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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03255096




Registration number
NCT03255096
Ethics application status
Date submitted
31/07/2017
Date registered
21/08/2017
Date last updated
24/01/2022

Titles & IDs
Public title
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
Scientific title
Open-Label, Dose Escalation/Expansion Phase Ib Study to Evaluate the Safety, Pharmacokinetics, and Clinical Activity of the Combination of RO6870810 and Venetoclax, With or Without Rituximab, in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) and/or High-Grade B-Cell Lymphoma With MYC and/or BCL2 and/or BCL6 Gene Rearrangements
Secondary ID [1] 0 0
2017-000357-39
Secondary ID [2] 0 0
NP39461
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Diffuse Large B-cell Lymphoma 0 0
High-Grade B-cell Lymphoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - RO6870810
Treatment: Drugs - Venetoclax
Treatment: Drugs - Rituximab

Experimental: Dose Escalation Phase (Part 1) - 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.

Experimental: Expansion Phase (Part 2) - 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.


Treatment: Drugs: RO6870810
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.

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

Treatment: Drugs: Rituximab
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.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Percentage of Participants With Dose-Limiting Toxiciities (DLT)- Part 1
Timepoint [1] 0 0
Cycle (C) 1 (21 days)
Primary outcome [2] 0 0
Percentage of Participants With Adverse Events (AEs) - Part 1
Timepoint [2] 0 0
Up to 36 months
Primary outcome [3] 0 0
Percentage of Participants With Clinically Significant Changes in Vital Signs, Physical Examination, Clinical Laboratory Results and Electrocardiogram (ECG) Findings- Part 1
Timepoint [3] 0 0
Up to 36 months
Primary outcome [4] 0 0
Complete Response (CR) Rate as Determined by Independent Radiological Central Review (ICR) Using Modified Lugano Response Criteria- Recommended Dose (RD) Expansion - Part 2
Timepoint [4] 0 0
Up to 36 months
Primary outcome [5] 0 0
Overall Response (OR) Rate as Determined by Independent Radiological Central Review (ICR) Using Modified Lugano Response Criteria- RD Expansion - Part 2
Timepoint [5] 0 0
Up to 36 months
Secondary outcome [1] 0 0
Percentage of Participants With Adverse Events (AEs) - Part 2
Timepoint [1] 0 0
Up to 36 months
Secondary outcome [2] 0 0
Percentage of Participants With Clinically Significant Changes in Vital Signs, Physical Examination, Clinical Laboratory Results and Electrocardiogram (ECG) Findings- Part 2
Timepoint [2] 0 0
Up to 36 months
Secondary outcome [3] 0 0
Maximum Concentration (Cmax) of RO6870810 and its Potential Metabolites- Part 1 and Part 2
Timepoint [3] 0 0
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)
Secondary outcome [4] 0 0
Trough Serum Concentration (Cmin) of RO6870810 and its Potential Metabolites- Part 1 and Part 2
Timepoint [4] 0 0
Pre-dose Cycle 2 and all other subsequent even Cycles (Up to 36 months)
Secondary outcome [5] 0 0
Time of Maximum Concentration (tmax) of RO6870810 and its Potential Metabolites- Part 1 and Part 2
Timepoint [5] 0 0
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)
Secondary outcome [6] 0 0
Clearance (CL) of RO6870810 and its Potential Metabolites- Part 1 and Part 2
Timepoint [6] 0 0
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)
Secondary outcome [7] 0 0
Volume of Distribution (Vd) of RO6870810 and its Potential Metabolites- Part 1 and Part 2
Timepoint [7] 0 0
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)
Secondary outcome [8] 0 0
Area Under the Curve (AUC) of RO6870810 and its Potential Metabolites- Part 1 and Part 2
Timepoint [8] 0 0
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)
Secondary outcome [9] 0 0
Complete Response (CR) Rate as Determined by the Investigator Based on the Modified Lugano Response Criteria- Part 1 and Part 2
Timepoint [9] 0 0
Up to 36 months
Secondary outcome [10] 0 0
Complete Response (CR) Rate, as Determined by the ICR and by the Investigator on the Basis of CT Scans Alone- Part 1 and Part 2
Timepoint [10] 0 0
Up to 36 months
Secondary outcome [11] 0 0
Objective Response Rate, as Determined by the ICR and by the Investigator on the Basis of Modified Lugano Response Criteria- Part 1 and Part 2
Timepoint [11] 0 0
Up to 36 months
Secondary outcome [12] 0 0
Objective Response Rate, as Determined by the ICR and by the Investigator on the Basis of CT Scans Alone- Part 1 and Part 2
Timepoint [12] 0 0
Up to 36 months
Secondary outcome [13] 0 0
Duration of Response (DoR)- Part 1 and Part 2
Timepoint [13] 0 0
Up to 36 months
Secondary outcome [14] 0 0
Progression-Free Survival (PFS)- Part 1 and Part 2
Timepoint [14] 0 0
Up to 36 months
Secondary outcome [15] 0 0
Event-Free Survival (EFS)- Part 1 and Part 2
Timepoint [15] 0 0
Up to 36 months
Secondary outcome [16] 0 0
Disease-Free Survival (DFS)- Part 1 and Part 2
Timepoint [16] 0 0
Up to 36 months
Secondary outcome [17] 0 0
Overall Survival (OS)- Part 1 and Part 2
Timepoint [17] 0 0
Up to 36 months
Secondary outcome [18] 0 0
Half-Life (t1/2) of RO6870810 and its Potential Metabolites- Part 1 and Part 2
Timepoint [18] 0 0
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)
Secondary outcome [19] 0 0
Percentage of Ant-Drug Antibodies (ADA) Against Rituximab - Part 1 and Part 2
Timepoint [19] 0 0
Pre-dose, End of Infusion Day 1 Cycle 1; Pre-dose Day 1 Cycle 2, 3, 4 , 6 and all other even Cycles (Up to 36 months)

