Clinical Trials /

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

NCT04479267

Description:

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.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • High Grade B-Cell Lymphoma with MYC and BCL2 and/or BCL6 Rearrangements
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 2019-135
  • SECONDARY ID: P30
  • NCT ID: NCT04479267

Conditions

  • Diffuse Large B-Cell Lymphoma
  • High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements
  • High Grade B-Cell Lymphoma With MYC, BCL2 and BCL6 Rearrangements

Interventions

DrugSynonymsArms
Prednisone.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-DomeTreatment (polatuzumab vedotin, R-CHP)
Prednisolone(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, CortisoloneTreatment (polatuzumab vedotin, R-CHP)
Methylprednisolone(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, EsametoneTreatment (polatuzumab vedotin, R-CHP)
Rituximab174722-31-7, 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-C2B8Treatment (polatuzumab vedotin, R-CHP)
Polatuzumab Vedotin1313206-42-6, ADC DCDS4501A, Antibody-Drug Conjugate DCDS4501A, DCDS4501A, FCU 2711, POLATUZUMAB VEDOTIN, polatuzumab vedotin-piiq, Polivy, RG7596, Ro 5541077-000Treatment (polatuzumab vedotin, R-CHP)
Cyclophosphamide1-bis(2-chloroethyl)-amino-1-oxo-2-aza-5-oxaphosphoridin monohydrate, 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrateTreatment (polatuzumab vedotin, R-CHP)
Doxorubicin Hydrochloride14-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-Treatment (polatuzumab vedotin, R-CHP)

Purpose

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.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine the rate of complete remission (CR) with polatuzumab vedotin plus rituximab,
      cyclophosphamide, doxorubicin hydrochloride, and prednisone (R-CHP) in patients with newly
      diagnosed previously untreated double or triple hit lymphoma as measured by positron emission
      tomography (PET)-defined CR rate using the modified Lugano response criteria at the time of
      primary response assessment (6-8 weeks after cycle 6 day 1 or last dose of study medication).

      PRIMARY OBJECTIVE:

      I. To determine the rate of complete remission (CR) with polatuzumab vedotin plus rituximab,
      cyclophosphamide, doxorubicin hydrochloride, and prednisone (R-CHP) in patients with newly
      diagnosed previously untreated double or triple hit lymphoma as measured by positron emission
      tomography (PET)-defined CR rate using the modified Lugano response criteria at the time of
      primary response assessment (6-8 weeks after cycle 6 day 1 or last dose of study medication).

      SECONDARY SAFETY OBJECTIVE:

      I. To evaluate the safety and tolerability of the combination of polatuzumab vedotin (PoV)
      plus R-CHP as defined by Common Terminology Criteria for Adverse Events (CTCAE) 5.0.

      SECONDARY EFFICACY OBJECTIVES:

      I. To assess the progression free survival (PFS) with PoV plus R-CHP in the above-mentioned
      patient population.

      II. To assess the overall survival (OS) with PoV plus R-CHP in the above-mentioned patient
      population.

      III. To assess the overall response rate (ORR; complete response [CR] or partial response
      [PR]) at the time of primary response assessment, based on modified Lugano PET-computed
      tomography (CT) criteria, as determined by the investigator.

      IV. To assess the duration of response (DOR) to PoV plus R-CHP based on PET-CT, as determined
      by the investigators in the above-mentioned patient population.

      EXPLORATORY OBJECTIVES:

      I. To explore the relationship between CD79b expression and response to treatment with PoV
      plus R-CHP.

      II. To explore the relationship between MYC expression and response to treatment with PoV
      plus R-CHP.

      III. To explore polatuzumab vedotin treatment on Myc protein expression.

      OUTLINE:

      Patients receive prednisone orally (PO), prednisolone intravenously (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.

      After completion of study treatment, patients are followed up every 3 months for 12 months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (polatuzumab vedotin, R-CHP)ExperimentalPatients 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.
  • Prednisone
  • Prednisolone
  • Methylprednisolone
  • Rituximab
  • Polatuzumab Vedotin
  • Cyclophosphamide
  • Doxorubicin Hydrochloride

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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

Measure:Incidence of adverse events
Time Frame:Up to 30 days after last dose of study treatment
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure:Overall response rate (ORR)
Time Frame:Up to 12 months
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Barbara Ann Karmanos Cancer Institute

Last Updated

July 16, 2020