Polatuzumab Vedotin in Combination With Chemotherapy in Subjects With Richter's Transformation
Polatuzumab Vedotin in Combination With Chemotherapy in Subjects With Richter's Transformation
This study evaluates the effectiveness and safety of Polatuzumab vedotin plus infusional
 chemoimmunotherapy containing rituximab, etoposide, prednisone, cyclophosphamide and
 hydroxydaunorubicin. This is a single arm study. Enrolled patients will receive up to six
 cycles (21-day cycles) of therapy. While on study, subjects will be monitored weekly until
 end of treatment, then followed for 52 weeks or until disease progression or discontinuation
 due to toxicity or death.
This is an open label, single arm, phase II investigator initiated clinical trial, evaluating
 efficacy and safety of Polatuzumab vedotin added to a modified infusional dose adjusted
 R-EPOCH like regimen, given on an inpatient basis, every 21 days, in subjects with Richter's
 Transformation.
Inclusion Criteria:

 -  Subject must have confirmed diagnosis of CLL based upon 2018 International Workshop on
 CLL (IwCLL) criteria, with biopsy proven Richter's Transformation to a DLBCL subtype.

 -  Subject must be ≥18 years of age.

 -  Subject must be able to sign informed consent

 -  Ability and willingness to comply with the study protocol procedures

 -  Life expectancy of at least 24 weeks

 -  Subject must have an Eastern Cooperative Oncology Group performance status of ≤2.

 -  Subject must have adequate bone marrow function and meet the below thresholds prior to
 treatment.

 -  Absolute neutrophil count of ≥1000 cell/uL

 -  Hemoglobin ≥ 7 g/dL

 -  Platelet count ≥ 30,000 cells/uL

 -  Subject must have adequate organ function and meet the thresholds below:

 -  Total bilirubin ≤ 1.5 times the upper limit of normal (ULN). Subjects with
 Gilbert's disease will be granted exception to this rule.

 -  Creatinine clearance >30 ml/min/1.73m2 as calculated by the MDRD equation.

 -  Ejection fraction ≥ 50% measured by transthoracic echocardiogram or MUGA scan

 -  For women of childbearing potential: agreement to remain abstinent or use of
 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 drug.

 -  A woman is considered to be of childbearing potential if she is post-menarcheal,
 has not reached a postmenopausal state (i.e. ≥ 12 months of amenorrhea with no
 identified cause other than menopause) and has not undergone surgical
 sterilization (removal of ovaries and or uterus)

 -  Acceptable forms of contraception are bilateral tubal ligation, male
 sterilization, or copper intrauterine devices.

 -  For women considered to have childbearing potential a negative serum pregnancy
 test within 7 days prior to study enrollment and dosing is required.

 -  For men, agreement to remain abstinent, or to use a condom plus an additional
 contraceptive method during the treatment period and for at least 5 months after the
 last dose of study drug.

 -  Men must agree not to donate sperm during that period of time. Male patients
 interested in preservation of fertility should be advised to sperm bank prior to
 enrollment and treatment initiation.

 Exclusion Criteria:

 -  Diagnosis of Richter's Transformation not of DLBCL subtype (including but not limited
 to Hodgkin lymphoma, PLL)

 -  Prior therapy targeting Richter's transformation.

 -  Any subject that initiates a targeted agent such as BTKi, venetoclax, or PI3K prior to
 enrollment (Continuation of a targeted CLL directed therapy such as a BTKi,
 venetoclax, or PI3K will be permitted as a bridge through screening but add on
 therapies or change in therapy will be exclusionary. These continuation therapies will
 be permitted up 72 hours prior to study initiation. Bridging therapy with steroid up
 to equivalent of 40mg of Dexamethasone daily will be allowed prior to study treatment
 and can be continued up to 24 hours prior to study treatment)

 -  Subject has undergone an allogeneic stem cell transplant for CLL within 6 months of
 study entry.

 -  Subject has an active or presumed secondary malignancy at time of enrollment. A
 subject will be eligible if a previous malignancy was treated with curative intent and
 there is no evidence of disease recurrence for the past 3 years. Non-melanomatous and
 cervical squamous cell cancers are an exception and if excised will be allowed to
 enroll regardless of timing of excision.

 -  Subject is known to be positive for HIV.

 -  Active hepatitis C or hepatitis B defined by positive PCRs for viral DNA/RNA. Subjects
 with a positive Hep B core antibody and negative PCR, are allowed to enroll
 (prophylaxis is strongly encouraged and monthly monitoring of Hep B PCR is mandatory).

 -  Subject has baseline ≥ Grade 2 or greater peripheral neuropathy.

 -  History of severe allergic or anaphylactic reactions to humanized or murine monoclonal
 antibodies

 -  Clinical evidence or known central nervous system involvement with transformed large
 cells

 -  Evidence of significant, uncontrolled concomitant diseases that could affect
 compliance with the protocol or interpretation of results

 -  Significant cardiovascular disease (such as New York Heart Association Class III or IV
 cardiac disease, congestive heart failure, myocardial infarction within the previous 6
 months, unstable arrhythmias, or unstable angina)

 -  Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection
 (excluding fungal infections of nail beds) at study enrollment or any major episode of
 infection requiring treatment with intravenous antibiotics or hospitalization within 4
 weeks before Cycle 1 day 1.

 -  Major surgery within 4 weeks before the start of Cycle 1 day 1. Superficial lymph node
 biopsies or laprascopic lymph node biopsies are exclusionary to this rule.