Clinical trial NCT02398058: Trabectedin Plus Olaparib in Metastatic or Advanced Sarcomas (TOMAS)
Official title: A Phase Ib Study on the Combination of Trabectedin and Olaparib in Unresectable Advanced/Metastatic Sarcomas After Failure of Standard Therapies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Soft Tissue Sarcoma
Bone Tumor
Keywords: trabectedin
olaparib
sarcoma
bone tumor
Lead sponsor: Italian Sarcoma Group
Sponsor class: NETWORK
Collaborators: name: PharmaMar
name: AstraZeneca
name: Istituto Di Ricerche Farmacologiche Mario Negri
First posted: 2015-03-25
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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

Primary outcomes:
measure: maximum tolerated dose
timeFrame: from start up to 6 weeks
Secondary outcomes:
measure: Best Overall Response
timeFrame: baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years
measure: Clinical Benefit Rate
timeFrame: baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years
measure: Growth Modulation Index
timeFrame: baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years
measure: Overall Survival
timeFrame: baseline and up to 2 years
measure: Duration of Tumor Response
timeFrame: baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years
measure: Progression-Free Survival (PFS)
timeFrame: baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years
measure: Pharmacokinetic of trabectedin (AUC)
timeFrame: baseline, days 1-2-3-4-5-8-15 of the first two cycles
measure: Pharmacokinetic of olaparib (steady state profile and so maximum concentration, minimal concentration, and AUC will be calculated)
timeFrame: baseline, day -5 cycle 1, day 1 cycle 2, of the first two cycles
measure: safety evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) v 4.03
timeFrame: baseline up to 28 days after last dose of study treatment up to 2 years
measure: Biomarkers (composite outcome)
timeFrame: baseline, day 1-2-8-15 of each cycle up to 2 years
Other outcomes:
Locations:
city: Candiolo
country: Italy
facility: Fondazione del Piemonte per l'Oncologia IRCC Candiolo
state: Torino
city: Bologna
country: Italy
facility: Istituti Ortopedici Rizzoli - Unit of Chemotherapy of Muscoloskeletal Tumors
city: Milano
country: Italy
facility: Istituto Nazionale Tumori - Unit of Medical Oncology
Study officials:
affiliation: Italian Sarcoma Group
name: Giovanni Grignani, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Grignani G, D'Ambrosio L, Pignochino Y, Palmerini E, Zucchetti M, Boccone P, Aliberti S, Stacchiotti S, Bertulli R, Piana R, Miano S, Tolomeo F, Chiabotto G, Sangiolo D, Pisacane A, Dei Tos AP, Novara L, Bartolini A, Marchesi E, D'Incalci M, Bardelli A, Picci P, Ferrari S, Aglietta M. Trabectedin and olaparib in patients with advanced and non-resectable bone and soft-tissue sarcomas (TOMAS): an open-label, phase 1b study from the Italian Sarcoma Group. Lancet Oncol. 2018 Oct;19(10):1360-1371. doi: 10.1016/S1470-2045(18)30438-8. Epub 2018 Sep 11.
citation: Vyse S, Thway K, Huang PH, Jones RL. Next-generation sequencing for the management of sarcomas with no known driver mutations. Curr Opin Oncol. 2021 Jul 1;33(4):315-322. doi: 10.1097/CCO.0000000000000741.