Clinical trial NCT03068351: Study of Bromodomain and Extra-Terminal Protein (BET) Inhibitor RO6870810 as Mono- and Combination Therapy in Advanced Multiple Myeloma
Official title: Open-label, Multicenter, Dose-escalation/Expansion Phase Ib Study to Evaluate Safety, Pharmacokinetics, and Activity of BET Inhibitor RO6870810, Given as Mono- and Combination Therapy to Patients With Advanced Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Multiple Myeloma
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2017-03-01
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This is a Phase Ib, open-label, multicenter, global study designed to assess the safety and tolerability of RO6870810 as monotherapy and in combination with daratumumab in participants with relapsed/refractory multiple myeloma. Each treatment cycle will be 21 days in length. There are two parts to this study. A dose-escalation phase (Part I) will be used to evaluate the safety and tolerability and dose limiting toxicities, and to establish the maximum tolerated dose (MTR)/optimum biological dose (OBD) of RO6870810 when given as monotherapy or in combination with daratumumab. A dose-expansion phase (Part II) will further characterize the safety, tolerability and activity of RO6870810 as monotherapy or in combination with daratumumab at the defined expansion dose-levels.


Eligibility criteria: Inclusion Criteria:

* Performance status \</=2 on the Eastern Cooperative Oncology Group (ECOG) scale
* Life expectancy \> 3 months
* Relapsed or refractory multiple myeloma. Participants with primary refractory myeloma only allowed in dose-escalation phase of the study.
* Prior treatment: Treated with at least three prior lines of multiple myeloma therapy including a proteasome inhibitor and an immuno modulatory agent or who are double refractory to a proteasome inhibitor and an immuno modulatory agent. Prior anti-CD38 antibody (e.g., daratumumab, isatuximab) treatment is acceptable only for participants receiving monotherapy treatment.
* Prior treatment: Treated with two or more lines of prior therapy, with disease refractory to both a proteasome inhibitor and an immunomodulatory agent, and disease progression (as defined by International Myeloma Working Group (IMWG) criteria) following treatment with an anti-CD38 monoclonal antibody given as monotherapy or in combination therapy. The most recent treatment regimen must have contained an anti-CD38 monoclonal antibody.
* Treatment with prior autologous transplant is permitted
* Documented diagnosis of symptomatic multiple myeloma, as defined by the IMWG
* Measurable disease defined as at least one of the following: serum M-protein \>/=1 grams/deciliter (g/dL), urine M-protein \>/= 200 milligrams/24 hours (mg/24h), serum free light chain (SFLC) assay: involved SFLCs \>/= 10 mg/dL (\>/= 100 mg/L) and an abnormal SFLC ratio (\<0.26 or \>1.65).
* Female participants of childbearing potential must have a negative serum pregnancy test within the 7 days prior to the first study drug administration.
* For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of \< 1% per year during the treatment period and for at least 2 months after the last dose of RO6870810 as monotherapy, or for at least 3 months after the last dose of daratumumab.
* For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm, as defined: With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 4 months after the last dose of RO6870810 as monotherapy, or for at least 3 months after the last dose of daratumumab.

Exclusion Criteria:

* Plasma cell leukemia defined as peripheral plasma cell count \> 2000/cubic millimeter (mm\^3)
* For expansion cohorts only: Primary refractory multiple myeloma defined as disease that is non-responsive in participants who have never achieved a minimal response or better with any therapy
* History of other malignancy within 2 years prior to screening, except for ductal carcinoma in situ not requiring chemotherapy, appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, low-grade, localized prostate cancer (Gleason score \</= 7) not requiring treatment or appropriately treated Stage I uterine cancer
* POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes)
* Current or prior disease or treatment that could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor
* Pregnant or breastfeeding female.
* Consumption of agents which strongly inhibit CYP3A4 enzyme, within 7 days prior to the first dose of study treatment and during the study.
* Consumption of agents which strongly induce CYP3A4 enzyme, within 14 days prior to the first dose of study treatment and during the study.
* Surgery within 21 days prior to study entry.
* Prior treatment with small molecule BET family inhibitor or receiving steroids \>the equivalent of 10mg prednisone daily
* participants who are currently receiving any other investigational agent or have received an investigational agent within 30 days or 5 half-lives, whichever is longer, prior to study entry
* Uncontrolled cancer pain
* Prior anti-cancer therapy (chemotherapy, targeted agents, radiotherapy, and immunotherapy) within 14 days except for alkylating agents (e.g., melphalan) within 28 days.

