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Study of Intratumoral G100 With Or Without Pembrolizumab In Patients With Follicular Non-Hodgkin's Lymphoma

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ClinicalTrials.gov Identifier: NCT02501473
Recruitment Status : Active, not recruiting
First Posted : July 17, 2015
Last Update Posted : August 16, 2019
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Immune Design

Brief Summary:
This is a Phase 1/2 open label trial of G100 in patients 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 following 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 clinical efficacy of G100 will be examined alone or with pembrolizumab.

Condition or disease Intervention/treatment Phase
Follicular Low Grade Non-Hodgkin's Lymphoma Drug: G100 Drug: Pembrolizumab Phase 1 Phase 2

Detailed Description:

This is a multi-center Phase 1/2 open label trial of intratumoral G100 in patients with low grade NHL. Patients with NHL will be enrolled and receive G100 to an accessable tumor mass. Clinical response will be evaluated in the injected lesion and systemic (abscopal) responses will be evaluated in distal areas involved with tumor.

The study will be conducted in 4 parts. In Part 1, Dose Escalation, 2 sequentially enrolled cohorts of patients 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 eligible. In Part 2, 2 groups of patients 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, patients 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 patients with follicular NHL will be enrolled to receive local radiation therapy and intratumoral G100 (no tumor size requirement in this arm). In Part 4, Dose Escalation and Expansion, a dose of 20µg of G100 will be examined as a treatment of 1 or more tumor lesions (up to 4) with pembrolizumab in order to establish safety and examine clinical and biomarker responses in patients receiving increasing total systemic doses of G100.

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 86 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1/2 Study of Intratumoral G100 With Or Without Pembrolizumab In Patients With Follicular Non-Hodgkin's Lymphoma
Actual Study Start Date : June 2015
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : March 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: Part 1: Dose Escalation Cohort 1
Intratumoral injections of G100 at 5μg
Drug: G100
GLA is a fully synthetic toll-like receptor-4 (TLR4) agonist
Other Name: glucopyranosyl lipid A stable emulsion, GLA-SE

Experimental: Part 1: Dose Escalation Cohort 2
or Intratumoral injections of G100 at 10μg
Drug: G100
GLA is a fully synthetic toll-like receptor-4 (TLR4) agonist
Other Name: glucopyranosyl lipid A stable emulsion, GLA-SE

Experimental: Part 2: Patient Expansion G100 and Pembrolizumab
Intratumoral injections G100 or sequential intratumoral G100 and pembrolizumab
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 Name: Keytruda

Experimental: Part 2: Large Tumor (Optional)
Intratumoral injections G100 at 20 μg
Drug: G100
GLA is a fully synthetic toll-like receptor-4 (TLR4) agonist
Other Name: glucopyranosyl lipid A stable emulsion, GLA-SE

Experimental: Part 3: Expansion of Dose Group
Intratumoral G100 at 20 µg/dose in patients without restriction of tumor size
Drug: G100
GLA is a fully synthetic toll-like receptor-4 (TLR4) agonist
Other Name: glucopyranosyl lipid A stable emulsion, GLA-SE

Experimental: Part 4: G100 Escalation and Expansion with pembrolizumab
Dose Escalation: Cohort 1: G100 20 μg (GLA component)/ lesion in 1 tumor Cohort 2: G100 20 μg/lesion in 2 tumor lesions (40 μg total) Cohort 3: G100 20 μg/lesion in 3 tumor lesions (60 μg total) Cohort 4: G100 20 μg/lesion in 4 tumor lesions (80 μg total). Patient Expansion at each dose level will be allowed after each cohort has been deemed safe.
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 Name: Keytruda




Primary Outcome Measures :
  1. Evaluate safety and preliminary clinical efficacy [ Time Frame: Up to 2 years ]
    Evaluate safety and preliminary clinical efficacy of intratumoral G100 at 20µg/lesion in single or multiple tumor lesions and pembrolizumab (anti-PD-1) therapy in patients with relapsed or refractory follicular NHL who have received at least 3 prior systemic treatments, one of which was or included an anti-CD20 antibody


Secondary Outcome Measures :
  1. Nature, frequency and severity of AEs and laboratory abnormalities [ Time Frame: Screening to End of Study Visit (expected average is 24 months) ]
    Safety information in the form of adverse event and laboratory data will be collected for all patients at every visit until 21 days after G100 regimen is completed or discontinued. Severity of adverse events will be assessed by CTCAE v4.03 or newer.

  2. Clinical Response Assessment as a preliminary indication of efficacy [ Time Frame: Day 1 to Progression (estimated 24 + months) ]
    Clinical response will be assessed by immune-related Response Criteria (irRC) using bi-dimensional measurements and time-to-progression (TTP) as a preliminary indication of efficacy. Clinical response will be expressed by partial response (PR), complete response (CR), stable disease (SD), or progressive disease (PD). Tumor staging by CT or MRI will be performed at Screening and every 8 weeks thereafter for the 1st year, every 3-4 months for the 2nd year, and then at least every 6 months for the 3rd and subsequent years.

