Study of Olaparib/Trabectedin vs. Doctor's Choice in Solid Tumors (NCT-PMO-1603)

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Cancers With DNA Repair-Deficiency
• Intervention / Treatment: Drug: Olaparib; Drug: Trabectedin; Drug: Physician's choice

• Study Type: Interventional
• Enrollment (Actual): 102
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Richard Schlenk, MD; Phone Number: 6228 +49622156; Email: studienzentrale@nct-heidelberg.de

Study Locations

• Germany
  • Dresden, Germany, 01307
    • Medizinische Fakultät der TU Dresden
  • Essen, Germany, 45147
    • Universitatsklinikum Essen
  • Frankfurt, Germany, 60590
    • Universitatsklinikum Frankfurt
  • Freiburg, Germany, 79106
    • Universitätsklinikum Freiburg
  • Heidelberg, Germany, 69120
    • National Center for Tumordiseases (NCT)
  • Mainz, Germany, 55131
    • Universitätsmedizin der Johannes-Gutenberg-Universität Mainz
  • München, Germany, 81377
    • Klinikum der Universität München-Großhadern
  • Stuttgart, Germany, 70376
    • Klinik Schillerhohe
  • Tuebingen, Germany, 72076
    • Universitatsklinikum Tubingen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: National Center for Tumor Diseases, Heidelberg
• Collaborators: AstraZeneca; German Cancer Research Center; PharmaMar
• Investigators: Principal Investigator: Stefan Froehling, MD, NCT / DKFZ Heidelberg

Study record dates

Study Major Dates

• Study Start (Actual): October 25, 2018
• Primary Completion (Estimated): December 1, 2023
• Study Completion (Estimated): December 1, 2023

Study Registration Dates

• First Submitted: March 31, 2017
• First Submitted That Met QC Criteria: April 24, 2017
• First Posted (Actual): April 25, 2017

Study Record Updates

• Last Update Posted (Actual): August 29, 2023
• Last Update Submitted That Met QC Criteria: August 28, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; DNA Repair-Deficiency Disorders; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Poly(ADP-ribose) Polymerase Inhibitors; Olaparib; Trabectedin
• Other Study ID Numbers: NCT-2017-0417

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No