| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Early relapsed or refractory diffuse large B-cell lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Early recurrence or not responding diffuse large B-cell lymphoma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10012857 |
| E.1.2 | Term | Diffuse large cell lymphoma (Diffuse large B-cell lymphoma) (Working Formulation) refractory |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10012856 |
| E.1.2 | Term | Diffuse large cell lymphoma (Diffuse large B-cell lymphoma) (Working Formulation) recurrent |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| Objective response rate (complete or partial responses; best response) defined by PET/CT scan and bone marrow examination (Lugano Criteria 2014) after 3 cycles. |
|
| E.2.2 | Secondary objectives of the trial |
- Safety: Incidence of dose-limiting toxicities of the combination treatment.
- Response duration (from first documented response)
- Progression-free survival
- Overall survival
- Ability to proceed to further stem cell transplantation (assessed by number of eligible patients reaching transplant) Identification of genetically/biomarker-defined subgroups regarding response and survival |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Patients ≥ 18 years of age
- Ability and willingness to comply with the study protocol procedures.
- Diffuse large B-cell lymphoma (DLBCL)
o with histologically confirmed relapse within 12 months after having achieved a PR or CR with initial R-anthracycline containing therapy, or
o with refractoriness to initial R-anthracycline containing therapy (not achieving at least a partial response)
o Bcl-2 protein expression detected by immunohistochemistry.
- Adequate organ function, defined as the following:
o Total bilirubin must be < 1.5 x the upper limit of the normal (ULN) unless the elevation is known to be due to Gilbert syndrome.
o ALT and AST must be ≤ 3 x the upper limit of the normal range. AST and ALT may be elevated up to 5 times the ULN if their elevation can be reasonably ascribed to the presence of lymphoma in the liver. Serum creatinine must be < 2.0 mg/dL and/or creatinine clearance or calculated creatinine clearance ≥ 50 mL/minute.
- Signed Informed Consent Form(s).
- At least one bi-dimensionally measurable lesion on CT scan defined as > 1.5 cm in its longest dimension.
- Confirmed availability of archival or freshly biopsied tumor tissue meeting protocol-defined-specifications prior to study enrolment.
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2.
- Adequate hematologic function (unless caused by underlying disease, as established by extensive bone marrow involvement or as a result of hypersplenism secondary to the involvement of the spleen by lymphoma per the investigator) defined as follows:
o Hemoglobin ≥ 9 g/dL
o Absolute neutrophil count ≥ 1.5 × 109/L and
o Platelet count ≥ 75 × 109/L.
- For women who are not postmenopausal (≥ 12 months of non−therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use single or combined non-hormonal 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 obinutuzumab. Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. Examples of non-hormonal contraceptive methods with a failure rate of < 1% per year include tubal ligation, male sterilization, and certain intrauterinedevices. Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of < 1% per year. Barrier methods must always be supplemented with the use of a spermicide.
- Non-vasectomized male patients must practice at least one of the following methods of birth control throughout the duration of study participation and for at least 12 months after completing therapy with obinutuzumab. A partner who is surgically sterile or postmenopausal (for at least 1 year) or who is taking hormonal contraceptives (oral, parenteral, vaginal ring, ortransdermal) for at least 3 months prior to study drug administration. Total abstinence from sexual intercourse; double-barrier method (condom + diaphragm or cervical cup with spermicidal, contraceptive sponge, jellies, or cream). Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
- Males must agree to abstain from sperm donation for at least 6 months after the last dose of obinutuzumab. |
|
| E.4 | Principal exclusion criteria |
Patient has received any other investigational treatment within 28 days before study entry.
Known hypersensitivity to recombinant proteins, murine proteins, or to any excipient contained in the drug formulation of obinutuzumab or venetoclax.
DLBCL transformed from other malignancies or CD20 negative DLBCL.
Radiation, chemotherapy, or immunotherapy or any other anticancer therapy ≤ 4 weeks prior to Cycle 1 Day 1.
