DIFFUSE LARGE B-CELL LYMPHOMA

This study will evaluate the efficacy, safety, pharmacokinetics, and patient reported outcomes of polatuzumab vedotin at 1.8 mg/kg plus chemoimmunotherapy (R-CHP) compared with SOC chemoimmunotherapy (R-CHOP) in previously untreated patients with CD20-positive DLBCL. The primary study endpoint will be progression-free survival (PFS) as assessed by the investigator.

Polatuzumab vedotin

polatuzumab vedotin

Injection

140 mg

This study will evaluate the efficacy, safety, pharmacokinetics, and patient reported outcomes of polatuzumab vedotin at 1.8 mg/kg plus chemoimmunotherapy (R-CHP) compared with SOC chemoimmunotherapy (R-CHOP) in previously untreated patients with CD20-positive DLBCL. The primary study endpoint will be progression-free survival (PFS) as assessed by the investigator.

Patients must meet the following criteria for study entry:
- Signed written Informed Consent Form
- Previously untreated patients with CD20-positive DLBCL, including one of the following diagnoses by 2016 WHO classification of lymphoid neoplasms:
– DLBCL, not otherwise specified (NOS) including germinal center B-cell type,activated B-cell type
– T-cell/histiocyte-rich large B-cell lymphoma
– Epstein-Barr viruspositive DLBCL, NOS
– ALK-positive large B-cell lymphoma
– HHV8-positive DLBCL, NOS
– High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements(double-hit or triple-hit lymphoma)
– High-grade B-cell lymphoma, NOS
 Availability of archival or freshly collected tumor tissue before study enrollment
The pathology report must be available for review and a tissue block sent for retrospective central confirmation of diagnosis.
Formalin-fixed, paraffin-embedded tissue blocks are preferred; however, in countries that use a different fixative, any tissue block available will be accepted and notation of the type of fixative included.
If a tissue block is not available, at least 15 unstained slides or freshly cut serial sections
(3−5 μm in thickness) with an accompanying block punch will be accepted. If archival tissue is unavailable or is determined to be inadequate, tumor tissue must be obtained from a biopsy performed at screening.
If central confirmation is unable to be performed on submitted material, stained slides used for diagnosis and/or additional tumor tissue specimens may also be requested.
- IPI score of 2-5
- Age 18-80 years at the time of signing Informed Consent Form
- ECOG Performance Status of 0, 1, or 2
- Life expectancy >=12 months
- At least one bi-dimensionally measurable lesion, defined as >=1.5 cm in its longest dimension as measured by CT or MRI
- Ability and willingness to comply with the study protocol procedures, including patient-reported outcome (PRO) measures
- Left ventricular ejection fraction (LVEF) >= 50% on cardiac multiple-gated acquisition (MUGA) scan or cardiac echocardiogram (ECHO)
- Adequate hematologic function (unless due to underlying disease, as established by extensive bone marrow involvement or due to hypersplenism secondary to the involvement of the spleen by DLBCL per the investigator), defined as follows:
– Hemoglobin >= 9.0 g/dL without packed RBC transfusion during 14 days before first treatment
– ANC >= 1,000/µL
– Platelet count >= 75,000/µL
- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of 1% per year during the treatment period and for at least 12 months after the last dose of study treatment.
A woman is considered to be of childbearing potential if she is post-menarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization
(removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception.
- For women of childbearing potential, a negative serum pregnancy test result within 7 days prior to commencement of dosing. Women who are considered not to be of childbearing potential are not required to have a pregnancy test.
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 5 months after the last dose of blinded polatuzumab vedotin/placebo, 3 months after the last dose of rituximab, and for at least 6 months after the last dose of blinded vincristine/placebo and cyclophosphamide to avoid exposing the embryo for the duration of the pregnancy.
Men must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and 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.
Male patients considering preservation of fertility should bank sperm before study treatment.
- For enrollment into the China extension cohort, residence in the People’s Republic of China

