Sirolimus and Cyclophosphamide in Metastatic or Unresectable Myxoid Liposarcoma and Chondrosarcoma

A Phase 2, Single Arm, Multi Center Trial Evaluating the Efficacy of the COmbination of Sirolimus and cYclophosphamide in Metastatic or Unresectable Myxoid Liposarcoma and chOndrosarcoma

Chondrosarcoma and liposarcoma consists of different subtypes with a wide range of patient survival. Current treatment options consist of wide surgical resection, however for patients with a local recurrence or metastatic disease the outcome is poor. New treatment options being evaluated and mouse models show in vivo that mammilian target of rapamycin (mTOR) inhibition can prevent tumour growth. mTOR is an kinase that is present in two complexes and thereby activates multiple pathways. Aberrant mTOR signalling is known to be involved in cancer cell survival. Several clinical studies for patients with bone or soft tissue sarcoma treated with mTOR inhibitors have been conducted and they show promising results. From these studies the investigators can conclude that the combination of an mTOR inhibitor with cyclophosphamide shows promising results in chondrosarcoma. With the lack of other treatment options for unresectable and metastatic chondrosarcoma or myxoid liposarcoma the Eurosarc consortium (www.eurosarc.eu) decided to treat these patients in a standardised way according to a common protocol with the combination of sirolimus and cyclophosphamide using the growth modulation index for evaluation in the current clinical study protocol.

Study Overview

• Status: Completed
• Conditions: Myxoid Liposarcoma; Mesenchymal Chondrosarcoma; Dedifferentiated Chondrosarcoma; Conventional Chondrosarcoma
• Intervention / Treatment: Drug: sirolimus and cyclophosphamide

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Leiden, Netherlands, 2333ZA
    • LUMC
• Spain
  • Barcelona, Spain
    • Hospital de Sant Pau
  • Barcelona, Spain
    • Hospital Val d'Hebron
  • Madrid, Spain
    • CIO Clara Campal
  • Sevilla, Spain
    • Hospital Universitario Virgen del Rocio
  • Valencia, Spain
    • Instituto Valenciano de Oncología
  • Valencia, Spain
    • Hospital Universitario y Politécnico de La Fe

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Pathologically proven conventional chondrosarcoma
• Or pathologically proven myxoid liposarcoma with PIK3CA mutation or Phosphatase and tensin homolog (PTEN) loss
• Or pathologically proven mesenchymal or dedifferentiated chondrosarcoma
• Patient is 18 years and up
• Documented radiographic progression of disease according to RECIST 1.1 criteria in last 6 months
• Written signed informed consent
• Adequate bone marrow function (Hb ≥ 6.0 mmol/L, absolute neutrophil count ≥ 1.5 x 109/L, platelets ≥ 80 x 109/L)
• Availability of archival tumor material for central review or be able to perform a 3 core fresh biopsy
• Ability to adhere to the study visits and all protocol requirements

Exclusion Criteria:

• Previously treated with an mTOR inhibitor
• Known to be allergic to cyclophosphamide
• Life expectancy of less than 3 months
• No measurable lesions according to RECIST 1.1
• Eastern cooperative oncology group (ECOG) Performance status >2
• Major surgery less than 4 weeks prior to start of treatment
• Known human immunodeficiency virus (HIV) positivity
• A decreased renal function with calculated glomerular filtration rate (GFR) < 30ml/min
• Systemic anti-cancer therapy within 28 days prior to the first dose of study drug , or radiotherapy to a target lesion within 21 days prior to the first dose of study drug
• Pregnant or lactating women
• Other invasive malignancies diagnosed within the last 5 years, except non-melanoma skin cancer and localised cured prostate and cervical cancer

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: sirolimus and cyclophosphamide; combining sirolimus 4mg daily orally and cyclophosphamide 200mg day 1 to 7 and 15 to 21 orally in a 4 week schedule	Drug: sirolimus and cyclophosphamide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The time to progression after start of treatment combination treatment of sirolimus and cyclophosphamide	16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparing pre-treatment tumor material and tumor material taken during treatment using immunohistochemistry to compare activation of the pS6, Bcl-2 and mTor pathway and DNA analysis for taqman analysis to search for hotspot mutations.		8 weeks
Register adverse events to evaluate the patient safety and tolerability of the sirolimus and cyclophosphamide combination in myxoid liposarcoma and chondrosarcoma		every 8 weeks until progression (average of 1 year)
To evaluate the response according to response evaluation criteria in solid tumors (RECIST) 1.1		every 8 weeks until progression (average of 1 year)
Using the growth modulation index (GMI) to evaluate treatment efficiency	GMI: Time to progression during sirolimus/cyclophosphamide treatment (TTP2) divided by time to progression before start of this treatment TTP1	every 8 weeks until progression (average of 1 year)
The overall survival after start of treatment till death		every 8 weeks until progression (average of 1 year)

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Investigators: Principal Investigator: Hans Gelderblom, Prof, Leiden University Medical Center

Study record dates

Study Major Dates

• Study Start: June 1, 2014
• Primary Completion (Actual): December 1, 2021
• Study Completion (Actual): December 1, 2021

Study Registration Dates

• First Submitted: January 9, 2016
• First Submitted That Met QC Criteria: June 30, 2016
• First Posted (Estimate): July 1, 2016

Study Record Updates

• Last Update Posted (Actual): April 20, 2022
• Last Update Submitted That Met QC Criteria: April 19, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Connective Tissue; Sarcoma; Neoplasms, Adipose Tissue; Liposarcoma; Liposarcoma, Myxoid; Chondrosarcoma; Chondrosarcoma, Mesenchymal; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Cyclophosphamide; Sirolimus
• Other Study ID Numbers: COSYMO