A Trial Comparing Two Medications as First Treatment in Elderly Patients With Metastatic or Advanced Soft Tissue Sarcoma

A Randomized Phase II Trial Comparing Pazopanib With Doxorubicin as First Line Treatment in Elderly Patients With Metastatic or Advanced Soft Tissue Sarcoma

Patients with a locally advanced or metastatic (i.e., there are already metastases of the diagnosed tumor in the body outside the primary lesion) soft tissue sarcoma will be recruited for this study. The minimum age to enter the study is 60 years.

Therapy with doxorubicin is the mainstay of palliative chemotherapy for these patients, which is associated with hematological toxicity and an increase of the infection rate. Pazopanib is known to rarely induce hematological toxicity or to trigger infection. We therefore assume that pazopanib exerts similar activity while decreasing neutropenia and neutropenic fever. Pazopanib is already approved in the U.S. and Europe for the treatment of advanced soft tissue sarcoma.

Doxorubicin and pazopanib will be randomly allocated to either receive doxorubicin or pazopanib in a phase II clinical trial. The aim of this study is to measure the treatment effect (reduction in tumor size or tumor stabilization) for both drugs, as well as the survival rate, and the duration of tumor control by the different therapies. A further objective is to measure the quality of life by standardized questionnaires throughout the course of treatment.

Inclusion Criteria:

• 1. Signed written informed consent and willingness to comply with treatment and follow-up. Procedures conducted within 3 weeks as part of routine clinical management (e.g. blood count, imaging) and obtained prior to signing consent may be used for screening or baseline purposes if they are conducted as specified in the protocol

• 2. Male and female patients age ≥ 60 years at day of inclusion

• 3. Histologically confirmed diagnosis of metastatic or advanced soft tissue sarcoma of intermediate or high grade with disease progression within 6 months prior to study inclusion:

  • Fibrosarcoma
  • Pleomorphic high grade sarcoma ("malignant fibrous histiocytoma")
  • Leiomyosarcoma
  • Liposarcoma
  • Malignant glomus tumor
  • Rhabdomyosarcoma, alveolar or pleomorphic (excluding embryonal)
  • Vascular sarcoma (epithelioid hemangioendothelioma, angiosarcoma)
  • Synovial sarcoma
  • Not otherwise specified (NOS)
  • Malignant peripheral nerve sheath tumors
  • Other types of sarcoma (not listed as ineligible), if approved by the study coordinator.

Excluding:

Uncertain differentiation (epithelioid, alveolar soft part, clear cell, desmoplastic small round cell, malignant mesenchymoma, PEComa), chondrosarcoma, Ewing sarcomas/PNET, chordoma, malignant solitary fibrous tumors, embryonal rhabdomyosarcoma, osteosarcoma, gastrointestinal stromal tumors, dermatofibrosarcoma protuberans, inflammatory myofibroblastic sarcoma (low-grade), neuroblastoma, malignant mesothelioma, and mixed mesodermal tumors of the uterus (Study inclusion is based on local histopathological diagnosis).

• 4. ECOG performance status of 0-2

• 5. Evidence of progressive disease prior to start of treatment with measurable disease according to RECIST 1.1

• 6. Preferably archived tumor tissue of the most recent histology or, if not available, tumor block or 8 representative unstained sections on slides must be provided for all subjects for biomarker analysis within first month of treatment for central review

• 7. Adequate organ system function

• 8. Male patients with female partners of childbearing potential must meet one of the following criteria:

  • At least 6 weeks after surgical sterilization by vasectomy with documentation of azoospermia
  • Correct use of two reliable contraception methods for 14 days before exposure to IMP, through the dosing period, and for at least 21 days after the last dose of IMP. This includes every combination of a hormonal contraceptive (such as oral, injection, transdermal patch, implant, cervical ring) or an IUD/IUS with a barrier method (diaphragm, cervical cap, Lea contraceptive, femidom, or condom).
  • Complete sexual abstinence for 14 days before exposure to IMP, through the dosing period, and for at least 21 days after the last dose of IMP.

