Trabectedin Plus Olaparib in Metastatic or Advanced Sarcomas (TOMAS)

Study Overview
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Brief Summary
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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.

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

Conditions
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Soft Tissue Sarcoma, Bone Tumor

Intervention / Treatment
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* Drug: trabectedin
* Drug: olaparib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trabectedin plus olaparib<br>All patients will be treated with trabectedin and olaparib in an open-label fashion. The dosage of the drugs at which each patient is treated depends on the dose level reached at the time of enrollment. | Drug: trabectedin<br>* trabectedin will be administered in a 24-h continuous i.v. infusion every 3 weeks<br>* Other names: Yondelis;Drug: olaparib<br>* olaparib will be administered in a continuous daily dose every 12 hours<br>* Other names: Lynparza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| maximum tolerated dose | safety will be evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 | from start up to 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response | best overall response will be defined according to the Response Evaluation Criteria in Solid Tumor version 1.1 (RECIST v 1.1) | baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years | 
| Clinical Benefit Rate | Clinical Benefit Rate (CBR): will be defined as the rate of CR (complete response) + PR (partial response) + stable disease lasting at least 12 weeks. CR, PR and stable disease will be defined according to RECIST v 1.1. | baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years | 
| Growth Modulation Index | Growth modulation index (GMI) will be calculated as: GMI=TTPn/TTPn-1. TTPn: Time To Progression on the new agent. TTP n-1: Time To Progression on the treatment the patient received just before the new agent was started. | baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years | 
| Overall Survival | time from the date of enrollment to date of death or to the date being censored at two years (whichever occurs first). | baseline and up to 2 years | 
| Duration of Tumor Response | Duration of Objective Response (complete or partial responses) will be measured from the date that a complete or partial response is first documented (whichever occurs first) to date of progression or death due to progressive disease, whichever occurs first. | baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years | 
| Progression-Free Survival (PFS) | PFS is defined as the time from the date of enrollment to the date of first documentation of disease progression, or to the death from any cause. | baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years | 
| Pharmacokinetic of trabectedin (AUC) | The concentration-time data will be used for a preliminary assessment of the effect of combination therapy on the single-dose pharmacokinetics of trabectedin and olaparib. The data will be analyzed by noncompartmental methods. Pharmacokinetic parameters for trabectedin: steady state profile, end of infusion concentration, area under the concentration-time curve (AUC), and, if data permit, terminal phase half-life. For these parameters, the following descriptive statistics will be calculated: mean, standard deviation, coefficient of variation, median, and geometric mean. Any drug-drug interaction will be thoroughly searched. For both trabectedin and olaparib all pharmacokinetic evaluations will be done only for the first 2 cycles. | baseline, days 1-2-3-4-5-8-15 of the first two cycles | 
| Pharmacokinetic of olaparib (steady state profile and so maximum concentration, minimal concentration, and AUC will be calculated) | The concentration-time data will be used for a preliminary assessment of the effect of combination therapy on the single-dose pharmacokinetics of trabectedin and olaparib. The data will be analyzed by noncompartmental methods. The following pharmacokinetic parameter values will be obtained for olaparib: steady state profile and so maximum concentration, minimal concentration, and AUC will be calculated. For these parameters, the following descriptive statistics will be calculated: mean, standard deviation, coefficient of variation, median, and geometric mean. Any drug-drug interaction will be thoroughly searched. For both trabectedin and olaparib all pharmacokinetic evaluations will be done only for the first 2 cycles. | baseline, day -5 cycle 1, day 1 cycle 2, of the first two cycles | 
| safety evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 | safety will be evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 | baseline up to 28 days after last dose of study treatment up to 2 years | 
| Biomarkers (composite outcome) | Several gene assessments (expression, amplification/ deletion, single nucleotide polymorphisms) on DNA-damage response-related markers (including but not limited to BRCA 1-2, ERCC 1-2-5, XRCC 1-2-3, RAD51 and 53BP1, PARP 1-2, P-histone H2AX and others) will be conducted. Statistical analysis will be performed to investigate the association between trial outcomes and polymorphisms of these genes. | baseline, day 1-2-8-15 of each cycle up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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trabectedin, olaparib, sarcoma, bone tumor