An Open-label, Phase I Trial to Determine the Maximum-tolerated Dose and Investigate Safety, Pharmacokinetics, and Efficacy of BI 754091 in Patients With Advanced Solid Tumours
Overview
- Phase
- Phase 1
- Intervention
- BI 754091
- Conditions
- Neoplasms
- Sponsor
- Boehringer Ingelheim
- Enrollment
- 110
- Locations
- 13
- Primary Endpoint
- Phase Ia Dose Escalation: Number of Participants With Dose-limiting Toxicities (DLTs) in the First Cycle (3 Weeks)
- Status
- Completed
- Last Updated
- 3 months ago
Overview
Brief Summary
The main objective of the dose-escalation part of the trial is to determine the safety and tolerability, and to determine the Maximum Tolerated Dose and/or the Recommended Phase 2 Dose (RP2D) of BI 754091 on the basis of patients with dose-limiting toxicities (DLTs) in patients with selected advanced solid malignancies. Safety and tolerability will be evaluated by monitoring the occurrence of adverse events (AEs), serious AEs (SAE), and laboratory parameter abnormalities, as well as changes to vital signs.
Secondary objectives are the determination of the PK profile of BI 754091 after single and multiple doses of BI 754091, and the preliminary assessment of antitumour activity.
In the dose-expansion part of the trial, the main objectives are to further assess the safety, efficacy, PK profile, and biomarkers of BI 754091 in tumours with specific tumour types and/or genetic mutations at the RP2D.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Provision of signed and dated, written Informed Consent Form (ICF) prior to any trial-specific procedures, sampling, or analyses. If a patient declines to participate in the voluntary pharmacogenetics component of the trial, he/she will not be excluded from other aspects of the trial.
- •Patients ≥18 years of age at the time of signature of the ICF
- •Phase Ia (dose-escalation)
- •patients with a histologically confirmed diagnosis of advanced, unresectable, and/or metastatic solid tumours (any type).
- •patients who have received all therapy known to confer clinical benefit (including anti-PD-1 or anti-PDL1 therapies, if relevant), or for whom no therapy of proven efficacy exists, or who are not amenable to standard therapies. Patients with anti- PD-1 or anti-PDL1 experience must have a minimum of 60 days between the last dose of the previous anti PD-1/PD-L1 and Cycle 1 Day 1 of BI 754091 treatment.
- •Patients may agree to provide optional paired biopsies.
- •Phase Ib (dose expansion)
- •patients with a histologically confirmed diagnosis of select advanced, unresectable, and/or metastatic solid tumours with either 1) high tumor mutation excluding high microsatellite instability or 2) refractory squamous cell cervical, anal and skin tumors, or 3) recurrent vaginal or vulvar squamous cell carcinoma.
- •All patients must have measurable lesions according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 must have at least 1 tumour lesion amenable to biopsy, and must be medically fit and willing to undergo a biopsy before first treatment and, unless clinically contraindicated, after 6 weeks on therapy
- •patients who are anti-PD-1 and anti-PDL-1naïve but have failed conventional treatment (excluding anti-PD-1 treatment), or for whom no therapy of proven efficacy exists, or who are not amenable to standard therapies.
Exclusion Criteria
- •Major surgery (major according to the Investigator's assessment) performed within 12 weeks prior to first trial treatment or planned within 12 months after screening, e.g.,hip replacement
- •Patients who must or wish to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial
- •Previous enrolment in this trial
- •Any investigational or anti-tumour treatment within 4 weeks or 5 half-life period (whichever is shorter) prior to the initial administration of BI
- •Presence of other active invasive cancers other than the one treated in this trial within 5 years prior to screening, with the exception of appropriately treated basal-cell carcinoma of the skin, in situ carcinoma of the uterine cervix, or other local tumours considered cured by local treatment.
- •Untreated brain metastasis(es) that may be considered active. Patients with previously treated brain metastases may participate provided they are stable (i.e., without evidence of Progression of Disease by imaging for at least 4 weeks prior to the first dose of trial treatment, and any neurologic symptoms have returned to baseline), and there is no evidence of new or enlarging brain metastases
- •Inadequate organ function or bone marrow reserve as demonstrated by the following laboratory values:
- •Absolute neutrophil count \<1.5 x 10\^9/L (\<1500/mm3)
- •Platelet count \<100 x 10\^9/L
- •Haemoglobin \<90 g/L (\<9 g/dL)
Arms & Interventions
Phase Ia dose escalation: Cohort 1
Low dose.
Intervention: BI 754091
Phase Ia dose escalation: Cohort 2
Medium dose.
