Polatuzumab Vedotin in Combination With Chemotherapy in Subjects With Richter's Transformation

• ClinicalTrials.gov Identifier: NCT04679012
• Recruitment Status: Recruiting
• First Posted: December 22, 2020
• Last Update Posted: December 21, 2022
• Sponsor: Weill Medical College of Cornell University
• Collaborator: Genentech, Inc.
• Information provided by (Responsible Party): Weill Medical College of Cornell University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Richter Syndrome; Chronic Lymphocytic Leukemia	Drug: Polatuzumab Vedotin; Drug: Rituximab; Drug: Etoposide; Drug: Prednisone; Drug: Cyclophosphamide; Drug: Hydroxydaunomycin	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Polatuzumab Vedotin in Combination With Chemotherapy in Subjects With Richter's Transformation
• Actual Study Start Date: September 24, 2021
• Estimated Primary Completion Date: September 2025
• Estimated Study Completion Date: September 2026

Arms and Interventions

Arm

Intervention/treatment

Experimental: Polatuzumab vedotin plus R-EPCH; Polatuzumab vedotin will be given in conjunction with 6 cycles of R-EPCH (rituximab, etoposide, prednisone, cyclophosphamide, hydroxydaunorubicin). The dosing schedule and regimen for R-EPCH will follow established protocols. Polatuzumab vedotin will be administered on Day 1 of each 21-day cycle.

Drug: Polatuzumab Vedotin; Polatuzumab vedotin will be administered as an IV infusion at 1.8mg/kg on Day 1 of each cycle, every 21 days.; Other Name: Polivy; Drug: Rituximab; Rituximab will be obtained from commercial supply, and will be given for a total of 6 cycles for all patients. The drug will be given by IV route.; Other Names: Rituxan; chimeric anti-CD20 monoclonal antibody; Drug: Etoposide; Etoposide will be obtained from commercial supply, and will be given for a total of 6 cycles for all patients. The drug will be given by IV route.; Other Names: VP-16; VePesid; etopophos; toposar; Drug: Prednisone; Prednisone will be obtained from commercial supply, and will be given for a total of 6 cycles for all patients. Prednisone will be given orally.; Other Names: Deltasone; Orasone; Paracort; Cortan; Drug: Cyclophosphamide; Cyclophosphamide will be obtained from commercial supply, and will be given for a total of 6 cycles for all patients. The drug will be given by IV route.; Other Name: cytoxan; Drug: Hydroxydaunomycin; Hydroxydaunomycin will be obtained from commercial supply, and will be given for a total of 6 cycles for all patients. The drug will be given by IV route.; Other Names: Doxorubicin Hydrochloride; Hydroxydoxorubicin Hydrochloride

Outcome Measures

Primary Outcome Measures :

1. Complete metabolic remission/complete remission (CMR/CR) rate of subjects at end of treatment (EOT) [ Time Frame: 19 weeks ]
   Percentage of subjects who achieve CMR/CR on study.

Secondary Outcome Measures :

1. Safety of polatuzumab vedotin plus infusional chemoimmunotherapy (CIT) containing rituximab, etoposide, prednisone, cyclophosphamide and hydroxydaunorubicin in patients with newly diagnosed Richter's Transformation. [ Time Frame: 1.5 years ]
   Percentage of subjects who experience 1 or more adverse events.
2. Overall response rate (ORR) [ Time Frame: 1.5 years ]
   Rate of subjects who achieve a partial or complete response.
3. Progression free survival (PFS) [ Time Frame: 1.5 years ]
   Measured from time of first study drug administration to objective or symptomatic progression or death.
4. Overall survival (OS) [ Time Frame: 1.5 years ]
   Measured from time of first study drug administration to death from any cause.
5. Allogeneic transplantation rate in eligible patients [ Time Frame: 1.5 years ]
   Percentage of eligible patients able to get allogeneic stem cell transplant.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Amelyn Rodriguez, R.N.; 2127461362; amr2017@med.cornell.edu

Contact: Katherine Greig, R.N.; 2127466738; kag9156@med.cornell.edu

Locations

United States, New York

Weill Cornell Medicine; Recruiting

New York, New York, United States, 10065

Contact: Amelyn Rodriguez, R.N. 212-746-1362 amr2017@med.cornell.edu

Contact: Katherine Greig, R.N. 2127466738 kag9156@med.cornell.edu

Principal Investigator: John Allan, M.D.

Sponsors and Collaborators

Weill Medical College of Cornell University

Genentech, Inc.

Investigators

• Principal Investigator: John Allan, M.D.; Weill Medical College of Cornell University

More Information

Additional Information:

WCM Joint Clinical Trials Office 

• Responsible Party: Weill Medical College of Cornell University
• ClinicalTrials.gov Identifier: NCT04679012
• Other Study ID Numbers: 20-08022533
• First Posted: December 22, 2020
• Last Update Posted: December 21, 2022
• Last Verified: December 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Weill Medical College of Cornell University:

Polatuzumab vedotin; CLL; Richter's Transformation

Additional relevant MeSH terms:

Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, B-Cell; Chronic Disease; Disease Attributes; Pathologic Processes; Prednisone; Cyclophosphamide; Rituximab; Doxorubicin; Etoposide; Liposomal doxorubicin; Polatuzumab vedotin; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological