Bone Tumor, Soft Tissue Sarcoma
Conditions
Keywords
trabectedin, olaparib, sarcoma, bone tumor
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.
Interventions
DRUGtrabectedin
trabectedin will be administered in a 24-h continuous i.v. infusion every 3 weeks
DRUGolaparib
olaparib will be administered in a continuous daily dose every 12 hours
Sponsors
PharmaMar
AstraZeneca
Istituto Di Ricerche Farmacologiche Mario Negri
Italian Sarcoma Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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) |
| 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. |
| 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. |
Countries
Italy
Outcome results
None listed