A Study to Evaluate Safety, Pharmacokinetics, and Clinical Activity of Combination of RO6870810 and Venetoclax, With or Without Rituximab, in Participants With Relapsed/Refractory DLBCL and/or High-Grade B-Cell Lymphoma and/or High Grade B-Cell Lymphoma With MYC and/or BCL2 and/or BCL6

NCT03255096 | Completed Phase 1 FDA Drug

• 2 other identifiers: NP394612017-000357-39
• Study Type: interventional
• Target: 39
• Locations: 4 countries
• Sites: 9

Brief Summary

The purpose of this study is to evaluate the safety, tolerability and clinical activity of RO6870810 in combination with venetoclax and when co-administered with rituximab in participants with relapse/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and/or high-grade B-cell lymphoma with myelocytomatosis oncogene (MYC) and/or B-cell lymphoma 2 (BCL2) and/or B-cell lymphoma 6 (BCL6) gene rearrangements (HGBL-DH/TH).

Conditions

Diffuse Large B-cell Lymphoma; High-Grade B-cell Lymphoma

Outcome Measures

Primary Outcomes (5)

• Percentage of Participants With Dose-Limiting Toxiciities (DLT)- Part 1

  DLT is defined as any of the toxicities- occurs within the first cycle for which the participant receives the full intended combination doses and number of administrations; is considered to be related to study treatment by the investigator; is not attributed to disease progression or another clearly identifiable cause.

  Cycle (C) 1 (21 days)

• Percentage of Participants With Adverse Events (AEs) - Part 1

  An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

  Up to 36 months

• Percentage of Participants With Clinically Significant Changes in Vital Signs, Physical Examination, Clinical Laboratory Results and Electrocardiogram (ECG) Findings- Part 1

  Up to 36 months

• Complete Response (CR) Rate as Determined by Independent Radiological Central Review (ICR) Using Modified Lugano Response Criteria- Recommended Dose (RD) Expansion - Part 2

  Up to 36 months

• Overall Response (OR) Rate as Determined by Independent Radiological Central Review (ICR) Using Modified Lugano Response Criteria- RD Expansion - Part 2

  Up to 36 months

Secondary Outcomes (19)

• Percentage of Participants With Adverse Events (AEs) - Part 2

  Up to 36 months

• Percentage of Participants With Clinically Significant Changes in Vital Signs, Physical Examination, Clinical Laboratory Results and Electrocardiogram (ECG) Findings- Part 2

  Up to 36 months

• Maximum Concentration (Cmax) of RO6870810 and its Potential Metabolites- Part 1 and Part 2

  Pre-dose Day 1,8,15; 0.25,0.5,1,2,4,6,8 hour (h) post-dose Day 1, 15; Day 2 C1; Pre-dose Day 1,8,15; 0.25h post-dose Day 1,8 C2; Pre-dose Day 1,15 C4; 0.25h post-dose Day 1 C4; Pre-dose, 0.25h post-dose Day 1 of subsequent even Cycles (Up to 36 months)

• Trough Serum Concentration (Cmin) of RO6870810 and its Potential Metabolites- Part 1 and Part 2

  Pre-dose Cycle 2 and all other subsequent even Cycles (Up to 36 months)

• Time of Maximum Concentration (tmax) of RO6870810 and its Potential Metabolites- Part 1 and Part 2

  Pre-dose Day 1,8,15; 0.25,0.5,1,2,4,6,8 hour (h) post-dose Day 1, 15; Day 2 C1; Pre-dose Day 1,8,15; 0.25h post-dose Day 1,8 C2; Pre-dose Day 1,15 C4; 0.25h post-dose Day 1 C4; Pre-dose, 0.25h post-dose Day 1 of subsequent even Cycles (Up to 36 months)

Study Arms (2)

Dose Escalation Phase (Part 1)

EXPERIMENTAL

Participants will receive either RO6870810 and venetoclax or RO6870810 and venetoclax along with rituximab until disease progression, unacceptable toxicities or withdrawal from treatment for other reasons, or death.

Drug: RO6870810; Drug: Venetoclax; Drug: Rituximab

Expansion Phase (Part 2)

EXPERIMENTAL

Participants will receive RO6870810 and venetoclax along with rituximab (or RO6870810 and venetoclax, if the combination of the 3 drugs is not tolerable) at a recommended dose established in dose escalation phase until disease progression, unacceptable toxicities or withdrawal from treatment for other reasons, or death.

Drug: RO6870810; Drug: Venetoclax; Drug: Rituximab

Interventions

RO6870810 DRUG

RO6870810 subcutaneously (SC) at dose of 0.30, 0.45, or 0.65 milligram per kilogram (mg/kg) on Days 1-14 of 21-day cycles.

Dose Escalation Phase (Part 1); Expansion Phase (Part 2)

Venetoclax DRUG

Venetoclax tablets orally at dose of 400 mg once daily (QD) continuously for 21 days.

Dose Escalation Phase (Part 1); Expansion Phase (Part 2)

Rituximab DRUG

Rituximab intravenously (IV) at dose of 375 mg/m\^2 weekly during the first 21-day cycle (C1) and on day 1 of each cycle thereafter.

