Study of Intratumoral G100 With Or Without Pembrolizumab or Rituximab In Participants With Follicular Non-Hodgkin's Lymphoma (MK-3475-174/IMDZ-G142)

Study Overview
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Brief Summary
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This is a Phase 1/2 open label trial of G100 in participants with low grade Non-Hodgkin's Lymphoma (NHL). G100 is composed of glucopranosyl lipid A in a stable emulsion and is a potent TLR4 (toll-like receptor-4) agonist. G100 will be administered by direct injection (intratumorally) into tumors of low grade NHL with or without standard low dose radiation therapy. Preclinical models and clinical studies in other cancers such as Merkel cell carcinoma have demonstrated that G100 administered in this manner can alter the tumor microenvironment, activate dendritic cells, T cells and other immune cells and induce systemic anti-tumor immune responses. In this trial, the safety, immunogenicity, and preliminary clinical efficacy of G100 will be examined alone or with pembrolizumab.

Detailed Description
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This is a multi-center Phase 1/2 open label trial of intratumoral G100 in participants with low grade NHL. Eligible participants with NHL will be enrolled and receive G100 to an accessible tumor mass. Clinical response will be evaluated in the injected tumor and systemic (abscopal) responses will be evaluated in distal areas involved with tumor. The study will be conducted in 5 parts. In Part 1, Dose Escalation, 2 sequentially enrolled cohorts of participants will be treated at one of 2 dose levels of G100 using a standard escalation design. In this portion of the study, both follicular and marginal zone NHL will be eligible. In Part 2, 2 groups of participants with follicular NHL may be examined. One group will be randomly assigned to receive either single agent G100 intratumorally at the maximum safe dose determined in Part 1 following local radiation or will receive the same treatment regimen sequentially administered with pembrolizumab. A second treatment group may be explored if the safety profile in Part 1 is acceptable. In this optional group, participants with injectable tumors of 4 cm or greater would be enrolled and treated with a higher dose of G100. In Part 3, expansion of a higher dose (20µg of G100) in participants with follicular NHL will be enrolled to receive local radiation therapy and intratumoral G100. In Part 4, Dose Escalation and Expansion, a dose of 20µg of G100 will be examined as a treatment of 1 or more tumors (up to 4) with pembrolizumab in order to establish safety and examine clinical and biomarker responses in participants receiving increasing total systemic doses of G100 and Part 5, will evaluate standard induction therapy with rituximab (anti-CD20) in combination of escalating doses of intratumoral G100 in single tumors. The primary goal of this study is to determine the safety and tolerability of different doses of G100 when administered by intratumoral injection. The development of anti-tumor immune responses and preliminary evidence of clinical responses in local and distal tumor sites will also be examined.

Official Title
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Phase 1/2 Study of Intratumoral G100 With Or Without Pembrolizumab or Rituximab In Patients With Follicular Non-Hodgkin's Lymphoma

Conditions
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Follicular Low Grade Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Drug: G100
* Drug: Pembrolizumab
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Follicular low-grade NHL: In Part 1-3: either treatment naïve (except for France) OR relapsed or refractory following at least one prior treatment. In Part 4, enrollment is limited to relapsed OR refractory follicular NHL participants. In Part 5, enrollment will include relapsed and refractory CD20+ follicular NHL following at least one but not more than 2 prior treatments. Tumor mass(es) accessible for intratumoral injection For Part 1-3, are being considered for local radiation therapy and at least one additional site of disease outside the radiation field for assessment of distal (abscopal) response. For Part 4 and 5, radiation therapy is omitted. Measurable tumor mass(es) accessible for intratumoral injection must be present for treatment and assessment of response. ≥ 18 years of age Life expectancy of ≥ 6 months per the investigator Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Electrocardiogram (ECG) without evidence of clinically significant arrhythmia or ischemia If female of childbearing potential (FCBP), willing to undergo pregnancy testing and agrees to use two methods of birth control or is considered highly unlikely to conceive during the dosing period and for three months after last study treatment, or if receiving pembrolizumab, four months after last treatment If male and sexually active with a FCBP, must agree to use highly effective contraception such as latex condom or is sterile (e.g. following a surgical procedure) during the dosing period and for three months after last study treatment, or if receiving pembrolizumab, four months after last treatment Exclusion Criteria: Cancer therapies, including chemotherapy, radiation (non-study regimen related), biologics or kinase inhibitors, granulocyte-colony stimulating factor (G-CSF) or granulocyte/monocyte-colony stimulating factor (GM-CSF) within 4 weeks prior to the first scheduled G100 dose Investigational therapy within 4 weeks prior to G100 dosing Prior administration of other intratumoral immunotherapeutics Inadequate organ function including: Marrow: Peripheral blood leukocyte count (WBC) < 3000/mm^3, absolute neutrophil count ≤ 1500/mm^3, platelets < 75000/mm^3, or hemoglobin < 10 gm/dL Hepatic: alanine aminotransferase (ALT), and aspartate aminotransferase (AST) > 2.5 x Upper Limit of Normal (ULN), total serum bilirubin > 1.5 x ULN (participants with Gilbert's Disease may be included if their total bilirubin is ≤3.0 mg/dL) Renal: Creatinine > 1.5x ULN Other: INR (international normalized ratio) or partial thromboplastin time (PTT) >1.5 x ULN Significant immunosuppression from: Concurrent, recent (≤ 4 weeks ago) or anticipated treatment with systemic corticosteroids at any dose, or Other immunosuppressive medications such as methotrexate, cyclosporine, azathioprine or conditions such as common variable hypogammaglobulinemia Pregnant or nursing Myocardial infarction within 6 months of study initiation, active cardiac ischemia or New York Heart Association (NYHA) Grade III or IV heart failure History of other cancer within 2 years (except non-melanoma cutaneous malignancies and cervical carcinoma in situ) Recent (<1 week ago) clinically significant infection, active tuberculosis or evidence of active hepatitis B, hepatitis C or HIV infection Central nervous system involvement with lymphoma, including parenchymal and leptomeningeal disease. Significant autoimmune disease, including active non-infectious pneumonitis, with the exception of alopecia, vitiligo, hypothyroidism or other conditions that have never been clinically active or were transient and have completely resolved and require no ongoing therapy Psychiatric, other medical illness or other condition that in the opinion of the principal investigator (PI) prevents compliance with study procedures or ability to provide valid informed consent History of significant adverse or allergic reaction to any component of G100 and, if enrolled in Part 2 or Part 4, pembrolizumab and/or any of its excipients, and if enrolled in Part 5, anti-CD20 antibodies including rituximab and/or any of its excipients Use of anti-coagulant agents or history a significant bleeding diathesis. (If a superficial lymph node or subcutaneous mass is to be injected, participants on agents such as non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, or clopidogrel are eligible and these agents do not have to be withheld. For procedures with moderate or significant risk of bleeding, long-acting agents such as aspirin or clopidogrel should be discussed with the Medical Monitor and may need to be discontinued before G100 therapy. For participants enrolled in Part 2 or Part 4 with the potential to receive pembrolizumab: History of (non-infectious) pneumonitis that required steroids or has current pneumonitis or interstitial lung disease Received a live virus vaccine within 30 days of planned study start Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years. (Participants who have had a transplant greater than 5 years ago are eligible as long as there are no symptoms of graft vs. host disease [GVHD]). Has had an allogeneic tissue/solid organ transplant Has received prior therapy with an anti-PD-1, anti-programmed death ligand (PD-L)1, or anti-PD-L2 agent or if the participant has previously participated in Merck MK-3475 clinical trials or was previously treated with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137) and was discontinued from that treatment due to a Grade 3 or higher immune-related adverse event.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Local Radiation + G100 5μg/tumor<br>Part 1: Local radiation and G100 [glucopyranosyl lipid A stable emulsion, GLA-SE] at 5μg/tumor administered intratumorally (IT) into accessible tumors for up to 8 weeks. | Drug: G100<br>* GLA is a fully synthetic toll-like receptor-4 (TLR4) agonist<br>* Other names: glucopyranosyl lipid A stable emulsion, GLA-SE;|
| Experimental: Part 1: Local Radiation + G100 10μg/tumor<br>Part 1: Local radiation and G100 at 10μg/tumor administered IT into accessible tumors for up to 8 weeks. | Drug: G100<br>* GLA is a fully synthetic toll-like receptor-4 (TLR4) agonist<br>* Other names: glucopyranosyl lipid A stable emulsion, GLA-SE;|
| Experimental: Part 2: Local Radiation + G100 10μg/tumor<br>Part 2: Local radiation and G100 at 10μg/tumor administered IT into accessible tumors for up to 8 weeks. | Drug: G100<br>* GLA is a fully synthetic toll-like receptor-4 (TLR4) agonist<br>* Other names: glucopyranosyl lipid A stable emulsion, GLA-SE;|
| Experimental: Part 2: Local Radiation + G100 10μg/tumor+Pembrolizumab 200mg<br>Part 2: Local radiation and G100 at 10μg/tumor administered IT into accessible tumors for up to 8 weeks; pembrolizumab 200mg intravenously (IV) administered every 3 weeks (Q3W) IV for up to 2 years. | Drug: G100<br>* GLA is a fully synthetic toll-like receptor-4 (TLR4) agonist<br>* Other names: glucopyranosyl lipid A stable emulsion, GLA-SE;Drug: Pembrolizumab<br>* PD-1 Inhibitor<br>* Other names: MK-3475;|
