Study of Olaparib/Trabectedin vs. Doctor's Choice in Solid Tumors

Study Overview
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Brief Summary
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Evaluation of the efficacy of the combination of olaparib and trabectedin in adult patients with locally advanced/metastatic solid tumors that failed standard treatment and whose molecular sequencing tumor profiles show homologous recombination repair (HRR) defects. The primary objective is to show superior disease control rate in patients with HRR-deficient tumors treated with olaparib and trabectedin compared to treatment according to current guidelines (physician's choice). This trial aims to establish whether the PARP-dependency of HRR-deficient tumors across entities can be exploited for therapeutic benefit.

Official Title
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A Randomized Phase-2 Study of Trabectedin/Olaparib Compared to Physician's Choice in Subjects With Previously Treated Advanced or Recurrent Solid Tumors Harboring DNA Repair Deficiencies

Conditions
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Cancers With DNA Repair-Deficiency

Intervention / Treatment
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* Drug: Olaparib
* Drug: Physician's choice
* Drug: Trabectedin


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Written informed consent Progressive locally advanced or metastatic malignancy Prior administration of standard treatment for primary and relapsed malignancy Eastern Cooperative Oncology Group Performance Status ≤1 Patients with central venous access device in place (central venous catheter or porta-cath) Age ≥18 and ≤70 years Identification of defective DNA repair via HR Adequate bone marrow, renal, and hepatic function Hemoglobin ≥10 g/dl Neutrophil count ≥1,500/mm3 Platelet count ≥100,000/µl Bilirubin ≤1.5 x upper limit of normal (ULN) ALT and AST ≤2.5 x ULN (≤5 x ULN in patients with hepatic tumor involvement) Alkaline phosphatase ≤2.5 x ULN PT-INR/PTT ≤1.5 x ULN Albumin ≥25 g/l Creatine kinase ≤2.5 x ULN Serum creatinine 1.5 mg/dl or creatinine clearance 51 ml/min Main Exclusion Criteria: Hematological malignancies and primary brain tumors. Concurrent treatment in another interventional clinical trial Prior treatment with PARP Inhibitors Patients with platinum-refractory disease, defined as progressive disease during or immediately after treatment with platinum based chemotherapy Persistent toxicity (> Grade 2 according to CTCAE 5.0) Dementia or significant impairment of cognitive state History of HIV infection Clinical signs of active infection (>Grade 2 according to CTCAE 4.03) History of viral hepatitis (HBV or HCV) Epilepsy requiring pharmacologic treatment Pregnancy Major surgical intervention 4 weeks prior to study inclusion Known hypersensitivity to any of the study drugs Hematologic malignancy QTc time prolongation >500 ms or history of familial long-QT-syndrome Heart failure NYHA III/IV Severe obstructive or restrictive ventilation disorder Concomitant use of known strong CYP3A Inhibitors Concomitant use of known strong CYP3A inducers

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm E: Olaparib / Trabectedin<br>Olaparib / Trabectedin | Drug: Olaparib<br>* Olaparib 150 mg tablet<br>Drug: Trabectedin<br>* Trabectedin 1.1mg/m² infusional solution<br>|
| Other: Arm C: Physician's choice<br>Physician's choice | Drug: Physician's choice<br>* treatment according to current guidelines<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate | Randomized, open-label, multicenter phase-II study comparing olaparib in combination with trabectedin versus physician's choice. Primary efficacy endpoint is the disease control rate after 5 cycles. | At week 16 (after 5 cycles of study medication) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | defined as the time from first administration of the IMP to time of death from any cause | Time from first administration of the IMP to time death from any cause until end of study (2.5 years) | 
| Incidence of Treatment-Emergent Adverse Events | This endpoint includes all AEs, their severity, SAEs, the relation of AEs to the study treatment, dose modifications for toxicity and discontinuation of study treatment during the trial phase. Toxic effects will be graded according to the National Cancer Institute Common Toxicity Criteria. | Time from first administration of the IMP to subjects end of trial (approximately month 6) | 
| Patient reported outcomes | Patient reported outcomes (PROs) including health-related quality of life (QoL) are calculated as the new European Organization for Research and Treatment of Cancer (EORTC). QLQ-C30 summary score recommended by teh EORTC Quality of Life Group. In addition, the EORTC QLQ function and symptom scores are calculated according to the actual EORTC Scoring Manual. | Before the first (week 0), at the third (week 8), and after the fifth treatment cycle (week 16) | 
| Tumor response rate | Defined as the sum of complete remission (CR) and partial remission (PR) according to RECIST version 1.1 after 5 cycles of study medication | At week 16 (after 5 cycles of study medication) |