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

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ClinicalTrials.gov Identifier: NCT02501473
Recruitment Status : Terminated (Business reasons)
First Posted : July 17, 2015
Results First Posted : September 9, 2020
Last Update Posted : September 9, 2020
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Immune Design

Tracking Information
First Submitted Date  ICMJE July 8, 2015
First Posted Date  ICMJE July 17, 2015
Results First Submitted Date  ICMJE July 21, 2020
Results First Posted Date  ICMJE September 9, 2020
Last Update Posted Date September 9, 2020
Actual Study Start Date  ICMJE February 3, 2016
Actual Primary Completion Date August 1, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 20, 2020)
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: July 15, 2015)
Safety and Tolerability by assessing the frequency and severity of adverse events [ Time Frame: Day 1 to End of Study Visit (Day 77) ]
To evaluate the safety and tolerability of ascending doses of intratumoral G100 in patients with follicular NHL receiving local radiation by assessing the frequency and severity of adverse events
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 20, 2020)
  • Overall Response Rate (ORR) by Immune-related Response Criteria (irRC) [ Time Frame: Up to approximately 42 months ]
    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.
  • Clinical Benefit Rate (CBR) Using Immune-related Response Criteria (irRC) [ Time Frame: Up to approximately 42 months ]
    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.
  • Clinical Benefit Rate (CBR) Using International Working Group (IWG) Criteria [ Time Frame: Up to approximately 42 months ]
    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.
  • Duration of Response (DOR) by Immune-related Response Criteria (irRC) [ Time Frame: Up to approximately 42 months ]
    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.
  • Duration of Clinical Benefit by Immune-related Response Criteria (irRC) [ Time Frame: Up to approximately 42 months ]
    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.
  • Progression-free Survival (PFS) [ Time Frame: Up to approximately 42 months ]
    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.
  • Overall Survival (OS) [ Time Frame: Up to approximately 42 months ]
    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.
  • Overall Tumor Response Based on irRC Abscopal Sites [ Time Frame: Up to approximately 42 months ]
    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.
  • Time to Response for Complete Response and Partial Response Participants [ Time Frame: Up to approximately 42 months ]
    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.
  • Time to Next Treatment (TTNT) [ Time Frame: Up to approximately 42 months ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 15, 2015)
  • Clinical Response Assessment as a preliminary indication of efficacy [ Time Frame: Day 1 to Progression (estimated up to 48 months) ]
    Assess clinical responses at local and distal sites of disease as a preliminary indication of efficacy
  • Exploratory Biomarkers of immunologic and tumor response [ Time Frame: Screening to End of Study Visit (expected average is Day 77) ]
    Assess blood and tumor samples for exploratory biomarkers of immunologic and tumor response
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Intratumoral G100 With Or Without Pembrolizumab or Rituximab In Participants With Follicular Non-Hodgkin's Lymphoma (MK-3475-174/IMDZ-G142)
Official Title  ICMJE Phase 1/2 Study of Intratumoral G100 With Or Without Pembrolizumab or Rituximab In Patients With Follicular Non-Hodgkin's Lymphoma
Brief 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. 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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Follicular Low Grade Non-Hodgkin's Lymphoma
Intervention  ICMJE
  • Drug: G100
    GLA is a fully synthetic toll-like receptor-4 (TLR4) agonist
    Other Name: glucopyranosyl lipid A stable emulsion, GLA-SE
  • Drug: Pembrolizumab
    PD-1 Inhibitor
    Other Names:
    • Keytruda
    • MK-3475
  • Drug: Rituximab
    Rituximab (anti-CD20 antibody)
Study Arms  ICMJE
  • Experimental: Part 1: Local Radiation + G100 5μg/tumor
    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.
    Intervention: Drug: G100
  • Experimental: Part 1: Local Radiation + G100 10μg/tumor
    Part 1: Local radiation and G100 at 10μg/tumor administered IT into accessible tumors for up to 8 weeks.
    Intervention: Drug: G100
  • Experimental: Part 2: Local Radiation + G100 10μg/tumor
    Part 2: Local radiation and G100 at 10μg/tumor administered IT into accessible tumors for up to 8 weeks.
    Intervention: Drug: G100
  • Experimental: Part 2: Local Radiation + G100 10μg/tumor+Pembrolizumab 200mg
    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.
    Interventions:
    • Drug: G100
    • Drug: Pembrolizumab
  • Experimental: Part 2: Local Radiation, G100 20 μg/tumor in Large Tumors
    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.
    Intervention: Drug: G100
  • Experimental: Part 3: Local Radiation + G100 20μg/tumor
    Part 3: Local radiation and G100 at 20μg/tumor administered IT into accessible tumors for up to 8 weeks.
    Intervention: Drug: G100
  • Experimental: Part 4: G100 20μg/tumor and pembrolizumab 200mg
    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.
    Interventions:
    • Drug: G100
    • Drug: Pembrolizumab
  • Experimental: Part 5: G100 + Rituximab 375mg/m^2
    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.
    Interventions:
    • Drug: G100
    • Drug: Rituximab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: January 23, 2020)
52
Original Estimated Enrollment  ICMJE
 (submitted: July 15, 2015)
36
Actual Study Completion Date  ICMJE August 1, 2019
Actual Primary Completion Date August 1, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. 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.
  2. 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.
  3. ≥ 18 years of age
  4. Life expectancy of ≥ 6 months per the investigator
  5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  6. Electrocardiogram (ECG) without evidence of clinically significant arrhythmia or ischemia
  7. 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
  8. 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:

