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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 : January 18, 2018
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 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 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 Lymphoma (Marginal Zone Allowed During Dose Escalation Only) 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 who are to be treated with local radiation 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 3 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).

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 : Interventional  (Clinical Trial)
Actual Enrollment : 51 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
Study Start Date : June 2015
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : March 2019

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




Primary Outcome Measures :
  1. Safety and Tolerability by assessing the frequency and severity of adverse events [ Time Frame: Up to 2 years ]
    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


Secondary Outcome Measures :
  1. Clinical Response Assessment as a preliminary indication of efficacy [ Time Frame: Day 1 to Progression (estimated 24 + months) ]
    Assess clinical responses at local and distal sites of disease as a preliminary indication of efficacy

  2. 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

  3. Exploratory Biomarkers of immunologic and tumor response [ Time Frame: Screening to End of Study Visit (expected average is 24 Months) ]
    Assess blood and tumor samples for exploratory biomarkers of immunologic and tumor response



Information from the National Library of Medicine

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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: either treatment naïve (except for France) or relapsed or refractory following at least one prior treatment. In Part 1 Dose Escalation only, in addition to follicular NHL, marginal zone B cell lymphomas: either treatment naïve or relapsed or refractory following at least one prior treatment.
  2. Tumor mass(es) accessible for intratumoral injection and 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
  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, anti-PD1 antibodies.
  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 with the potential to receive pembrolizumab:

  15. History of 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 received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or if the patient has previously participated in Merck MK-3475 clinical trials.

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
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
Study Director: Lisa Knapp Clinical Trial Manager

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: January 18, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Immune Design:
follicular lymphoma
fNHL
low-grade lymphoma
Non-Hodgkin's Lymphoma
follicular NHL
Marginal Zone

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Follicular
Lymphoma, Non-Hodgkin
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Pembrolizumab
Antineoplastic Agents