A Two Part Study of RO6870810. Dose-Escalation Study in Participants With Advanced Solid Tumors and Expansion Study in Participants With Selected Malignancies

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

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.

Study Overview

• Status: Completed
• Conditions: Solid Tumors, Advanced Solid Tumors
• Intervention / Treatment: Drug: RO6870810

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Center
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals of Cleveland

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RO6870810 (Part 1); Participants will receive escalated doses of RO67870810 SC. RO6870810 will be escalated at a starting dose of 0.03 milligrams per kilogram (mg/kg) to a maximum of 0.85 mg/kg. Treatment will be administered in treatment cycles of either 21 days or 28 days and continued until PD, adverse events which justify treatment withdrawal, non-adherence, non-compliance, investigator decision, lost to follow-up, enrollment in other clinical study, or unacceptable toxicity.	Drug: RO6870810; 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.; Other Names: TEN-010
Experimental: RO6870810 (Part 2); Participants will receive RO6870810 at doses up to the MTD or up to the highest dose tested if the MTD is not defined. Treatment will be administered in treatment cycles of either 21 days or 28 days and continued until PD, adverse events which justify treatment withdrawal, non-adherence, non-compliance, investigator decision, lost to follow-up, enrollment in other clinical study, or unacceptable toxicity.	Drug: RO6870810; 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.; Other Names: TEN-010

What is the study measuring?

Primary Outcome Measures

Outcome 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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Concentration Versus Time Curve from Time 0 (Pre-dose) to Time 24 Hours (AUC0-24) of RO6870810	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)	Baseline up to 47 months (detailed timeframe is provided in the outcome description)
Maximum Plasma Concentration (Cmax) of RO6870810	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)	Baseline up to 47 months (detailed timeframe is provided in the outcome description)
Time to Reach Cmax (Tmax) of RO6870810	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)	Baseline up to 47 months (detailed timeframe is provided in the outcome 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	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)	Baseline up to 47 months (detailed timeframe is provided in the outcome description)
Median Time Taken for the First Response Based on RECIST v 1.1 as Determined by the Investigator	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)	Baseline up to 47 months (detailed timeframe is provided in the outcome description)
Median Time Taken for the Best Overall Response Based on RECIST v 1.1 as Determined by the Investigator	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)	Baseline up to 47 months (detailed timeframe is provided in the outcome description)
Progression Free Survival Based on RECIST v 1.1 as Determined by the Investigator	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)	Baseline up to 47 months (detailed timeframe is provided in the outcome description)
Duration of Response Based on RECIST v 1.1 as Determined by the Investigator	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)	Baseline up to 47 months (detailed timeframe is provided in the outcome description)
Overall Survival		Screening up to death due to any cause (up to approximately 47 months)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 16, 2013
• Primary Completion (Actual): October 11, 2017
• Study Completion (Actual): October 11, 2017

Study Registration Dates

• First Submitted: November 5, 2013
• First Submitted That Met QC Criteria: November 12, 2013
• First Posted (Estimate): November 19, 2013

Study Record Updates

• Last Update Posted (Actual): January 5, 2018
• Last Update Submitted That Met QC Criteria: January 3, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: NP39141; TEN-010-001 (Other Identifier: Tensha)