PNT2258 for Treatment of Patients With r/r DLBCL (Wolverine)

Study Overview
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Brief Summary
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This study is sponsored by Sierra Oncology, Inc. formerly ProNAi Therapeutics, Inc. It is a multi-center, nonrandomized, open label, phase II investigation of PNT2258 to characterize anti-tumor activity and collect safety data on patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma.

Official Title
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A Phase II Study of PNT2258 in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Conditions
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Lymphoma, Diffuse Large B-Cell

Intervention / Treatment
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* Drug: PNT2258


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed diffuse large B-cell lymphoma that is refractory to prior therapy or relapsed after prior therapy. FDG PET-CT (disease) positive baseline scan with measurable disease. The patient must have received prior therapy that included: CD20-targeted therapy (for example, rituximab), Alkylating agent (for example, cyclophosphomide), and Steroid, unless the patient is steroid intolerant Exposure to at least 1 or 2 (but no more than 3) prior systemic cytotoxic chemotherapeutic regimens. Note: Only those subjects who are not eligible for high-dose chemotherapy and autologous stem cell transplant (HD-ASCT), or who refuse HD-ASCT, are eligible with exposure to only 1 prior cytotoxic chemotherapeutic regimen. ECOG performance status of 0-1. The patient must be a stable baseline with CTCAE grade ≤ 2 regarding any acute or chronic toxicity associated with prior therapy, and have discontinued prior anti-cancer therapy for ≥ 14 days prior to C1D1; mitomycin-C for at least 6 weeks prior to C1D1; SCT ≥ 2 months prior to C1D1. Note: Palliative steroids for control of disease-related symptoms are allowed and maintenance hormone therapy is allowed. Adequate organ function including: Hematologic: ANC ≥ 0.5 x 10^9/L. and platelets ≥ 50 x 10^9/L. Hepatic: Total Bilirubin ≤ 2 x ULN (patients with Gilbert's syndrome must have total bilirubin ≤ 3 x ULN) and serum transaminase levels ≤ 2.5 x ULN. In the case of known liver metastasis (i.e., radiological or biopsy documented), serum transaminase levels must be ≤ 5 x ULN. Renal: Serum creatinine ≤ 2 x ULN, or creatinine clearance ≥ 60 mL/min/1.73 m2 for subjects with serum creatinine levels above 2 x ULN. Willingness to: 1.) undergo pre-treatment biopsy to obtain adequate tissue for analysis (e.g., core needle, excisional or incisional tumor biopsy) or 2.) provide archived tumor (e.g., FFPE block) for analysis. Exclusion Criteria: Eligibility for high-dose chemotherapy (HDT) and stem cell transplant (SCT). Note: Subjects who progressed ≥ 2 months after HDT/SCT are eligible Concurrent malignancies requiring treatment. Primary mediastinal (thymic) large B-cell lymphoma Symptomatic CNS or leptomeningeal involvement of lymphoma. Concurrent clinically significant illness, medical condition, surgical history, physical finding, electrocardiogram or laboratory finding that, in the opinion of the investigator, could adversely affect the safety of the patient or impair the assessment of the study results. Signs or symptoms of heart failure characterized as greater than NYHA Class II or other significant cardiac abnormalities. Pregnant or breast-feeding. Prior exposure to PNT2258. Life expectancy less than 3 months.

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PNT2258<br>PNT2258 will be administered at 120 mg/m2 on days 1-5 of a 21-day cycle. Treatment may continue unless there is disease progression or the occurrence of unacceptable toxicity for a total of 8 induction cycles of therapy. Subjects with CR/CMR, PR/PMR or SD/NMR at the end-of-cycle 8 scan then receive ongoing PNT2258 therapy at a dose of 100 mg/m2 on days 1-4 of a 28 day cycle until progressive disease, the occurrence of unacceptable toxicity, non-compliance, voluntary withdrawal or if in the opinion of the investigator the subject is no longer benefiting from exposure to PNT2258. | Drug: PNT2258<br> <br> * Other names: DNAi, BCL2 targeted therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | The proportion of patients with complete response (CR/complete metabolic response [CMR]) or partial response (PR/partial metabolic response [PMR]) according to the revised 2014 International Working Group (IWG) criteria for lymphoma (Cheson 2014) | 19 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate | The proportion of patients who have a response of stable disease (SD/no metabolic response [NMR]) or better by investigator assessment | 19 months | 
| Time to Response | The number of months from Cycle 1 Day 1 until the date of the first documented response | 19 months | 
| Progression-free Survival | The number of months from C1D1 until the date of DLBCL progression or death from any cause, or to the last date at which progression status was adequately assessed for censored observation | 19 months | 
| Safety - Assessment of Adverse Events | Characterization of the type, frequency, severity, timing of onset, duration, and relationship to study drug of any treatment-emergent adverse events, laboratory abnormalities, serious adverse events or adverse events leading to discontinuation of study treatment | 36 months | 
| Overall Survival | The number of months from C1D1 until the date of death from any cause, or to the last date at which survival status was adequately assessed for censored observations | 19 months | 
| Duration of Overall Response | The time from the initial CMR or PMR until the date of progression or death from any cause, or to the last date at which progression status was adequately assessed for censored observations | 19 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PNT2258, DLBCL, Diffuse Large B-cell Lymphoma, NHL, Non-Hodgkin's Lymphoma, Lymphoma