Follicular Low Grade Non-Hodgkin's LymphomaPhase 1/2NCT02501473
Study of Intratumoral G100 With Or Without Pembrolizumab or Rituximab In Participants With Follicular Non-Hodgkin's Lymphoma (MK-3475-174/IMDZ-G142)
A Phase 1/2 study testing G100, Pembrolizumab and Rituximab in people with Follicular Low Grade Non-Hodgkin's Lymphoma, run by Immune Design, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA).
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Follicular Low Grade Non-Hodgkin's Lymphoma
- What is being tested?
- G100, Pembrolizumab and Rituximab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 52 participants
- Where
- No sites listed yet
- Study dates
- 3 Feb 2016to 1 Aug 2019
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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
Who cannot join
- 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)
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- 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.
About this study
Official title: Phase 1/2 Study of Intratumoral G100 With Or Without Pembrolizumab or Rituximab In Patients With Follicular Non-Hodgkin's Lymphoma
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.
Read the detailed description
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.
- Being tested
- G100, Pembrolizumab, Rituximab
- Keywords
- follicular lymphoma, FL, low-grade lymphoma, Non-Hodgkin's Lymphoma, follicular NHL, Marginal Zone
- Medical subject headings
- Lymphoma, Follicular, Lymphoma, Non-Hodgkin
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
G100Drug
Also called glucopyranosyl lipid A stable emulsion, GLA-SE
GLA is a fully synthetic toll-like receptor-4 (TLR4) agonist
PembrolizumabDrug
Also called Keytruda, MK-3475
PD-1 Inhibitor
RituximabDrug
Rituximab (anti-CD20 antibody)
| Study group | Role | What they receive |
|---|---|---|
| Part 1: Local Radiation + G100 5μg/tumor | Experimental | 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. Receives: Drug: G100 |
| Part 1: Local Radiation + G100 10μg/tumor | Experimental | Part 1: Local radiation and G100 at 10μg/tumor administered IT into accessible tumors for up to 8 weeks. Receives: Drug: G100 |
| Part 2: Local Radiation + G100 10μg/tumor | Experimental | Part 2: Local radiation and G100 at 10μg/tumor administered IT into accessible tumors for up to 8 weeks. Receives: Drug: G100 |
| Part 2: Local Radiation + G100 10μg/tumor+Pembrolizumab 200mg | Experimental | 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. Receives: Drug: G100; Drug: Pembrolizumab |
| Part 2: Local Radiation, G100 20 μg/tumor in Large Tumors | Experimental | 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. Receives: Drug: G100 |
| Part 3: Local Radiation + G100 20μg/tumor | Experimental | Part 3: Local radiation and G100 at 20μg/tumor administered IT into accessible tumors for up to 8 weeks. Receives: Drug: G100 |
| Part 4: G100 20μg/tumor and pembrolizumab 200mg | Experimental | 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. Receives: Drug: G100; Drug: Pembrolizumab |
| Part 5: G100 + Rituximab 375mg/m^2 | Experimental | 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. Receives: Drug: G100; Drug: Rituximab |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: Up to approximately 105 weeks
Secondary outcomes (10)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Up to approximately 42 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Jul 2015 (estimated)
- Study start3 Feb 2016
- Primary completion1 Aug 2019
- Study completion1 Aug 2019
Why it stopped: Business reasons
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Follicular Low Grade Non-Hodgkin's LymphomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 52 participants (actual)
Sponsor and investigators
- Lead sponsor
- Immune Design, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Merck Sharp & Dohme LLC
- Responsible party
- Sponsor
- Investigators
- Lisa Knapp, Study director, Clinical Trial Manager
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02501473
- Sponsor's protocol ID
- 3475-174
- Other IDs
- IMDZ-G142, MK-3475-174, 2015-005382-23, 2015
- Status last verified
- Aug 2020
- First submitted
- 8 Jul 2015
- Last updated
- 9 Sep 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
Publications
Halwani AS, Panizo C, Isufi I, Herrera AF, Okada CY, Cull EH, Kis B, Chaves JM, Bartlett NL, Ai W, de la Cruz-Merino L, Bryan LJ, Houot R, Linton K, Briones J, Chau I, von Keudell GR, Lu H, Yakovich A, Chen M, Meulen Jh T, Yurasov S, Hsu FJ, Flowers CR. Phase 1/2 study of intratumoral G100 (TLR4 agonist) with or without pembrolizumab in follicular lymphoma. Leuk Lymphoma. 2022 Apr;63(4):821-833. doi: 10.1080/10428194.2021.2010057. Epub 2021 Dec 6.
