Clinical trial NCT01987362: A Two Part Study of RO6870810. Dose-Escalation Study in Participants With Advanced Solid Tumors and Expansion Study in Participants With Selected Malignancies
Official title: A Two-Part, Phase I, Multicenter, Open-Label Study of RO6870810/TEN-010 Given Subcutaneously: Part A: A Dose-Escalation Study in Patients With Advanced Solid Tumors. Part B: An Expansion Cohort in Patients With Selected Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumors, Advanced Solid Tumors
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2013-11-19
Enrollment: 52
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants with DLTs
timeFrame: Day 1 up to Day 28 (or Day 21)
measure: MTD of RO6870810
timeFrame: Day 1 up to Day 28 (or Day 21)
measure: Percentage of Participants with Adverse Events
timeFrame: Baseline up to approximately 47 months
Secondary outcomes:
measure: Area Under the Concentration Versus Time Curve from Time 0 (Pre-dose) to Time 24 Hours (AUC0-24) of RO6870810
timeFrame: Baseline up to 47 months (detailed timeframe is provided in the outcome description)
measure: Maximum Plasma Concentration (Cmax) of RO6870810
timeFrame: Baseline up to 47 months (detailed timeframe is provided in the outcome description)
measure: Time to Reach Cmax (Tmax) of RO6870810
timeFrame: Baseline up to 47 months (detailed timeframe is provided in the outcome description)
measure: 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
timeFrame: Baseline up to 47 months (detailed timeframe is provided in the outcome description)
measure: Median Time Taken for the First Response Based on RECIST v 1.1 as Determined by the Investigator
timeFrame: Baseline up to 47 months (detailed timeframe is provided in the outcome description)
measure: Median Time Taken for the Best Overall Response Based on RECIST v 1.1 as Determined by the Investigator
timeFrame: Baseline up to 47 months (detailed timeframe is provided in the outcome description)
measure: Progression Free Survival Based on RECIST v 1.1 as Determined by the Investigator
timeFrame: Baseline up to 47 months (detailed timeframe is provided in the outcome description)
measure: Duration of Response Based on RECIST v 1.1 as Determined by the Investigator
timeFrame: Baseline up to 47 months (detailed timeframe is provided in the outcome description)
measure: Overall Survival
timeFrame: Screening up to death due to any cause (up to approximately 47 months)
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Center
state: Michigan
city: Cleveland
country: United States
facility: University Hospitals of Cleveland
state: Ohio
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Shapiro GI, LoRusso P, Dowlati A, T Do K, Jacobson CA, Vaishampayan U, Weise A, Caimi PF, Eder JP, French CA, Labriola-Tompkins E, Boisserie F, Pierceall WE, Zhi J, Passe S, DeMario M, Kornacker M, Armand P. A Phase 1 study of RO6870810, a novel bromodomain and extra-terminal protein inhibitor, in patients with NUT carcinoma, other solid tumours, or diffuse large B-cell lymphoma. Br J Cancer. 2021 Feb;124(4):744-753. doi: 10.1038/s41416-020-01180-1. Epub 2020 Dec 14.