| Experimental: Part 2: Local Radiation, G100 20 μg/tumor in Large Tumors<br>Part 2: Local radiation and G100 at 20 μg/tumor administered IT into accessible large tumors [injectable lymphoma mass(es) ≥ 4 cm in total size] for up to 8 weeks. | Drug: G100<br>* GLA is a fully synthetic toll-like receptor-4 (TLR4) agonist<br>* Other names: glucopyranosyl lipid A stable emulsion, GLA-SE;|
| Experimental: Part 3: Local Radiation + G100 20μg/tumor<br>Part 3: Local radiation and G100 at 20μg/tumor administered IT into accessible tumors for up to 8 weeks. | Drug: G100<br>* GLA is a fully synthetic toll-like receptor-4 (TLR4) agonist<br>* Other names: glucopyranosyl lipid A stable emulsion, GLA-SE;|
| Experimental: Part 4: G100 20μg/tumor and pembrolizumab 200mg<br>Part 4: G100 at 20μg/tumor administered IT into accessible tumors for up to 8 weeks and pembrolizumab 200mg IV and administered Q3W for up to 2 years. | Drug: G100<br>* GLA is a fully synthetic toll-like receptor-4 (TLR4) agonist<br>* Other names: glucopyranosyl lipid A stable emulsion, GLA-SE;Drug: Pembrolizumab<br>* PD-1 Inhibitor<br>* Other names: MK-3475;|
| Experimental: Part 5: G100 + Rituximab 375mg/m^2<br>Part 5: G100 at 20, 40, 60, or 80μg/tumor administered IT for up to 6 weeks and rituximab administered as an IV infusion at 375mg/m^2 on Day 0 and then QW for up to 3 weeks. | Drug: G100<br>* GLA is a fully synthetic toll-like receptor-4 (TLR4) agonist<br>* Other names: glucopyranosyl lipid A stable emulsion, GLA-SE;Drug: Rituximab<br>* Rituximab (anti-CD20 antibody)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With an Adverse Event (AE) | An adverse event (AE) is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. | Up to approximately 42 months | 
| Number of Participants Who Discontinued Study Drug Due to an Adverse Event | An adverse event (AE) is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. | Up to approximately 105 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) by Immune-related Response Criteria (irRC) | Overall response rate was defined as the number and percent of participants with best overall response of immune-related complete response (irCR) or immune-related partial response (irPR). irRC requires confirmatory restaging to determine if tumor size increase is due to true progression instead of immune inflammation and that new tumors add to tumor size calculations are not determinants of progressive disease by themselves. An immune-related Complete Response (irCR) is the disappearance of all tumors, measured or unmeasured, and no new tumors; an immune-related Partial Response (irPR) is a ≥50% drop in tumour burden from baseline as defined by the irRC; and immune-related Progressive Disease (irPD) is a ≥25% increase in tumour burden from the lowest level recorded. Everything else is considered immune-related Stable Disease (irSD). Tumor staging using bi-dimensional measurements was performed by CT or MRI. | Up to approximately 42 months | 
| Clinical Benefit Rate (CBR) Using Immune-related Response Criteria (irRC) | Clinical benefit rate (CBR) was defined as the number and percent of participants with best overall response of complete response, partial response or stable disease (irCR+irPR+irSD). Clinical response was assessed by Immune-related Response Criteria (irRC) using bi-dimensional measurements as a preliminary indication of efficacy. irRC requires confirmatory restaging to determine if tumor size increase is due to true progression instead of immune inflammation and that new tumors add to tumor size calculations are not determinants of progressive disease by themselves. An immune-related Complete Response (irCR) is the disappearance of all tumors, and no new tumors; an immune-related Partial Response (irPR) is a ≥50% drop in tumor burden from baseline; and immune-related Progressive Disease (irPD) is a ≥25% increase in tumor burden from the lowest level recorded. Everything else is considered immune-related Stable Disease (irSD). Tumor staging by CT or MRI was performed. | Up to approximately 42 months | 
| Clinical Benefit Rate (CBR) Using International Working Group (IWG) Criteria | Clinical benefit rate (CBR) will be defined as the number and percent of participants with best overall response of complete response, partial response or stable disease (CR+PR+SD). The IWG criteria (Cheson et al 2014) for a CR is a complete radiologic response (target nodes/nodal masses must regress to ≤1.5 cm in longest transverse diameter (LDi), no extralymphatic sites of disease, and no new tumors. A PR is a ≥50% decrease in SPD (sum of the product of the perpendicular diameters for multiple tumors) of up to 6 target measurable nodes and extranodal sites, spleen must have regressed by >50% in length beyond normal, and no new tumors. Stable disease is a <50% decrease from baseline in SPD of up to 6 dominant, measurable nodes and extranodal sites; no criteria for progressive disease are met, and no new tumors. | Up to approximately 42 months | 
