Trabectedin Plus Olaparib in Metastatic or Advanced Sarcomas (TOMAS)

A Phase Ib Study on the Combination of Trabectedin and Olaparib in Unresectable Advanced/Metastatic Sarcomas After Failure of Standard Therapies

This is a Phase 1b, multi-site, open-label, non-randomized clinical trial evaluating the safety, tolerability, and pharmacokinetics of escalating doses of olaparib and trabectedin in patients with unresectable advanced/metastatic sarcomas. Patients will continue to be treated on this combination regimen in the absence of disease progression, intolerable toxicity or patient's decision.

Inclusion Criteria:

• written informed consent
• histologically documented and not surgically resectable or metastatic sarcomas which progressed after first or further line treatments for relapsing disease
• Measurable disease as defined by RECIST v1.1.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0/1. ECOG PS 2 are eligible if depends solely on orthopedic problems
• Estimated life expectancy of ≥ 4 months
• Age ≥18 years
• Adequate organ function: Hemoglobin > 10.0 g/dl; Absolute neutrophil count (ANC) >1,500/mm3; Platelet count >= 100,000/μl; Total bilirubin < 1.5 times the upper limit of normal (ULN); ALT and AST < 2.5 x ULN (< 5 x ULN for patients with liver involvement of their cancer); Alkaline phosphatase < 2.5 x ULN; PT-INR/PTT < 1.5 x ULN; Serum creatinine < 1.5 x ULN or creatinine clearance ≥ 50 ml/min; Albumin > 25 g/l; Creatine phosphokinase (CPK) < 2.5 x ULN

Exclusion Criteria:

• Involvement in the planning and/or conduct of the study
• Previous enrolment in the present study
• Participation in another clinical study with an investigational product during the last month
• Persistent toxicities (≥CTCAE grade 2) with the exception of alopecia, caused by previous anticancer therapies
• Dementia or significantly altered mental status
• Patients with any severe and/or uncontrolled medical conditions
• HIV infection
• Active clinically serious infections (> grade 2 NCI-CTCAE version 4.03).
• Active viral hepatitis (HBV or HCV infection)
• Symptomatic metastatic brain or meningeal tumors (unless the patient is > 6 months from definitive therapy, does not require corticosteroid treatment, has a negative imaging study within 4 weeks of study entry and is clinically stable with respect to the tumor at the time of study entry).
• Patients with seizure disorders requiring medication (such as steroids or anti-epileptics)
• Pregnant or breast-feeding patients. Women of childbearing potential must have a negative pregnancy test performed within 7 days before the start of treatment. Both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial and 5 months after last dose of study drug
• Patients with evidence or history of bleeding diathesis
• Patients undergoing renal dialysis
• Patients unable to swallow oral medications
• Uncontrolled diabetes (fasting glucose > 2 x ULN)
• Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent (except corticosteroids with a daily dosage equivalent to prednisone ≤ 20 mg for adrenal insufficiency). Topical or inhaled corticosteroids are permitted
• Patients with a history of another malignancy within 5 years prior to study entry, except curatively treated non-melanotic skin cancer or in-situ cervical cancer or other solid tumors curatively treated with no evidence of disease for ≥5 years.
• Anticancer chemotherapy or immunotherapy during the study or within 4 weeks of treatment start
• Radiotherapy during study or within 3 weeks of start of study drug. (Palliative radiotherapy allowed)
• Major surgery within 4 weeks of start of study
• Prior exposure to the study drugs or their analogues
• Patients with known hypersensitivity to trabectedin, olaparib or to their excipients
• Patients can receive a stable dose of bisphosphonates for bone metastases before and during the study as long as these were started at least 4 weeks prior to treatment with the study drugs
• Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
• A history of noncompliance to medical regimens or inability or unwillingness to return for scheduled visits
• Corrected QT interval on the 12-lead ECG (QTc) >470 msec (Bazett Formula)
• use of strong CYP3A4 inhibitors/inducers
• Patients with myelodysplastic syndrome/acute myeloid leukemia