Description:
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.
Title
- Brief Title: 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
Clinical Trial IDs
- ORG STUDY ID:
TOMAS
- SECONDARY ID:
2013-003638-33
- NCT ID:
NCT02398058
Conditions
- Soft Tissue Sarcoma
- Bone Tumor
Interventions
Drug | Synonyms | Arms |
---|
trabectedin | ET-743, Yondelis | Trabectedin plus olaparib |
olaparib | AZD-2281, Lynparza | Trabectedin plus olaparib |
Purpose
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.
Trial Arms
Name | Type | Description | Interventions |
---|
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. | |
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
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | maximum tolerated dose |
Time Frame: | from start up to 6 weeks |
Safety Issue: | |
Description: | safety will be evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 |
Secondary Outcome Measures
Measure: | Best Overall Response |
Time Frame: | baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years |
Safety Issue: | |
Description: | best overall response will be defined according to the Response Evaluation Criteria in Solid Tumor version 1.1 (RECIST v 1.1) |
Measure: | Clinical Benefit Rate |
Time Frame: | baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years |
Safety Issue: | |
Description: | 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. |
Measure: | Growth Modulation Index |
Time Frame: | baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years |
Safety Issue: | |
Description: | 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. |
Measure: | Overall Survival |
Time Frame: | baseline and up to 2 years |
Safety Issue: | |
Description: | time from the date of enrollment to date of death or to the date being censored at two years (whichever occurs first). |
Measure: | Duration of Tumor Response |
Time Frame: | baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years |
Safety Issue: | |
Description: | 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. |
Measure: | Progression-Free Survival (PFS) |
Time Frame: | baseline and every 2 cycles (6 weeks +/- 1 week) up to 2 years |
Safety Issue: | |
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. |
Measure: | Pharmacokinetic of trabectedin (AUC) |
Time Frame: | baseline, days 1-2-3-4-5-8-15 of the first two cycles |
Safety Issue: | |
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. 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. |
Measure: | 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 Issue: | |
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. |
Measure: | 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 |
Safety Issue: | |
Description: | safety will be evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 |
Measure: | Biomarkers (composite outcome) |
Time Frame: | baseline, day 1-2-8-15 of each cycle up to 2 years |
Safety Issue: | |
Description: | 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. |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Completed |
Lead Sponsor: | Italian Sarcoma Group |
Trial Keywords
- trabectedin
- olaparib
- sarcoma
- bone tumor
Last Updated
April 14, 2021