Patients who meet any of the following criteria will be excluded from study entry:
 History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products
 Contraindication to any of the individual components of CHOP, including prior receipt of anthracyclines
 Prior organ transplantation
 Current Grade >1 peripheral neuropathy by clinical examination
 Demyelinating form of Charcot-Marie-Tooth disease
 History of indolent lymphoma
 Follicular lymphoma grade 3B
 B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma (grey-zone lymphoma)
 Primary mediastinal (thymic) large B-cell lymphoma
 Burkitt lymphoma
 Prior treatment with cytotoxic drugs within 5 years of screening for any condition (e.g.,cancer, rheumatoid arthritis) or prior use of any anti-CD20 antibody
 Prior use of any monoclonal antibody within 3 months of the start of Cycle 1
 Prior therapy for DLBCL, with the exception of nodal biopsy. Corticosteroids are addressed in the next point
 Corticosteroid use > 30 mg/day of prednisone or equivalent, for purposes other than lymphoma symptom control Patients receiving 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 the start of Cycle 1. If glucocorticoid treatment is urgently required for lymphoma symptom control prior to the start of study treatment, prednisone 100 mg or equivalent could be given for a maximum of 7 days as a prephase treatment (Days −7 to −1), but all tumor assessments must be completed prior to starting glucocorticoid treatment. As part of the prephase treatment, vincristine may not be administered.
 Patients with CNS lymphoma (primary or secondary involvement), primary effusion DLBCL, and primary cutaneous DLBCL
 Vaccination with live vaccines within 28 days prior to the start of Cycle 1
 Any investigational therapy within 28 days prior to the start of Cycle 1
 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 melanoma of the skin or in situ carcinoma of the cervix at any time prior to the study are eligible.
Patients with any other malignancy that has been treated with surgery alone with
curative intent and the malignancy has been in remission without treatment for 2 years prior to enrollment are eligible.
 Evidence of significant, uncontrolled, concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease (including obstructive pulmonary disease and history of bronchospasm)
 Recent major surgery (within 4 weeks prior to the start of Cycle 1), other than for diagnosis
 History or presence of an abnormal ECG that is clinically significant in the investigator’s opinion, including complete left bundle branch block, second- or third-degree heart block, or evidence of prior myocardial infarction
 Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment or significant infections within 2 weeks before the start of Cycle 1
 Clinically significant liver disease, including active viral or other hepatitis, current alcohol abuse, or cirrhosis
 Prior radiotherapy to the mediastinal/pericardial region
 Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator’s judgment
Any of the following abnormal laboratory values (unless any of these abnormalities are due to underlying lymphoma):
INR > 1.5 × upper limit of normal (ULN) in the absence of therapeutic anticoagulation
PTT or aPTT > 1.5 × ULN in the absence of a lupus anticoagulant
Serum AST and ALT ≥2.5 × ULN
Total bilirubin ≥1.5 × ULN.
Patients with documented Gilbert disease may be enrolled if total bilirubin is ≤3.0 × ULN.
Serum creatinine clearance < 40 mL/min (using Cockcroft-Gault formula)
 Patients with suspected active or latent tuberculosis (as confirmed by a positive interferon-gamma release assay)
 Positive test results for chronic hepatitis B infection (defined as positive hepatitis B surface antigen [HBsAg] serology)
Patients with occult or prior hepatitis B infection (defined as positive total hepatitis B core antibody and negative HBsAg) may be included if hepatitis B virus (HBV) DNA is undetectable at the time of screening. These patients must be willing to undergo monthly DNA testing and appropriate antiviral therapy as indicated.
 Positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology testing)
Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
 Known history of HIV seropositive status
For patients with unknown HIV status, HIV testing will be performed at screening if required by local regulations.
 Positive results for the human T-lymphotrophic 1 virus (HTLV-1) HTLV testing is required for patients at sites in endemic countries (Japan and Melanesia and countries in the Caribbean basin, South America, Central America,
and sub-Saharan Africa).
 Patients with a history of progressive multifocal leukoencephalopathy
 Pregnancy or lactation or intending to become pregnant during study
 Women of childbearing potential must have a negative serum pregnancy test result within 7 days prior to Cycle 1, Day 1