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Brentuximab Vedotin and Chemotherapy in CD30+ PMBL, Diffuse Large B-Cell, and Grey Zone Lymphoma Patients

Primary Purpose

CD30 Positive Primary Mediastinal Large B-cell Lymphoma, CD30-Positive Diffuse Large B-Cell Lymphoma, CD30-Positive Gray Zone Lymphoma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
brentuximab vedotin
Sponsored by
Abramson Cancer Center at Penn Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for CD30 Positive Primary Mediastinal Large B-cell Lymphoma

Eligibility Criteria

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

Inclusion Criteria:

  • Age 18 and above
  • Histologically confirmed CD30-positive, CD20-positive untreated primary mediastinal B-cell lymphoma (any Ann Arbor stage), diffuse large B-cell lymphoma (Ann Arbor stage III or IV), or grey zone lymphoma (any Ann Arbor stage). Patients with heterogeneous, weak or equivocal CD30 staining will also be included (no specific cut off percentage for CD30 stain is required).
  • Measurable disease, defined by the Revised Response Criteria for Malignant Lymphoma
  • Absolute neutrophil count ≥1,000/mmᶟ and platelet count ≥75,000/µL(unless documented bone marrow involvement with lymphoma).
  • Normal left ventricular ejection fraction of ≥50% estimated by MUGA scan or echocardiogram.
  • Estimated creatinine clearance (using Cockcroft-Gault equation) must be >50 mL/min.
  • Serum bilirubin ≤1.5 x upper limit of normal (ULN). Bilirubin ≤ 3 x ULN is permitted in individuals with documented liver involvement by lymphoma or if due to known Gilbert syndrome.
  • Aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase ≤ 3 x ULN.
  • Performance status of ECOG 0-2; patients with ECOG of 3 may be allowed to enroll after discussion with the Regulatory-Sponsor/Principal Investigator and medical monitor, and if the performance status is believed to be secondary to lymphoma related symptoms and performance status is expected to improve once chemotherapy commences.
  • Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent. In patients who are not able to consent to the trial due to medical circumstances, the next of kin or power
  • Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (b-hcG) pregnancy test result within 7 days prior to the first dose of brentuximab vedotin and must agree to use an effective contraception method during the study and for 30 days following the last dose of study drug; females of non-childbearing potential are those who are post-menopausal for more than 1 year or who have had bilateral tubal ligation or hysterectomy.
  • Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 6 months following the last dose of study drug.
  • Must be able to comply with the study and follow-up requirements.

Exclusion Criteria:

  • Previous use of investigational agents, chemotherapy or immunotherapy for lymphoma any time prior to enrollment (i.e. must have untreated disease). Prior allogeneic or autologous transplants are also not allowed.
  • Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol. Consolidative radiation therapy (RT) after completion of planned course and/or concurrent intrathecal chemotherapy for CNS disease prophylaxis is permissible.
  • Treatment with systemic steroids for > 4 weeks prior to Cycle 1 Day 1 of study therapy. Prior radiation therapy, with the exception of an abbreviated course (not more than 3 days) if used for SVC syndrome.
  • History of serious organ dysfunction or disease involving the heart (left ventricular ejection fraction < 50%; unstable angina, acute myocardial infarction within 6 months prior to randomization, congestive heart failure NYHA III-IV, and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalities.), the kidney (creatinine clearance <50 mL/min), the liver (chronic hepatitis B as defined below or elevated AST, ALT or alkaline phosphatase > 3 ULN; serum bilirubin > 1.5 x ULN; bilirubin up to 3 x ULN is permitted in individuals with documented liver involvement by lymphoma or if due to known Gilbert syndrome) ot other organ system that may place the patient at undue risk to undergo treatment.
  • Uncontrolled systemic fungal, bacterial, viral, or serious infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment). May be enrolled if controlled on treatment.
  • Significant concurrent disease, illness or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow-up, or interpretation of study results.
  • Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver involved with lymphoma or stable chronic liver disease per investigator's assessment).
  • History of significant cerebrovascular disease in the past 6 months or ongoing event with active symptoms or sequelae.
  • Other malignancy, unless the patient has been disease-free for at least 3 years following the completion of curative intent therapy, with the following exceptions: Treated non-melanoma skin cancer, any in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease -free duration, are eligible for this study if definitive treatment for the condition has been completed.Organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen (PSA) values are also eligible for this study if hormonal therapy has been initiated, or radical prostatectomy or definitive prostate irradiation has been performed.
  • Positive test for the Human Immunodeficiency Virus (HIV) unless undetectable viral load within 3 months of enrollment (HIV RNA less than 48 copies/mL) and on HAART therapy.
  • Positive serology for hepatitis B (HB) defined as a positive test for hepatitis B surface antigen or hepatitis B core antibody.
  • Active involvement of the central nervous system (CNS) by lymphoma. Work-up for CNS involvement at diagnosis will be directed as per the treating physician and will depend on specific clinical circumstances (no brain imaging or lumbar puncture is required by this protocol).
  • Pregnant or lactating women.