Intervention: BI 754091
Phase Ia dose escalation: Cohort 3
High dose.
Intervention: BI 754091
Phase Ib dose expansion: Cohort 4
Patients with solid tumours including NSCLC, bladder cancer, melanoma, gastric cancer, ovarian cancer, triple-negative breast cancer, and renal-cell cancer
Intervention: BI 754091
Phase Ib dose expansion: Cohort 5
Patients with tumours with high TMB excluding those with high microsatellite instability (MSI-high)
Intervention: BI 754091
Phase Ib dose expansion: Cohort 6
Patients with refractory squamous cell cervical, anal, and skin tumours.
Intervention: BI 754091
Phase Ib dose escalation: Cohort 7
Patients with recurrent human papillomavirus (HPV)-positive, or HPV-negative, vaginal or vulvar squamous cell carcinoma (VSCC)
Intervention: BI 754091
Outcomes
Primary Outcomes
Phase Ia Dose Escalation: Number of Participants With Dose-limiting Toxicities (DLTs) in the First Cycle (3 Weeks)
Time Frame: Up to 3 weeks.
Number of participants experiencing dose-limiting toxicities (DLTs) graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 / 5.0 observed in the first cycle (3 weeks) in order to meet the objective of assessment of the maximum tolerated dose (MTD) of ezabenlimab.
Phase Ib Dose Expansion: Number of Participants With Dose-limiting Toxicities (DLTs) During the Entire Treatment Period
Time Frame: From first infusion of study treatment until end of study treatment at the time of interim database lock plus 30 days, up to 853 days.
Phase Ib dose expansion: Number of participants with dose-limiting toxicities (DLTs) during the entire treatment period
Phase Ib Dose Expansion: Confirmed Objective Response (OR), Defined as the Best Overall Response of Confirmed Complete Response (CR) or Partial Response (PR) According to RECIST v1.1 as Assessed by the Investigator
Time Frame: From first infusion of study treatment until end of study treatment at the time of interim database lock plus 30 days, up to 853 days.
Confirmed objective Response (OR), defined as the best overall response of confirmed complete response (CR) or partial response (PR) according to RECIST v1.1 assessed by the Investigator, where the best overall response is the best time point response recorded from the first administration of BI 754091 until the earliest of disease progression according to RECIST v1.1, death or last evaluable tumor assessment before start of subsequent anti-cancer therapy, loss to follow- up or withdrawal of consent.
Secondary Outcomes
- Phase Ia Dose Escalation: Confirmed Objective Response According to RECIST v.1.1 as Assessed by the Investigator(From the first administration of BI 754091 until the earliest of disease progression, death or last evaluable tumor assessment before start of subsequent anti-cancer therapy, loss to follow- up or withdrawal of consent, up to 511 days.)
- Phase Ia Dose Escalation: Maximum Measured Concentration (Cmax) of Ezabenlimab in Plasma(5 minutes prior to BI 754091 infusion start and 0.5, 1, 1.5, 2, 4, 7, 24, 72, 168 and 336 hours after start of BI 754091 infusion.)
- Phase Ia Dose Escalation: Area Under the Concentration-time Curve of Ezabenlimab in Plasma Over the Time Interval From 0 to 504 Hours (AUC0-504)(5 minutes prior to BI 754091 infusion start and 0.5, 1, 1.5, 2, 4, 7, 24, 72, 168, 336 and 504 hours after start of BI 754091 infusion.)
- Phase Ia Dose Escalation: Number of Participants Experiencing Dose-limiting Toxicities (DLTs) From the Start of Treatment Until End of Treatment(From first infusion of study treatment until the last infusion of study treatment plus 30 days, up to 511 days.)
- Phase Ib Dose Expansion: Confirmed Progression-free Survival (PFS) Defined From Date of Start of Ezabenlimab to the Date of Disease Progression or Death, Whichever Was Earlier, According to RECIST v1.1 as Assessed by the Investigator(From first BI 754091 infusion until disease progression or death, whichever is earlier up to 1668 days.)
- Phase Ib Dose Expansion: Percentage of Participants With Adverse Events (AEs)(From first infusion of study treatment until end of study treatment plus 30 days, up to 1668 days.)
- Phase Ib Dose Expansion: Percentage of Participants With Serious Adverse Events (SAEs)(From first infusion of study treatment until end of study treatment at the time of interim database lock plus 30 days, up to 853 days.)
- Phase Ib Dose Expansion: Percentage of Participants With Clinically Relevant Abnormalities in Laboratory Evaluations(From first infusion of study treatment until end of study treatment plus 30 days, up to 1668 days.)