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Trial details imported from ClinicalTrials.gov

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




Registration number
NCT03255096
Ethics application status
Date submitted
31/07/2017
Date registered
21/08/2017
Date last updated
7/02/2020

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 - 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.
Timepoint [1] 0 0
Cycle (C) 1 (21 days)
Primary outcome [2] 0 0
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.
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 - 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.
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
Gender
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
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)
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
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).
Trial website
https://clinicaltrials.gov/show/NCT03255096
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