Sites / Locations

  • Abramson Cancer Center of the University of Pennsylvania

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Phase I/II

Arm Description

Total of six 21-day cycles of brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin and prednisone (R-CHP). Cycle 1 rituximab dose divided between Days 1 and 2 to prevent severe infusion reactions in rituximab naïve patients; brentuximab vedotin and cytotoxic chemotherapy administered on Day 2. Cycles 2 through 6 brentuximab vedotin and R-CHP administered on Day 1. Prednisone (or steroid equivalent) administered Days 1-5 of each cycle (prior to rituximab infusion). Cycle 1: Days 1-5: Prednisone (or equivalent) 100 mg PO/IV; Day 1: Rituximab 100 mg/m2 IV; Day 2: Rituximab 275 mg/m2 IV, Cyclophosphamide 750 mg/m2 IV, Doxorubicin 50 mg/m² IV, Brentuximab vedotin 1.8 mg/kg or 1.2 mg/kg (Phase I data established a MTD of 1.8 mg/kg brentuximab vedotin) Cycles 2-6: Days 1-5: Prednisone (or equivalent) 100 mg PO/IV; Day 1: Rituximab 375 mg/m2 IV, Cyclophosphamide 750 mg/m2 IV, Doxorubicin 50 mg/m² IV, Brentuximab vedotin 1.8 mg/kg

Outcomes

Primary Outcome Measures

Number of Subjects With Dose-limiting Toxicities
Dose-limiting toxicity (DLT) is any grade 3 or 4 new non-hematologic toxicity occurring during Cycle 1 requiring a dose delay of >14 days from the planned Day 1 of Cycle 2 (21 days from Day 1 of Cycle 1). The initial planned dose of brentuximab vedotin for the Phase I cohort of 6 patients is 1.8 mg/kg. This cohort will be evaluated for DLT in the first cycle of treatment. Dose de-escalation to 1.2 mg/kg will occur if ≥ 2 of 6 patients at the 1.8 mg/kg dose level experience a DLT.
Overall Response Rate (ORR)
Overall response rate (ORR) is defined as the proportion of patients with CR or PR according to the International Working Group Response Criteria for non-Hodgkin Lymphoma at the conclusion of systemic therapy.

Secondary Outcome Measures

Full Information

First Posted
November 20, 2013
Last Updated
December 14, 2020
Sponsor
Abramson Cancer Center at Penn Medicine
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1. Study Identification

Unique Protocol Identification Number
NCT01994850
Brief Title
Brentuximab Vedotin and Chemotherapy in CD30+ PMBL, Diffuse Large B-Cell, and Grey Zone Lymphoma Patients
Official Title
A Phase I/II Study Of Brentuximab Vedotin In Combination With Multi-Agent Chemotherapy As Front-Line Treatment In Patients With CD30 Positive Primary Mediastinal Large B-Cell, Diffuse Large B-Cell, And Grey Zone Lymphomas
Study Type
Interventional

2. Study Status

Record Verification Date
December 2020
Overall Recruitment Status
Completed
Study Start Date
November 2013 (Actual)
Primary Completion Date
August 2017 (Actual)
Study Completion Date
January 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Abramson Cancer Center at Penn Medicine

