Study of Bromodomain and Extra-Terminal Protein (BET) Inhibitor RO6870810 as Mono- and Combination Therapy in Advanced Multiple Myeloma

NCT ID: NCT03068351

Last Updated: 2020-02-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-06-26
• Study Completion Date: 2019-08-01

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.

Conditions

Multiple Myeloma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

RO6870810

Intervention Type: DRUG

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).

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.

Group Type: EXPERIMENTAL

RO6870810

Intervention Type: DRUG

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).

daratumumab

Intervention Type: BIOLOGICAL

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.

Interventions

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).

Intervention Type: DRUG

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 Type: BIOLOGICAL

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

City of Hope

Duarte, California, United States

Stanford Cancer Center

Stanford, California, United States

Mayo Clinic

Jacksonville, Florida, United States

Emory Uni - Winship Cancer Center; Hematology/Oncology

Atlanta, Georgia, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Mount Sinai - PRIME; Icahn School of Medicine at Mount Sinai

New York, New York, United States

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States

Duke Clin Rsch Institute

Durham, North Carolina, United States

Scientia Clinical Research Limited

Randwick, New South Wales, Australia

St Vincent's Hospital Melbourne

Fitzroy, Victoria, Australia

University College London Hospitals; Clinical Research Facility

London, , United Kingdom

Oxford University Hospitals NHS Trust; Churchill Hospital

Oxford, , United Kingdom

Countries

United States; Australia; United Kingdom

Other Identifiers

2016-003615-35

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

NP39403

Identifier Type: -

Identifier Source: org_study_id