• 9. Female patients of childbearing potential must have a negative serum pregnancy test within 14 days of first dose of study treatment and agree to use effective contraception, as defined in Section "3.1 Inclusion criteria" during the study and for 14 days following the last dose of investigational product.

Exclusion Criteria:

• 1. Prior malignancy Excluding: Subjects who have had another malignancy and have been disease-free for 2 years, or subjects with a history of completely resected nonmelanomatous skin carcinoma, or successfully treated in situ carcinoma or incidental prostate cancer (TNM stage T1a or T1b) are eligible.

• 2. History or clinical evidence of CNS metastases Excluding: Subjects who have previously-treated CNS metastases (radiotherapy, surgery ± radiotherapy, radiosurgery, or gamma knife) and who meet both of the following criteria: a) are asymptomatic and b) have no requirement for steroids or enzyme-inducing anticonvulsants 12 weeks prior to study inclusion. Screening with CNS imaging (CT or MRI) is required only if clinically indicated or if the subject has a history of CNS metastases.

• 3. Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including but not limited to:

  • Active peptide ulcer disease
  • Known intraluminal metastatic lesion(s) with risk of bleeding
  • Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease) or other gastrointestinal conditions with increased risk of perforation
  • History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning of study treatment

• 4. Clinically significant gastrointestinal abnormalities that may affect absorption of IMP including but not limited to:

  • Malabsorption syndrome
  • Major resection of the stomach or small bowels

• 5. Presence of uncontrolled infection

• 6. QTc > 480 msecs using Bazett's formula

• 7. History of any one or more of the following cardiovascular conditions within the past 6 months:

  • Cardiac angioplasty or stenting
  • Myocardial infarction
  • Unstable angina
  • Coronary artery bypass graft surgery
  • Symptomatic peripheral vascular disease

• 8. Class III or IV congestive heart failure as defined by NYHA

• 9. Poorly controlled hypertension (SBP of ≤ 150 mmHg or DBP of ≤95 mmHg is acceptable provided that BP will be treated and monitored at least weekly. The goal is to attain controlled hypertension within 4 weeks of start of IMP which is defined as grade ≤1 hypertension CTCAE Version 4.0) Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. BP must be re-assessed twice with an interval of at least

  1h before start of treatment and should be ≤140/90 mmHg for a subject to be eligible for the study. However, BP of ≤150/95 mmHg is acceptable provided the above measures are employed.

• 10. History of cerebrovascular accident including TIA, pulmonary embolism, or untreated DVT within the past 6 months Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible.

• 11. Major surgery or trauma within 28 days before first dose of IMP and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement are not considered to be major)

• 12. Evidence of active bleeding or bleeding diathesis

• 13. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels

• 14. Hemoptysis in excess of 2.5 mL once within 8 weeks of first dose of IMP

• 15. Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures

• 16. Unable or unwilling to discontinue use of prohibited medications (see Section 5.5.5) for at least 14 days or 5 half-lives of a drug (whichever is longer) prior to the first dose of IMP and for the duration of the study

• 17. Treatment with any of the following anti-cancer therapies:

  • Radiation therapy, surgery, or tumor embolization within 14 days prior to the first dose of IMP OR
  • Chemotherapy, immunotherapy, biologic therapy, investigational therapy, or hormonal therapy within 14 days or 5 half-lives of a drug (whichever is longer) prior to the first dose of IMP 18. Any ongoing toxicity from prior anti-cancer therapy that is CTCAE > grade 1 and/or that is progressing in severity except alopecia

• 19. Prior systemic therapy for metastatic or advanced disease. Neoadjuvant or adjuvant chemotherapy is allowed, unless disease progression occurred within 6 months following end of treatment (see protocol chapter 5.4.2 for specifics)

• 20. Current participation in any other clinical trial and/or participation in another clinical trial within 30 days before the study begins

• 21. Known hypersensitivity to any component of IMPs