Dose Escalation Phase (Part 1); Expansion Phase (Part 2)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2.
• Life expectancy \>3 months as per investigator's assessment.
• Part 1 and Part 2 Group 1: Participantts with diffuse large B-cell lymphoma (DLBCL) relapsed or refractory to ≥ 1 course of chemotherapy including an anti-CD20 monoclonal antibody, and not eligible for autologous stem cell transplantation (ASCT) (including due to chemorefractory disease). Participants with transformed FL are eligible, provided DLBCL or HGBL-DH/TH histology is biopsy-confirmed prior to study entry and a treatment regimen as described above has been administered. The Sponsor retains the option to limit the number of participants enrolled with transformed FL.
• Part 2, Group 2: Patients identified with DE-DLBCL (expression MYC ≥40%, BCL2 \> 50%) and or HGBL-DH/TH, relapsed or refractory to \>= 1 course of chemotherapy including an anti-CD20 monoclonal antibody, and not eligible for ASCT (including due to chemorefractory disease). Patients with transformed follicular lymphoma (FL) are eligible, provided DE-DLBCL and/or HGBL-DH/TH histology is biopsy-confirmed prior to study entry and a treatment regimen as described above has been administered. The Sponsor retains the option to limit the number of participants enrolled with transformed FL.
• Part 1 and Part 2: Willing to provide the protocol specified tumor biopsy(ies): at screening a fresh biopsy (if no archival biopsy tissue of less than 3 months prior to treatment and without intercurrent treatment is available); Part 2: Willing to provide an additional biopsy on Cycle 2 Day 15 (+ 2 days).
• Acceptable liver function, as specified below:
• Total bilirubin ≤ 2 times upper limit of normal (ULN). (Participants with known Gilbert's disease who has serum bilirubin ≤ 3 × ULN may be enrolled).
• Aspartate transaminase (AST; SGOT), alanine transaminase (ALT; SGPT) ≤ 2.5 × ULN, (or ≤ 5 × ULN if tumor involvement (liver) is present).
• Gamma-glutamyl transferase (GGT) alkaline phosphatase ≤ 2.5 × ULN.
• Acceptable renal function, as specified below:
• Creatinine clearance (CrCl) calculated by Cockroft-Gault formula of ≥ 60 mL/min.
• Acceptable hematologic status (growth factors cannot be used within the previous 7 days), as specified below:
• Absolute neutrophil count (ANC) ≥ 1000 cells/μL
• Hemoglobin ≥ 9 g/dL
• Platelet count ≥ 75,000 (platelets/μL)

You may not qualify if:

• Current central nervous system (CNS) lymphoma or leptomeningeal infiltration.
• New York Heart Association (NYHA) Class III or IV cardiac disease, myocardial infarction, within the past 6 months, unstable arrhythmia, or known pericardial disease.
• Fredericia-corrected QT interval (QTcF) \>470 msec (female) or \>450 msec (male), or history of congenital long QT syndrome.
• Any electrocardiogram (ECG) abnormality, which in the opinion of the Investigator would preclude safe participation in the study.
• Active, uncontrolled bacterial, viral, or fungal infections, within 7 days of study entry requiring systemic therapy.
• Clinically important respiratory impairment
• Grade ≥ 3 sensory or motor neuropathy.
• Any Grade \>1 (according to the NCI CTCAE 4.03) adverse reaction unresolved from previous treatments and not readily managed and controlled with supportive care.
• Serious non-malignant disease that could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor.
• History of progressive multifocal leukoencephalopathy (PML).
• 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.
• Completion of ASCT within 100 days prior to Day 1 of Cycle1.
• Prior standard or investigational anti-cancer therapy, as specified below:
• Radio-immunoconjugate 4 weeks or 5 half-lives, whichever is longer prior to Day 1 of Cycle 1.
• Monoclonal antibody or antibody-drug conjugate (ADC) therapy within 3 weeks prior to Day 1 of Cycle 1.

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (9)

City of Hope National Medical Center

Duarte, California, 91010, United States

Location

Stanford Cancer Center

Stanford, California, 94305-5820, United States

Location

Weill Cornell Medical College

New York, New York, 10065, United States

Location

Levine Cancer Institute - Blythe

Charlotte, North Carolina, 28203, United States

Location

Peter MacCallum Cancer Centre-East Melbourne

Melbourne, Victoria, 3000, Australia

Location

Rigshospitalet; Hæmatologisk Klinik

København Ø, 2100, Denmark

Location

Hospital de la Santa Creu i Sant Pau; Servicio de Hematologia

Barcelona, 08025, Spain

Location

Hospital Duran i Reynals; Servicio de Hematologia

Barcelona, 08907, Spain

Location

START Madrid-FJD, Hospital Fundacion Jimenez Diaz

Madrid, 28040, Spain

Location

Related Publications (1)

• Dickinson M, Briones J, Herrera AF, Gonzalez-Barca E, Ghosh N, Cordoba R, Rutherford SC, Bournazou E, Labriola-Tompkins E, Franjkovic I, Chesne E, Brouwer-Visser J, Lechner K, Brennan B, Nuesch E, DeMario M, Ruttinger D, Kornacker M, Hutchings M. Phase 1b study of the BET protein inhibitor RO6870810 with venetoclax and rituximab in patients with diffuse large B-cell lymphoma. Blood Adv. 2021 Nov 23;5(22):4762-4770. doi: 10.1182/bloodadvances.2021004619.

  PMID: 34581757 DERIVED

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse

Interventions

RO6870810; venetoclax; Rituximab

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 31, 2017
• First Posted: August 21, 2017
• Study Start: August 28, 2017
• Primary Completion: July 3, 2019
• Study Completion: July 3, 2019
• Last Updated: January 24, 2022

Record last verified: 2022-01

Locations

AU (1); ES (3); US (4); DK (1)