Ongoing corticosteroid use > 30 mg/day of prednisone or equivalent. Patients who received corticosteroid treatment with ≤ 30 mg/day of prednisone or equivalent must be documented to be on a stable dose of at least 4 weeks duration prior to randomization (Cycle 1 Day 1). Patients may have received a brief (< 7 days) course of systemic steroids (≤ 100 mg prednisone equivalent) prior to initiation of study therapy for control of lymphoma-related symptoms.
ECOG performance status ≥ 3.
Female patients who are pregnant or breast-feeding.
Acute or uncontrolled chronic infections.
Known diagnosis of HIV (HIV testing is not required as part of this study).
Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to the protocol.
Known cerebral or meningeal disease, including signs or symptoms of PML.
Symptomatic neurologic disease compromising normal activities of daily living or requiring medications.
Any sensory or motor peripheral neuropathy greater than or equal to Grade 2.
Known history of any of the following cardiovascular conditions:
o myocardial infarction within 2 years of study entry,
o NYHA Class III or IV heart failure,
o evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure, angina, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities,
o recent evidence (within 6 months before first dose of study drug) of a left-ventricular ejection fraction <50% .
Diagnosed or treated for another malignancy within 3 years before the first dose or previously diagnosed with another malignancy and have evidence of residual disease.
Patients with transformed lymphoma.
Primary CNS lymphoma.
Vaccination with live vaccines within 28 days prior to treatment.
History of other malignancy that could affect compliance with the protocol or interpretation of results (Patients with a history of curatively treated basal or squamous cell carcinoma or Stage 1 melanoma of the skin or in situ carcinoma of the cervix are eligible).
Patients with a malignancy that has been treated with surgery alone with curative intent will also be excluded, unless the malignancy has been in documented remission without treatment for ≥ 3 years prior to enrollment.
Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results or that could increase risk to the patient.
Significant pulmonary disease
Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to Cycle 1 Day 1.
Requires the use of warfarin (because of potential drug-drug interactions that may potentially increase the exposure of warfarin).
Received the following agents within 7 days prior to the first dose of venetoclax:
o CYP3A inhibitors such as fluconazole, ketoconazole, and clarithromycin
o Strong CYP3A inducers such as rifampin, carbamazepine
Consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing 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.
Presence of positive test results for Hepatitis B virus core (HBcAb) or hepatitis B surface antigen (HBsAg) antibody
o Patients with occult or prior HBV infection (defined as positive total hepatitis B core antibody [HBcAb] and negative HBsAg) may be included if HBV DNA is undetectable. These patients must be willing to undergo monthly DNA testing until 12 months after last treatment cycle.
• Presence of positive test results for Hepatitis C and CMV (PCR value).
Recent major surgery (within 6 weeks prior to the start of Cycle 1 Day 1), other than for diagnosis.
Any of the following abnormal laboratory values:
o AST or ALT > 3 ×ULN
o Total bilirubin ≥ 1.5 × ULN (or > 3 × ULN for patients with documented Gilbert syndrome)
o INR > 1.5 ×ULN
o PTT or aPTT > 1.5 ×ULN |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective response rate (complete or partial responses; best response) defined by PET/CT scan and bone marrow examination examination (Lugano Criteria 2014) after 3 cycles. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Primary efficacy endpoint is the objective response rate (CR, PR) after 3 cycles. |
|
| E.5.2 | Secondary end point(s) |
- Safety: Incidence of dose-limiting toxicities of the combination treatment.
- Response duration (from first documented response)
- Progression-free survival
- Overall survival
- Ability to proceed to further stem cell transplantation (assessed by number of eligible patients reaching transplant)
- Identification of genetically/biomarker defined subgroups regarding response and survival |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Visits after cycle 1, 3, 6, 9, 12 and Final Visit (within 3 months after last treatment within the study) |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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 | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| 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 | 1 |
| 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 | 6 |
| 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 | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
| 72 weeks after end of treatment of last patient |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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