Eligibility
Key inclusion criteria
Inclusion Criteria

* 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)
* Uncontrolled symptomatic hypercalcemia.
* Acceptable coagulation status, as specified below:

* Prothrombin time (PT) and partial thromboplastin time (PTT) = 1.2 × ULN (unless receiving anticoagulation therapy, if receiving anticoagulation therapy, eligibility will be based upon international normalized ratio [INR]).
* INR = 1.6 (unless receiving anticoagulation therapy).
* If receiving warfarin: INR = 3.0 and no active bleeding (i.e., no bleeding within 14 days prior to first dose of study therapy).
* Acceptable method of contraception
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria

* 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.
* Radiotherapy, chemotherapy, or targeted small-molecule therapy within 2 weeks prior to Day 1 of Cycle 1.
* CAR T-cell therapy 30 days prior to Day 1 of Cycle 1.
* History of major solid organ transplant (i.e., heart, lungs, liver and kidney).
* History of an allogeneic bone marrow transplant.
* Major surgical procedure within 28 days prior to Day 1 of Cycle 1.
* Treatment with systemic corticosteroids = 20 mg/day prednisone or equivalent, for non-lymphoma treatment reasons. For lower acceptable doses, documentation of a stable dose for at least 4 weeks prior to Day 1 of Cycle 1 is required.

18. Treatment with strong to moderate CYP3A inhibitors or moderate CYP3A inducers within 7 days prior to the first dose of study treatment.
* Treatment with strong CYP3A inducers within 14 days prior to the first dose of study treatment of RO6870810/venetoclax.
* Consumption of grapefruits, grapefruit products, Seville oranges (including marmalade that contains Seville oranges), or star fruit within 3 days prior to the first dose of venetoclax.
* Participants who are currently receiving any other investigational agent ((other than anti-cancer therapy as specified in exclusion criteria number 13) or have received an investigational agent within 30 days or 5 half-lives prior to Day 1 of Cycle 1, whichever is longer.
* Prior treatment with small molecule bromodomain and extra terminal (BET) family inhibitor.
* Known to be human immunodeficiency virus (HIV) positive.
* Presence of positive test results for hepatitis B surface antigen (HBsAg) or hepatitis C antibodies (HcAb) (for participants receiving regimen including rituximab)
* Pregnant or breastfeeding female.
* Significant allergy to a biological pharmaceutical therapy that, in the opinion of the Investigator, poses an increased risk to the participant.
* Uncontrolled cancer pain. Participants requiring pain medication must be on a stable regimen at study entry. Symptomatic lesions amenable to palliative radiotherapy should be treated prior to enrollment.
* History of severe allergic or anaphylactic reaction to humanized or murine monoclonal antibodies (for participants receiving regimen including rituximab).
* Known sensitivity or allergy to murine products or any component of RO6870810, venetoclax, or rituximab.

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
28/08/2017
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
3/07/2019
Sample size
Target
Accrual to date
Final
39
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
Peter MacCallum Cancer Centre-East Melbourne - Melbourne
Recruitment postcode(s) [1] 0 0
3000 - Melbourne
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
New York
Country [3] 0 0
United States of America
State/province [3] 0 0
North Carolina
Country [4] 0 0
Denmark
State/province [4] 0 0
København Ø
Country [5] 0 0
Spain
State/province [5] 0 0
Barcelona
Country [6] 0 0
Spain
State/province [6] 0 0
Madrid

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

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
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

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results not provided in https://clinicaltrials.gov/study/NCT03255096