Relapsed or refractory (R/R) follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL). MedDRA version: 20.0 Level: HLGT Classification code 10025320 Term: Lymphomas non-Hodgkin's B-cell System Organ Class: 10005329 - Blood and lymphatic system disorders
Conditions
Interventions
Product Name: idasanutlin
Product Code: RO5503781/F17-01
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: idasanutlin
Curren
Sponsors
F. Hoffmann-La Roche Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: -- Ages >= 18 years - Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 - B-cell lymphoma classified as either of the following: • R/R FL after treatment with at least one prior chemoimmunotherapy regimen that included an anti-CD20 monoclonal antibody • Relapsed or refractory DLBCL after treatment with at least one prior chemoimmunotherapy regimen that included an anti-CD20 monoclonal antibody in patients who are not eligible for second-line combination chemotherapy and autologous stem-cell transplantation, have failed second line combination chemotherapy, or experienced disease progression following autologous stem-cell transplantation - Histologically documented CD20-positive lymphoma, as determined by a local laboratory - Fluorodeoxyglucose-avid lymphoma (i.e., positron Emission tomography [PET]-positive lymphoma) - At least one bi-dimensionally measurable lesion (> 1.5 centimetre [cm] in its largest dimension by computed tomography [CT] scan or magnetic resonance imaging) - Availability of a representative tumour specimen and the corresponding pathology report for retrospective central confirmation of the diagnosis of FL or DLBCL • If the archival tissue is unavailable or unacceptable, a pre-treatment core-needle, excisional or incisional tumour biopsy is required. Cytological or fine-needle aspiration samples are not acceptable • If a patient received anti-lymphoma treatment between the time of the most recent available biopsy and initiation of study treatment, a core-needle biopsy is strongly recommended. - For women of childbearing potential: agreement to remain abstinent or use contraceptive methods with a failure rate of =65 years) yes F.1.3.1 Number of subjects for this age range 40
Exclusion criteria
Exclusion criteria: - Known CD20-negative status at relapse or progression - Prior allogeneic SCT - Completion of autologous SCT within 100 days prior to Day 1 of Cycle 1 - Prior standard or investigational anti-cancer therapy received as radioimmunoconjugate within 12 weeks prior Day 1 of Cycle 1 or monoclonal antibody, or antibody-drug conjugate therapy within 4 weeks prior to Day 1 of Cycle 1 or radiotherapy, chemotherapy, hormonal therapy, or targeted small-molecule therapy within 2 weeks prior to Day 1 of Cycle 1 - Clinically significant toxicity (other than alopecia) from prior therapy that has not resolved to Grade 20 mg/day, prednisone, or equivalent - Clinical conditions requiring treatment with oral or parenteral anticoagulants or antiplatelet agents unless treatment can be discontinued 7 days (or 5 half-lives) prior to initiation of study treatment - Refusal of blood products and/or sensitivity to blood products - History of severe allergic or anaphylactic reaction to humanized or murine monoclonal antibodies - Known hypersensitivity or allergy to murine products or any component of the obinutuzumab,rituximab, idasanutlin, or venetoclax formulation - Infection considered by the investigator to be clinically uncontrolled or poses an unacceptable risk to the patient upon the induction of neutropenia. The patient should be afebrile and hemodynamically stable for at least 72 hours at the time of study treatment initiation. Caution should be exercised when considering the use of obinutuzumab or rituximab in patients with a history of recurring or chronic infections - Treatment with the following agents within 7 days prior to the first dose of venetoclax and idasanutlin: Strong and moderate CYP3A inhibitors such as fluconazole, ketoconazole, and clarithromycin, Moderate CYP3A inducers such as bosentan, CYP2C8 substrates such as repaglinide, UGT1A3 inhibitor gemfibrozil, OATP1B1/3 substrates such as statin drugs - Treatment with the following agents within 14 days prior to the first doses of venetoclax and idasanutlin: Strong CYP3A inducers such as rifampin (also a CYP2C8 inducer) and carbamazepine - Chronic use of CYP2C8 or OATP1B1/3 substrates - Consumption of grapefruit, grapefruit products, Seville oranges (including marmalade that contains Seville oranges), or star fruit within 3 days prior to the first dose of venetoclax - Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis - Current or history of hepatitis B or hepatitis C virus infection - Known history of HIV-positive status - History of progressive multifocal leukoencephalopathy - Vaccination with a live virus vaccine within 28 days prior to Day 1 of Cycle 1
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: • To determine the recommended Phase II doses (RP2Ds) for idasanutlin and venetoclax when given in combination with a fixed dose of obinutuzumab or rituximab during the dose-escalation phase • To evaluate the safety and tolerability of obinutuzumab or rituximab in combination with idasanutlin and venetoclax during the dose-escalation phase, and expansion phases, including dose-limiting toxicities (DLTs) • To evaluate the efficacy of obinutuzumab in combination with idasanutlin and venetoclax in R/R FL and rituximab in combination with idasanutlin and venetoclax in R/R DLBCL, on the basis of complete response (CR) at the end of induction (EOI), as determined by the independent review committee (IRC) on the basis of positron emission tomography-computed tomography (PET-CT) scans. ; Secondary Objective: • To evaluate the efficacy of obinutuzumab in combination with idasanutlin and venetoclax in R/R FL and rituximab in combination with idasanutlin and venetoclax in R/R DLBCL, on the basis of - CR at the EOI, as determined by the investigator on the basis of PET-CT scans - CR at the EOI, as determined by the IRC and by the investigator on the basis of CT scans alone - Objective response (defined as a CR or partial response [PR]) at the EOI, as determined by the IRC and by the investigator on the basis of PET-CT scans, and on the basis of CT scans alone - Best response of CR or PR during the study, as dertermine by the investigator on the basis of CT scans alone • To characterize the pharmacokinetic (PK) profiles of obinutuzumab or rituximab, idasanutlin (and its metabolites, if appropriate), and venetoclax to support dose escalation • To assess potential PK interactions between idasanutlin, venetoclax, and obinutuzumab or rituximab. ; Primary end point(s): 1. Inc | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. CR at the EOI, as determined by the investigator on the basis of PET-CT scans 2. Objective response (defined as a CR or PR) at the EOI, as determined by the IRC and by the investigator on the basis of PET-CT scans 3. CR at the EOI, as determined by the IRC and by the investigator on the basis of CT scans alone 4. Objective response (defined as a CR or PR) at the EOI, as determined by the IRC and by the investigator on the basis of CT scans alone 5. Best response of CR or PR during the study, as determined by the investigator on the basis of CT scans alone 6. Observed serum obinutuzumab concentration 7. Observed serum rituximab concentration 8. Observed plasma idasanutlin concentration 9. Observed plasma venetoclax concentration. ; Timepoint(s) of evaluation of this end point: 1-4. 6-8 weeks after Day 1 of the last induction cycle 5. Approximately 4 years 6-7. Dose escalation phase (DP) and expansion phase (EP): Cycle(C)1 Day (D)1, C2D1, C4D1, and C6D1; Post induction phase: Month (M) 1 D1, M7D1, M13D1 and M19D1 (obinutuzumab only); 120 days and 1-2 years after the last dose of obinutuzumab; at treatment discontinuation 8-9. DP and EP: C1D1, C1D5, C2D1, C2D5, C4D1, C4D5, and at end of induction. | — |
Countries
Australia, Germany, Korea, Republic of, New Zealand, United States
Contacts
Public ContactTrial Information Support Line-TISL
F. Hoffmann-La Roche Ltd
Outcome results
None listed