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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03068351




Registration number
NCT03068351
Ethics application status
Date submitted
27/02/2017
Date registered
1/03/2017
Date last updated
7/02/2020

Titles & IDs
Public title
Study of Bromodomain and Extra-Terminal Protein (BET) Inhibitor RO6870810 as Mono- and Combination Therapy in Advanced Multiple Myeloma
Scientific 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
Secondary ID [1] 0 0
2016-003615-35
Secondary ID [2] 0 0
NP39403
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Myeloma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - RO6870810
Other interventions - daratumumab

Experimental: RO6870810 - Participants will be administered RO6870810 monotherapy at ascending-dose levels during the dose escalation phase followed by an expansion phase during which RO6870810 will be administered as monotherapy at the recommended dose. Participants will continue to receive study drug as long as they experience clinical benefit in the opinion of the Investigator or until unacceptable toxicity or symptomatic deterioration attributed to disease progression, as determined by the Investigator after an integrated assessment of IMWG response criteria, biopsies/aspirate (if applicable), and clinical status, or withdrawal of consent.

Experimental: RO6870810 + Daratumumab - Participants will be administered RO6870810 at ascending-dose levels in combination with daratumumab at the recommended dose during the dose escalation phase followed by an expansion phase during which both RO6870810 and daratumumab will be administered each at their recommended dose. Participants will continue to receive the study drugs as long as they experience clinical benefit in the opinion of the Investigator or until unacceptable toxicity or symptomatic deterioration attributed to disease progression, as determined by the Investigator after an integrated assessment of IMWG response criteria, biopsies/aspirate (if applicable), and clinical status, or withdrawal of consent.


Treatment: Drugs: RO6870810
RO6870810 will be administered subcutaneously (SC) at ascending-dose levels (from 0.30 milligrams/kilogram [mg/kg] to 0.65 mg/kg). In Cycle 1, RO6870810 will be given on Day 1 (omitted on Day 2) and then every day from Day 3 through to Day 15. Starting at Cycle 2, it will be given every day from Day 1 to Day 14 of each 21-day cycle. In the first combination therapy cohort RO6870810 will be administered at one dose-level below the maximum tolerated dose (MTD).

Other interventions: daratumumab
Daratumumab will be administered intravenously (IV) at a dose of 16 milligrams/kilogram (mg/kg) of body weight weekly for the first 8 weeks, every two weeks for the following 16 weeks, and every four weeks thereafter, until disease progression.

