| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or refractory (R/R) follicular lymphoma or diffuse large B-cell lymphoma. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL) are the most common non-Hodgkin's lymphomas (type of blood cell cancer of the immune system). |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10025320 |
| E.1.2 | Term | Lymphomas non-Hodgkin's B-cell |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To determine the recommended Phase II dose (RP2D) for idasanutlin when given in combination with a fixed dose of obinutuzumab or rituximab
• To evaluate the safety and tolerability of obinutuzumab or rituximab in combination with idasanutlin, including DLTs
• To evaluate the efficacy of obinutuzumab in combination with idasanutlin in R/R FL and rituximab in combination with idasanutlin in R/R DLBCL. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of obinutuzumab in combination with idasanutlin in R/R FL and rituximab in combination with idasanutlin in R/R DLBCL.
• To characterize the PK profiles of obinutuzumab or rituximab and of idasanutlin and its metabolites (if appropriate) to support dose escalation.
• To assess potential PK interactions between idasanutlin and obinutuzumab or rituximab.
• To explore exposure−effect (including PD, efficacy, and adverse event) relationships. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Age >= 18 years
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
- Patients with relapsed or refractory FL with at least two prior lines of
therapy including at least one immunochemotherapy regimen that
contained an anti-CD20 mAb and for which no other more appropriate
treatment option exists as determined by the investigator
- Relapsed or refractory DLBCL after treatment with at least one prior
immunochemotherapy regimen that included an antiCD20 mAb in
patients who are not eligible for second line combination therapy and
autologous SCT, have failed 2L combination chemotherapy or
experienced disease progression following autologous SCT
- Histologically documented CD20-positive non-Hodgkin’s lymphoma by local laboratory
- FDG-avid lymphoma (i.e., positron emission tomography -positive lymphoma)
- At least one bi-dimensionally measurable lesion (> 1.5 centimeter in its largest dimension by CT or magnetic resonance imaging [MRI] scan)
- For women who are not postmenopausal or surgically sterile: agreement to remain abstinent or use contraceptive methods that result in a failure rate of 1% per year during the treatment period and for at least 18 months after the last dose of study treatment.
- For men: agreement to remain abstinent or use contraceptive measures and agreement to refrain from donating sperm. |
|
| E.4 | Principal exclusion criteria |
- Known CD20 negative status at relapse/progression
- Central nervous system lymphoma or leptomeningeal infiltration
- Prior allogeneic stem-cell transplantation (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 or monoclonal antibody, or antibody−drug conjugate therapy within 4 weeks or Radiotherapy, chemotherapy, hormonal therapy, or targeted small-molecule therapy.
- Clinically significant toxicity (other than alopecia) from prior therapy that has not resolved to Grade =< 2 (according to the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE], v4.03) prior to Day 1 of Cycle 1
- Treatment with systemic corticosteroids > 20 milligram/day prednisone or equivalent
- Treatment with the following agents within 7 days prior to the first dose of idasanutlin: CYP2C8 inhibitors including gemfibrozil (also a UGT1A3 inhibitor), CYP2C8 substrates, OATP1B1/3 substrates
- Treament with the following agents within 14 days prior to the first dose of idasanutlin: Strong CYP3A inducers including rifampin (also a CYP2C8 inducer)
- Chronic use of CYP 2C8 or OATP1B1/3 substrates
- Clinical conditions requiring treatment with oral or parenteral anticoagulants/antiplatelet agents. low-molecular-weight heparin is allowed for use as flushes for indwelling catheters
- Patients that may refuse blood products and/or have sensitivity to blood products
- History of severe allergic or anaphylactic reaction to humanized or murine monoclonal antibodies
- Active bacterial, viral, fungal, or other infection
- Positive for hepatitis B surface antigen (HBsAg), total hepatitis B core antibody (HBcAb), or hepatitis C virus (HCV) antibody at screening
- 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
- Grade 3b follicular lymphoma
- History of transformation of indolent disease to DLBCL
- History of other malignancy that could affect compliance with the protocol or interpretation of results
- Evidence of any significant, uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results.
- Major surgical procedure other than for diagnosis within 28 days prior to Day 1 of Cycle 1 or anticipation of a major surgical procedure during the study
- Inadequate hematologic function (unless due to underlying lymphoma)
- Any of the following abnormal laboratory values (unless due to underlying lymphoma): Creatinine, aspartate aminotransferase or alanine transaminase , serum total bilirubin, international normalized ratio or prothrombin time, partial thromboplastin time or activated partial thromboplastin time
- Pregnant or lactating, or intending to become pregnant during the study
- life expectancy <3 months
- Unable to comply with the study protocol, in the investigator’s judgment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Incidence of DLTs during the DLT window of study treatment
2. Nature, frequency, and severity of adverse events
3. Changes in vital signs, ECG and clinical laboratory results
4. Complete response (CR) at end of induction (EOI) as determined by the IRC through use of the PET-CT−based modified Lugano 2014 criteria. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. One cycle or two cycles depending on treatment regimen
2. Up to 4 years
3. Up to 4 years
4. 6-8 weeks after Day 1 of the last induction cycle.
|
|
| E.5.2 | Secondary end point(s) |
1. CR at EOI, as determined by the IRC and the investigator on the basis of PET-CT scans
2. CR at EOI, as determined by the IRC and the investigator of CT scans alone
3. Objective response (defined as a CR or PR) at EOI, as determined by the IRC and by the investigator on the basis of PET-CT scans
4. Objective response (defined as a CR or PR) at 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 at specified timepoints
7. Observed serum rituximab concentration
8. Observed plasma idasanutlin concentration at specified timepoints. |
|
| E.5.2.1 | 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 and Expansion Phase:
Induction Phase: Cycle 1 Day 1, Cycle 2 Day 1, Cycle 4 Day 1, and Cycle 6 Day 1
Maintenance Phase: Month 1 Day 1, Months 7, 13 and 19 Day 1, 120 days after last dose of obinutuzumab, and 1-2 year after the last dose of obinutuzumab and at treatment discontinuation
8. Dose Escalation Phase and Expansion Phase:
Induction Phase; Cycle 1 Days 1 and 5, Cycle 2 Days 1 and 5, Cycle 4 Days 1 and 5. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability of obinutuzumab or rituximab in combination with idasanutlin. |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Germany |
| Korea, Republic of |
| New Zealand |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of this study is defined as the time when both of the following conditions are met:
• All enrolled patients with FL have completed or discontinued maintenance treatment
And
• All enrolled patients with DLBCL have been followed for at least 1 year after they have completed or discontinued study treatment (including induction treatment and consolidation treatment, as applicable). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 48 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 48 |
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