Polatuzumab Vedotin With R-GDP in Relapsed/Refractory Diffuse Large B-cell Lymphoma

Study Overview
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Brief Summary
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This study aimed to evaluate the efficacy of a novel regimen consisting of polatuzumab vedotin in combination with rituximab, gemcitabine, dexamethasone, and cisplatin (PV-RGDP) for the treatment of diffuse large B-cell lymphoma that either came back or did not improve after the treatments (rrDLBCL). This combination has not been approved by the Food and Drug Administration (FDA) for the treatment of rrDLBCL. Salvage therapy (treatment after standard treatment failed) needs to be improved. Rituximab, gemcitabine, dexamethasone, and cisplatin combination is a standard therapy for rrDLBCL and polatuzumab vedotin (PV) is a novel antibody-drug conjugate targeting CD79b. PV has shown efficacy in the setting of rrDLBCL and can improve the response rates of standard salvage therapy. This study will focus on subjects in the first relapse (one prior regimen) and will include both subjects who are transplant eligible and those who are transplant ineligible.

Official Title
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A Phase II Trial Evaluating the Efficacy of Polatuzumab Vedotin With Rituximab, Gemcitabine, Dexamethasone, and Cisplatin (PV-RGDP) Chemotherapy for Relapsed or Refractory Diffuse Large B-cell Lymphoma

Conditions
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Diffuse Large B-cell Lymphoma

Intervention / Treatment
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* Drug: Polatuzumab vedotin (PV)
* Drug: Rituximab
* Drug: Hyaluronidase
* Drug: Gemcitabine
* Drug: Cisplatin
* Drug: Dexamethasone
* Drug: GCSF


Participation Criteria
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Eligibility Criteria
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In order to participate in this study, a subject must meet all of the eligibility criteria outlined below. Inclusion Criteria: Written informed consent obtained to participate in the study and HIPAA authorization for release of personal health information. Biopsy proven diffuse large B-cell lymphoma (DLBCL) in the first relapse (biopsy can be from initial diagnosis). The study will allow high-grade B cell lymphoma, but not including Burkitt's lymphoma. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2. Radiologic evidence of active disease within 28 days of starting trial therapy. Only one prior line of therapy. Prior cancer treatment must be completed at least 14 days prior to the start of treatment and the subject must have recovered from all reversible acute toxic effects of the regimen (other than alopecia) to ≤ Grade 1 or start of treatment. Subjects may be eligible or ineligible for autologous stem cell transplant Exclusion Criteria: Known severe, active bacterial, viral, fungal, mycobacterial, parasitic, or other infections at study enrollment that may put the subject at undue risk as determined by the investigator. Subjective hearing loss interfering with daily activities or evidence of greater than mild hearing loss compared to age appropriate normal on screening audiometry are excluded. Women who are pregnant or breastfeeding or who intend to become pregnant within a year of the last dose of study treatment. Subjects with a history of prior or concurrent second primary malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the study drugs are eligible for enrollment in the trial. Previous exposure to polatuzumab vedotin. History of severe allergic or anaphylactic reaction to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine. Contraindication to gemcitabine or cisplatin, or dexamethasone or similar corticosteroid. Symptomatic cardiac disease including ventricular dysfunction, left ventricular ejection fraction < 40%, symptomatic coronary artery disease or symptomatic arrhythmias. Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygenation > 91% on room air.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: The study will use a Simon two-stage design. In the first stage 27 evaluable subjects will be recruited. If there are at least 13 (≥ 13) subjects with a partial or complete response after 4 cycles, another 17 subjects will be enrolled and treated in the second stage of the trial, for a total of 44 evaluable subjects.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br>The subjects with diffuse large B-cell lymphoma were relapsed or refractory after the first treatment and receiving the study protocol treatment. | Drug: Polatuzumab vedotin (PV)<br>* 1.8 mg/kg, intravenous, at day 1, in every 21 days<br>Drug: Rituximab<br>* 375 mg/m2 intravenous, at day 1 or day 2, in every 21 days<br>Drug: Hyaluronidase<br>* 1,400 mg/23,400 units sub-cutaneous, starts at cycle 2, in every 21 days<br>Drug: Gemcitabine<br>* 1,000 mg/m2 intravenous at day 1 and 8, in every 21 days<br>Drug: Cisplatin<br>* 75 mg/m2, intravenous, at day 1, in every 21 days<br>Drug: Dexamethasone<br>* 40 mg intravenous at day 1, Per oral days at days 2-4<br>Drug: GCSF<br>* granulocyte-colony stimulating factor (GCSF )<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) | ORR is defined as the proportion of subjects who received the study treatment, and achieved complete response (CR) or partial response (PR) by Lugano classification. Complete Response: Complete metabolic response on Positron emission tomography (PET) image or Target nodes/nodal masses must regress to ≤ 1.5 cm in the largest transverse diameter (LDi) or no extra lymphatic sites of disease on Computerized Tomography (CT). Partial Response: Score of 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size on PET and ≥50% decrease in the sum of the products of diameters (SPD) of up to 6 target measurable nodes and extranodal sites on CT. | Up to 4 months (End of Treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response rate (CR) | CR is defined as the proportion of subjects who received the study treatment, achieved complete response (CR) by the Lugano classification. | Up to 4 months (End of Treatment) | 
| Progression free survival (PFS) | PFS is defined as the time from the start of study treatment until progression by Lugano classification or death. Progressive Disease: Score 4 or 5 with an increase in the intensity of uptake from baseline and/or new fluorodeoxyglucose (FDG) -avid foci consistent with lymphoma at the interim or end-of-treatment assessment on PET, or an individual node/lesion must be abnormal with LDi > 1.5 cm, increase by ≥ 50% from the cross product of the shortest axis perpendicular to LDi (SDi) nadir and an increase in LDi or SDi from nadir: 0.5 cm for lesions ≤ 2 cm, 1.0 cm for lesions > 2 cm. | Up to 2 years | 
| Overall Survival (OS) | OS is defined as the time from the start of treatment until death from any cause. | Up to 2 years | 
| Number of participants with adverse events | The number of participants with adverse events will be listed and tabulated by grade to determine the safety and toxicity. Adverse Events will be graded according to The National Cancer Institute (NCI) of Common Terminology Criteria for Adverse Events (CTCAE) version 5. The scale is provided for each AE term. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed, refractory, polatuzumab vedotin, rituximab, gemcitabine, cisplatin