant bone tumour, is treated by a standard chemotherapy regimen including high-dose methotrexate, This study aims to evaluate the efficacy and safety of combination therapy with GD for bone sarcoma and STS. If GD therapy proves to be acceptable, we can provide it as second, third or later lines for sarcoma patients (especially for bone sarcomas). In the future, the role of these treatments, including GD therapy, in specific subtypes of sarcoma may be further clarified.
Limitations of this study include that the sample size is small and that patients with all subtypes of sarcoma will be enrolled, including both bone and soft tissue lesions. A multi-institutional study is needed to achieve a larger sample size and investigate the efficacy of GD therapy for individual subtypes in Japan.