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of Dose-Limiting Toxicities (DLTs) - DLTs are defined as the toxicities known and expected of RO6870810 and daratumumab that occur during a DLT assessment window of 21 days from the first administration of RO6870810 or study combination treatments, and are considered by the Investigator to be related to study treatment. DLTs are defined at specific severity levels for each term and include, but are not limited to the following Common Terminology Criteria for Adverse Events (CTCAE) terms: neutropenia, febrile neutropenia, thrombocytopenia, anemia and injection site reaction.
Timepoint [1] 0 0
From first drug administration to end of dose-escalation phase (up to approximately 1 year)
Primary outcome [2] 0 0
Objective Response Rate (ORR) - ORR is defined as the percentage of participants whose confirmed best overall response is either complete response (CR, including stringent complete response [sCR]) or partial response (PR, including very good partial response [VGPR]), assessed with use of the IMWG criteria. CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow aspirates. sCR: CR plus normal free light chain (FLC) ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. PR: >/=50% reduction of serum M-protein plus reduction in 24h urinary M-protein by >/=90% or to <200 mg/24h. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis; or >/=90% reduction in serum M-protein plus urine M-protein level <100 mg/24h. ORR= CR + sCR + PR + VGPR
Timepoint [2] 0 0
From baseline to end of study (up to approximately 2.5 years)
Primary outcome [3] 0 0
Progression Free Survival (PFS) - PFS is defined as the time from first study treatment to the first occurrence of disease progression (per IMWG criteria) or death, whichever occurs first. Disease progression is defined as an increase of >/= 25% from lowest response value in any one or more of the following: serum M-component, urine M-component, in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels (the absolute increase must be >10 mg/dL), bone marrow plasma cell percentage (absolute level >/= 10%), definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas, development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder.
Timepoint [3] 0 0
From baseline to end of study (up to approximately 2.5 years)
Primary outcome [4] 0 0
Duration of Response (DoR) - DoR is defined as the time from the first occurrence of a documented objective response (sCR, CR, VGPR, or PR) to the time of first disease progression per IMWG criteria or death from any cause, whichever occurs first. Disease progression is defined as an increase of >/= 25% from lowest response value in any one or more of the following: serum M-component, urine M-component, in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels (the absolute increase must be >10 mg/dL), bone marrow plasma cell percentage (absolute level >/= 10%), definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas, development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder.
Timepoint [4] 0 0
From baseline to end of study (up to approximately 2.5 years)
Primary outcome [5] 0 0
Overall survival (OS) - OS is defined as the time from study enrollment until death from any cause.
Timepoint [5] 0 0
From baseline to end of study (up to approximately 2.5 years)
Secondary outcome [1] 0 0
Percentage of Participants with Adverse Events - An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Timepoint [1] 0 0
From baseline to end of study (up to approximately 2.5 years)
Secondary outcome [2] 0 0
Maximum Observed Plasma Concentration (Cmax) of RO6870810 - Maximum observed concentration of RO6870810 as determined by measuring drug concentration in blood samples over time.
Timepoint [2] 0 0
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)
Secondary outcome [3] 0 0
Time to Reach Maximum Observed Plasma Concentration (tmax) of RO6870810 - Time from dose administration to observed maximum serum concentration for RO6870810 as determined by measuring drug concentration in blood samples over time.
Timepoint [3] 0 0
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)
Secondary outcome [4] 0 0
Apparent Plasma Clearance (CL/F) of RO6870810 - Apparent clearance (CL/F) of RO6870810, where CL is clearance and F is bioavailability (relative amount of extravascularly-administered drug that reaches systemic circulation unchanged). Determined by measuring drug concentration in blood samples over time.
Timepoint [4] 0 0
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)
Secondary outcome [5] 0 0
Apparent Volume of Distribution (V/F) of RO6870810 - Apparent volume of distribution (V/F) for RO6870810, where V is the volume of distribution and F is bioavailability (relative amount of extravascularly-administered drug that reaches systemic circulation unchanged). Determined by measuring drug concentration in blood samples over time.
Timepoint [5] 0 0
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)
Secondary outcome [6] 0 0
Area Under the Plasma Concentration-Time Curve (AUC) of RO6870810 - AUC for RO6870810 describes the extent of absorption from time of dose administration to time of sampling as determined by measuring drug concentration in blood samples over time.
Timepoint [6] 0 0
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)
Secondary outcome [7] 0 0
Half-life (t1/2) of RO6870810 - Half-life of RO6870810 is the time elapsed for the drug concentration to decrease by half as determined by measuring drug concentration in blood samples over time.
Timepoint [7] 0 0
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)
Secondary outcome [8] 0 0
Renal Clearance (CLr) of RO6870810 - Clearance of RO6870810 through the kidneys as determined by measuring drug concentration in urine samples over time.
Timepoint [8] 0 0
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
Secondary outcome [9] 0 0
M-Protein Levels - M-protein levels pre- and post-treatment will be monitored as a measure of biological response.
Timepoint [9] 0 0
At baseline, end of study (up to approximately 2.5 years)

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
Scientia Clinical Research Limited - Randwick
Recruitment hospital [2] 0 0
St Vincent's Hospital Melbourne - Fitzroy
Recruitment postcode(s) [1] 0 0
2031 - Randwick
Recruitment postcode(s) [2] 0 0
3065 - Fitzroy
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Florida
Country [3] 0 0
United States of America
State/province [3] 0 0
Georgia
Country [4] 0 0
United States of America
State/province [4] 0 0
Massachusetts
Country [5] 0 0
United States of America
State/province [5] 0 0
New York
Country [6] 0 0
United States of America
State/province [6] 0 0
North Carolina
Country [7] 0 0
United Kingdom
State/province [7] 0 0
London
Country [8] 0 0
United Kingdom
State/province [8] 0 0
Oxford

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Hoffmann-La Roche
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT03068351
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Clinical Trials
Address 0 0
Hoffmann-La Roche
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications