Solid Tumors, Advanced Solid Tumors
Conditions
Brief summary
This is a Phase 1, non-randomized, dose-escalating, open label, multi-center study to be conducted in two parts (Part A and Part B). RO6870810 is a small molecule, non-covalent inhibitor of bromodomain and extra-terminal (BET) family of bromodomains. This study is designed to characterize the safety, tolerability, pharmacokinetics and anti-tumor activity of RO6870810 in participants with histologically confirmed solid tumors with progressive disease (PD) which is refractory or intolerant to standard/approved therapies. In Part A, RO6870810 will be administered by subcutaneous (SC) injection daily for either 21 consecutive days in a 28-day cycle or for 14 consecutive days in a 21-day treatment cycle in participants with advanced solid tumor malignancies to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT). In Part B, RO6870810 will be administered at a dose up to the MTD to further characterize the safety profile and biological effect in a subset of participants with advanced solid tumor malignancies. It is anticipated that a total of 84 participants will be enrolled in to this study (54 in Part A and 30 in Part B). In addition, it is expected that up to 20 participants with histologically confirmed nuclear protein in testis (NUT)-midline carcinoma (NMC) with progressive disease requiring therapy will be enrolled in the sub-study of Parts A and B. In addition, up to 20 participants with diffuse large B-cell lymphoma (DLBCL) may be enrolled at selected study sites.
Interventions
DRUGRO6870810
Participants will receive RO6870810 at different planned doses with a starting dose of 0.03 mg/kg to a maximum dose of 0.85 mg/kg SC on Days 1 to 14 in a 21-day treatment cycle or on Days 1 to 21 in a 28-day treatment cycle.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
General: * Participants with solid tumors must have one or more metastatic tumors evaluable or measurable on radiographic imaging * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (or 2 upon approval by the medical monitor) * Life expectancy of greater than or equal to (\>/=) 3 months * Disease-free of active second/secondary or prior malignancies \>/= 2 years with the exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix or breast * Adequate hematological, renal, hepatic and coagulation laboratory test results * Women of child bearing potential and men must agree to use adequate contraception during the study and for 4 months after the last dose of study drug Advanced Solid Malignancies: * Participants with previously treated, histologically confirmed advanced solid malignancy with progressive disease requiring therapy * Participants must be refractory or intolerant to standard therapy NUT-midline carcinoma: * Participants with histologically confirmed newly diagnosed or relapsed/refractory NMC with PD requiring therapy * Diagnosis of one of the following is required: 1. NUT Midline Carcinoma based on ectopic expression of NUT protein as determined by Immunohistochemistry (IHC) and/or; 2. Detection of NUT gene translocation as determined by Fluorescence In-Situ Hybridization (FISH) Advanced Aggressive DLBCL * Histologically confirmed advanced aggressive B-cell lymphoma with abnormal MYC expression with persistent disease requiring treatment * Participants must have relapsed or progressed after at least 2 lines of prior therapy and not eligible for any curative treatment * Participants must have measurable disease
Exclusion criteria
* Participants with hematologic malignancies * New York Heart Association Class III or IV, cardiac disease, myocardial infarction within the past 6 months, unstable arrhythmia * Have Fridericia-corrected QT interval (QTcF) greater than (\>) 470 milliseconds (msec) (female) or \> 450 (male), or history of congenital long QT syndrome * Active, uncontrolled bacterial, viral, or fungal infections * Known clinically important respiratory impairment * Positive for human immunodeficiency virus (HIV), hepatitis B surface antigen, or hepatitis C antibodies * History of major organ transplant * History of an autologous or allogeneic bone marrow transplant. For DLBCL participants only: DLBCL participants may have had a previous autologous transplant but not within 90 days of study entry * Symptomatic central nervous system malignancy or metastasis * Pregnant or nursing * Treatment with surgery or chemotherapy within 28 days prior to study entry * Prior treatment with small molecule (BET) family inhibitor * Radiation for symptomatic lesions within 14 days of study enrollment
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Participants with DLTs | Day 1 up to Day 28 (or Day 21) |
| MTD of RO6870810 | Day 1 up to Day 28 (or Day 21) |