  3. Clinical response based on International Working Group Response Criteria for Malignant Lymphoma [ Time Frame: Screening to End of Study Visit (expected average is 24 months) ]
    Lymphoma response assessment by computerized tomography (CT) will be performed at Screening and every 8 weeks thereafter for the 1st year, every 3-4 months for the 2nd year, and then at least every 6 months for the 3rd and subsequent years. For determining PD, the irRC criteria will be used. Sponsor will assess for clinical responses by the Lugano criteria for lymphomas.

  4. Abscopal tumor response in non-treated, distal tumor sites [ Time Frame: Screening to End of Study Visit (expected average is 24 Months) ]
    To assess abscopal tumor responses in non-treated, distal tumor sites


Other Outcome Measures:
  1. Evaluate pre- and post-regimen tumor tissue and blood for exploratory biomarkers of immunologic and tumor response [ Time Frame: Screening to End of Study Visit (expected average is 24 Months) ]

    Biomarker changes will be measured in patients with clinical benefit treated with G100 alone at a dose of 20 μg/lesion injected in single or multiple lesions, or a combination of G100 plus pembrolizumab.

    Peripheral blood and sequential tumor biopsies are collected before start of treatment, and at Weeks 5 and 8.

    Serum samples will be assessed for levels of cytokines. DNA will be obtained from biopsies and normal white blood cells (peripheral blood) and will be submitted for whole genome sequencing. The obtained data will contribute to identifying potential biomarkers in patients with clinical benefit.


  2. Area Under the Plasma Concentration-Time Curve (AUC) [ Time Frame: Screening to First Dose of G100 ]
    For Part 4 and Part 5 patients, blood samples will be taken at Screening, within 2 hours prior to first G100 administration, and 6 hours after the first G100 administration

  3. Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Screening to First Dose of G100 ]
    For Part 4 and Part 5 patients, blood samples will be taken at Screening, within 2 hours prior to first G100 administration, and 6 hours after the first G100 administration

  4. Minimum Observed Plasma Concentration (Cmin) [ Time Frame: Screening to First Dose of G100 ]
    For Part 4 and Part 5 patients, blood samples will be taken at Screening, within 2 hours prior to first G100 administration, and 6 hours after the first G100 administration

  5. Half life (t1/2) [ Time Frame: Screening to First Dose of G100 ]
    For Part 4 and Part 5 patients, blood samples will be taken at Screening, within 2 hours prior to first G100 administration, and 6 hours after the first G100 administration



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 patients.
  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 Parts 4, 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. 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, G-CSF or 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/mm3, absolute neutrophil count ≤ 1500/mm3, platelets < 75000/mm3, 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 (patients 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 (prothrombin time 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 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
  14. Use of anti-coagulant agents or history a significant bleeding diathesis. (If a superficial lymph node or subcutaneous mass is to be injected, patients 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 patients 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. (Subjects who have had a transplant greater than 5 years ago are eligible as long as there are no symptoms of 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 patient 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02501473


Locations
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United States, California
City of Hope
Duarte, California, United States, 91010
University of California, San Francisco
San Francisco, California, United States, 94143
United States, Connecticut
Yale Comprehensive Cancer Center
New Haven, Connecticut, United States, 06519
United States, Florida
Moffitt Cancer Center
Tampa, Florida, United States, 33612
United States, Georgia
Winship Cancer Institute of Emory University
Atlanta, Georgia, United States, 30322
Georgia Cancer Center at Augusta University
Augusta, Georgia, United States, 30912
United States, Missouri
Washington University
Saint Louis, Missouri, United States, 63130
United States, Oregon
Oregon Health & Science University
Portland, Oregon, United States, 97239
United States, South Carolina
Greenville Health System
Greenville, South Carolina, United States, 29605
United States, Utah
Huntsman Cancer Institute
Salt Lake City, Utah, United States, 84112
United States, Washington
Northwest Medical Specialties
Tacoma, Washington, United States, 98405
France
CHU de Rennes - Hopital Pontchailou
Rennes, Bretagne, France, 35033
Spain
Clinica Universitaria de Navarra
Pamplona, Navarra, Spain, 31008
Hospital Santa Creu i Sant Pau
Barcelona, Spain, 08025
Hospital Universitario Virgen Macarena
Sevilla, Spain, 41009
United Kingdom
The Christie NHS Foundation Trust
Manchester, United Kingdom, M20 4BX
Royal Marsden Hospital
Sutton, United Kingdom, SM2 5PT
Sponsors and Collaborators
Immune Design
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Lisa Knapp Clinical Trial Manager

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Responsible Party: Immune Design
ClinicalTrials.gov Identifier: NCT02501473     History of Changes
Other Study ID Numbers: IMDZ-G142
First Posted: July 17, 2015    Key Record Dates
Last Update Posted: August 16, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by Immune Design:
follicular lymphoma
FL
low-grade lymphoma
Non-Hodgkin's Lymphoma
follicular NHL
Marginal Zone
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, Follicular
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents