Study to Compare a Treatment with Trabectedin and Olaparib to Physician’s Choice in Subjects with Previously Treated Solid Tumors Having a Special lack of Cellular Repair Mechanism

Phase 1

• Conditions: Previously Treated Advanced or Recurrent Solid Tumors Harboring DNA Repair Deficiencies; MedDRA version: 21.1Level: LLTClassification code 10065147Term: Malignant solid tumorSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2017-001755-31-DE
• Lead Sponsor: Ruprecht-Karls-Universität Heidelberg, Medical Faculty

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2018-03-22
• Last Update Posted: 20 February 2023

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 108

Inclusion Criteria

1.Provision of a written informed consent
2.Patients is able to understand and comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations
3.Progressive locally advanced or metastatic malignancy as determined by local investigator.
4.At least one measurable lesion that can be accurately assessed at baseline by CT or MRI and is suitable for repeated assessment
5.Prior administration of at least one standard treatment for primary and/or relapsed malignancy according to current guidelines
6.Eastern Cooperative Oncology Group Performance Status = 1
7.Patients with central venous access device in place (central venous catheter or port-a-cath)
8.Male or female patient aged = 18 and = 70 years
9.Postmenopausal or evidence of non-childbearing status. For women of childbearing potential: negative urine or serum pregnancy test within 14 days prior to study treatment and highly effective forms of contraception in place thereafter as well as confirmed negative urine or serum pregnancy test prior to treatment on day 1 of every cycle
Postmenopausal or evidence of non-childbearing status is defined as:
oAmenorrheic for 1 year or more following cessation of exogenous hormonal treatments
oLuteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post menopausal range for women under 50 except in patients with a history of surgical sterilisation (bilateral oophorectomy or hysterectomy)
oRadiation-induced oophorectomy with last menses >1 year ago
oChemotherapy-induced menopause with >1 year interval since last menses
oSurgical sterilisation (bilateral oophorectomy or hysterectomy)
10.Female patients of child bearing potential and male patients with partners of child bearing potential, who are sexually active, must agree to the use of highly effective forms of contraception. This should be started from the signing of the informed consent and continue throughout period of taking study treatment and for 1 month (female patients) / 3 months (male patients) after last dose of study drug.
11.Identification of defective DNA repair via Homologous Recombination, as determined by molecular analysis within NCT/DKTK MASTER (Heidelberg Ethics Committee Reference No.: S-206/2011). Eligibility for the study is defined by the molecular tumorboard of NCT on the basis of whole-exome/genome sequencing and the presence of genomic markers for BRCAness”.
12.Adequate bone marrow, renal, and hepatic function defined by laboratory tests within 14 days prior to study treatment:
oHemoglobin = 10 g/dl
oNeutrophil count = 1,500/mm3
oPlatelet count = 100,000/µl
oBilirubin = 1.0 x upper limit of normal (ULN)
oALT and AST = 2.5 x ULN
oAlkaline phosphatase = 2.5 x ULN
oPT-INR/PTT = 1.5 x ULN
oAlbumin = 25 g/l
oCreatine kinase = 2.5 x ULN
oSerum creatinine ? 1.5 mg/dl or creatinine clearance ? 51 ml/min (calculation according to Crockroft-Gault)

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 90
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 18

Exclusion Criteria

1.Hematological malignancies and primary brain tumors. Patients with known progressive brain metastases determined by serial imaging or declining neurologic function in the opinion of the treating physician are not eligible. Patients with symptomatic uncontrolled brain metastases and patients with symptomatic uncontrolled spinal cord compression are not eligible. Patients with previously treated brain metastases are eligible, provided that the patient has not experienced a seizure or had a clinically significant change in neurological status within the three months prior to enrollment. All patients with previously treated brain metastases must be clinically stable for at least 1 month after completion of treatment and off steroid treatment for one month, both prior to study enrollment
2.Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial carcinoma, or other solid tumours including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for =5 years
3.Concurrent or previous treatment within 4 weeks in another interventional clinical trial
4.Treated with an investigational anticancer therapy less than 4 weeks prior to study treatment. Inclusion may be possible after > five half-lifes of previous treatment after consultation with the coordinating investigator on a case by case decision.
5.Prior treatment with PARP inhibitors
6.Patients with platinum-refractory disease, defined as progressive disease during or immediately after treatment with platinum based chemotherapy
7.Persistent toxicity (=Grade 2 according to Common Terminology Criteria for Adverse Events [CTCAE] version 5.0) caused by previous cancer therapy, excluding alopecia
8.Clinical signs of active infection (>Grade 2 according to CTCAE version 5.0)
9.History of HIV infection and immunocompromised patients
10.Viral active or chronic hepatitis (HBV or HCV)
11.Dementia or significant impairment of cognitive state
12.Epilepsy requiring pharmacologic treatment
13.Pregnancy and breast feeding (women)
14.Inability to take oral medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
15.Major surgery within 4 weeks of starting study treatment. Patients must have reco-vered from any effects of any major surgery.
16.Patients receiving any systemic chemotherapy or radiotherapy within 2 weeks prior to study treatment or a longer period depending on the defined characteristics of the agents used
17.Known hypersensitivity to any of the study drugs or other ingredients of the investigational medicinal products
18.Resting ECG with QTc > 450 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
19.Abnormal left ventricular ejection fraction, defined as ejection fraction of <50% on echocardiography
20.Heart failure NYHA III/IV
21.Severe obstructive or restrictive ventilation disorder
22.Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is at least five half-lifes.
23.Concomita

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To assess clinical activity of combination therapy with trabectedin and olaparib in adult patients with advanced or recurrent solid tumors harboring DNA repair deficiency. Clinical efficacy is determined by disease control rate (DCR) at week 16 ;Secondary Objective: •To assess progression-free survival (PFS) of combination therapy with trabectedin and olaparib in comparison to treatment as per physician’s choice<br>•To assess overall survival (OS) <br>•To assess Tumor Response Rate (TRR) including CR and PR according RECIST v1.1 criteria after 16 weeks <br>•Safety/tolerability of combination therapy with trabectedin and olaparib<br>•Quality of life<br>;Primary end point(s): Primary efficacy endpoint is the disease control rate (DCR) at week 16 ;Timepoint(s) of evaluation of this end point: week 16 after five 21-days cycles of treatment in the experimental arm and either also after five 21-days cycles or alternatively four 28-days cycles in the physician’s choice arm

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): - Tumor response rate<br>- Survival analysis: Progression Free Survival, Overall Survival<br>- Safety analysis: frequency of adverse events <br>- Patient reportet outcomes including quality of life analysis;Timepoint(s) of evaluation of this end point: After treatment period (week 16) plus (optional) extended treatment period (until progression or End of Study) and safety follow-up (28 days).