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a Phase I/II multicenter single arm non-randomized open label study of the investigational drug, brentuximab vedotin, given in combination with routine chemotherapy (rituximab, cyclophosphamide, doxorubicin and prednisone) every 3 weeks for a total of 6 cycles.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
CD30 Positive Primary Mediastinal Large B-cell Lymphoma, CD30-Positive Diffuse Large B-Cell Lymphoma, CD30-Positive Gray Zone Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
32 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Phase I/II
Arm Type
Experimental
Arm Description
Total of six 21-day cycles of brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin and prednisone (R-CHP). Cycle 1 rituximab dose divided between Days 1 and 2 to prevent severe infusion reactions in rituximab naïve patients; brentuximab vedotin and cytotoxic chemotherapy administered on Day 2. Cycles 2 through 6 brentuximab vedotin and R-CHP administered on Day 1. Prednisone (or steroid equivalent) administered Days 1-5 of each cycle (prior to rituximab infusion). Cycle 1: Days 1-5: Prednisone (or equivalent) 100 mg PO/IV; Day 1: Rituximab 100 mg/m2 IV; Day 2: Rituximab 275 mg/m2 IV, Cyclophosphamide 750 mg/m2 IV, Doxorubicin 50 mg/m² IV, Brentuximab vedotin 1.8 mg/kg or 1.2 mg/kg (Phase I data established a MTD of 1.8 mg/kg brentuximab vedotin) Cycles 2-6: Days 1-5: Prednisone (or equivalent) 100 mg PO/IV; Day 1: Rituximab 375 mg/m2 IV, Cyclophosphamide 750 mg/m2 IV, Doxorubicin 50 mg/m² IV, Brentuximab vedotin 1.8 mg/kg
Intervention Type
Drug
Intervention Name(s)
brentuximab vedotin
Intervention Description
Trade name: Adcetris
Primary Outcome Measure Information:
Title
Number of Subjects With Dose-limiting Toxicities
Description
Dose-limiting toxicity (DLT) is any grade 3 or 4 new non-hematologic toxicity occurring during Cycle 1 requiring a dose delay of >14 days from the planned Day 1 of Cycle 2 (21 days from Day 1 of Cycle 1). The initial planned dose of brentuximab vedotin for the Phase I cohort of 6 patients is 1.8 mg/kg. This cohort will be evaluated for DLT in the first cycle of treatment. Dose de-escalation to 1.2 mg/kg will occur if ≥ 2 of 6 patients at the 1.8 mg/kg dose level experience a DLT.
Time Frame
21 days (Cycle 1)
Title
Overall Response Rate (ORR)
Description
Overall response rate (ORR) is defined as the proportion of patients with CR or PR according to the International Working Group Response Criteria for non-Hodgkin Lymphoma at the conclusion of systemic therapy.
Time Frame
Three to five weeks after the completion of Cycle 6 (approximately 5 months after start if treatment)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age 18 and above Histologically confirmed CD30-positive, CD20-positive untreated primary mediastinal B-cell lymphoma (any Ann Arbor stage), diffuse large B-cell lymphoma (Ann Arbor stage III or IV), or grey zone lymphoma (any Ann Arbor stage). Patients with heterogeneous, weak or equivocal CD30 staining will also be included (no specific cut off percentage for CD30 stain is required). Measurable disease, defined by the Revised Response Criteria for Malignant Lymphoma Absolute neutrophil count ≥1,000/mmᶟ and platelet count ≥75,000/µL(unless documented bone marrow involvement with lymphoma). Normal left ventricular ejection fraction of ≥50% estimated by MUGA scan or echocardiogram. Estimated creatinine clearance (using Cockcroft-Gault equation) must be >50 mL/min. Serum bilirubin ≤1.5 x upper limit of normal (ULN). Bilirubin ≤ 3 x ULN is permitted in individuals with documented liver involvement by lymphoma or if due to known Gilbert syndrome. Aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase ≤ 3 x ULN. Performance status of ECOG 0-2; patients with ECOG of 3 may be allowed to enroll after discussion with the Regulatory-Sponsor/Principal Investigator and medical monitor, and if the performance status is believed to be secondary to lymphoma related symptoms and performance status is expected to improve once chemotherapy commences. Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent. In patients who are not able to consent to the trial due to medical circumstances, the next of kin or power Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (b-hcG) pregnancy test result within 7 days prior to the first dose of brentuximab vedotin and must agree to use an effective contraception method during the study and for 30 days following the last dose of study drug; females of non-childbearing potential are those who are post-menopausal for more than 1 year or who have had bilateral tubal ligation or hysterectomy. Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 6 months following the last dose of study drug. Must be able to comply with the study and follow-up requirements. Exclusion Criteria: Previous use of investigational agents, chemotherapy or immunotherapy for lymphoma any time prior to enrollment (i.e. must have untreated disease). Prior allogeneic or autologous transplants are also not allowed. Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol. Consolidative radiation therapy (RT) after completion of planned course and/or concurrent intrathecal chemotherapy for CNS disease prophylaxis is permissible. Treatment with systemic steroids for > 4 weeks prior to Cycle 1 Day 1 of study therapy. Prior radiation therapy, with the exception of an abbreviated course (not more than 3 days) if used for SVC syndrome. History of serious organ dysfunction or disease involving the heart (left ventricular ejection fraction < 50%; unstable angina, acute myocardial infarction within 6 months prior to randomization, congestive heart failure NYHA III-IV, and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalities.), the kidney (creatinine clearance <50 mL/min), the liver (chronic hepatitis B as defined below or elevated AST, ALT or alkaline phosphatase > 3 ULN; serum bilirubin > 1.5 x ULN; bilirubin up to 3 x ULN is permitted in individuals with documented liver involvement by lymphoma or if due to known Gilbert syndrome) ot other organ system that may place the patient at undue risk to undergo treatment. Uncontrolled systemic fungal, bacterial, viral, or serious infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment). May be enrolled if controlled on treatment. Significant concurrent disease, illness or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow-up, or interpretation of study results. Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver involved with lymphoma or stable chronic liver disease per investigator's assessment). History of significant cerebrovascular disease in the past 6 months or ongoing event with active symptoms or sequelae. Other malignancy, unless the patient has been disease-free for at least 3 years following the completion of curative intent therapy, with the following exceptions: Treated non-melanoma skin cancer, any in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease -free duration, are eligible for this study if definitive treatment for the condition has been completed.Organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen (PSA) values are also eligible for this study if hormonal therapy has been initiated, or radical prostatectomy or definitive prostate irradiation has been performed. Positive test for the Human Immunodeficiency Virus (HIV) unless undetectable viral load within 3 months of enrollment (HIV RNA less than 48 copies/mL) and on HAART therapy. Positive serology for hepatitis B (HB) defined as a positive test for hepatitis B surface antigen or hepatitis B core antibody. Active involvement of the central nervous system (CNS) by lymphoma. Work-up for CNS involvement at diagnosis will be directed as per the treating physician and will depend on specific clinical circumstances (no brain imaging or lumbar puncture is required by this protocol). Pregnant or lactating women.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jakub Svoboda, MD
Organizational Affiliation
Abramson Cancer Center at Penn Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Abramson Cancer Center of the University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
17242396
Citation
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai K, Vose JM, Connors JM, Federico M, Diehl V; International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007 Feb 10;25(5):579-86. doi: 10.1200/JCO.2006.09.2403. Epub 2007 Jan 22.
Results Reference
result
PubMed Identifier
32414850
Citation
Svoboda J, Bair SM, Landsburg DJ, Dwivedy Nasta S, Nagle SJ, Barta SK, Khan N, Filicko-O'Hara J, Gaballa S, Strelec L, Chong E, Mitnick S, Waite TS, King C, Ballard H, Youngman M, Gerson J, Plastaras JP, Maity A, Bogusz AM, Hung SS, Nakamura H, Nejati R, Steidl C, Lim M, Ruella M, Schuster SJ. Brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone as frontline treatment for patients with CD30-positive B-cell lymphomas. Haematologica. 2021 Jun 1;106(6):1705-1713. doi: 10.3324/haematol.2019.238675.
Results Reference
derived
Links:
URL
https://www.ncbi.nlm.nih.gov/pubmed/17242396
Description
Abstract: Revised response criteria for malignant lymphoma.

Learn more about this trial

Brentuximab Vedotin and Chemotherapy in CD30+ PMBL, Diffuse Large B-Cell, and Grey Zone Lymphoma Patients

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