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

Primary Purpose

Richter Syndrome, Chronic Lymphocytic Leukemia

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Polatuzumab Vedotin
Rituximab
Etoposide
Prednisone
Cyclophosphamide
Hydroxydaunomycin
Sponsored by
Weill Medical College of Cornell University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Richter Syndrome focused on measuring Polatuzumab vedotin, CLL, Richter's Transformation

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Weill Cornell MedicineRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Polatuzumab vedotin plus R-EPCH

Arm Description

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.

Outcomes

Primary Outcome Measures

Complete metabolic remission/complete remission (CMR/CR) rate of subjects at end of treatment (EOT)
Percentage of subjects who achieve CMR/CR on study.

Secondary Outcome Measures

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

Full Information

First Posted
December 16, 2020
Last Updated
December 19, 2022
Sponsor
Weill Medical College of Cornell University
Collaborators
Genentech, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT04679012
Brief Title
Polatuzumab Vedotin in Combination With Chemotherapy in Subjects With Richter's Transformation
Official Title
Phase II Study of Polatuzumab Vedotin in Combination With Chemotherapy in Subjects With Richter's Transformation
Study Type
Interventional

2. Study Status

Record Verification Date
December 2022
Overall Recruitment Status
Recruiting
Study Start Date
September 24, 2021 (Actual)
Primary Completion Date
September 2025 (Anticipated)
Study Completion Date
September 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Weill Medical College of Cornell University
Collaborators
Genentech, Inc.

4. Oversight

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
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Richter Syndrome, Chronic Lymphocytic Leukemia
Keywords
Polatuzumab vedotin, CLL, Richter's Transformation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Polatuzumab vedotin plus R-EPCH
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Polatuzumab Vedotin
Other Intervention Name(s)
Polivy
Intervention Description
Polatuzumab vedotin will be administered as an IV infusion at 1.8mg/kg on Day 1 of each cycle, every 21 days.
Intervention Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
Rituxan, chimeric anti-CD20 monoclonal antibody
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Etoposide
Other Intervention Name(s)
VP-16, VePesid, etopophos, toposar
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Prednisone
Other Intervention Name(s)
Deltasone, Orasone, Paracort, Cortan
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
cytoxan
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Hydroxydaunomycin
Other Intervention Name(s)
Doxorubicin Hydrochloride, Hydroxydoxorubicin Hydrochloride
Intervention Description
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.
Primary Outcome Measure Information:
Title
Complete metabolic remission/complete remission (CMR/CR) rate of subjects at end of treatment (EOT)
Description
Percentage of subjects who achieve CMR/CR on study.
Time Frame
19 weeks
Secondary Outcome Measure Information:
Title
Safety of polatuzumab vedotin plus infusional chemoimmunotherapy (CIT) containing rituximab, etoposide, prednisone, cyclophosphamide and hydroxydaunorubicin in patients with newly diagnosed Richter's Transformation.
Description
Percentage of subjects who experience 1 or more adverse events.
Time Frame
1.5 years
Title
Overall response rate (ORR)
Description
Rate of subjects who achieve a partial or complete response.
Time Frame
1.5 years
Title
Progression free survival (PFS)
Description
Measured from time of first study drug administration to objective or symptomatic progression or death.
Time Frame
1.5 years
Title
Overall survival (OS)
Description
Measured from time of first study drug administration to death from any cause.
Time Frame
1.5 years
Title
Allogeneic transplantation rate in eligible patients
Description
Percentage of eligible patients able to get allogeneic stem cell transplant.
Time Frame
1.5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Amelyn Rodriguez, R.N.
Phone
2127461362
Email
amr2017@med.cornell.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Katherine Greig, R.N.
Phone
2127466738
Email
kag9156@med.cornell.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John Allan, M.D.
Organizational Affiliation
Weill Medical College of Cornell University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Weill Cornell Medicine
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Amelyn Rodriguez, R.N.
Phone
212-746-1362
Email
amr2017@med.cornell.edu
First Name & Middle Initial & Last Name & Degree
Katherine Greig, R.N.
Phone
2127466738
Email
kag9156@med.cornell.edu
First Name & Middle Initial & Last Name & Degree
John Allan, M.D.

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
http://jcto.weill.cornell.edu/
Description
WCM Joint Clinical Trials Office

Learn more about this trial

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

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