Trabectedin Plus Olaparib in Metastatic or Advanced Sarcomas (TOMAS)
Study Details
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Trabectedin plus olaparib 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. |
Drug: trabectedin
trabectedin will be administered in a 24-h continuous i.v. infusion every 3 weeks
Other Names:
Drug: olaparib
olaparib will be administered in a continuous daily dose every 12 hours
Other Names:
|
Outcome Measures
Primary Outcome Measures
- maximum tolerated dose [from start up to 6 weeks]
safety will be evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) v 4.03
Secondary Outcome Measures
- Best Overall Response [baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years]
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 [baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years]
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 [baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years]
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 [baseline and up to 2 years]
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 [baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years]
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) [baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years]
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) [baseline, days 1-2-3-4-5-8-15 of the first two cycles]
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) [baseline, day -5 cycle 1, day 1 cycle 2, of the first two cycles]
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 [baseline up to 28 days after last dose of study treatment up to 2 years]
safety will be evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) v 4.03
- Biomarkers (composite outcome) [baseline, day 1-2-8-15 of each cycle up to 2 years]
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.
Eligibility Criteria
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
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Measurable disease as defined by RECIST v1.1.
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Eastern Cooperative Oncology Group (ECOG) Performance Status of 0/1. ECOG PS 2 are eligible if depends solely on orthopedic problems
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Estimated life expectancy of ≥ 4 months
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Age ≥18 years
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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:
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Involvement in the planning and/or conduct of the study
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Previous enrolment in the present study
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Participation in another clinical study with an investigational product during the last month
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Persistent toxicities (≥CTCAE grade 2) with the exception of alopecia, caused by previous anticancer therapies
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Dementia or significantly altered mental status
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Patients with any severe and/or uncontrolled medical conditions
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HIV infection
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Active clinically serious infections (> grade 2 NCI-CTCAE version 4.03).
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Active viral hepatitis (HBV or HCV infection)
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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).
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Patients with seizure disorders requiring medication (such as steroids or anti-epileptics)
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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
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Patients with evidence or history of bleeding diathesis
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Patients undergoing renal dialysis
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Patients unable to swallow oral medications
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Uncontrolled diabetes (fasting glucose > 2 x ULN)
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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
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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.
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Anticancer chemotherapy or immunotherapy during the study or within 4 weeks of treatment start
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Radiotherapy during study or within 3 weeks of start of study drug. (Palliative radiotherapy allowed)
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Major surgery within 4 weeks of start of study
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Prior exposure to the study drugs or their analogues
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Patients with known hypersensitivity to trabectedin, olaparib or to their excipients
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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
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Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
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A history of noncompliance to medical regimens or inability or unwillingness to return for scheduled visits
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Corrected QT interval on the 12-lead ECG (QTc) >470 msec (Bazett Formula)
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use of strong CYP3A4 inhibitors/inducers
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Patients with myelodysplastic syndrome/acute myeloid leukemia
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Fondazione del Piemonte per l'Oncologia IRCC Candiolo | Candiolo | Torino | Italy | 10060 |
| 2 | Istituti Ortopedici Rizzoli - Unit of Chemotherapy of Muscoloskeletal Tumors | Bologna | Italy | 40136 | |
| 3 | Istituto Nazionale Tumori - Unit of Medical Oncology | Milano | Italy | 20133 |
Sponsors and Collaborators
- Italian Sarcoma Group
- PharmaMar
- AstraZeneca
- Istituto Di Ricerche Farmacologiche Mario Negri
Investigators
- Principal Investigator: Giovanni Grignani, MD, Italian Sarcoma Group
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- TOMAS
- 2013-003638-33