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Prospective, open-label, dose-ranging, uncontrolled phase I/II study of Lurbinectedin in combination with irinotecan. The study will be divided into two stages: a Phase I dose escalation stage and a Phase II expansion stage.
Full description
Phase I dose escalation stage.
During the Phase I escalation stage, patients with selected advanced solid tumors will be divided into three groups: the Lurbinectedin Escalation Group, the Irinotecan Escalation Group and the Intermediate Escalation Group. Each group will have a different dose escalation scheme. A treatment cycle is defined as an interval of three weeks.
Three to six patients will be included at each dose level. If dose-limiting toxicity (DLT) occurs in less than one third of evaluable patients in each cohort, escalation can proceed to the next dose level within each group.
The MTD in each group will be the lowest dose level explored during dose escalation in which one third or more of evaluable patients develops a DLT in Cycle 1. At any dose level, if one among the first three evaluable patients has a DLT, the dose level should be expanded up to six patients. Dose escalation will be terminated once the MTD or the last dose level is reached, whichever occurs first, except if all DLTs occurring at a given dose level are related to neutropenia (i.e., febrile neutropenia, grade 4 neutropenia lasting > 3 days or neutropenic sepsis) in which case dose escalation may be resumed, starting at the same dose level and following the same original schedule but with mandatory primary G-CSF prophylaxis.
Once the MTD has been reached, a minimum of nine evaluable patients will be recruited at the immediately lower dose level (or at the last dose level if the MTD is not defined yet): this level will be confirmed as the RD if less than one third of the first nine evaluable patients develop DLT during Cycle 1.
Phase II expansion stage.
If signs of activity are observed in one or more tumor types, there will be a phase II expansion stage after the RD is defined for each group. A tumor-specific expansion cohort (or cohorts if signs of activity are observed in more than one of the permitted tumor types) at each of these RDs may include approximately 20 treated patients per tumor type. If no indication of efficacy is observed in the dose escalation phase of a specific group, then recruitment of patients into that group may be terminated.
Furthermore, one new cohort of patients with neuroendocrine neoplasms (NENs), with approximately 40 treated patients, will be included in the Phase II expansion stage of this study. Patients in this cohort will be treated at the RD determined during the Phase I escalation stage in the Lurbinectedin Escalation Group (Lurbinectedin 2.0 mg/m2 plus irinotecan 75 mg/m2 with the administration of G-CSF). These patients will be divided into two groups of 20 treated patients each:
Following the finding of promising efficacy to date, two expansion cohorts in the Lurbinectedin Escalation Group will be further expanded:
Only in these two expansion cohorts, an Independent Review Committee (IRC) will determine the response evaluation at each tumor assessment necessary to derive the best patient's response and assign the date of first documentation of response and progression/censoring according to RECIST v.1.1. Operational details for the IRC and the algorithm and its validation by an expert panel are described in detail in the IRC charter.
Enrollment
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Inclusion criteria
Voluntarily signed and dated written informed consent prior to any specific-study procedure.
Age ≥ 18 years.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1.
Life expectancy ≥ 3 months.
Histologically or cytologically confirmed diagnosis of advanced disease of any of the following tumor types:
For the Lurbinectedin Escalation Group and the Irinotecan Escalation Group:
For the Intermediate Escalation Group:
For the Phase II expansion stage:
Glioblastoma.
Soft tissue sarcoma (including synovial sarcoma),
Endometrial carcinoma.
SCLC.
Neuroendocrine tumors.
The number of prior lines of therapy allowed per patient will be as follows:
For the Phase I Escalation Stage:
No more than two prior lines of cytotoxic-containing chemotherapy regimens for advanced disease
For the Phase II Lurbinectedin Expansion Stage:
For SCLC, one prior line of platinum-containing chemotherapy with/without antibodies against programmed cell death protein-1 (PD-1) or programmed death ligand-1 (PD-L1).
For NENs,
For all other tumor types, no more than two prior lines of cytotoxic-containing chemotherapy regimens for advanced disease.
There is no limit for prior targeted therapy, hormonal therapy and immunotherapy (such as nivolumab).
Phase II expansion stage: Tumor-specific cohort(s) at the RD:
At least three weeks since the last anticancer therapy, (including immunotherapy, investigational drugs and radiotherapy), and at least six weeks since nitrosoureas and mitomycin C (systemic).
For biological/investigational anticancer therapies given orally, the aforementioned period of at least three weeks could be changed for one of at least five half-lives (whichever occurred first), provided that the therapy is given as single agent and not combined with other drugs. If this is not the case, this exception will not be acceptable.
For patients with glioblastoma: at least 12 weeks since the end of radiotherapy, except if:
Note: washout periods will be referred to the day of first cycle administration (Day 1), not to the day of registration (Day 0).
Adequate bone marrow, renal, hepatic, and metabolic function (assessed ≤ 7 days before inclusion in the trial):
Recovery to grade ≤ 1 or to baseline from any adverse event (AE) derived from previous treatment (excluding alopecia and/or cutaneous toxicity and/or peripheral neuropathy and/or fatigue grade ≤ 2).
Exclusion criteria
Concomitant diseases/conditions:
Prior treatment with lurbinectedin, trabectedin (Yondelis®) or topoisomerase I inhibitors (irinotecan, topotecan, etc.). Prior topoisomerase inhibitors (e.g., irinotecan) are only allowed in patients with colorectal carcinoma or NENs.
Prior bone marrow or stem cell transplantation, or radiation therapy in more than 35% of bone marrow.
Known brain metastases or leptomeningeal disease involvement. Glioblastoma lesions (primary or locally advanced) are eligible. Exception: patients with brain metastases are eligible provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment (patients taking steroids in the process of already being tapered within two weeks prior to screening are allowed). Brain CT-scan or MRI results must be provided at baseline.
Women who are pregnant or breast feeding and fertile patients (men and women) who are not using an effective method of contraception. Women of childbearing potential (WOCBP) must agree to use an effective contraception method to avoid pregnancy during the course of the trial (and for at least six months after the last infusion). Fertile male patients must agree to refrain from fathering a child or donating sperm during the trial and for four months after the last infusion.
Limitation of the patient's ability to comply with the treatment or follow-up protocol.
Primary purpose
Allocation
Interventional model
Masking
320 participants in 3 patient groups
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Central trial contact
Pharma Mar Clinical Oncology
Data sourced from clinicaltrials.gov
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