| Percentage of Participants with Adverse Events | Baseline up to approximately 47 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants with Objective Response (Complete Response [CR] or Partial Response [PR]) Based on Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 as Determined by the Investigator | Baseline up to 47 months (detailed timeframe is provided in the outcome description) | Screening up to PD/death whichever occurs first (assessed at screening, Day 1 of Cycle 1 and every odd numbered cycle up to treatment completion \[up to 47 months\], end of treatment visit \[up to 47 months\], and every 12 weeks thereafter up to study completion \[up to 47 months\]) up to 47 months (cycle length=21 or 28 days) |
| Median Time Taken for the First Response Based on RECIST v 1.1 as Determined by the Investigator | Baseline up to 47 months (detailed timeframe is provided in the outcome description) | Screening up to PD/death whichever occurs first (assessed at screening, Day 1 of Cycle 1 and every odd numbered cycle up to treatment completion \[up to 47 months\], end of treatment visit \[up to 47 months\], and every 12 weeks thereafter up to study completion \[up to 47 months\]) up to 47 months (cycle length = 21 or 28 days) |
| Median Time Taken for the Best Overall Response Based on RECIST v 1.1 as Determined by the Investigator | Baseline up to 47 months (detailed timeframe is provided in the outcome description) | Screening up to PD/death whichever occurs first (assessed at screening, Day 1 of Cycle 1 and every odd numbered cycle up to treatment completion \[up to 47 months\], end of treatment visit \[up to 47 months\], and every 12 weeks thereafter up to study completion \[up to 47 months\]) up to 47 months (cycle length = 21 or 28 days) |
| Area Under the Concentration Versus Time Curve from Time 0 (Pre-dose) to Time 24 Hours (AUC0-24) of RO6870810 | Baseline up to 47 months (detailed timeframe is provided in the outcome description) | Pre-injection (Hour 0), immediately post-injection, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 24 and 28 hours post-injection on Day 1 Cycle 1; Pre-injection (Hour 0), immediately post-injection, 0.25, 0.5, 1, 2, and 4 hours post-injection on Day 15 Cycle 1; random samples on Days 8, 22 of Cycle 1 and on Day 1 of Cycle 2 and every cycle thereafter up to treatment completion (up to 47 months), end of treatment visit/early termination (up to 47 months) (cycle length = 21 or 28 days) |
| Duration of Response Based on RECIST v 1.1 as Determined by the Investigator | Baseline up to 47 months (detailed timeframe is provided in the outcome description) | Screening up to PD/death whichever occurs first (assessed at screening, Day 1 of Cycle 1 and every odd numbered cycle up to treatment completion \[up to 47 months\], end of treatment visit \[up to 47 months\], and every 12 weeks thereafter up to study completion \[up to 47 months\]) up to 47 months (cycle length = 21 or 28 days) |
| Overall Survival | Screening up to death due to any cause (up to approximately 47 months) | — |
| Progression Free Survival Based on RECIST v 1.1 as Determined by the Investigator | Baseline up to 47 months (detailed timeframe is provided in the outcome description) | Screening up to PD/death whichever occurs first (assessed at screening, Day 1 of Cycle 1 and every odd numbered cycle up to treatment completion \[up to 47 months\], end of treatment visit \[up to 47 months\], and every 12 weeks thereafter up to study completion \[up to 47 months\]) up to 47 months (cycle length = 21 or 28 days) |
| Maximum Plasma Concentration (Cmax) of RO6870810 | Baseline up to 47 months (detailed timeframe is provided in the outcome description) | Pre-injection (Hour 0), immediately post-injection, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 24 and 28 hours post-injection on Day 1 Cycle 1; Pre-injection (Hour 0), immediately post-injection, 0.25, 0.5, 1, 2, and 4 hours post-injection on Day 15 Cycle 1; random samples on Days 8, 22 of Cycle 1 and on Day 1 of Cycle 2 and every cycle thereafter up to treatment completion (up to 47 months), end of treatment visit/early termination (up to 47 months) (cycle length = 21 or 28 days) |
| Time to Reach Cmax (Tmax) of RO6870810 | Baseline up to 47 months (detailed timeframe is provided in the outcome description) | Pre-injection (Hour 0), immediately post-injection, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 24 and 28 hours post-injection on Day 1 Cycle 1; Pre-injection (Hour 0), immediately post-injection, 0.25, 0.5, 1, 2, and 4 hours post-injection on Day 15 Cycle 1; random samples on Days 8, 22 of Cycle 1 and on Day 1 of Cycle 2 and every cycle thereafter up to treatment completion (up to 47 months), end of treatment visit/early termination (up to 47 months) (cycle length = 21 or 28 days) |
Countries
United States
Outcome results
None listed