PubMed 34865586
Study at a glance
From the registry record, last updated by the sponsor on 9 Sep 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase 1/2 Study of Intratumoral G100 With Or Without Pembrolizumab or Rituximab In Patients With Follicular Non-Hodgkin's Lymphoma
- ClinicalTrials.gov ID
- NCT02501473
- Acronym / sponsor ID
- 3475-174
- Keywords
- follicular lymphoma, FL, low-grade lymphoma, Non-Hodgkin's Lymphoma, follicular NHL, Marginal Zone
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Business reasons
- Enrolment
- 52 participants (actual)
- Lead sponsor
- Immune Design, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)Industry (pharma, biotech, devices)
- Collaborators
- Merck Sharp & Dohme LLC
- Study start
- 3 Feb 2016 (actual)
- Primary completion
- 1 Aug 2019 (actual)
- Study completion
- 1 Aug 2019 (actual)
- First posted
- 17 Jul 2015 (estimated)
- Results
- Posted 9 Sep 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 8
| Arm | Type | Receives |
|---|---|---|
| Part 1: Local Radiation + G100 5μg/tumor | Experimental | Drug: G100Part 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. |
| Part 1: Local Radiation + G100 10μg/tumor | Experimental | Drug: G100Part 1: Local radiation and G100 at 10μg/tumor administered IT into accessible tumors for up to 8 weeks. |
| Part 2: Local Radiation + G100 10μg/tumor | Experimental | Drug: G100Part 2: Local radiation and G100 at 10μg/tumor administered IT into accessible tumors for up to 8 weeks. |
| Part 2: Local Radiation + G100 10μg/tumor+Pembrolizumab 200mg | Experimental | Drug: G100, Drug: PembrolizumabPart 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. |
| Part 2: Local Radiation, G100 20 μg/tumor in Large Tumors | Experimental | Drug: G100Part 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. |
| Part 3: Local Radiation + G100 20μg/tumor | Experimental | Drug: G100Part 3: Local radiation and G100 at 20μg/tumor administered IT into accessible tumors for up to 8 weeks. |
| Part 4: G100 20μg/tumor and pembrolizumab 200mg | Experimental | Drug: G100, Drug: PembrolizumabPart 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. |
| Part 5: G100 + Rituximab 375mg/m^2 | Experimental | Drug: G100, Drug: RituximabPart 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- Follicular low-grade NHL:
- Tumor mass(es) accessible for intratumoral injection
- ≥ 18 years of age
- Life expectancy of ≥ 6 months per the investigator
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Key exclusion criteria (26 listed)
- 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:
- Significant immunosuppression from:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| G100Also: glucopyranosyl lipid A stable emulsion, GLA-SEGLA is a fully synthetic toll-like receptor-4 (TLR4) agonist | Drug | Part 1: Local Radiation + G100 10μg/tumor, Part 1: Local Radiation + G100 5μg/tumor, Part 2: Local Radiation + G100 10μg/tumor, Part 2: Local Radiation + G100 10μg/tumor+Pembrolizumab 200mg, Part 2: Local Radiation, G100 20 μg/tumor in Large Tumors, Part 3: Local Radiation + G100 20μg/tumor, Part 4: G100 20μg/tumor and pembrolizumab 200mg, Part 5: G100 + Rituximab 375mg/m^2 |
| PembrolizumabAlso: Keytruda, MK-3475PD-1 Inhibitor | Drug | Part 2: Local Radiation + G100 10μg/tumor+Pembrolizumab 200mg, Part 4: G100 20μg/tumor and pembrolizumab 200mg |
| RituximabRituximab (anti-CD20 antibody) | Drug | Part 5: G100 + Rituximab 375mg/m^2 |
Primary outcome
Number of Participants With an Adverse Event (AE)
Time frame: Up to approximately 42 months
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.
Number of Participants Who Discontinued Study Drug Due to an Adverse Event
Time frame: Up to approximately 105 weeks
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.
10 secondary outcomes
Overall Response Rate (ORR) by Immune-related Response Criteria (irRC)
Time frame: Up to approximately 42 months
Clinical Benefit Rate (CBR) Using Immune-related Response Criteria (irRC)
Time frame: Up to approximately 42 months
Clinical Benefit Rate (CBR) Using International Working Group (IWG) Criteria
Time frame: Up to approximately 42 months
Duration of Response (DOR) by Immune-related Response Criteria (irRC)
Time frame: Up to approximately 42 months
Duration of Clinical Benefit by Immune-related Response Criteria (irRC)
Time frame: Up to approximately 42 months
Progression-free Survival (PFS)
Time frame: Up to approximately 42 months
Overall Survival (OS)
Time frame: Up to approximately 42 months
Overall Tumor Response Based on irRC Abscopal Sites
Time frame: Up to approximately 42 months
Time to Response for Complete Response and Partial Response Participants
Time frame: Up to approximately 42 months
Time to Next Treatment (TTNT)
Time frame: Up to approximately 42 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Sep 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 34865586Halwani AS, Panizo C, Isufi I, Herrera AF, Okada CY, Cull EH, Kis B, Chaves JM, Bartlett NL, Ai W, de la Cruz-Merino L, Bryan LJ, Houot R, Linton K, Briones J, Chau I, von Keudell GR, Lu H, Yakovich A, Chen M, Meulen Jh T, Yurasov S, Hsu FJ, Flowers CR. Phase 1/2 study of intratumoral G100 (TLR4 agonist) with or without pembrolizumab in follicular lymphoma. Leuk Lymphoma. 2022 Apr;63(4):821-833. doi: 10.1080/10428194.2021.2010057. Epub 2021 Dec 6.
- Individual participant dataSharing planned: Yes. http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Lisa Knapp study director
Clinical Trial Manager
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing G100, Pembrolizumab and Rituximab in people with Follicular Low Grade Non-Hodgkin's Lymphoma, run by Immune Design, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA).
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 9 Sep 2020. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 9 Sep 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With an Adverse Event (AE) (time frame: Up to approximately 42 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02501473, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Sep 2020.