Primary outcomes:
measure: Number of Dose-Limiting Toxicities (DLTs)
timeFrame: From first drug administration to end of dose-escalation phase (up to approximately 1 year)
measure: Objective Response Rate (ORR)
timeFrame: From baseline to end of study (up to approximately 2.5 years)
measure: Progression Free Survival (PFS)
timeFrame: From baseline to end of study (up to approximately 2.5 years)
measure: Duration of Response (DoR)
timeFrame: From baseline to end of study (up to approximately 2.5 years)
measure: Overall survival (OS)
timeFrame: From baseline to end of study (up to approximately 2.5 years)
Secondary outcomes:
measure: Percentage of Participants with Adverse Events
timeFrame: From baseline to end of study (up to approximately 2.5 years)
measure: Maximum Observed Plasma Concentration (Cmax) of RO6870810
timeFrame: Cycle 1, Days 1 and 15: predose, 0.25 hours (h), 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h, 48 h; Cycle 1, Day 8 predose; all subsequent cycles predose on Day 1 and at end of treatment (EOT- up to approximately 2.5 years)
measure: Time to Reach Maximum Observed Plasma Concentration (tmax) of RO6870810
timeFrame: Cycle 1, Days 1 and 15: predose, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h, 48 h; Cycle 1, Day 8 predose; all subsequent cycles predose on Day 1 and at end of treatment (EOT - up to approximately 2.5 years)
measure: Apparent Plasma Clearance (CL/F) of RO6870810
timeFrame: Cycle 1, Days 1 and 15: predose, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h, 48 h; Cycle 1, Day 8 predose; all subsequent cycles predose on Day 1 and at end of treatment (EOT - up to approximately 2.5 years)
measure: Apparent Volume of Distribution (V/F) of RO6870810
timeFrame: Cycle 1, Days 1 and 15: predose, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h, 48 h; Cycle 1, Day 8 predose; all subsequent cycles predose on Day 1 and at end of treatment (EOT - up to approximately 2.5 years)
measure: Area Under the Plasma Concentration-Time Curve (AUC) of RO6870810
timeFrame: Cycle 1, Days 1 and 15: predose, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h, 48 h; Cycle 1, Day 8 predose; all subsequent cycles predose on Day 1 and at end of treatment (EOT - up to approximately 2.5 years)
measure: Half-life (t1/2) of RO6870810
timeFrame: Cycle 1, Days 1 and 15: predose, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h, 48 h; Cycle 1, Day 8 predose; all subsequent cycles predose on Day 1 and at end of treatment (EOT - up to approximately 2.5 years)
measure: Renal Clearance (CLr) of RO6870810
timeFrame: Cycle 1, Day 1: predose, 0-1 h, 1-4 h, 4-8 h; Cycle 1, Day 15: predose, 0 h, 2 h, 6 h
measure: M-Protein Levels
timeFrame: At baseline, end of study (up to approximately 2.5 years)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Stanford
country: United States
facility: Stanford Cancer Center
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Atlanta
country: United States
facility: Emory Uni - Winship Cancer Center; Hematology/Oncology
state: Georgia
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Mount Sinai - PRIME; Icahn School of Medicine at Mount Sinai
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke Clin Rsch Institute
state: North Carolina
city: Randwick
country: Australia
facility: Scientia Clinical Research Limited
state: New South Wales
city: Fitzroy
country: Australia
facility: St Vincent's Hospital Melbourne
state: Victoria
city: London
country: United Kingdom
facility: University College London Hospitals; Clinical Research Facility
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Trust; Churchill Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: