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Polatuzumab Vedotin and Combination Chemotherapy for the Treatment of Previously Untreated Double or Triple Hit Lymphoma

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ClinicalTrials.gov Identifier: NCT04479267
Recruitment Status : Recruiting
First Posted : July 21, 2020
Last Update Posted : April 6, 2021
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Dipenkumar Modi, Barbara Ann Karmanos Cancer Institute

Brief Summary:
This phase II trial studies how well polatuzumab vedotin and combination chemotherapy work in treating patients with previously untreated double or triple hit lymphoma. Polatuzumab vedotin is a monoclonal antibody that works by binding with cancer cells and releasing another chemotherapy drug, called monomethyl auristatin E, into the cell causing the cancer cells to die or stop growing. Chemotherapy drugs, such as rituximab, cyclophosphamide, doxorubicin, and prednisone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving polatuzumab vedotin with combination chemotherapy may work better in treating patients with double or triple hit lymphoma compared to combination chemotherapy alone.

Condition or disease Intervention/treatment Phase
Diffuse Large B-Cell Lymphoma High Grade B-Cell Lymphoma w/MYC & BCL2 or BCL6 Rearrangements High Grade B-Cell Lymphoma w/MYC, BCL2 & BCL6 Rearrangements Drug: Prednisone Drug: Prednisolone Drug: Methylprednisolone Biological: Rituximab Drug: Polatuzumab Vedotin Drug: Cyclophosphamide Drug: Doxorubicin Hydrochloride Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 49 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study Evaluating Safety and Efficacy of Polatuzumab Vedotin in Combination With Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone in Patients With Previously Untreated Double and Triple Hit Lymphoma
Actual Study Start Date : August 21, 2020
Estimated Primary Completion Date : December 1, 2022
Estimated Study Completion Date : December 1, 2022


Arm Intervention/treatment
Experimental: Treatment (polatuzumab vedotin, R-CHP)
Patients receive prednisone PO, prednisolone IV, or methylprednisolone IV on days 1-5. Patients also receive rituximab IV, polatuzumab vedotin IV over 30-90 minutes, cyclophosphamide IV, and doxorubicin hydrochloride IV on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Drug: Prednisone
Given PO
Other Name: .delta.1-Cortisone, 1, 2-Dehydrocortisone, 17,21-Dihydroxypregna-1,4-diene-3,11,20-trione, 53-03-2, Adasone, Cortancyl, Dacortin, , Decortisyl, Decorton, Delta 1-Cortisone, Delta-Dome

Drug: Prednisolone
Given IV
Other Name: (11beta)-11,17,21-Trihydroxypregna-1,4-diene-3,20-dione, .delta.1-Hydrocortisone, 1,2-Dehydrohydrocortisone, 50-24-8, 9120, Adnisolone, Aprednislon, Capsoid, Cortalone, Cortisolone

Drug: Methylprednisolone
Given IV
Other Name: (6alpha,11beta)-11,17,21-Trihydroxy-6-methylpregna-1,4-diene-3,20-dione, 6Alpha-Methylprednisolone, Adlone, Caberdelta M, DepMedalone, Depo Moderin, Depo-Nisolone, Duralone, Emmetipi, Esametone

Biological: Rituximab
Given IV
Other Name: 174722-31-7, 687451, ABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT-P10, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8

Drug: Polatuzumab Vedotin
Given IV
Other Name: 1313206-42-6, ADC DCDS4501A, Antibody-Drug Conjugate DCDS4501A, DCDS4501A, FCU 2711, POLATUZUMAB VEDOTIN, polatuzumab vedotin-piiq, Polivy, RG7596, Ro 5541077-000

Drug: Cyclophosphamide
Given IV
Other Name: 1-bis(2-chloroethyl)-amino-1-oxo-2-aza-5-oxaphosphoridin monohydrate, 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate

Drug: Doxorubicin Hydrochloride
Given IV
Other Name: 14-Hydroxydaunorubicin Hydrochloride, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-




Primary Outcome Measures :
  1. Rate of complete remission [ Time Frame: Up to 6-8 weeks after cycle 6 day 1 (cycles = 21 days) or last dose of study medication ]
    Will be assessed by modified Lugano response criteria for malignant lymphoma. The complete remission rate will be summarized by a binomial response rate and its associated 2-sided 80% confidence interval (CI) using Pearson-Klopper method. The primary efficacy analysis will be also performed based on all response evaluable subjects as a sensitivity analysis.


Secondary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 30 days after last dose of study treatment ]
    Safety will be assessed through summaries of adverse events, summaries of changes from screening assessments in laboratory test results, electrocardiograms, and changes in vital signs. All adverse events occurring on or after first study treatment will be summarized by mapped term, appropriate thesaurus levels, and National Cancer Institute (NCI) Common Terminology Criteria Adverse Events version (v) 4.03 toxicity grade. All serious adverse events will be listed separately and summarized. Deaths reported during the study treatment period and those reported during follow-up after treatment discontinuation will be listed. Relevant laboratory and vital sign (temperature, heart rate, respiratory rate, pulse oximetry, and blood pressure) data will be displayed by time, with NCI Common Terminology Criteria for Adverse Events v5.0. Grade 3 and 4 values identified where appropriate.

  2. Progression-free survival (PFS) [ Time Frame: From the start date of the treatment until the date of progression or death from any cause, whichever occurs first, assessed up to 12 months ]
    The distribution of PFS will be graphically summarized using the Kaplan-Meier (KM) curve and the median PFS and its associated 2-sided CI will be estimated using the KM estimator. The median follow-up time and its 2-sided CI will be estimated using the reverse KM estimator.

  3. Overall response rate (ORR) [ Time Frame: Up to 12 months ]
    Will be defined as complete response (CR) or partial response (PR) at primary response assessment based on positron emission tomography/computed tomography as determined by the investigator and assessed using modified Lugano response criteria. CR and PR will be summarized using frequency and percentage. The ORR will be summarized by a binomial response rate and its associated 2-sided CI using Pearson-Klopper method.

  4. Duration of response (DOR) [ Time Frame: From the date of CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is documented among all treated subjects who had a confirmed CR or PR, assessed up to 12 months ]
    The distribution of DOR will be graphically summarized using the KM curve and the median PFS and its associated 2-sided CI will be estimated using the KM estimator.


Other Outcome Measures:
  1. Biomarker assessment [ Time Frame: Up to time of disease progression, assessed up to 12 months ]
    Exploratory analyses of biomarkers related to tumor biology and the mechanisms of action of polatuzumab vedotin and rituximab will be conducted. Analyses will assess prognostic and/or predictive value of candidate biomarkers separately for each histological subtype and both investigator and Independent Review Committee assessed outcomes. Specifically, the association between candidate biomarkers and positron emission tomography (PET)-computed tomography (CT) CR rate and objective response rate and potentially other measures of efficacy and safety, independent of treatment, will be explored to assess potential prognostic value. In addition, the potential effect modification of treatment effect on PET-CT CR rate and OR rate and potentially other measures of efficacy and safety, by biomarker status, will be explored to assess potential predictive value.



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

Inclusion Criteria:

  • Signed informed consent form (ICF)
  • Previously untreated patients with diffuse large B-cell lymphoma (DLBCL) as determined by local pathology. World Health Organization (WHO) histologies will include:

    • Double hit lymphoma (DHL) or triple hit lymphoma (THL) confirmed by fluorescence in situ hybridization (FISH) testing by local pathology (defined as MYC and BCL2 and/or BCL6 rearrangements)
    • High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements
  • Availability of archival formalin-fixed paraffin-embedded (FFPE) tissue blocks or 15 unstained slides serial sections (3-5 um in thickness) prior to study enrollment. The pathology report must be available for review and a tissue block sent for retrospective central confirmation of diagnosis. 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

    * For clarification: Availability of tumor sample must be verified prior to cycle 1, day 1 (C1D1) however treatment can commence prior to completion of central review

  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
  • Life expectancy of at least 24 weeks
  • At least one bi-dimensionally measurable lesion > 1.5 cm in its longest dimension as measured by CT or magnetic resonance imaging (MRI)
  • Ability and willingness to comply with the study protocol procedures
  • Left ventricular ejection fraction (LVEF) >= 45% on cardiac multiple-gated acquisition (MUGA) scan or cardiac echocardiogram (ECHO)
  • Hemoglobin >= 8.0 g/dL without packed RBC transfusion during 14 days before first treatment (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)
  • Absolute neutrophil count (ANC) >= 1,000/uL (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)
  • Platelet count >= 75,000/uL (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)
  • 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
    • Women must refrain from donating eggs during the 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 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 polatuzumab vedotin, 3 months after the last dose of rituximab, and for at least 6 months after the last dose of cyclophosphamide to avoid exposing the embryo for the duration of the pregnancy. Men must refrain from donating sperm during this same period

  • 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
  • CRITERIA FOR TISSUE SUBMISSION:
  • Eligible patients must have available at the study site a representative formalin-fixed, paraffin-embedded tumor specimen that enabled the definitive diagnosis of DLBCL

    • The specimen must contain adequate evaluable tumor cells (>= 20% for excisional biopsy and >= 50% if sample is a core biopsy) to enable relevant biomarker analysis
    • A tissue block (preferred) or 15 serial, freshly cut, unstained slides plus punch biopsy of the tissue block accompanied by an associated pathology report will be requested. Punch biopsy is required only with the slide submission. Cytological or fine-needle aspiration samples are not acceptable
    • If the archival tissue is unavailable or insufficient on the basis of the above criteria, the patient may still be eligible if the patient is willing to provide tissue from a pretreatment core or excisional/incisional biopsy of the tumor. Cytological or fine-needle aspiration samples are not acceptable. The sample should be shipped according to instructions provided in the laboratory manual. Tissue collected on study will not be returned to sites. If needed, additional slides from previously collected samples may be requested. Cases received from each of the participating institutes should be histological confirmed according to the 2016 WHO classification of tumors of hematopoietic and lymphoid neoplasm. The evaluation process by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) requires the possession of representative amount of tissues in a paraffin embedded block to be sent to the primary testing institution (Karmanos Cancer Center, Detroit, Michigan). Shipped slides should be placed in proper containers to avoid breakage during shipping. Blocks of paraffin embedded tissue or slides should be sent with a tracking number the address. In addition, the participation institution should call the laboratory at 313-576-8351 (Julie Boerner) for any sample that they ship and provide tracking number

Exclusion Criteria:

  • Contraindication to any of the individual components of R-cyclophosphamide, doxorubicin hydrochloride, oxaliplatin, prednisone (CHOP) or any component of PoV, including prior receipt of anthracyclines or history of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies (MAbs) (or recombinant antibody-related fusion proteins) or known sensitivity or allergy to murine products
  • Contraindication to rituximab or prior administration of an anti CD 20 antibody
  • Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive therapy, or any investigational agent for the purposes of treating cancer prior to cycle 1 day 1 with the following exceptions:

    • Glucocorticoid treatment required for lymphoma symptom control prior to the start of study treatment, prednisone 100 mg or equivalent can be given for a maximum of 13 days as a prephase treatment, with all tumor assessments completed prior to starting prednisone
    • One dose of prophylactic intrathecal chemotherapy with methotrexate
  • Grade 3b follicular lymphoma
  • History of transformation of indolent disease to DLBCL
  • Primary mediastinal (thymic) large B-cell lymphoma
  • Burkitt lymphoma
  • Primary or secondary central nervous system (CNS) lymphoma (primary or secondary involvement), primary effusion DLBCL, and primary cutaneous DLBCL
  • Current grade 2 peripheral neuropathy per Common Terminology Criteria for Adverse Events (CTCAE) 5.0
  • History of other malignancy that could affect compliance with the protocol or interpretation of results. Exceptions include, but are not limited to:

    • Patients with a history of curatively treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or ductal carcinoma in situ of the breast at any time prior to the study are eligible
    • A patient with any other malignancy that has been treated with surgery alone with curative intent and the malignancy has been in remission without treatment for >= 3 years prior to enrollment is eligible
    • Patients with low-grade, early-stage prostate cancer with no requirement for therapy at any time prior to study 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 significant pulmonary disease (including obstructive pulmonary disease and history of bronchospasm)
  • History or presence of an abnormal electrocardiogram (ECG) that is clinically significant in the investigator's opinion, including complete left bundle branch block, second- or third-degree heart block
  • 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 (IV) antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to cycle 1 day 1
  • Patients with clinical suspicion of active or latent tuberculosis (to be confirmed by a positive interferon gamma release assay)
  • Positive test results for chronic hepatitis B virus (HBV) infection (defined as positive hepatitis B surface antigen [HBsAg] serology)

    * Patients with occult or prior HBV infection (defined as negative HBsAg and positive hepatitis B core antibody [HBcAb]) may be included if HBV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) is undetectable, provided that they are willing to undergo DNA testing on day 1 of every cycle and monthly for at least 12 months after the last cycle of study treatment. Patients who have protective titers of hepatitis B surface antibody (HBsAb) after vaccination or prior but cured hepatitis B are eligible

  • Positive test results for hepatitis C virus (HCV) antibody

    * Patients who are positive for HCV antibody are eligible only if PCR is negative for HCV ribonucleic acid (RNA)

  • Known history of human immunodeficiency virus (HIV) seropositive status

    * For patients with unknown HIV status, HIV testing will be performed at screening

  • Vaccination with a live vaccine within 28 days prior to treatment
  • Recent major surgery (within 6 weeks before the start of cycle 1 day 1) other than for diagnosis
  • Women who are pregnant or lactating or who intend to become pregnant within a year of the last dose of study treatment
  • Patients with a history of progressive multifocal leukoencephalopathy
  • Creatinine > 1.5 x ULN or a measured creatinine clearance < 40 mL/min (unless abnormal laboratory values are due to underlying lymphoma per the investigator)
  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x ULN (unless abnormal laboratory values are due to underlying lymphoma per the investigator)
  • Total bilirubin >= 1.5 x ULN (unless abnormal laboratory values are due to underlying lymphoma per the investigator)

    * Patients with documented Gilbert disease may be enrolled if total bilirubin is =< 3 x ULN

  • International normalized ratio (INR) or prothrombin time (PT) > 1.5 x ULN in the absence of therapeutic anticoagulation (unless abnormal laboratory values are due to underlying lymphoma per the investigator)
  • Partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) > 1.5 x ULN in the absence of a lupus anticoagulant (unless abnormal laboratory values are due to underlying lymphoma per the investigator)
  • Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04479267


Contacts
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Contact: Charles Schiffer, M.D. (313) 576-8737 schiffer@karmanos.org

Locations
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United States, Michigan
Barbara Ann Karmanos Cancer Institute Recruiting
Detroit, Michigan, United States, 48201
Contact: Clinical Trials Office    800-527-6266      
Sub-Investigator: Asif Alavi, M.D.         
Sub-Investigator: Abhinav Deol, M.D.         
Sub-Investigator: Andrew Kin, M.D.         
Sub-Investigator: Dipenkumar Modi, M.D.         
Sub-Investigator: Melissa Runge-Morris, M.D.         
Sub-Investigator: Dahlia Sano, M.D.         
Sub-Investigator: Erlene Seymour, M.D.         
Sub-Investigator: Jay Yang, M.D.         
Sub-Investigator: Jeffrey Zonder, M.D.         
Principal Investigator: Charles Schiffer, M.D.         
Sponsors and Collaborators
Barbara Ann Karmanos Cancer Institute
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Charles Schiffer, M.D. Barbara Ann Karmanos Institute
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Responsible Party: Dipenkumar Modi, Principal Investigator, Barbara Ann Karmanos Cancer Institute
ClinicalTrials.gov Identifier: NCT04479267    
Other Study ID Numbers: 2019-135
P30 ( Other Grant/Funding Number: NIH )
First Posted: July 21, 2020    Key Record Dates
Last Update Posted: April 6, 2021
Last Verified: February 2021

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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
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Prednisone
Methylprednisolone
Methylprednisolone Acetate
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone acetate
Hydrocortisone
Cortisone
Cyclophosphamide
Rituximab
Doxorubicin
Liposomal doxorubicin
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Immunoconjugates
Prednisolone hemisuccinate
Prednisolone phosphate
Immunosuppressive Agents
Immunologic Factors