  1. 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
  2. Investigational therapy within 4 weeks prior to G100 dosing
  3. Prior administration of other intratumoral immunotherapeutics
  4. Inadequate organ function including:

    1. Marrow: Peripheral blood leukocyte count (WBC) < 3000/mm^3, absolute neutrophil count ≤ 1500/mm^3, platelets < 75000/mm^3, or hemoglobin < 10 gm/dL
    2. 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)
    3. Renal: Creatinine > 1.5x ULN
    4. Other: INR (international normalized ratio) or partial thromboplastin time (PTT) >1.5 x ULN
  5. Significant immunosuppression from:

    1. Concurrent, recent (≤ 4 weeks ago) or anticipated treatment with systemic corticosteroids at any dose, or
    2. Other immunosuppressive medications such as methotrexate, cyclosporine, azathioprine or conditions such as common variable hypogammaglobulinemia
  6. Pregnant or nursing
  7. Myocardial infarction within 6 months of study initiation, active cardiac ischemia or New York Heart Association (NYHA) Grade III or IV heart failure
  8. History of other cancer within 2 years (except non-melanoma cutaneous malignancies and cervical carcinoma in situ)
  9. Recent (<1 week ago) clinically significant infection, active tuberculosis or evidence of active hepatitis B, hepatitis C or HIV infection
  10. Central nervous system involvement with lymphoma, including parenchymal and leptomeningeal disease.
  11. 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
  12. 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
  13. 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
  14. 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:

  15. History of (non-infectious) pneumonitis that required steroids or has current pneumonitis or interstitial lung disease
  16. Received a live virus vaccine within 30 days of planned study start
  17. 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]).
  18. Has had an allogeneic tissue/solid organ transplant
  19. 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries France,   Spain,   United Kingdom,   United States
 
Administrative Information
NCT Number  ICMJE NCT02501473
Other Study ID Numbers  ICMJE 3475-174
IMDZ-G142 ( Other Identifier: Immune Design Protocol Number )
MK-3475-174 ( Other Identifier: Merck Protocol Number )
2015-005382-23 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php
Responsible Party Immune Design
Study Sponsor  ICMJE Immune Design
Collaborators  ICMJE Merck Sharp & Dohme Corp.
Investigators  ICMJE
Study Director: Lisa Knapp Clinical Trial Manager
PRS Account Immune Design
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP