Advanced Soft-tissue Sarcoma
Conditions
Brief summary
This is an open label, dose-seeking phase 1/2 study using escalating doses of LURBINECTEDIN administered intravenously with fixed doses of IPILIMUMAB and NIVOLUMAB administered intravenously.
Detailed description
This is an open label, dose-seeking phase 1/2 study using escalating doses of LURBINECTEDIN administered intravenously with fixed doses of IPILIMUMAB and NIVOLUMAB administered intravenously. I. Dose Escalation Phase 1 of Study: The study will employ the standard cohort of three design (Storer, 1989). Three participants are treated at each of the 2 ascending dose levels. An additional 3 participants will be enrolled if a DLT is observed in one of the three initially-enrolled participants at each dose level. If no DLT occurs after the third participant in a dose level is on study for 6 weeks, enrollment will be opened for escalation to the next highest planned dose level. The DLT window is a total of 6 weeks. The MTD is defined as the highest safely tolerated dose of lurbinectedin, where not more than one participant experienced a DLT, with the next higher dose level having at least two participants who experienced DLT. Participants in the dose escalation study may continue treatment at their designated dose levels until disease progression or unacceptable toxicity occurs or up to a maximum of one year of therapy (up to a maximum of 18 doses of LURBINECTEDIN, 26 doses of NIVOLUMAB, and 5 doses of IPILIMUMAB). No intra-participant dose escalation will take place. Dose of IPILIMUMAB: 1 mg/kg IV over 30 min. q 12 weeks, beginning 2 weeks after the first dose of LURBINECTEDIN, until disease progression or unacceptable toxicity, up to a maximum of 5 doses Dose of NIVOLUMAB: 3 mg/kg over 30 min. q 2 weeks, beginning 2 weeks after first dose of LURBINECTEDIN, until disease progression or unacceptable toxicity, up to a maximum of 26 doses Dose of LURBINECTEDIN: Escalating doses of LURBINECTEDIN IV over 60 minutes q 3 weeks up to a maximum of 18 doses: LURBINECTEDIN # Pts. Dose Level Dose,mg/m2 Max.Volume/24 hrs Every 3 weeks 3-6 I 2.6 1000 ml Every 3 weeks 3-6 II 3.2 1000 ml No dose-escalation will be performed until all the subjects have completed the DLT period of 6 weeks and evaluation of all clinical and laboratory data has been conducted. The phase 2 part of the study will not proceed until either the maximum tolerated dose (MTD) or maximum administered dose (MAD) has been determined. Participants who do not complete the DLT period for reasons other than study drug-related toxicity will be replaced in the same dose cohort. At the discretion of the principal investigator/sponsor, dose escalation may be stopped before an MTD is reached. In this case, the MAD may be chosen based on the standard dose of LURBINECTEDIN of 3.2 mg/m2.
Interventions
DRUGLurbinectedin
This is an open label, dose-seeking phase 1/2 study using escalating doses of LURBINECTEDIN administered intravenously with fixed doses of IPILIMUMAB and NIVOLUMAB administered intravenously.
Sponsors
ERLINDA M GORDON
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is an open label, dose-seeking phase 1/2 study using escalating doses of LURBINECTEDIN administered intravenously with fixed doses of IPILIMUMAB and NIVOLUMAB administered intravenously.
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
Individuals must meet all of the inclusion criteria in order to be eligible to participate in the study, as follows: 1. Male or Female ≥ 18 years of age 2. Pathologically confirmed diagnosis of locally advanced unresectable or metastatic soft tissue sarcoma 3. For the Phase 1 Part of Study, only previously treated participants will be enrolled. For the Phase 2 Part of Study, previously untreated participants will be enrolled. 4. Ability to understand the purposes and risks of the study and has signed and dated a written informed consent form approved by the principal investigator's IRB/Ethics Committee 5. Willingness to comply with all study procedures and availability for the duration of the study. 6. Measurable disease by RECIST v1.1 7. ECOG performance status ≤ 1 8. Life expectancy of at least 3 months 1. Acceptable liver function: Bilirubin \< 1.5 times upper limit of normal (ULN; except subjects with Gilbert Syndrome who must have a total bilirubin level \< 3.0 ULN); 2. AST (SGOT), ALT (SGPT) and alkaline phosphatase \< 3 x ULN (\< 5 x ULN if liver metastases) 3. Acceptable renal function: Creatinine \< 1.5 times ULN or \> 60 mL/min (using the Cockcroft Gault formula) 9. Acceptable hematologic status (without hematologic support e.g. growth factors or transfusion within 21 days of first dose of study agents): ANC \>= 1500 cells/μL; Platelet count \>= 100,000/μL; Hemoglobin \>= 9.0 g/dL; Normal PT, PTT, INR 10. All women of childbearing potential must have a negative pregnancy test and all subjects must agree to use highly effective means of contraception (surgical sterilization or the use of barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel or an IUD) with their partner from entry into the study through 5 months for women and 7 months for men after the last dose.
Exclusion criteria
All individuals meeting any of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum tolerated dose | 6 months | The maximum tolerated dose (MTD) is defined as the highest safely tolerated dose of lurbinectedin, where not more than one participant experienced a dose limiting toxicity (DLT), with the next higher dose level having at least two participants who experienced DLT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective response rate | 24 months | The number of patients achieving a complete response and partial response divided by the number of patients who completed at least one treatment cycle and had a follow up computerized tomography (CT) scan |
| Progression free survival at 6 months | 12 months | The length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse. |
| Overall survival | 36 months | The length of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, that patients diagnosed with the disease are still alive. I |
| Correlation of response with circulating tumor DNA | 36 months | Correlation of response with circulating tumor DNA |
Countries
United States
Contacts
Primary ContactErlinda M Gordon, MD
Backup ContactVictoria Chua-Alcala, MD
Outcome results
None listed