Trabectedin Plus Olaparib in Metastatic or Advanced Sarcomas (TOMAS)

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.


Eligibility Criteria:
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