Soft Tissue SarcomaPhase 1TOMASNCT02398058
Trabectedin Plus Olaparib in Metastatic or Advanced Sarcomas (TOMAS)
A Phase 1 study testing trabectedin and olaparib in people with Soft Tissue Sarcoma and Bone Tumor, run by Italian Sarcoma Group at 3 sites in Italy.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Soft Tissue Sarcoma, Bone Tumor
- What is being tested?
- trabectedin and olaparib
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 50 participants
- Where
- 3 sitesItaly
- Study dates
- 20 Jul 2014to 1 Dec 2019
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
3 sites in 1 country.
Italy3 sites
Istituti Ortopedici Rizzoli - Unit of Chemotherapy of Muscoloskeletal Tumors
Bologna, 40136
Fondazione del Piemonte per l'Oncologia IRCC Candiolo
Candiolo, Torino, 10060
Istituto Nazionale Tumori - Unit of Medical Oncology
Milan, 20133
About this study
Official title: A Phase Ib Study on the Combination of Trabectedin and Olaparib in Unresectable Advanced/Metastatic Sarcomas After Failure of Standard Therapies
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.
- Conditions
- Soft Tissue Sarcoma, Bone Tumor
- Being tested
- trabectedin, olaparib
- Keywords
- trabectedin, olaparib, sarcoma, bone tumor
- Medical subject headings
- Sarcoma, Bone Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
trabectedinDrug
Also called ET-743, Yondelis
trabectedin will be administered in a 24-h continuous i.v. infusion every 3 weeks
olaparibDrug
Also called AZD-2281, Lynparza
olaparib will be administered in a continuous daily dose every 12 hours
| Study group | Role | What they receive |
|---|---|---|
| Trabectedin plus olaparib | Experimental | 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. Receives: Drug: trabectedin; Drug: olaparib |
What is being measured
The primary outcome is the main question the study is designed to answer.
maximum tolerated dose
safety will be evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) v 4.03
Measured: from start up to 6 weeks
Secondary outcomes (10)
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)
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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.
Measured: baseline, day 1-2-8-15 of each cycle up to 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Mar 2015 (estimated)
- Study start20 Jul 2014
- Primary completion1 Dec 2019
- Study completion1 Dec 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Soft Tissue SarcomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 50 participants (actual)
Sponsor and investigators
- Lead sponsor
- Italian Sarcoma Group
- Sponsor type
- Research network
- Collaborators
- PharmaMar, AstraZeneca, Istituto Di Ricerche Farmacologiche Mario Negri
- Responsible party
- Sponsor
- Investigators
- Giovanni Grignani, MD, Principal investigator, Italian Sarcoma Group
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02398058
- Sponsor's protocol ID
- TOMAS
- Other IDs
- 2013-003638-33
- Acronym
- TOMAS
- Status last verified
- Apr 2021
- First submitted
- 14 Jan 2015
- Last updated
- 14 Apr 2021
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 30217671Vyse 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.
PubMed 33927108
Study at a glance
From the registry record, last updated by the sponsor on 14 Apr 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase Ib Study on the Combination of Trabectedin and Olaparib in Unresectable Advanced/Metastatic Sarcomas After Failure of Standard Therapies
- ClinicalTrials.gov ID
- NCT02398058
- Acronym / sponsor ID
- TOMAS / TOMAS
- Conditions
- Soft Tissue Sarcoma, Bone Tumor
- Keywords
- trabectedin, olaparib, sarcoma, bone tumor
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 50 participants (actual)
- Lead sponsor
- Italian Sarcoma GroupResearch network
- Collaborators
- PharmaMar, AstraZeneca, Istituto Di Ricerche Farmacologiche Mario Negri
- Study start
- 20 Jul 2014 (actual)
- Primary completion
- 1 Dec 2019 (actual)
- Study completion
- 1 Dec 2019 (actual)
- First posted
- 25 Mar 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Trabectedin plus olaparib | Experimental | Drug: trabectedin, Drug: olaparibAll 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (29 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| trabectedinAlso: ET-743, Yondelistrabectedin will be administered in a 24-h continuous i.v. infusion every 3 weeks | Drug | Trabectedin plus olaparib |
| olaparibAlso: AZD-2281, Lynparzaolaparib will be administered in a continuous daily dose every 12 hours | Drug | Trabectedin plus olaparib |
Primary outcome
maximum tolerated dose
Time frame: from start up to 6 weeks
safety will be evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) v 4.03
10 secondary outcomes
Best Overall Response
Time frame: baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years
Clinical Benefit Rate
Time frame: baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years
Growth Modulation Index
Time frame: baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years
Overall Survival
Time frame: baseline and up to 2 years
Duration of Tumor Response
Time frame: baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years
Progression-Free Survival (PFS)
Time frame: baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years
Pharmacokinetic of trabectedin (AUC)
Time frame: 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)
Time frame: 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
Time frame: baseline up to 28 days after last dose of study treatment up to 2 years
Biomarkers (composite outcome)
Time frame: baseline, day 1-2-8-15 of each cycle up to 2 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Apr 2021.
- Results publication: PubMed 30217671Grignani 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.
- Derived from this study: PubMed 33927108Vyse 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Giovanni Grignani, MD principal investigator
Italian Sarcoma Group
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing trabectedin and olaparib in people with Soft Tissue Sarcoma and Bone Tumor, run by Italian Sarcoma Group at 3 sites in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 14 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
maximum tolerated dose (time frame: from start up to 6 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02398058, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Apr 2021.