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Trabectedin Plus Olaparib in Metastatic or Advanced Sarcomas (TOMAS) (TOMAS)

Primary Purpose

Soft Tissue Sarcoma, Bone Tumor

Status

Completed

Phase

Phase 1

Locations

Italy

Study Type

Interventional

Intervention

trabectedin

olaparib

About this trial

This is an interventional treatment trial for Soft Tissue Sarcoma focused on measuring trabectedin, olaparib, sarcoma, bone tumor

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Fondazione del Piemonte per l'Oncologia IRCC Candiolo
Istituti Ortopedici Rizzoli - Unit of Chemotherapy of Muscoloskeletal Tumors
Istituto Nazionale Tumori - Unit of Medical Oncology

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Trabectedin plus olaparib

Arm Description

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.

Outcomes

Primary Outcome Measures

maximum tolerated dose

safety will be evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) v 4.03

Secondary Outcome Measures

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)

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.

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.

Overall Survival

time from the date of enrollment to date of death or to the date being censored at two years (whichever occurs first).

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.

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.

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.

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.

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

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.

Full Information

NCT ID

NCT02398058

First Posted

January 14, 2015

Last Updated

April 13, 2021

Sponsor

Italian Sarcoma Group

Collaborators

PharmaMar, AstraZeneca, Istituto Di Ricerche Farmacologiche Mario Negri

1. Study Identification

Unique Protocol Identification Number

NCT02398058

Brief Title

Trabectedin Plus Olaparib in Metastatic or Advanced Sarcomas (TOMAS)

Acronym

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

2. Study Status

Record Verification Date

April 2021

Overall Recruitment Status

Completed

Study Start Date

July 20, 2014 (Actual)

Primary Completion Date

December 1, 2019 (Actual)

Study Completion Date

December 1, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Italian Sarcoma Group

Collaborators

PharmaMar, AstraZeneca, Istituto Di Ricerche Farmacologiche Mario Negri

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Soft Tissue Sarcoma, Bone Tumor

Keywords

trabectedin, olaparib, sarcoma, bone tumor

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

50 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Trabectedin plus olaparib

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

trabectedin

Other Intervention Name(s)

ET-743, Yondelis

Intervention Description

trabectedin will be administered in a 24-h continuous i.v. infusion every 3 weeks

Intervention Type

Drug

Intervention Name(s)

olaparib

Other Intervention Name(s)

AZD-2281, Lynparza

Intervention Description

olaparib will be administered in a continuous daily dose every 12 hours

Primary Outcome Measure Information:

Title

maximum tolerated dose

Description

safety will be evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) v 4.03

Time Frame

from start up to 6 weeks

Secondary Outcome Measure Information:

Title

Best Overall Response

Description

best overall response will be defined according to the Response Evaluation Criteria in Solid Tumor version 1.1 (RECIST v 1.1)

Time Frame

baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years

Title

Clinical Benefit Rate

Description

Time Frame

baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years

Title

Growth Modulation Index

Description

Time Frame

baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years

Title

Overall Survival

Description

time from the date of enrollment to date of death or to the date being censored at two years (whichever occurs first).

Time Frame

baseline and up to 2 years

Title

Duration of Tumor Response

Description

Time Frame

baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years

Title

Progression-Free Survival (PFS)

Description

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.

Time Frame

baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years

Title

Pharmacokinetic of trabectedin (AUC)

Description

Time Frame

baseline, days 1-2-3-4-5-8-15 of the first two cycles

Title

Pharmacokinetic of olaparib (steady state profile and so maximum concentration, minimal concentration, and AUC will be calculated)

Description

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.

Time Frame

baseline, day -5 cycle 1, day 1 cycle 2, of the first two cycles

Title

safety evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) v 4.03

Description

safety will be 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

Title

Biomarkers (composite outcome)

Description

Time Frame

baseline, day 1-2-8-15 of each cycle up to 2 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Giovanni Grignani, MD

Organizational Affiliation

Italian Sarcoma Group

Official's Role

Principal Investigator

Facility Information:

Facility Name

Fondazione del Piemonte per l'Oncologia IRCC Candiolo

City

Candiolo

State/Province

Torino

ZIP/Postal Code

10060

Country

Italy

Facility Name

Istituti Ortopedici Rizzoli - Unit of Chemotherapy of Muscoloskeletal Tumors

City

Bologna

ZIP/Postal Code

40136

Country

Italy

Facility Name

Istituto Nazionale Tumori - Unit of Medical Oncology

City

Milano

ZIP/Postal Code

20133

Country

Italy

12. IPD Sharing Statement

Citations:

PubMed Identifier

30217671

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.

Results Reference

result

PubMed Identifier

33927108

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.

Results Reference

derived

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Trabectedin Plus Olaparib in Metastatic or Advanced Sarcomas (TOMAS)

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