| Duration of Response (DOR) by Immune-related Response Criteria (irRC) | Duration of response (DOR) was defined as the time interval between the date of the earliest qualifying confirmed/unconfirmed response using irRC and the date of disease progression (PD) or death for any cause, whichever occurs first. DOR in months was calculated as: (date of PD or death minus date of first confirmed/unconfirmed irCR/CR or irPR/PR + 1)/30.4375. DOR analysis included only participants with confirmed/unconfirmed response of irCR/irPR using irRC. Immune-related Progressive Disease (irPD) is a ≥25% increase in tumor burden from the lowest level recorded. Summary of DOR including median was estimated using the Kaplan-Meier method in each treatment group. | Up to approximately 42 months | 
| Duration of Clinical Benefit by Immune-related Response Criteria (irRC) | Duration of clinical benefit was defined as the time interval between the date of the earliest qualifying confirmed/unconfirmed best response using irRC and the date of progression disease (PD) or death for any cause, whichever occurred first. Duration of clinical benefit in months was calculated as: (date of PD or death - date of first confirmed/unconfirmed irCR/irPR or irSD + 1)/30.4375. Duration of clinical benefit included only participants with confirmed/unconfirmed response of irCR/irPR or irSD using irRC. For participants who were alive without documentation of disease progression following the qualifying response, duration of clinical benefit was censored following the same rule defined for PFS. Summary of duration of clinical benefit including median was estimated using the Kaplan Meier method in each treatment group. | Up to approximately 42 months | 
| Progression-free Survival (PFS) | PFS was defined as time from date of first study treatment to date of first disease progression by irRC criteria, symptomatic deterioration, or death due to any cause, whichever occurs first. Progression-free survival in months is calculated as: (date of first progression, symptomatic deterioration, or death (any reason) - date of first dose +1)/30.4375. The irRC modification required a PD confirmation no less than 4 weeks from first documentation of PD; once confirmed, the date of progression was defined as date of the first PD. Participants without progression, symptomatic deterioration, or death were censored at the date of the last tumor assessment. Immune-related Progressive Disease (irPD) is a ≥25% increase in tumor burden from the lowest level recorded. Summary of PFS including median was estimated using the Kaplan-Meier method in each treatment group. | Up to approximately 42 months | 
| Overall Survival (OS) | Overall Survival (OS) was defined as the time from date of first study treatment to death due to any cause. Overall survival in months was calculated as: (date of death - date of first dose) +1)/30.4375. Participants who were alive at the end of study were censored at the last date the participant was known to be alive or data analysis cutoff date, whichever was earlier. Summary of OS including median was estimated using the Kaplan-Meier method in each treatment group. | Up to approximately 42 months | 
| Overall Tumor Response Based on irRC Abscopal Sites | Abscopal tumor responses were assessed in non-treated, distal tumor sites. Clinical response was assessed by Immune-related Response Criteria (irRC) using bi-dimensional measurements as a preliminary indication of efficacy. irRC requires confirmatory restaging to determine if tumor size increase is due to true progression instead of immune inflammation and that new tumors add to tumor size calculations are not determinants of progressive disease by themselves. An immune-related Complete Response (irCR) is the disappearance of all tumors, measured or unmeasured, and no new tumors; an immune-related Partial Response (irPR) is a ≥50% drop in tumour burden from baseline as defined by the irRC; and immune-related Progressive Disease (irPD) is a ≥25% increase in tumour burden from the lowest level recorded. Everything else was considered immune-related Stable Disease (irSD). Tumor staging by CT or MRI was performed. | Up to approximately 42 months | 
| Time to Response for Complete Response and Partial Response Participants | Time to Response for CR and PR participants was defined as time from date of first study treatment to the date of CR or PR response first documented. Complete Response (irCR) is the disappearance of all tumors, and no new tumors; an immune-related Partial Response (irPR) is a ≥50% drop in tumor burden from baseline. Time to response in months was calculated as: (date of first CR or PR minus date of first dose +1)/30.4375. Summary of Time to Response including median was estimated using Kaplan-Meier method in each treatment group. | Up to approximately 42 months | 
| Time to Next Treatment (TTNT) | Time to next treatment was defined as the time from the date of first study treatment to the start date of subsequent therapy after PD. Immune-related Progressive Disease (irPD) is a ≥25% increase in tumor burden from the lowest level recorded. Participants who did not receive subsequent therapy after PD were censored at the date of last contact or death. Summary of TTNT including median was estimated using the Kaplan-Meier method in each treatment group. | Up to approximately 42 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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follicular lymphoma, FL, low-grade lymphoma, Non-Hodgkin's Lymphoma, follicular NHL, Marginal Zone